11 Production

Printed by: 168305-3 Date: 15.04.
2014 GMP MANUAL © Maas & Peither AG

11 Production
11.A Sanitation
11.A.1 Organisational prerequisites
11.A.2 Sources of contamination
11.A.3 Responsibilities and implementation
11.B Personnel hygiene

11.B.1 Clothing
11.B.1.1 Clothing material
11.B.1.2 Design of the clothing
11.B.1.3 Preparation/Cleaning
11.B.1.4 Gowning procedure
11.B.2 Code of Conduct

11.B.2.1 Personal hygiene
11.B.2.2 General requirements
11.B.2.3 Special requirements for clean rooms
11.B.2.4 Policies to be established
11.B.3 Hand disinfection

11.B.4 Health requirements
11.B.5 Training
11.C Production hygiene

11.C.1 Sources of contamination
11.C.1.1 Premises and facilities
11.C.1.2 Starting materials
11.C.1.3 Packaging materials
11.C.1.4 Cleansing agents, disinfectants and aids
11.C.1.5 Equipment and utensils
11.C.1.6 Process gases
11.C.1.7 Ambient air
11.C.1.8 Processes
11.C.2 Cleaning
11.C.2.1 Cleaning procedure for equipment
11.C.2.2 Cleaning procedure for rooms
11.C.3 Disinfection
11.D Sanitation programme

11.D.1 Organisation of room cleaning
11.D.1.1 Hygienic areas
11.D.1.2 General room cleaning
11.D.1.3 Cleansing agents and disinfectants
11.D.1.4 Cleaning process and aids
11.D.2 Documentation
11.E Environmental monitoring
11.E.1 General
11.E.2 Sampling plan
11.E.3 Establishment of limits and frequencies
11.E.3.1 European requirements
11.E.3.2 US requirements
11.E.3.3 ISO standards
11.E.4 Methods
11.E.4.1 Direct contact test
11.E.4.2 Measurement of airborne microbes
11.E.5 Investigation areas

11.E.5.1 Surfaces
11.E.5.2 Air
11.E.5.3 Cleansing agents and disinfectants
11.E.5.4 Personnel
11.E.5.5 Utilities
11.E.6 Evaluation
11.E.6.1 Report
11.E.6.2 Trend analyses
11.E.6.3 Measures when limit is exceeded
11.F GMP in the production process

11.G Weigh-in
11.G.1 Legal requirements
11.G.2 Weigh-in principles
11.G.2.1 Product-specific weigh-in
11.G.2.2 Raw material-specific weigh-in
11.G.2.3 Central/local weigh-in systems
11.G.2.4 Manual weigh-in
11.G.2.5 Automatic weigh-in
11.G.3 Weigh-in procedure

11.G.3.1 Allocation of raw materials
11.G.3.2 Weigh-in
11.G.3.3 Return
11.G.3.4 Allocation for production
11.G.3.5 Cleaning
11.G.4 Documentation
11.H Identification
11.H.1 Handling of labels
11.H.2 Labelling of starting materials
11.H.3 Labelling of equipment and containers
11.H.3.1 General
11.H.3.2 Rejection / Quarantine
11.H.3.3 Cleaning status
11.H.4 Labelling of rooms
11.I In-process control

11.I.1 Objectives
11.I.1.1 Quality control
11.I.1.2 Process control
11.I.2 Organisation and responsibilities

11.I.3 Carrying out
11.I.3.1 Scope and kind of tests
11.I.3.2 Location
11.I.3.3 Sampling
11.I.3.4 Testing
11.I.4 Documentation and evaluation of data
11.J Prevention of cross-contamination

11.J.1 Causes of cross-contamination
11.J.1.1 Rooms
11.J.1.2 Equipment
11.J.1.3 Processes
11.J.1.4 Personnel
11.J.2 Measures to prevent cross-contamination

11.J.3 Manufacture of critical products
11.K Empty Chapter

11.L Reworking
11.L.1 Definitions
11.L.1.1 Rework
11.L.1.2 Reprocessing
11.L.1.3 Recovery
11.L.2 Procedure
11.L.2.1 Reasons for rework/reprocessing
11.L.2.2 Request for rework/reprocessing
11.L.2.3 Risk assessment
11.L.2.4 Responsibilities
11.L.2.5 Documentation requirements
11.L.2.6 Regulatory submission requirements
11.L.3 Rework/Reprocessing of rejected products

11.L.4 Rework of returned products
11.L.5 Rework of products that have not been rejected
11.M Warehouse and logistics

11.M.1 Regulatory requirements
11.M.2 Stock management system
11.M.3 Responsibilities
11.M.4 Personnel
11.M.5 Storage areas
11.M.5.1 Size
11.M.5.2 Illumination
11.M.5.3 Incoming goods and dispatch
11.M.5.4 Sampling
11.M.5.5 Quarantine
11.M.5.6 Special storage areas
11.M.6 Storage conditions

11.M.6.1 Temperature and humidity
11.M.6.2 Monitoring
11.M.6.3 Deviation handling
11.M.7 Sanitation and pest control

11.M.8 Material Flow
11.M.8.1 Stock rotation
11.M.8.2 Reconciliation
11.M.8.3 Storage systems
11.M.9 Process Flow

11.M.9.1 Receipt
11.M.9.2 Identification
11.M.9.3 Dispatch and transport
11.N References
Printed by: 168305-3 Date: 15.04.2014 GMP MANUAL © Maas & Peither AG
11.A Sanitation
Up07 Dr. Christian Gausepohl, Paolomi Mukherji
Here you will find answers to the following questions:

■ What is sanitation and who is responsible for it?
■ What are the potential sources of contamination?
Sanitation can be understood as the interaction of production hygiene and personnel hygiene. Often the terms sanitation and production hygiene
are used as synonyms. In addition to hygienic measures in the narrower sense, precautions and measures to prevent cross-contamination, confusion
and mix-ups are assigned to the term production hygiene. Sanitation measures are a pre-requisite to carry out pharmaceutical production.
The aim is to achieve and retain a defined cleanliness status. The required cleanliness grade is prescribed by the production step or dosage form. A
cross-plant structure must be developed, which ultimately leads to the integration of systematic hygiene measures in the production process.
Defined measures are expected, which stipulate how to deal with the field of sanitation. A list of important regulatory documents is given in Figure 11.A-
1.
Figure 11.A-1 Regulatory basics of sanitation requirements
Regulatory basics of sanitation requirements
■ EU-GMP Guide Part I

■ EU-GMP Guide Annex 1
■ 21 CFR Part 210/211
■ FDA Guidance for Industry: Sterile Products Produced by Aseptic Processing – current Good Manufacturing Practice
■ PIC/S PI 007 Recommendations on the Validation of Aseptic Processes
■ WHO Technical Report Series, Annex 4, No 908 (2003)
11.A.1 Organisational prerequisites

The organisation of the material and personnel flow is an important criterion for the quality of sanitation. A logical and consistent workflow
organisation leads to reproducible conditions on which established procedures can be based. The definition and documentation of the material and
personnel flows allow for critical consideration of these areas. Deviations from these flows increase the risks to an unforeseeable degree. It is
disproportionately more difficult to provide for adequate hygiene measures for material flows that cross over each other, e.g. by limited space, as the risk
of contamination rises sharply. Inadequately defined flows will bring further risks. (See Chapter 3.B Material flow, personnel flow and layout.)
Before defining the sanitation measures, the material and personnel workflow must be accurately defined and established. The flow of components, drug
product containers, closures, labeling, in-process materials, and drug-products through the building(s) should be designed adequately in order to prevent
contamination. The design of new buildings and production rooms should ideally include this as part of qualification or risk analysis. Worst case
scenarios, as e.g. the simultaneous occurrence of spilling of liquids and malfunction of the air handling system, should also be considered.
Knowledge of possible malfunctions in the normal process means it is possible to take these into consideration when compiling standard sanitation
programmes. Dedicated target/actual analysis of deviations is enabled through the process descriptions obtained or parts of the job description.
For further information see Chapter D.1.2, Subpart C - Buildings and Facilities.
Figure 11.A-2 Principles of sanitation
Principles of sanitation
■ Definition of the material flow

■ Definition of the personnel flow
■ Definition of processes
11.A.2 Sources of contamination

Contamination of products can be both physical particulate and microbial and can take place in various ways. This encompasses the fields of
personnel, including visitors and all those involved in the production area, surfaces of the production rooms and facilities and bordering rooms in the wider
sense. Likewise, raw materials (including water and packaging), cleansing agents and the processes themselves, can be a cause for impurities.
Contaminants can also enter via the utilities used (e.g. product contact nitrogen) and the ambient air (Figure 11.A-3).
Figure 11.A-3 Sources of contamination
Sources of contamination
■ Personnel
■ Surfaces (rooms, facilities)
■ Raw materials (including water)
■ Packaging materials
■ Processes
■ Utilities (nitrogen gasing, compressed air)
■ Ambient air
The combination of all influence factors results in the real actual status of sanitation. All factors of personnel and production hygiene shoud be
qualified/validated prior to routine manufacturing. Permanent as well as periodic monitoring measures are performed to evaluate the appropriateness of
the defined systems and limits. Based on the results, any necessary adjustments are to be made.
11.A.3 Responsibilities and implementation

The responsibility for sanitation is subject to the head of production (for manufacturing area) respectively the head of Quality Control (for laboratory area).
Monitoring can be co-ordinated and evaluated by quality assurance in collaboration with quality control.Depending on product type and room
classification, the results are added to the evaluation of batches (e.g. for filling under a laminar flow) by quality control.
The implementation of sanitation requires written procedures that assign responsibility for sanitation and describe in sufficient detail the cleaning
schedules, methods, equipment and materials used in cleaning the buildings and facilities. In addition, the procedures must include the use of suitable
insecticides, rodenticides, fungicides, fumigating agents, cleaning and sanitizing agents per the processes occuring in the specific facility/area (see
Chapter 11.D Sanitation programme).
Establish policy and promote employee practice of good sanitation and health habits by creating a policy level document that contains the following
information:
■ Address need to protect integrity of product
■ Address need to provide for worker safety
■ Emphasize individual responsibility
■ Give supervisors authority to enforce policy
Summary
Sanitation can be understood as the interaction of production hygiene and personnel hygiene.
Sources of contamination in the production process include personnel, starting materials, utilities, equipment, rooms and the process itself. This must
be specifically controlled during monitoring.
The responsibility for ensuring compliance with sanitation is subject to the head of production in the manufacturing area, respectively the head of quality
control in the laboratory area. They are supplied with information, e.g. on monitoring data, from quality assurance.
11.B Personnel hygiene
■ What are the requirements for working clothing?
■ What code of conduct has to be followed?
■ How is hand disinfection performed correctly?
■ What is the function of medical assessment?
■ What special aspects have to be considered for hygiene trainings?
Both the EU-GMP-Guide (Chapter C) and the CFR Part 211 (Chapter D.1) clearly stipulate that detailed hygiene plans must also be compiled for
personnel. In addition to requirements on protective and working clothing, codes of conduct for personnel and visitors are also required. These codes of
conduct are to be fixed in the form of work and organisation instructions. Different sub-areas are dealt with and discussed below.
According to 21 CFR Sec. 211.28 Personnel responsibilities., personnel should wear clean clothing appropriate for the duties performed. As applicable,
protective apparel such as head, face, hand and arm coverings should be worn to protect drug products from contamination. Personnel should practice
good sanitation and health habits and personnel with apparent illness or open lesions that may adversely affect the safety or quality of drug products
should be excluded from direct contact with these operations.
Training on hygiene aspects should be imparted to employees as part of:
■ Orientation of new hires
■ training plan for working in an area
■ training plan for learning new procedures
11.B.1 Clothing
In principle, working clothing must perform different functions:
■ To protect the personnel from contamination by the product
■ To protect the product from contamination by the personnel
■ To signal the activity being performed (e.g. as a warning)
To ensure occupational health and safety, the safety clothing function is very important. Plant-specific requirements are defined here based on evaluation
of potential harm coming from process and/or materials.
The function of clothing as a barrier to protect the product is intended to keep back flakes of skin, the body's own bacterial flora, particles and humidity
(sweat) and prevent their penetration as far as possible. This function is the most relevant one from the GMP view.
The selection of specific colours for assigned areas means a signal function can be achieved, e.g. as a warning for the processing of sensitive products.
These tasks are to be taken into account at the time of selection.
Clothing must be changed regularly in prescribed intervals, or even more frequently when it becomes contaminated or damaged. The higher the
cleanliness grade and the greater the probability and intensity of a contamination (depending on the activity), the more often clothing must be changed
(at least 1x weekly, or with grades A and B at least 1x daily). These intervals are based on the monitoring results, which should provide samples of worn
clothing and fresh clothing for comparison.
Figure 11.B-1 shows a comparative overview of the requirements and necessities of the different clothing, depending on the cleanliness grade (see
Chapter 3.C Room classes). It is recommended that an intermediate layer of clothing be worn between the sterile room clothing and personal underwear.
This can help achieve a significant reduction in the release of skin particles onto the clean room clothing and then into the environment. The intermediate
clothing should be antistatic and autoclavable.
Figure 11.B-1 Pharmaceutical clothing in different cleanliness grades
A, B C D
Grade (ISO 5) (ISO 7) (ISO 8) E* Comment
Clothing over the entire body length one or two-piece, high collar, protective clothing, one or two-piece, short sleeves are not
(overall), sleeves and trouser legs closed cuffs at wrists closed cuffs at wrists closed cuffs at wrists permissible
tucked into gloves or boots are recommended are recommended
Material synthetic fibres (e.g. polyamide), cotton or blended fabric, no cotton or blended cotton or blended depending on the
sterilisable or disinfectable particle or fibre release fabric fabric permissible particle
count or particle
release
External not permitted not recommended not recommended not recommended to avoid mixes and
pockets cross-contaminations
Change at least 1 x daily, or again with periodically, at least 1–2x per periodically, at least periodically, at least more often in case of
each change of area week 1–2x per week 1x per week contamination
Head integrated hood or neck covering fleece material fleece material, fleece material, all hair must be covered
covering (connection to over-clothing, change with each new inward changed daily changed daily
similar material) transfer
Face sterile, permanent wear or no permanent wearing is permanent wearing by Face mask: only change when
mask/beard beard, multiple change in each recommended men with beards is when working with penetrated by humidity
covering working period recommended open products
Beards: permanent
coverage is
recommended
Gloves disinfectable, wear permanently, disinfectable, permanent only when working only when working obligatory when product
change with each working period wearing is recommended, with open products with open products is changed and when
change with each working damaged
period
Shoes covering shoes, sterilisable or production shoes or covering production shoes or production shoes or non-slip, but without
disinfectable shoes covering shoes covering shoes profile due to possible
product transfer
Cosmetics avoid not recommended not recommended not recommended, exception: pure care
not critical cosmetics
Jewellery, avoid avoid avoid avoid also for occupational

watches health and safety
reasons
* Grade for the production of non-sterile dosage forms, packaging
When establishing a Policy on working clothes and safety apparel required in various work situations, the following items should be addressed:
■ Determine areas where special clothing is required (laboratory, controlled areas, aseptic filling areas, sterility testing areas, animal areas, others)
■Determine what clothing is appropriate for the duties performed (uniforms, coats, sterile garments, head covers, beard covers, shoe covers, gloves,
other protective apparel)
■ Determine areas where safety apparel is required (laboratory, warehouse, manufacturing, maintenance, animal area, others)
■Determine what safety apparel is needed for areas and duties performed (safety glasses, laboratory coats, face shields, gloves, shoes (steel toed),
hard hats, hearing protection, others)
■ Describe procedure for donning protective apparel, provide for disposal of used protective apparel
■ Provide for storage of street clothing
11.B.1.1 Clothing material

In the meaning of GMP, the work clothing material must protect the products against particles and microorganisms which can be released by
humans. The clothing itself must only release defined quantities of particles. As high as possible a particle retention rate must be achieved, i.e. the re-
emission by the coated surface should be hampered. The specific requirements are defined by the target cleanliness grade in line with the available
rooms and facilities (see Figure 11.B-2 and Figure 11.B-3).
Figure 11.B-2 Work clothing: Choice of material
Criteria for the choice of material
■ Particle release (from the fabric)

■ Particle retention capacity (by adsorbed material)
■ Disinfectability or sterilisability
■ Wearing comfort (humidity penetration)
■ Conductivity (antistatic)
The design of the facilities should therefore be included in the risk assessment. Completely closed systems allow for a different clothing quality to be
used than systems that expose the product to the environment temporarily.
In contrast to the requirements for the production of sterile preparations, the cleanliness classification does not assert any requirements regarding the
particle count in the production of drugs for oral application. In terms of the microbiological purity, on the other hand, limits for preparations are defined in
the European Pharmacopoeia. It is therefore advisable, even for the production of non-sterile drugs, to establish requirements for the work clothes’
material in view of particle release and cleanability.
For sterile forms, pure synthetic fibres such as polyester or polyamide (area A, B) or mixed fabrics with cotton are usually used. Here, trapped heat and
perspiration make the material uncomfortable to wear. A higher proportion of cotton in fabrics makes the material more comfortable, but releases more
particles. It should be possible to disinfect the different fabric types depending on their application, and clean room clothing should be sterilisable e.g.
autoclavable. It must be ensured that objects such as closures are not affected during application of disinfectant in the preparation process.
11.B.1.2 Design of the clothing
The design chosen for the clothing is important for its functionality and its acceptance by staff.
Figure 11.B-3 Work clothing: Design selection
Requirements for design selection
■ Sufficient coverage (good fit)

■ Practical manageability (sufficient mobility)
■ Easy to put on
Cut of the clothing

The clothing must be appropriate for the activity. This also presents requirements in terms of practical manageability. For working steps in sterile
preparation, there are explicit clothing requirements. It must cover the full length of the body (one or two-piece) and cover the neck, e.g. as an overall with
a hood or a neck covering (see Figure 11.B-8).
For lower cleanliness grades, coverage of the complete body area is not necessary (see Figure 11.B-9 and Figure 11.B-10). Only exposed areas must
be covered. The clothing must be closed at the wrists, e.g. through elasticated cuffs. The length of sleeves and trouser legs should be designed so that
no uncovered areas remain when gloves and shoes are worn, e.g. if the sleeves are too short. Closure at the wrists enables gloves or arm cuffs to be
rolled over, so that the lower arm is not uncovered. In addition, this helps prevent the transfer of particels or product that may be carried around in open
sleeves (see Figure 11.B-4 and Figure 11.B-5). Personnel often roll their sleeves up during cleaning work with extensive washing activities in non-aseptic
areas. In order to protect product contact surfaces, the use of water-repellent materials should be provided for here, e.g. through long-cuff gloves. Through
individual assignment, the correct fit of the clothing can be guaranteed for the employee in question. This means that the clothing must be uniquely
identifiable, e.g. through sewn-in barcodes, numbers or the name of the employee.
Figure 11.B-4 Clean room clothing with sleeve cuffs
Putting on
It must be possible to put the clothing on with a minimum amount of contamination. In clean rooms working clothes should be changed before re-
entering. Surface microbial count determinations show that the exterior and interior both become contaminated depending on the wearing time, intensity
of movement and perspiration. In addition, it is barely possible to remove and hang up the clothing without contaminating the exterior. When putting the
clothing on, it is greatly beneficial to have an adequate mirror to ensure the correct position of the clothing. This also applies for areas in which face
masks or head coverings are worn.
Gloves
In the field of sterile production, un-powdered gloves (possibly γ-radiation sterilised) are used to prevent possible particle loading. The cuffs of the overalls
are tucked into the gloves to avoid leaving uncovered areas. For safety, additional sterile sleeve cuffs can be used which cover the sleeve/glove
connection area (see Figure 11.B-4).
Gloves are to be changed immediately if they become damaged, and after they have been used to touch non-sterile objects, as when lifting objects that
have been dropped. Unnecessary contamination (e.g. through scratching, making telephone calls) is to be avoided. Entry into a critical area always
requires disinfection of the gloves. For use in grade A and B, gloves should be treated with disinfectants which are sterile at the time of application. It
must be ensured that the disinfectant is compatible with the material of the glove. Otherwise, latent penetration with maceration effects may occur. It is
recommended to aim to co-operate with the manufacturers of disinfectants in order to take advantage of their experience and avoid errors. The use of
70% isopropanol is usually adequate for disinfection. The pharmaceutical manufacturer verifies and evaluates the system so that there is no dependency
on subjective supplier recommendations.
Figure 11.B-5 Class E clothing with inadequate sleeves or gloves
External pockets
External pockets are not permitted in clean rooms. On the one hand they hold the hazard of accidental cross-contaminations, and on the other hand the
unintentional bringing of non-sterile or non-disinfected objects, e.g. pen, tissues, into the clean room. In principle, this requirement can also be applied to
manufacturing in lower cleanliness grades down to non-sterile drugs. In this case, the problem is primarily the involuntary carrying of parts or products
with subsequent mix-ups. Therefore, there should be no external pockets on clothing in these areas either.
Head coverings
The head coverings must be complete, i.e. the hair must be completely covered. For work in non-sterile areas, fleece material is usually used, while in
cleanliness grade A–B the same material is sometimes used as for the suits. The head covering is integrated in the suit or must be tucked into the collar
(see Figure 11.B-6).
Figure 11.B-6 Example of coverings in clean rooms
People with very long hair sometimes have to wear two head coverings (fleece fabric) at the same time to ensure complete coverage. One of the
management's tasks is to ensure that the head coverings used are suitable for all employees. Consistent execution, i.e. the same rules for managers
and visitors, is of absolute importance.
The problem of beards and moustaches in sterile areas is dealt with explicitly. The risk of releasing particles is accounted for with the requirement to
cover or remove the beard. For non-sterile areas, the correct manner of wearing the beard shield is also important. It may be that glasses are required in
clean rooms to protect the products against the employees' uncovered eyes (e.g. eyelashes). The individual necessity of this measure must be checked
during risk analysis. Apparative devices, such as air flow control (e.g. laminar flow) may make this unnecessary. This does not affect the safety aspects
of wearing glasses.
When establishing a policy on facial hair, the following aspects should be addressed:
■ Identify areas and duties where exposed facial hair is permitted
■ Identify areas and duties where exposed facial hair is not permitted
■ Identify areas where use of beard covers is required
Mouth mask/face mask

The mouth and nose are covered by masks. These masks are to be changed periodically (at the latest when penetrated by moisture), to prevent a critical
penetration of microbes.
As the mask is only effective when dry, conversations in the sterile working area should be reduced to the inevitable degree. The masks used consist of
various materials (integration in the hood fabric, multilayer fleece material, paper, etc.). The flexibility of the mask and the way of fixing it to the head
covering are essential criteria for good fitting in clean room areas A/B. Moreover, mouth masks for sterile working areas have to be sterile.
It is also important to wear the face mask in non-aseptic areas. In these areas, it is not generally necessary to cover the mouth, nose and hands.
However, these measures are essential when working on open products and on product contact surfaces (see Figure 11.B-7). In this case, it is important
to define these activities clearly in the practical workflow and demonstrate them to the staff in a comprehensible manner. The analysis of production
processes or individual working steps enables precise specification of the measures for each activity. For practical reasons, open products are to be
avoided as far as possible by using closed containment, as this can significantly reduce the effort required, i.e. putting on, wearing and removing masks
or gloves.
Figure 11.B-7 Coverings when working on the open product (grade E)
Shoes
In principle, the same requirements apply for shoes as for the clothing material. Overshoes should, as far as possible, be tearproof (especially single use
shoes). Here, the GMP requirements must be brought in line with the safety requirements (e.g. anti-slip). It should be possible to clean the shoes. This
can be done, for example, using a sole cleaning machine or by use of dust-binding mats.
For sterile areas, the leg openings of the clothing must be as tight as possible and must be tucked into the overshoes. For grade A and B, it must be
possible to sterilise or disinfect the boots.
Figure 11.B-8Example of clean Figure 11.B-9 Figure 11.B-10
room clothing Example 1 for grade E clothing Example 2 for grade E clothing
11.B.1.3 Preparation/Cleaning
Working clothing is only used as single-use clothing in exceptional cases, as the costs for this are usually very high. Therefore, processing steps are
carried out to prepare the clothing for reuse. The processing can be carried out within the plant or can be outsourced as a service. In the field of sterile
manufacturing, a number of requirements must be taken into account. The ageing process of the clothing caused by cleaning processes must be taken
into consideration, as this could result in a higher release of particles. There is no need for separate processing of clean room clothing for non-sterile
manufacturing.
The logistical organisation, i.e. responsibilities and processes, such as collecting, checking, dispatching, dispensing, etc. must be regulated. In addition
to checking the number of particles in the fabric, microbiological testing should also be carried out after preparation. For quality assurance purposes, the
service provider should be inspected and evaluated as part of the supplier qualification. The reduction in microbes through the preparation procedure is
reviewed during monitoring.
There are different processing requirements:
■ The preparation of the clothing must remove the particles released by people (dandruff, etc.).
■Production dust must be removed in order to avoid cross-contamination. Different items of clothing contaminated with different products should not
be cleaned together. This is to be considered in light of the potential risk.
■Preparation must be carried out as gently as possible so that no changes are caused in the fabric. This also helps achieve longer usability of the
clothing.
■ A visual inspection is carried out for wear and tear: thin spots, damage, condition of the seams.
■The preparation steps must be executed in a defined manner. Reproducibly should be warranted by defining temperature, time and cleansing agent
by type and quantity. The exact processes (e.g. flows) are prescribed in order to avoid secondary contamination from external areas, for example.
Drying, packaging and possibly sterilisation and storage are defined.
Special requirements for clean room clothing:

■ Keeping a kind of log or identification and traceability by means of barcodes, which are applied to the inside, is recommended.
■ Via single part tracking, it is possible to assign batches to cleaning and sterilising processes with the associated documentation.
■A usability date should be documented for sterilised clothing in order to avoid excessive storage periods. This is especially important for reserve
clothing with an unspecified storage time, e.g. in visitor locks.
■In the case of external preparation, the clean, decontaminated and sterilised clean room clothing should be heat-sealed air tight and returned in
closed boxes. Quality control before heat sealing can be carried out with laser particle counters.
■Disinfection of the laundry can be carried out in washing machines in combination with drying under a laminar flow (for clean room clothing that
cannot be sterilised in autoclaves).
11.B.1.4 Gowning procedure

The hygiene procedure includes a clear, area-specific definition of gowning. This must be logical and consistent. It should also be coordinated with the
structural circumstances so that different areas which require a change of clothing can be easily identified as such. The area assignment can be
visualised by using pictograms or colour codes. Here, different cleanliness areas across the plant can be identified via specific pictures or colours on
walls or doors.
Imprecision in terms of unclearly defined areas is to be avoided for acceptance reasons. Passage between areas is via personnel locks. The exact
procedure for the transfer between areas and the associated clothing change is described in process descriptions. These processes are to be discussed
in-depth in training courses, in order to achieve the necessary understanding and motivation of the staff. Compliance should be permanently monitored.
It goes without saying that a change of activities on different products is critical in terms of clothing. As re-entry into clean rooms requires a change of
clothing in any case, this is of particular importance for non-sterile areas. Activities that involve such a change should be examined separately during the
risk analysis and a precise procedure should be established.
In addition to the production staff, visitors and service employees must also be provided with the appropriate clothing. For sterilised qualities, the sterility
expiration date of the stored clothing must be noted.
11.B.2 Code of Conduct

In order to comply with limits for particulates and microbial contamination in defined clean room areas, a code of conduct has to be established.
Requirements increase with the level of the clean room area. Generally, any behavior that potentially impacts the product quality or the status of rooms
and equipment, is not tolerated. Supervisors should always keep an eye on the operators’ behavior, especially in clean rooms.
The code of conduct should be part of continuous training. The following aspects are essential for its implementation:
■ supervisors acting as a role model
■ consistency of the sanitation programme
■ open-minded culture where discrepancies and deviations may be dicussed in a constructive way
11.B.2.1 Personal hygiene

Employees are expected to maintain a high level of personal hygiene. This is understandable, as existing hygiene plans are based on defined average
values of microbial counts. Therefore, care of finger nails, hair and skin must be defined. In addition to a disproportionate increase in the microbial count if
care is neglected, there is also the hazard that finger nails could damage the gloves and clothing.
Regular personnel training and testing should make personnel aware of the significance of personal hygiene. The initial conditions for the change of
clothes are dependent on the individual personal hygiene prior to work (shower, shave, dental hygiene, hair care, moisture cream etc). It can be
advantageous for the company to provide utensils such as soap and towels, in addition to sufficient washing and cleaning rooms.
11.B.2.2 General requirements
Figure 11.B-11 General code of hygienic conduct
General code of hygienic conduct
■ NO eating, drinking or chewing

■ NO smoking
■ NO jewelry and watches
■ NO cosmetics (only for skin care)
■ NO critical behavior (fast movements, sneeze, cough)
■ Reduced number of employees in the relevant area
Food, cigarettes, jewellery and other personal objects (e.g. newspapers) must not be brought to the place of work. Eating, chewing, drinking and
smoking is strictly forbidden in the production areas. Suitable recreational rooms must be provided for this purpose. The transition between areas is to be
consistently via a lock, in which the production clothing is changed or (depending on the production cleanliness grade) at least sufficiently covered.
Before entering the production area, openly worn jewellery and watches must be removed. This is also required for safety at work.
Coughing and sneezing must not be directed towards the product. This can result in direct contamination. Raising awareness during training can clarify
the hazard potential.
Clothes and gloves should be controlled regularly in order to detect damages or contaminations.
If different products are handled simultaneously at different locations (e.g. manufacturing of tablets or capsules), measurements have to be defined in
order to avoid cross-contamination, such as change of gloves and cleaning of shoes before entering the production rooms.
11.B.2.3 Special requirements for clean rooms
Employees working in clean rooms should – at least during their total working time – not smoke. The time dependency between particle release with
exhaled air and the rest time since smoking has been proven. Only approx. 20 minutes after finishing smoking the average particle release value of non-
smokers is achieved. This is demonstrated very effectively in training courses.
Cosmetics must be used sparingly or preferably not at all by people who work in clean rooms. The hazard of contamination through particle release must
not be underestimated. A stipulation of the absence of any cosmetics avoids the differentiation between permissible and non-permissible quantities.
In clean rooms, speaking should be kept to an absolute minimum in order to prevent accelerated humidification of the mask with a penetration of
microbes.
Gloves should be disinfected regularly. In order to facilitate compliance, application systems should be provided in a sufficient number.
Only the absolutely necessary number of people should work in clean rooms at any one time. Operators who are not involved in the manufacturing
process should leave the clean room. The most effective way to minimise the number of employees in the sterile area is to execute only the absolutely
necessary production steps in clean rooms. Activities such as coding ampoules or visual checks on products can be carried out outside the clean rooms
in lower cleanliness grades.
The movement of people in clean rooms should be calm and uniform as this will have the least negative effect on flow ratios and causes the lowest
release of particles. In any case, movement should be as minimum as possible. Simply folding your arms can lead to contamination of your gloves. The
hands are placed near the armpits which, even on the outside of the fabric, are the areas with the highest microbial count.
11.B.2.4 Policies to be established
Policy for storage of food and drink
■ Identify specific areas where food and drink can be stored or consumed (lunch room, specially designated area for storage)
■Identify areas where food and drink can not be stored or consumed
(laboratory, manufacturing, aseptic filling area, sterility testing area, warehouse area, animal area, other)
Policy on the use of cosmetics
■ Identify areas where cosmetics can be worn
■ Identify areas where certain cosmetics are restricted
■Identify areas where cosmetics can not be worn
(aseptic filling area, sterility testing area, animal area)
■List what cosmetics are restricted for specific work areas
(eye makeup, rouge, face powder, hair spray, fingernail polish, others as listed)
Policy on the wearing of jewelry

■Identify when and where wearing jewelry is not permitted
(areas with machinery with moving parts, controlled areas, aseptic filling areas, sterility testing area, animal area)
■Identify what jewelry is not permitted for wearing
(watches, rings, ear rings, bracelets, necklaces)
Policy on smoking or eating in facility

■ Identify areas where smoking and eating can be done
■ Identify areas where smoking and eating cannot be done
11.B.3 Hand disinfection

Before starting any activity in the production area, the hands or gloves must be disinfected regardless of the type of production. As microbes are
continuously reproducing, periodic disinfection must also be carried out. The frequency of this measure depends on the cleanliness grade, the activity
and the technical circumstances (closed or open systems). The frequency and exact method of execution are to be specified in an operating procedure.
The disinfectant manufacturer's specifications are to be taken into account (for example, see Figure 11.B-12).
Figure 11.B-12 Hand disinfection (example)
Carrying out hand disinfection
■ Wet the hands

■ 1 squirt of soap – wash
■ Rinse thoroughly
■ Dry
■ 1 squirt of disinfectant – rub in for approx. 30 seconds
In any case (even for non-sterile production), the hands must be disinfected after going to the toilet or eating, drinking or smoking.
Hand cleaning and disinfection solutions are available individually and as combined products. The design of the facilities in the washing area should
enable operation without using the hands. This means considering the process with all individual elements: Control of the water supply (e.g. activation via
motion sensor, foot operated switch), dosage of the cleansing agent (elbow lever), drying (paper towels or hot air dryer), waste disposal (pedal bins), etc.
The use of hand towels and bars of soap should be avoided. Most disinfectants are applied as rub in disinfections. This means that the disinfectant is
rubbed into dry hands for a certain period of time. The disinfectants used should be approved by the respective national test centre. There must be an
adequate number of dispensers for disinfectant solutions. This will avoid long waiting times in the current work process and will increase acceptance
levels. As part of monitoring, the microbial status of the cleansing agent and disinfectant dispensers must be regularly reviewed.
Pictograms or clear instructions are helpful. This is important for visitors or external workers who are not familiar with these procedures.
When establishing a policy on hand washing, the following items should be addressed:
■Identify specific causes for hand washing (visit to restroom, after manufacturing, laboratory analyses, animal area, controlled/classified rooms,
other)
■ Identify duties and tasks requiring hand washing (preparation for gowning for entry into aseptic filling areas, others )
■Identify acceptable hand sanitizing compounds (cleansers, bacteriocidal agents, chlorine solutions, quaternary ammonium compounds, iodine-
based compounds, alcohols, others)
■ Specify whether sanitizers must be sterile or nonsterile
■ Identify requirements for signage (lavatories, at entry to controlled areas, reminder/instruction posters, gowning areas, others)
11.B.4 Health requirements

Only persons who do not have any infectious diseases at the time of production may be employed to manufacture drugs. This is ensured through health
monitoring. (See Chapter 2.B.2 Health requirements.)
In a medical fitness policy for employees, work areas have to be identified where physical requirements and/or psychological characteristics are
important, e.g. aseptic filling area, animal area. Furtheron it has to be specified what examinations or tests are required for employment, e.g. health
history questionnaire, physical examination, laboratory tests, abuse drug screening program. When doing so, privacy aspects, local laws and labor-
management agreements have to be considered.
As a crucial aspect for health monitoring, a system has to be established that ensures reporting of all health related conditions of employees to the
company medical officer.
A procedure should be established which adderesses the following aspects:
■ Identify illnesses which restrict employee from working in certain areas
■ Identify injuries which restrict employee from working in certain areas
■ Identify cuts and abrasions which restrict employee from working in certain areas
■Identify work areas where employees with illness, injuries or cuts and abrasions can not work (aseptic filling area, sterility testing area, animal
area, others)
When determining the need for monitoring the health of personnel by physical examinations, a differentiation between the following areas is reasonable:
■ areas and jobs where physical examination may be needed before employment or start of work (animal area, aseptic filling area, others)
■ areas and jobs where periodic physical examinations may be needed (animal area, aseptic areas)
■ areas where exposure to hazards may occur
11.B.5 Training
For the field of hygiene in particular, training courses represent an essential basis for the necessary measures. Without correct explanation, sufficient
compliance with the guidelines by the employees cannot be counted on. This results in inconsistent, partly incorrect handling of the requirements. In the
field of sterile production in particular, the smallest microbial contaminations are extremely critical by nature. In this respect, dialogue between the
management and production employees must be encouraged. In cases of doubt, unclear description in the requirements and unclear labelling of rooms
can lead to different interpretations by the employees.
In this dialogue, the principles of microbiology can be communicated and the requirements can be explained. The involvement of the staff in the selection
of working clothing, e.g. as part of a test phase, can give an indication of the practical suitability of the clothing. In addition, a high level of acceptance by
the staff can be achieved. (See Chapter 2.C Training.)
Summary
The working clothing requirements are directly linked to the cleanliness grade in which production is being carried out. Cleanability, particle release,
suitability and wearing comfort must be taken into account when selecting the clothing. The clothing must be cleaned (prepared) in accordance with an
established procedure in order not to affect the quality of the material. For each cleanliness area, there should be a gowning procedure which is taught
intensively.
Personnel hygiene includes the health check and training on special codes of conduct.
11.C Production hygiene

■ What sources of contamination must be taken into consideration in the production sequence?
■ Which cleaning procedures and cleaning agents are suitable?
■ What has to be considered for selection and handling of disinfectants?
Compliance with the measures for production hygiene is an indispensable requirement for pharmaceutical manufacturing. The type of measures for
cleaning rooms and their facilities is based on the cleanliness grade that must be achieved. This is prescribed by the production method or the dosage
form.
Both in the EU-GMP-Guide (Chapter C) and in the 21 CFR (Chapter D.1), a lot of requirements regarding production hygiene can be found. The relevant
topics can be assigned to different subject areas as listed in Figure 11.C-1.
Figure 11.C-1 Aspects of production hygiene
Basic aspects of production hygiene
Subject Considerations
■ Premises and facilities ■ Size, positioning of machines

■ Equipment ■ Suitability, cleaning status
■ Drains ■ Design, disinfection
■ Lighting ■ Brightness
■ Sewage and Refuse ■ Organisation
■ Sanitary facilities ■ Location, construction
■ Cleansing agent ■ Suitability
■ Personnel ■ Number
■ Social rooms ■ Location
■ Plumbing ■ Design, conducting
■ Ventilation, Air Filtration, Air Heating & Cooling ■ Construction, filter types, pressure differences, monitoring system
The type of cleaning depends on the type of contamination. This trivial statement however conceals a knowledgeable, detailed consideration of the
production sequences. On the one hand, the cleanliness grade prescribed by the production step is specified as the cleaning target, and on the other
hand the bordering areas must also be considered from a hygiene perspective. So, for example, finished medicinal product warehouses and warehouses
for primary packaging material should be included in the consideration. The cleanliness requirements must be complied with in particular at interfaces to
the production area. The maximum permissible microbial counts for the different pharmaceutical preparations are stipulated in the European
Pharmacopoeia (see Figure 11.C-2).
Figure 11.C-2 Microbial quality of pharmaceutical preparations (acc. to Ph. Eur. 5.1.4)
TAMC TYMC
(CFU/g (CFU/g
or or Specified micro-
Route of administration CFU/ml) CFU/ml) organisms
Non-aqueous preparations for oral use 103 102 Absence of E. coli

(1 g or 1 ml)
Aqueous preparations for oral use 102 101 Absence of E. coli

(1 g or 1 ml)
Rectal use 103 102 –
Oromuscosal use 102 101 Absence of St. aureus

Gingival use (1 g or 1 ml)
Absence of Ps.
Cutaneous use aeruginosa
Nasal use (1 g or 1 ml)
Auricular use
Vaginal use 102 101 Absence of Ps.

aeruginosa
(1 g or 1 ml)
Absence of St. aureus
(1 g or 1 ml)
Absence of C. albicans
(1 g or 1 ml)
Transdermal patches (limits for one patch including adhesive layer and backing) 102 101 Absence of St. aureus
(1 patch)
Absence of Ps.
aeruginosa
(1 patch))
Inhalation use (special requirements apply to liquid preparations for nebulisation 102 101 Absence of St. aureus
(1 g or 1 ml)
Absence of Ps.
aeruginosa
(1 g or 1 ml)
Absence of bile-tolerant
gram-negative bacteria
(1 g or 1 ml)
Special Ph. Eur. Provision for oral dosage forms containing raw materials of natural (animal, vegetal or 104 102 Not more than 102 CFU
mineral) origin for which antimicrobial pretreatment is not feasible and for which the competent authority of bile-tolerant gram-
accepts TAMC of the raw material exceeding 10 CFU per gram or per ml negative bacteria (1 g or
1 ml)
Absence of Salmonella
(10 g or 10 ml)
Absence of E. coli
(1 g or 1 ml)
Absence of St.aureus
(1 g or 1 ml)
Special Ph. Eur. Provision for herbal medicinal products consisting solely of one or more herbal drugs
(whole, reduced or powdered):
■ Herbal medicinal products to which boiling water is added before use 107 105 Not more than 102 CFU
of
E. coli (1 g or 1 ml)
■ Herbal medicinal products to which boiling water is not added before use 105 104 Not more than 103 CFU
of bile-tolerant gram-
negative bacteria (1 g or
1 ml)
Absence of E. coli
(1 g or 1 ml)
Absence of Salmonella
(10 g or 10 ml)
TAMC: Total Aerobic Microbial Count

TYMC: Total Yeasts and Moulds Count
11.C.1 Sources of contamination

Besides personnel as an influencing factor, the following additional sources of contamination are also evaluated:
■ Premises and facilities
■ Starting materials (including water)
■ Cleansing agents, disinfectants and aids
■ Equipment and utensils
■ Process gases
■ Ambient air
■ Processes
11.C.1.1 Premises and facilities

The GMP requirements concerning suitability of the rooms and facilities is important not only from a production perspective, but also from a hygienic
perspective. For cleaning, the term sufficiently large means sufficient room for movement by the cleaning staff as well as accessibility of all possible
points. Experience shows that small rooms are often set up in such a way that cleaning is made difficult, due to the best possible utilisation of the
available space. Thus, for example, machine parts that are located near the walls are difficult to reach during cleaning (3.38 EU-GMP Guide) (see
Chapter 11.C.2.2 Cleaning procedure for rooms).
According to 21 CFR Sec. 211.42 Design and construction features., any building used in the manufacture, processing, packing or holding of a drug
product should be of a suitable size, construction and location to facilitate cleaning, maintenance, and proper operations.
Written procedures should be established for assigning responsibility for sanitation and describing in sufficient detail the cleaning schedules, methods
and equipment, and materials to be used in cleaning the buildings and facilities (21 CFR Sec. 211.56 Sanitation. b)
It should be possible to clean technical facilities such as pipes, light fittings, etc. (C EU Directives and Guidelines, 3.10). This requires fully wainscotted
environments as far as possible, e.g. through integration in suspended, sealed ceilings. This avoids classic problem areas such as pipes and hanging
light fittings, which could potentially form dusty surfaces. (See Chapter 3.D Construction elements.)
Drains
From a hygiene perspective, waste water disposal is critical. The construction must prevent a jam or back flow of waste water. This also means there
must be a sufficient number of drains of an adequate size. The capacity should be designed during room planning in view of production. Drains that are
too small will cause blockages despite a sufficient pipe diameter. In any case, a back flow flap must be provided for safety reasons (C EU Directives and
Guidelines, 3.11), as the hazard from the entry of standing, contaminated water is high. The last section of the drains in the floor should be arranged with
a slope to the outlet. The remaining floor areas should be level, in order to avoid puddles. It goes without saying that this slope must not cause risks to
safety at work.
The drains must be disinfected regularly, for the residual waste water standing here offers an ideal reproduction basis for microorganisms. This is not
only significant for sterile operations, but also for non-sterile production areas, e.g. in solid dosage forms productions. Here, residues of solids, which act
as a culture medium for various cultures, are washed away with the waste water (e.g. starch, cellulose, lactose, etc.). As a certain initial contamination
is present in the raw materials, especially from a plant-based origin, a big increase in the bioburden must be reckoned on here. Disinfection is thus
indispensable. The disinfectant should be changed regularly in order to counteract the development of resistances (see Chapter 11.C.3 Disinfection).
According to 21 CFR Sec. 211.48 Plumbing. (b), drains should be of adequate size and where connected directly to a sewer should be provided with an
air break or other mechanical device to prevent back-siphonage.
Lighting
The requirement for good lighting in the rooms is also significant for cleaning. Only in adequately lit up rooms can visual clean be carried out, i.e. an
acceptable cleaning result be achieved.
Sanitary facilities
Sanitary facilities carry a high hygienic risk due to the potential entry of organisms. Here, there is a discrepancy between workplace regulations and the
GMP requirement. On the one hand, the immediate proximity of toilets to the place of work is prescribed, and on the other hand, this cannot be
accepted for hygienic reasons. Ideally, there should be no toilets in the production area without locks. They should at least have an anteroom which
enables cleaning and disinfection of the hands and the removal of the pharmaceutical clothing.
Recreation rooms
To avoid an excessive entry of microorganisms, rooms that are used for food consumption or smoking must be completely separated from production (C
EU Directives and Guidelines 3.30). It is crucial that locks be installed with prescribed change of clothing, in order to prevent contamination of clothing
and the consumption of product dust (by inhalation or with food).
Pest control
Pest control in the entire surrounding area (warehouse, direct environment around the manufacturing sites, within the plant) makes it possible to estimate
a possible hazard through different small animals (insects, rodents) and the measures to be taken. This should be undertaken by competent persons, as
the location of the installation and the type and number of traps require zoological or behavioural biology knowledge. Assignment to specialist service
providers offers a good alternative to internal installation and evaluation. The results should be evaluated by quality assurance or the head of production.
Written procedures should be estabilished for the use of suitable rodenticides, insecticides, fungicides, fumigating agents, and cleaning and sanitizing
agents that have been registered and used in accordance with the Federal Insecticide, Fungicide and Rodenticide Act (7 U.S.C. 135).
More information on the establishment of pest control is given in Chapter 11.M.7 Sanitation and pest control.
11.C.1.2 Starting materials
The raw materials used in production must comply with the specifications of the valid pharmacopoeia and the markting authorization.
In terms of the permissible microbial contamination, herbal extracts should be considered as critical starting materials. Microbiological testing as part of
the control of incoming materials is of great importance. In terms of risk minimization, all suppliers should be qualified. The conditions during
transportation and storage have to be considered.
Water as a raw material is of great importance due to the volume in which it is used and its ubiquitous application. (See Chapter 5 Pharmaceutical
Water.) Threshold values for microbial loading can lead to violations of the specifications in the further course of production in terms of the microbial
count of the final product. Alert limits must be defined. According to 21 CFR Sec. 211.48 Plumbing. (a), potable water should be supplied under
continuous positive pressure in a plumbing system free of defects that could contribute contamination to any drug product. Potable water should meet
standards prescribed in the EPA’s primary drinking water regulations set forth in 40 CFR Part 141.
Prior to weigh-in of raw materials, the outside of the packing drums which is a potential location of particulate as well as microbial contamination should
be cleaned. This can be performed manually or with automated systems. Care should be taken when opening containers in order to avoid contamination
of the interior.
The microbiological status of raw materials is not only a relevant issue for sterile drugs, but also for the production of non-sterile drugs, because the
materials used (e.g. lactose, cellulose, starch, water) provide ideal conditions for microbial growth.
The assurance of a controlled raw material quality is a task where several departments are involved. The specific responsibilities are shown in Figure
11.C-3.
Figure 11.C-3 Responsibilities for control of raw material quality
Department Responsibilities
Purchasing ■ Purchase contract lists component and container/closure requirements;

■ Obtain components and container/closure from approved sources
Production ■ Only use tested and approved components

■ Only use tested and approved containers and closures
Laboratories ■ Analyze samples of components

■ Determine conformance with specifications
Engineering and ■ Maintain area where samples are taken
Maintenance
QC Unit ■ Provide oversight,

■ Perform Periodic review of receiving activities,
■ Collect samples of received components and container/closures,
■Review and approve specifications for all materials including: labelling, manufacturing materials, lubricants and cleaning
agents, materials from sub-contractors, materials from other divisions of the company)
11.C.1.3 Packaging materials

Handling of primary packaging materials exerts a great influence on the microbiological stability of the product. Procedures to maintain a controlled
status of particulate and microbial status have to be established. This is of particular importance for sterile drug products, but should also be considered
for non-sterile products. (See Chapter 13.A Packaging material.)
Paperboard containers which are often used as a secondary packaging material may also represent a source of particulate contamination (emission of
fabrics). Moreover, in combination with humidity they provide good conditions for microbial growth. Therefore paperboard containers should not be
handled in rooms where open product is handled.
11.C.1.4 Cleansing agents, disinfectants and aids
The cleansing agents and disinfectants to be used must not become a source of contamination themselves. To ensure this, complete removal from
surfaces after treatment is required. Reproducibility of cleaning and disinfection is a prerequisite for this.
Cleansing agents and disinfectants should be obtained only from qualified suppliers ensuring consistent quality and timely information about changes in
the composition, if any. Cleansing agents and disinfectants should be subject to control of incoming materials and batch release.
Incompatibility of cleansing agents and disinfectants may cause alterations of the treated surfaces which may impact the effectivity of further cleaning
and disinfection. This should be considered when cleansing agents and disinfectants are selected.
Generally, lubricants should not come into contact with products or product contact surfaces. If the use of lubricants is unavoidable for technical reasons
(e.g. moving mechanical parts), the conformity or official approval of the grease used must be ensured (e.g. FDA conformity certification), in addition to
its compatibility with the product. To avoid contamination, the first parts of a batch for partial discharges (e.g. ointment filling, tablet presses) are
discarded.
This is advisable as possible contaminations, such as traces of grease remaining after assembly of components, can be removed in this way. Cleaning
through neutral fillers, such as placebo compounds, is not recommended as it must be proven that there is no cross-contamination. For parts which do
not come into contact with the product, such as table tops, it must be ensured that no influence is exerted.
11.C.1.5 Equipment and utensils
According to 21 CFR Sec. 211.67 Equipment cleaning and maintenance., equipment and utensils should be cleaned, maintained and sanitized at
appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality or purity of the drug product. In
addition, written procedures should be established and followed for cleaning and maintenance of equipment including utensils used in the manufacture,
processing, packing or holding of a drug product.
The procedures should contain the following minimum information:
■ Assignment of responsibility for cleaning and maintaining equipment
■ Maintenance of cleaning schedules, including where appropriate sanitizing schedules
■Detailed description of the methods, equipment and materials used in cleaning and maintenance operations and the methods for disassembling
and reassembling equipment as necessary to assure proper cleaning and maintenance
■ Removal of previous batch identification
■ Protection of clean equipment from contamination prior to use
■ Inspection of equipment for cleanliness before use
■Records that need to be kept for the maintenance, cleaning, sanitizing and inspection as specified in 21 CFR Sec. 211.180 General requirements.
and Sec. 211.182 Equipment cleaning and use log. (see Chapter D.1 Code of Federal Regulations).
As part of the product-specific cleaning validation, the parts that come into contact with the product are subject to critical analysis and are differentiated
in a risk assessment (see Chapter 8 Cleaning Validation).
Parts which do not come into contact with the product are only investigated in exceptional cases. If contaminated areas remain due to inadequate
cleaning results (machine parts, walls, floors or ceilings), there is a risk that subsequent products may become contaminated.
Only cleaned, faultless equipment, machines, containers or aids may be used. Microbiologically critical materials or objects, e.g. wooden pallets and
cardboard boxes, must therefore not find their way into production.
11.C.1.6 Process gases
Process gases, such as nitrogen for inertisation or compressed air that comes into contact with the product, may also represent a source of
contamination.Facilities and distribution systems as well as the suppliers have to be qualified. The purity of these utilities must be checked regularly at
the point of use during monitoring.
Generally the following parameters are monitored:
■ microbial count
■ particle count
■ water content
■ oil content
11.C.1.7 Ambient air

Ventilation systems create air with low microbial and particle counts. Compliance with the requirements is supervised through monitoring. (See Chapter
3.J Monitoring of HVAC systems.)
According to 21 CFR Sec. 211.46 Ventilation, air filtration, air heating and cooling., adequate ventilation should be provided, adequate equipment for
controlling air pressure, micro-organisms, dust, humidity and temperature should be provided, and air filtration systems including pre-filters and
particulate matter air filters should be used on air supplies to production areas (see Chapter D.1 Code of Federal Regulations). If air is recirculated to
production areas, measures should be taken to control re-circulation of dust from production. In areas where contamination occurs during production,
there should be adequate exhaust systems to control contaminants.
In case of dysfunction or breakdown of ventilation systems or laminar flow units, risk of product contamination is high. A system must be installed that
reflects the actual status of the HVAC system. Alarm functions have to be checked during maintenance and calibration activities. Filter integrity tests
have to be performed after filter changes in order to assure appropriateness and correct assembling.
Identification of filter equipment needed to prevent air contamination should encompass the evaluation of the following aspects:
■ Need for prefilter: Reduction of particulate matter as necessary
■Need for HEPA-filter: Prevent contamination from entering (outside of area to inside of area, one area to another area, environment to product),
control of microorganisms, control of particulate matter
■ Need for unidirectional flow hood: prefilter for reduction of particulate matter, HEPA filters for the control of microbial contamination
■ Need for isolators: prefilter for reduction of particulate matter, HEPA filters for control of microbial contamination, Environment to product
■Identify the tests for HEPA filters:
■ Detect leaks in the filters (Integrity testing),
■ Determine the rating of the filter (efficiency test, obtain test results from filter vendor),
■Determine which tests to perform (airflow velocity measurements across entire filter face; aerosol challenge: dioctylphthalate (DOP), Emery
3004; other substances that will not support microbial growth; visual examination of filter element for damage and holes; measure pressure
differential across filter element),
■ Determine the frequency for performing the tests (perform test semi-annually)
■ Maintain records of tests and results
For more information on filters see Chapter 3.G.3 Filters.

11.C.1.8 Processes
Production processes can lead to an increase in microbial counts. Thermal manufacturing steps (solution steps, drying processes) in combination with
humidity usually lead to increased microbial reproduction at temperatures of 20–50 °C or to a reduction in the microbial count at temperatures above 80
°C. This is especially significant for long processes.
Examples of this are
■ insufficient heating during the manufacturing of ointment or gel,
■ the preparation of a suspension or solution with heating
■ drying of moist granulates on trays.
It must be ensured that no residues of compounds with a high starting contamination are left for a long time after production, e.g. weekend. Whereas
cleaning of equipment is subject to cleaning validation (see Chapter 8 Cleaning Validation), contamination of rooms has to be considered in view of
microbiological status and potential cross-contamination. Prompt cleaning and disinfection must be ensured in this case. Manufacturing waste should be
removed as quickly as possible. The containers should be emptied into collection containers outside the production area (prevention of contamination).
The containers must be adequately labelled. It is recommended to use colours with a signalling effect throughout the plant for clear identification.
11.C.2 Cleaning
The task of cleaning is to remove organic and inorganic contamination. This includes an uncontrolled and random microbial count reduction (wash away
effect). In terms of disinfection, cleaning is carried out to remove dirt, polysaccharide, lipids and proteins, as these reduce the effectiveness of the
disinfectant through embedding effects.
The level of purity to be achieved for product contact surfaces is defined by the cleaning validation requirements (see Chapter 8.E Acceptance criteria
and limit calculation). Production rooms and bordering areas, e.g. corridors, are cleaned according to the visual clean criterion, taking into account the
monitoring results.
11.C.2.1 Cleaning procedure for equipment
Written procedures should be established to enable reproducibility. By nature, this is easier in automatic procedures than in purely manual cleaning
processes (see Chapter 8.B How to validate cleaning procedures).
Even with surfaces that do not come into contact with the product, the factors of mechanics, time, temperature and concentration of the rinsing solution
are important for the quality of the result. Excessively high concentrations of rinsing concentrate lead to massive adsorption effects, especially on
stainless steel surfaces. The compatibility of the cleansing agent with the surfaces to be cleaned must be ensured in order not to cause any damage.
After rinsing, product contact surfaces are subject to a final rinse with water of the highest cleanliness grade in the procedure. This is not necessary
when cleaning areas that do not come into contact with the product.
It should be possible to blow through rinsing pipes in order to prevent standing water after the rinse process is completed. This also applies for feeds into
facilities. Facilities may have to be dismantled in order to dry the components (e.g. ball valves). Under no circumstances should water remain standing,
as this would cause a massive growth in bacteria. Feed pipes used for self-conserving, highly viscous syrups, are not emptied if there is a short standing
time. A multiple amount of the pipe volume is rejected as start-up waste.
The effectiveness of the cleaning process is proven during cleaning validation and is reviewed through ongoing monitoring and optimised as required (see
Chapter 8.E.3 Determination of the microbial status and Chapter 8.F.5 Microbiological testing of surfaces).
The respective cleaning and disinfection measures are documented in the log books of the machine and room cleaning records. Confirmation of the
measures is recorded in the batch records.
This topic is dealt with 21 CFR Sec. 211.67 Equipment cleaning and maintenance.
11.C.2.2 Cleaning procedure for rooms
Cleaning procedures for room cleaning are usually non-specific, but are fixed in writing. They are based on the visual clean criterion. There are currently
no definitive legal requirements for cleaning rooms. Depending on the structural and facility-related circumstances, the current cleanliness grade must
ultimately be complied with. The efficiency of the measures is checked during monitoring (see Chapter 11.E Environmental monitoring).
Written cleaning schedules are compiled on the basis of defined sequences and processes (see Chapter 11.D Sanitation programme). They contain
precise specifications on the type and frequency of the cleaning measures to be carried out. Depending on the cleanliness grade, different degrees of
disinfection measures must also be carried out. The respective cleaning process must be established, i.e. how, when, with what and by whom cleaning
is carried out. The selection of the appropriate cleansing agent or disinfectant and their application can be difficult and causes long test phases. Using
the experiences and know-how of the manufacturers of cleaning agents and disinfectants through direct collaboration can be useful in compiling such
instructions. The specifications, however, are defined by the pharmaceutical plant. There should be no dependency on a specific vendor. The person
responsible for cleaning and disinfection, i.e. who does it, and the person who is responsible for checking that it has been carried out are both stipulated.
Figure 11.C-4 Cleaning procedure
Aspects of cleaning procedures
■ Intervals
■ Responsibilities (execution, checking)
■ Procedure (cleaning agent and disinfectant, aids)
A production room can be cleaned in various ways. Machines and facilities are cleaned according to the existing cleaning procedures, based on the
results of the cleaning validation (see Chapter 8 Cleaning Validation). To this end, it may be necessary to dismantle machines in order to achieve
sufficient cleaning. If individual parts of the equipment are taken out of the room, it must be ensured that no product residues, which could cause cross-
contamination in other rooms, adhere to the individual parts. Therefore, preliminary cleaning, e.g. aspiration and/or covering of containers must be carried
out. After the machine has been cleaned, the rest of the room is cleaned. In doing so, it must be ensured that the cleaned machine does not become
contaminated again. It may have to be covered to protect it from splash water, for example.
This topic is dealt with 21 CFR Sec. 211.56 Sanitation.
11.C.3 Disinfection
It is the task of disinfection to achieve a specified reduction in the microbial count of surfaces. The target microbial count is prescribed by the cleanliness
grade. Sterilisation procedures may also be necessary to achieve the desired target. This may depend on the average starting contamination and on the
production cleanliness grade.
General procedure
The factors that apply for cleaning are generally also valid for disinfection. The method of application and the residence time are important aspects for
sufficient effectiveness of the disinfection procedure. Dilution and evaporation effects lead to a massive loss in effectiveness of the disinfectant.
The effectiveness of the procedure is reviewed as part of the monitoring and optimised as required (see Chapter 11.E Environmental monitoring).
Annex 1 of the EU-GMP-Guide on the manufacturing of sterile drugs gives detailed information on the handling of disinfectants (see Figure 11.C-5).
Figure 11.C-5 Handling of disinfectants
Handling of disinfectants
■ Regular change
■ No refilling of partially empty containers
■ Long-term storage in sterilised containers
■ Sterile at time of application
A key principle for avoiding the build up of resistance is to regularly change the disinfectant. Although the combination of different disinfectant types does
not lead to any scientifically proven development of resistance, there can be problems with the effectiveness of the disinfectant due to application errors
and gradual breeding of an internal flora. The frequency, e.g. monthly, and the sequence of the change are defined and recordehd in the cleaning
procedures and in order to enable retrospective assessment.
Storage containers which are partially empty, e.g. after changing the disinfectant, must not be refilled. This is partly due to the notion of batch purity,
moreover the hazard of contamination through the layer formation of disinfectants is high. This applies especially for dilutions that are produced from
concentrates. Under certain circumstances, e.g. in central dosing facilities, dilutions for use can become microbially contaminated, in particular if they
are underdosed for a long period of time. A so-called biofilm could form, which protects the microoorganisms against the direct attack of the disinfectant.
Sources for this are usually the water-carrying piping of the dosing facility. The dissolution of such a film can be very problematic.
If long-term storage is necessary, sterilised containers should be used in order to counteract the hazard of the breeding of resistant strains.
Disinfectants must be sterile at the time of application (for cleanliness grades A–D). The disinfectants now available commercially are usually irradiated
with gamma rays, in order to offer the necessary sterility. Alcohols should be sterile-filtered before being brought into the sterile room, provided they have
not already been filtered by the vendor, as spores in alcohol are not killed. With the dispersion of the alcohol, the spores are distributed and can multiply
again.
The disinfectants used should be approved by the respective national test centre. It checks and evaluates them according to different methods and
effectiveness requirements in circumstances relatively close to practice. This ensures their basic suitability. Medical and safety data sheets are
available.
Figure 11.C-6 Requirements of cleansing agents and
disinfectants
Requirements of cleansing agents and disinfectants
■ Efficacy
■ No development of resistance
■ Applicability
■ Material compatibility
■ Environmental compatibility (waste water)
■ Tolerability (allergic reaction, irritation)
■ Costs
Summary
In addition to the personnel, there are further sources of contamination in manufacturing, such as product contact surfaces, the environment (room and
air) and the starting materials (including water, process gases and packaging).
It is therefore of the utmost importance that facilities and rooms be cleaned and disinfected with suitable agents and according to established, validated
procedures.
11.D Sanitation programme

■ What is a sanitation programme?
■ What does a cleaning instruction for rooms consist of?
The requirement for a written sanitation programme is made in the EU-GMP-Guide (see Chapter C EU Directives and Guidelines) and in 21 CFR Sec.
211.56 Sanitation. The sanitation programme defines all necessary plant hygiene measures. In addition to personnel sanitation programmes (including
clothing requirements, zonal behaviour, general code of conduct, personal hygiene, etc.), the specific assignment of the individual rooms in the plant to
the defined cleanliness grades is also part of the sanitation programme. It is completed by schedules for cleaning and disinfection.
11.D.1 Organisation of room cleaning

The organization of room cleaning encompasses the following aspects:
■ Hygienic areas
■ General room cleaning
■ Cleansing agents and disinfectants
■ Cleaning process
11.D.1.1 Hygienic areas

All rooms of the plant have to be assigned to the respective hygienic areas (cleanliness grades). This involves the definition of requirements and limits for
the environmental monitoring (see Figure 11.E-4 and Figure 11.E-5).
It should be specified for each cleanliness grade, which surfaces (ceilings, walls, floors, benches) have to be cleaned and/or sanitized in what intervals.
The application method (wiping, spraying) has to be mentioned.
An example for this is given in Figure 11.D-1. The concrete definition of measures and frequencies depends on the monitoring results.
Figure 11.D-1 Definition of cleaning and disinfection measures for different cleanliness
grades
cleanliness grade
Area/surface A,B (ISO 5) C (ISO 7) D (ISO 8) E

Ceilings C/D: daily to weekly C/D: weekly C: weekly C: weekly
D: monthly D: monthly
wipe wipe wipe wipe

Walls C/D: daily to weekly C/D: weekly C: weekly C: weekly
D: monthly D: monthly
wipe or spray wipe or spray wipe wipe

Floors C/D: daily C/D: daily C/D: daily C: daily
D: weekly
wipe wipe wipe wipe

critical benches C/D: daily C/D: daily C/D: daily C: daily
D: daily to weekly
wipe and spray wipe and spray wipe and spray wipe and spray
C: cleaning, D: disinfection
11.D.1.2 General room cleaning

This instruction lists all individual rooms of the plant. The responsibilities for cleaning and disinfection measures and for the required execution intervals
are listed. Groups of cleansing agents and disinfectants are assigned with the corresponding aids for application. The necessary change of disinfectants
is established (see Figure 11.D-2).
Figure 11.D-2 Overview of room cleaning
Location A001 A002 A003 A004 A005 A006 A007 A008 A009 A010
Procedure Disinfection as X X X X X X X X X X
req.
yr. _ _ _ _ _ _ _ _ _ _
mthly: _ _ _ _ _ _ _ _ _ _
wkly: _ _ X _ _ _ _ _ X _
dly: X X _ X _ _ _ X _ _
Cleaning as req. X X X X X X X X X X
yr. _ _ _ _ X _ _ _ _ _
mthly: _ _ _ _ _ X _ _ _ X
wkly: _ _ X _ _ _ X _ X _
dly: X X _ X _ _ _ X _ _
Medium Cleaning and disinf. code F _ _ _ _ _ _ _ _ _ _
E _ _ _ _ _ _ _ _ X _
D _ X _ _ _ X _ _ _ _
C _ _ _ _ _ _ _ X _ _
B _ _ X _ _ _ _ _ _ _
A X _ _ X _ _ _ _ _ X
Aids 6 _ _ _ _ _ _ X _ _ _
5 _ _ _ _ X _ _ _ _ _
4 _ _ X _ _ _ _ _ _ _
3 X X - X _ _ _ _ _ _
2 _ X _ _ _ _ _ _ _ _
1 _ _ _ _ X X _ _ _ _
Responsibility Cleaning _ _ _ _ X X _ _ X X
group
Product X X X X _ _ X X _ _
group
11.D.1.3 Cleansing agents and disinfectants

This section of the sanitation programme is where the different permissible cleansing agents and disinfectants are named. They are coded in groups, e.g.
by application or by physical-chemical characteristics (see Figure 11.D-3). This enables a simple connection to general room cleaning and a simple
replacement of agents, e.g. in case of changes. These instructions should also specify the necessary concentration and acting times of the respective
agents, in order to enable proper application. In addition to separate systems, combined agents for cleaning and disinfecting are also available on the
market.
Figure 11.D-3 Grouping of cleansing
agents and disinfectants (Example)
Cleansing agent and disinfectant code
A B C D E F
Cleanfix AS X _ X _ _ _
Cleanfix AF X _ _ _ _ _
Superclean S X _ X _ _ _
Superclean V _ X _ _ _ _
Desinform X _ X _ _ _ _
Desi-Sept NA _ _ _ X _ _
Antisept Super _ _ _ X _ _
DS 45 _ _ _ _ X _
Anti-Micro 3 _ _ _ _ _ X
Compatibility with the material is very important. It is expected that the cleansing agents used will not cause any interaction with the surfaces, i.e.
will not bond with later release, and will not cause any modification of the surface structures. This must be taken into account above all if different
materials are processed in one room (e.g. floor tiles, walls). For example, if aluminium surfaces are cleaned with acid cleaners (e.g. citric acid), the
roughness is increased.
For production and filling rooms in aseptic or clean room areas, disinfection with formaldehyde can be carried out depending on the technical
circumstances. With an acting time of 6 to 16 hours, overnight disinfection is practical. Various agents are available for disinfecting tables, floors, walls
and drains (alcohols, aldehydes, quaternary ammonium compounds or phenols).
When selecting the cleansing agent or disinfectant, it is also of importance to include the criterion of the tolerability of the agent for the employee.
11.D.1.4 Cleaning process and aids
This section of the sanitation programme lists the different aids. The code grouping is used for classification in the procedure for room cleaning (see
Figure 11.D-4).
Figure 11.D-4 Grouping of the aids
(Example)
Aid code 123456
Floor cloth X_ _ _ _ _
Mop X_ _ _ _ _
Brushes X_ _ _ _ _
Rubber squeegees _ X_ _ X_
Spray guns _ XX_ _ _
Low pressure foam device _ _ _ X _ _
Dry aspirator X_ _ _ _ _
Scrub suction device _____X
Water aspirator _ _ XXX_
The method of execution is important for the cleaning and disinfection result. Therefore the application, dispensing and, if necessary removal of the
cleansing agent or disinfectant solutions must be fixed in writing as well as the concentrations used. In doing so, the experiences of the employees and
the results from the monitoring should be consolidated. Simply wiping the floor with a mop is sometimes not sufficient.
This simply redistributes the dirt, and mixes it with disinfectant. As an alternative, the floor can be flooded with subsequent aspiration. Automatic floor
cleaning machines are another alternative for large area applications (e.g. corridors). In order to prevent transporting dust across the entire working area,
it must be ensured that the aspirated dust is not blown out again.
Cleaning is carried out in steps: application of the cleansing solution, floor wiping, and aspiration of the dirt solution; rinsing may also be included.
Depending on the location, it should ideally be possible to qualify such machines and thus enable reproducible cleaning. The procedure must be
matched to the individual circumstances.
11.D.2 Documentation
Room cleaning or disinfection is documented in the form of records. These are effectively room log books, which enable the traceability of products or
batches. In addition to confirmation that the work has been carried out, they also give a status report on the room, which shows its cleaning status.
The type of production (product name, batch name for traceability) and the executed cleaning or disinfection are documented (see Figure 11.D-5).
Records that are hung up can be viewed easily, i.e. if they are hung up directly on site (outside a room, as a record inside the room could potentially
become contaminated or could act as a contaminant), so that the cleaning status of a room can be seen directly from outside. The length of time for
which this status can be retained must be defined, above all from a microbiological perspective. This means that, as with production devices for the
production rooms, an expiration date for the cleanliness status must be defined.
The records should be checked in regular intervals by the head of department and compared with the current status. During monitoring, they should be
critically reviewed in terms of their quality. The retention time for this data, as pharmaceutical secondary documentation, is the expiration time of the
products produced in the rooms plus one year (at least 5 years).
Figure 11.D-5 Example of a room cleaning record
Logo GMP Pharma
Room cleaning record Acc. to SOP xyz Room no. C003
No. Product Batch number Cleaning Disinfection Disinfectant group Signature

Note: After 14 days, cleaning/disinfection must be carried out again
Explanation
No.: Serial numbers mean completeness can be checked quickly
Product: Product name
Batch number: Batch ID for unique identification
Cleaning: Recording of the date of cleaning
Disinfection: Recording of the date of disinfection
Disinfectant: Documentation of the disinfectant used
Signature: Identification of the executor
Summary
In the sanitation programme, the rooms are assigned to the cleanliness grades. The sanitation programme also regulates what should be cleaned or
disinfected, how often, with what means and how.
The sanitation programme relates exclusively to the cleaning of rooms and non-product contact surfaces. Associated documents are the room cleaning
instructions and the room cleaning records.
11.E Environmental monitoring

■ How can monitoring be prepared, carried out and evaluated?
11.E.1 General
Monitoring is used to review the effectiveness of the plant hygiene measures. The constant evaluation of the hygiene status is used to verify the
classification of the cleanliness grades. This can result in optimisation of cleaning and disinfection measures. Trend analysis uncovers deviations prior to
occurrence and enables early changes to processes. In addition to microbiological investigations, the particle load is checked in sterile areas.
It is recommended to have the co-ordination of the monitoring measures and the evaluation and trend analysis carried out by quality assurance as an
independent group. Depending on the size of the plant, it may be advisable to appoint a hygiene officer. Evaluation is carried out in collaboration with
quality control and the head of production. The resulting measures are defined by the head of production.
Monitoring is carried out in several stages (see Figure 11.E-1). As the sampling plan is often subject to change, it can be designed practically in the form
of an appendix to the procedural instructions.
Figure 11.E-1 Monitoring process
Monitoring process
■ Risk analysis with limit definition

■ Sampling plan
■ Sampling
■ Evaluation
■ Modifications
As a first step, the environmental standards for each production and laboratory area should be determined:
■Define the needs of each area
Uncontrolled, controlled, aseptic, sterility testing area
■Define the activity that is to occur in each area
Identify formulating and manufacturing areas, washing and cleaning areas, sterilization areas, non-sterile filling areas, aseptic filling areas, labeling
and packaging areas.
■Define the environmental parameters
■ Identify the temperature range, humidity range and the frequency of air changes for each area,
■ Identify airflow rate and patterns required in each area, pressure differentials required between different classes and areas within a class,
■ Identify the particulate matter requirements and the viable microorganism quality requirements for each area
■Define other environmental requirements:

Identify the lighting requirements for each area & the noise control requirements for each area
In a second step, it should be determined what environmental tests need to be performed in each area:
■Define the classification of each area:
Uncontrolled, Class 100, Class 1000, Class 10000, Class 100000
■Determine the parameters to measure:
Non-viable airborne particles, Viable particles, Airborne, Surface, Personnel
For microbiological aspects of environmental monitoring, see Chapter 12.J Microbiological monitoring for detailed information.
11.E.2 Sampling plan

When defining the sampling points for routine monitoring, the experiences from the initial monitoring and the product features should be taken into
account. You should try to find the points at which the microbial count is estimated to be at its highest (near wash basins, door handles, etc.) or which
are directly next to the product. In sterile areas, so-called mapping is also carried out to compile the sampling plan. This involves splitting the entire
room into squares, from each of which a direct contact test is taken. The points with the highest microbial count are included in the sampling plan. The
plan contains various details, which are listed in Figure 11.E-2.
Figure 11.E-2 Content of the sampling plan
Sampling plan
■ Sampling points (related to the location and function)

■ Number of samples
■ Frequency of sampling
■ Sampling method (for quantitative or qualitative determinations)
■ Sample size
■
■ Auxiliary liquids (dilutions, rinsing agents, neutralisers, etc.)
■ Factors with possible impact on incubation results
■ Operating conditions/at rest
It is subject to an in-plant approval procedure, i.e. it requires the approval of the responsible persons (quality control, head of production, quality
assurance).
Sampling is carried out according to the authorised plan and written procedures. Each sample is declared as clearly identifiable. The sampling carried
out is documented in the record. An easy way to generate the record is to turn the sampling instructions into the record by signing them accordingly.
Important contents of the sampling procedure are given in Figure 11.E-3.
Figure 11.E-3 Content of a sampling procedure for environmental monitoring
Sampling procedure
■Take samples when area is at rest:

■ Non-viable particulates - only during facility qualification,
■ Viable particulates – critical surface and personnel samples only,
■ Airflow Patterns – only during facility and equipment qualification
■Take samples when area is in operation:

All routine airborne samples – non-viable and viable
■Determine sample sites:
Include maps of sampling sites in the procedure (Non-viable sampling points, Viable sampling points (Airborne, Surface), Personnel sampling
points)
■ Determine frequency of sampling
11.E.3 Establishment of limits and frequencies

11.E.3.1 European requirements
The limits for clean rooms can be taken from the Annex 1 Manufacture of Sterile Medicinal Products of the EU-GMP-Guide (see chapter C.6.1). In
addition to the cleanliness grades A–D prescribed by the classifications, it is also advisable to define levels for bordering areas as well as for non-sterile
production steps (Figure 11.E-4 and Figure 11.E-5). Alert and action limits must be established for all classes. Such values are established according to
experience with similar facilities, as well as the values from the qualification phase.
Figure 11.E-4 Limits of cleanliness grades A–G (air)
A B C D E F G
cleanliness grade Annex 1 EU-GMP-Guide Own definition

Particle load
(at rest) 0,5 µm 3,520 3,520 352,000 3,520,000 n.d. n.d. n.d.
0,5 µm 20 29 2,900 29,000 n.d. n.d. n.d.
(in operation) 0,5 µm 3,520 352,000 3,520,000 n.d. 3,520,000 3,520,000 n.d.
5 µm 20 2,900 29,000 n.d. 29,000 29,000 n.d.

Microbiological load
(in operation) Air <1 10 100 200 200 500 n.d.
[CFU/m3]
Settling plate <1 5 50 100 100 200 n.d.

(90 mm)
[CFU/4 hours]
Contact plate <1 5 25 50 100 150 (300)

(55 mm)
[CFU/plate]
Gloves <1 5 n.d. n.d n.d n.d. n.d.

(5 fingers)
n.d. = not defined; CFU = colony-forming unit
Figure 11.E-5 Categorisation of the cleanliness grades

Assignment of the cleanliness grades to production areas
A Sterile preparations aseptic processing and filling
B Sterile preparations surrounding area in sterile rooms of A
C Sterile preparations weigh-in for sterile preparations, preparation of solution (subsequent sterile filtration)
D Sterile preparations preparation of solution (subsequent sterilisation) with additional measures to minimise contamination, e.g. closed containers
Non-sterile products inhalation preparations

E Non-sterile products production and primary packaging area for ointments, liquids
F Non-sterile products production and primary packaging area for solid oral dosage forms
G Surrounding area of F
Alert and action levels should be set by using historically generated levels for each area and operation, considering the use of statistical program(s). In
order to verify if levels are appropriate, they should be compared to actual readings as well as to published guidance or requirements1. If the actual
readings are significantly different from the specified alert and action levels, a root cause analysis should be initiated.
Exceeding the alert limit is a clear deviation from the base value, which does not, however, lead to remedial action. The number of samples and the
frequency of sampling are usually increased during further observation. When the action limit is reached, remedial action is taken immediately, such as
modification of the disinfecting procedure. This is to be established in advance (see Figure 11.E-6).
Figure 11.E-6 Alert and action values
Limits and consequences when exceeded
Alert level Modification of the sampling plan
Action level Immediate action
For aseptic processes, microbiological monitoring during production is required for air testing. As the cleanliness grade decreases, the sampling
frequency falls. Precise requirements for sterile production are given in Annex 1 of the EU-GMP-Guide. The frequency of sampling should also be fixed
for non-sterile production areas (see Figure 11.E-7)
Figure 11.E-7 Frequencies of sampling
A, B C D E F G
Annex 1 EU GMP Guideline Own definition
Air Batch-based at the end of production or Room “in operation”: daily to Room “in quarterly to half- half-yearly to yearly
microbes during use, if this does not result in an fortnightly (depending on exposition of operation”: yearly (depending yearly
increased risk through measurement the product) monthly on risk to (depending on
Room “at rest”: weekly, if no product) risk to product)
measurement could be carried out in
the operated room within a week (not
used)
Surfaces Table, wall: batch-based at the end of Table, wall, floor: weekly to monthly monthly quarterly to yearly quarterly to yearly
production or during use, if this does not (depending on use) yearly
result in an increased risk through
measurement.
Floor: weekly to monthly (depending on use
of room)
Personnel
Hand Batch-based at end of production not not yearly yearly

defined defined
Forearm monthly not not

defined defined
Hood/face monthly not not

mask defined defined
11.E.3.2 US requirements
The US requirements for airborne particulate cleanliness classes are defined in the FDA Guidance for Industry: Sterile drug products produced by aseptic
processing – current Good Manufacturing Practice (see Chapter D.10). This Guidance was issued to help manufacturers to meet the requirements in the
FDA's cGMP regulations as compiled in the legally enforceable federal regulations 21 CFR 210 and 211. Contrary to the European determinations, FDA
has established class limits only for particles ≥0.5 µm and for the occupancy state in operation (Figure 11.E-8). FDA distinguishes between critical areas
and supporting clean areas. For more detailed informations see Chapter 3.C.3 Corresponding FDA Determinations.
Figure 11.E-8 Air cleanliness classifications for aseptic manufacturing operations according to the FDA Guidance for Industry for aseptic processing.
FDA air cleanliness classificationsa according to the aseptic processing guide
Particles Microbiological active air action Microbiological settling plates action

levelsc
Clean area classification (0.5 µm ISO ≥0.5 levelsc levelsc,d
particles/ft3) designationb µm/m3 (cfu/m3) (diam. 90 mm, cfu/4 hours)
100 5 3 520 1e 1e
1 000 6 35 200 7 3
10 000 7 352 000 10 5
100 000 8 3 520 000 100 50
a All classifications based on data measured in the vicinity of exposed materials/articles during periods of activity.
b ISO 14644-1 designations provide uniform particle concentration values for cleanrooms in multiple industries. An ISO 5 particle concentration is equal
to Class 100 and equals EU Grade A.
c Values represent recommended levels of environmental quality. You may find it appropriate to establish alternative microbial action levels due to the
nature of the operation or method of analysis.
d The additional use of settling plates is optional.
e Samples from Class 100 (ISO 5) environments should normally yield no microbiological contaminants.
11.E.3.3 ISO standards

Because of the large number of cleanroom standards produced by individual countries it is very desirable that one world-wide standard of cleanroom
classification is produced. The first ISO standard on cleanrooms has been published in June 1999 as 14644-1 Classification of Air Cleanliness. It has
then been adopted as a European standard and hence a standard for all countries in the EU. This standard is available from standard organisations
throughout the world and in the UK is available from the BSI. Shown in Figure 11.E-9 is the classification that has been adopted.
Figure 11.E-9 Airborne particulate cleanliness classes for cleanrooms and clean zones according to ISO 14644-1
Maximum concentration limits (particles/m3 of air) for particles equal to and larger than the considered sizes shown below
Classification
numbers (N) 0.1 µm 0.2 µm 0.3 µm 0.5 µm 1 µm 5.0 µm
ISO 1 10 2
ISO 2 100 24 10 4
ISO 3 1 000 237 102 35 8
ISO 4 10 000 2 370 1 020 352 83
ISO 5 100 000 23 700 10 200 3 520 832 29
ISO 6 1 000 000 237 000 102 000 35 200 8 320 293
ISO 7 352 000 83 200 2 930
ISO 8 3 520 000 832 000 29 300
ISO 9 35 200 000 8 320 000 293 000
The table is derived from the following formula:
where:
■ Cn represents the maximum permitted concentration (in particles/m3 of air) of airborne particles that are equal to or larger than the considered
particle size. Cn is rounded to the nearest whole number.
■N is the ISO classification number, which shall not exceed the value of 9. Intermediate ISO classification numbers may be specified, with 0.1 the
smallest permitted increment of N.
■ D is the considered particle size in µm.
■ 0.1 is a constant with a dimension of µm.
The occupancy state is defined in this standard as follows:

■As built: the condition where the installation is complete with all services connected and functioning but with no production equipment, materials,
or personnel present.
■At-rest: The condition where the installation is complete with equipment installed and operating in a manner agreed between the customer and
supplier, but with no personnel present.
■Operational: The condition where the installation is functioning in the specified manner, with the specified number of personnel present and
working in the manner agreed upon.
The ISO 14644 standard also gives a method by which the performance of a cleanroom may be verified i.e. sampling locations, sample volume etc.
These are similar to FS 209 which is valid for US. It also includes a method for specifying a room using particles outside the size range given in Figure
11.E-9. Smaller particles (ultrafine) will be of particular use to the semiconductor industry and the large (>5 µm macroparticles) will be of use in
industries such as parts of the medical device industry, where small particles are of no practical importance.
11.E.4 Methods
11.E.4.1 Direct contact test
Direct contact tests are usually used for surfaces, with the help of RODAC plates (corresponding to 25 cm2 area). These consist of a convex agar culture
medium. The plate is pressed against the area to be sampled for about 5 seconds with average pressure (do not turn!) and immediately sealed and
labelled. As a film of the culture medium always remains on the surface, it must be cleaned afterwards with 70% isopropanol. Curved surfaces can be
sampled with flexible agar foils. The culture mediums contain usually already substances to deactivate the disinfectant, so that the microbial count is not
negatively influenced by residues of disinfectant.
11.E.4.2 Measurement of airborne microbes
Measurement of airborne microbes can be split into passive and active procedures. Passive collection of airborne microbes is carried out via settling
plates (with Petri dishes filled with culture medium). The pertinence of such a determination is very limited, as it only reflects a small section of a
possible microbial particle load in the air (dependencies on flow rates, particle size, affinities). However, it is deployed in accordance with the EU-GMP-
Guide. Active microbe collectors are used with different procedures, e.g. RCS collector. The equipment used for sampling must be calibrated. Equipment
parameters, such as aspiration speed and time, must be exactly complied with in order to achieve reproducible results. Depending on the requirements,
measurements are taken when at rest or in operation.
A basic requirement for all sampling procedures is that they influence the environment as little as possible. It goes without saying that measuring
instruments and sample collectors must be subject to the same hygiene measures as the equipment or instruments used for production. The
determination methods used for monitoring must, like other methods in microbiological quality control, be validated and measuring instruments (airborne
microbes counters, particle counters) must be calibrated. A statement of the method used is important for the evaluation of the results, as results in the
microbiological area indicate strong variations between the individual methods. When establishing a viable particulate air monitoring program, the
following steps have to be considered (see Figure 11.E-10):
Figure 11.E-10 Viable particulate air monitoring program
Viable particulate air monitoring program
Define parameters
■ Establish room classifications,
■ Identify critical and non-critical areas,
■ Determine levels when area is active
Establish passive air sampling program

■ Note: FDA does not accept passive air sampling alone!
■ Identify procedure for use of fallout plates,
■ Establish exposure times (minimum –4 hours),
■ Describe procedures for collection and transportation to laboratory,
■ Describe media used, procedures and incubation parameters
Establish active air sampling program

■ Note: FDA requires active air sampling
■ Identify which system(s) will be used (impaction on agar, liquid impingers, membrane filtration),
■Establish volume of air to be sampled
■ Class 100: minimum 10 ft3, preferably 35.3 ft3 or 1.0 m3;
■ Class 10,000 or greater: minimum 1.0 ft3, preferably 10 ft3 or 0.28 m3),

Establish sampling plan

■ Determine locations for different types of sampling,
■ Determine frequencies for sampling,
■ Include a map of the sampling locations
Establish alert and action limits for the different types of sampling and locations
■Based on sampling history,
EU-GMP-Guide Annex 1, USP-Guidance, FDA-Guidance
11.E.5 Investigation areas

All possible influencing factors that come into question for contamination are investigated.
Figure 11.E-11 Investigation areas
Investigation areas
■ Surfaces
■ Air
■ Cleansing agent and disinfectant
■ Personnel
■ Utilities
11.E.5.1 Surfaces
This includes the product contact surfaces and the rooms and facilities in the wider sense. It is recommended that you also consider bordering areas, in
addition to the actual production rooms. In this way, deterioration with possible implications for critical areas can be ascertained in advance.
The aspects to be considered when establishing a surface monitoring program are given in Figure 11.E-12.
Figure 11.E-12 Surface Monitoring Program
Surface monitoring program
Define parameters
■ Identify product contact and non-product contact surfaces,
■ Determine levels when area is active
Identify which means of sampling will be used

■ RODAC plates, Swabs

■ Determine locations to be sampled,
■ Include a map of the sampling locations,
■ Determine frequency of sampling,
Establish alert and action limits for the different classes, areas and sites sampled
■ Based on historical data collected during media fills, EU-GMP-Guide Annex 1, USP Guidelines, Parenteral Society Guidelines (UK)
11.E.5.2 Air
The bioburden and particle count of the air are checked as standard. The flow rate, flow direction and pressure differential are also of interest for sterile
production (see Chapter 3.G Heating Ventilation Air Conditioning (HVAC)).
Important aspects to be considered for the implementation of a physical environment monitoring program are described in Figure 11.E-13.
Figure 11.E-13 Physical environment monitoring program
Physical environment monitoring program
Define what parameters require monitoring
■ Determine critical elements product requirements, process requirements,
■ Define monitoring parameters temperature, humidity, differential pressure and airflow,

velocity of air (unidirectional air flow), non-viable particulates
■ Base program on the requirements of the processes and products
Define responsibilities for each part of the program
■ Sampling,
■ Analysis of data,
■ Calibration of measuring equipment,
■ Reaction to failing results
Temperature and Humidity

■ Define areas that need temperature and humidity control cleanrooms, general manufacturing and packaging areas, bulk manufacturing
area, laboratory
■ Define specifications based on product or process requirements, operating ranges, alarm levels
■ Define system for monitoring temperature and humidity frequency of monitoring, frequency of recording data, validate monitoring system
Differential Pressure and Airflow
■ Define areas to be monitored cleanrooms, areas where product is exposed to the environment, areas where
product containment is required
■ Define system for monitoring differential pressure frequency of monitoring pressures or differential pressure, frequency of recording
data, validate monitoring system
■ Perform smoke studies doors open, doors closed, verify correct direction of airflow during above tests
■ Define specifications ■ between different cleanliness classes,

■ between areas where containment is required,
■positive or negative pressure
■ positive: protection of product,
■ negative: containment of product,
■ minimum 12.5 Pascals
■ Calibrate pressure sensors and or manometers
Air velocity (Applies to unidirectional flow)
■ Establish measurement frequency minimum: 90 ft/min ±20% or 0.45 m/s ± 20%
■ Measure at work height,
■ Use calibrated measurement instrument
Non-viable particulates
Develop counting method
■ particle counter operation operating SOP, personnel training
■ establish size of particles to be measured ■ U.S.: only ≥0.5 µm;

■ EU: ≥0.5 and ≥5.0 µm
■ sampling procedure ■ individual particle counters,

■ multi-port sampling system with one sensor,
■ remote sensors with data acquisition
■ Decide sample size for each room classification ■ Class 100 (Class A): minimum 10 ft3 per site;
■ Class 10,000 (Class B): minimum 1.0 ft3 per site;
■ Class 100,000 (Class C): minimum 1.0 ft3 per site
■ Determine sample locations Document sampling locations, include a map of the sampling locations, based on
data obtained during facility qualification studies
■Samples measured within 12 inches (30 cm) of critical ■ Infeed of open containers
operations, Samples taken at critical operations ■ Filling operation
■ Stoppering operation
■ Samples taken during manufacturing operations ■ Samples taken minimum of once per shift per filling room
■ Samples taken at work height in room
Develop action and alert levels for each class
■ Based on regulatory requirements or expectations: ■ Action Levels (EU GMPs, Annex 1; US Federal Standard 209E),
■ Alert Levels (Historical data from monitoring program
■ Issue notice if alert level is exceeded ■ review past results for sample site and area,
■ if two alert notices in one week, follow-up as if action level exceeded,
■ initiate failure investigation if action level exceeded
11.E.5.3 Cleansing agents and disinfectants

These must be checked regularly for microbiological contamination in order to disclose the development of resistant strains. In accordance with Annex 1
of the EU-GMP-Guide, disinfectants used in the production of sterile drugs must be sterile at the time of application. It is advisable to investigate
samples that are taken directly at the application point, e.g. from the dispenser system. For sterile productions, dilutions for use should be
microbiologically tested once a month and also according to the frequency with which the disinfectant is changed. Attention should be paid to an
extended incubation time, as there may be predamaged organisms.
11.E.5.4 Personnel
For the production of sterile drugs, precise specifications are made regarding personnel testing (depending on the cleanliness grade). Clean room
clothing should be changed after sampling, as agar residue from the contact plates always sticks to the textiles and cannot be reliably removed with
disinfectants. Checking the microbial count on hands allows conclusions to be drawn about compliance with the hand hygiene regulations. When a
personnel monitoring program is set up, the aspects described in Figure 11.E-14 should be considered.
Figure 11.E-14 Personnel monitoring program
Personnel monitoring program
Develop monitoring procedures
■ Gowning training and assessment ■ test prior to entering aseptic facility,

■ must put on new gown after sampling,
■ initial training – three consecutive passing gownings
■ Aseptic technique assessment ■ test to assess a person’s ability to keep gown sterile,
■ test prior to exit of aseptic facility
Develop monitoring tests
■ Finger touch plates, Gown touch plates
■ Determine sites for sampling: ■Gowning training and assessment:

■ clavicle,
■ above both gloves on forearm,
■ above both boots,
■ fingers on both hands;
■Aseptic technique assessment:

■ clavicle,
■ above both gloves on forearm,
■ to one side of the front closure,
■ forehead,
■ fingers on both hands,
■ Determine frequency and time for sampling personnel and facilities,
■ Describe procedures for collection and transportation of samples to laboratory,

Establish alert and action limits for the different sampling locations
■ Based on sampling history, EU-GMP-Guide Annex 1, USP-Guidance , FDA-Guidance
11.E.5.5 Utilities
Utilities are e.g. water and process gases (e.g. nitrogen, product contact compressed air). These must be reviewed regularly. See Chapter 5.D.7
Process validation/performance qualification (PQ) for microbiological testing of water.
11.E.6 Evaluation
11.E.6.1 Report
An evaluation is compiled after receipt of all individual measured values and summarised in a report. This report should contain the following information
(see Figure 11.E-15).
Figure 11.E-15 Report
Content of the sampling report
■ Type of sample
■ Test method
■ Sampling method, sampling aids
■ Sampling point
■ Status (in operation/at rest)
■ Number of persons in the room at the time of sampling (in clean rooms)
■ Time of sampling
■ Duration of sampling
■ Test date
■ Incubation conditions
■ Deviations, special features
■ Result
■ Compiler of the report
11.E.6.2 Trend analyses

Summaries of data over periods of time should be developed, where counts over time and microorganisms isolated over time are evaluated. Trend
analyses should also be carried out as part of monitoring (EU-GMP-Guide). These make it possible to identify deviations from the regular status and
trends even before the alert and action limits are exceeded. Numerical data for microbiological contaminations should be considered as uncertain due to
the spread of measuring values and moderate reproducibility in terms of quantification. Therefore, trending offers an additional level of certainty in critical
areas. Graphical execution is an easy way to visualise noticeable problems.
11.E.6.3 Measures when limit is exceeded
If a limit is exceeded, microbial identification should be carried out (see Chapter 12.J.8 Measures if levels are exceeded and Chapter 12.J.9 Organism
identification). The type of organism can help you draw conclusions about the origin of the contamination, as there is a typical microbial flora for water,
air and humans.
The cleansing agent and disinfectant (diluted and concentrated solution) should also always be checked for possible contamination. In sterile areas, the
daily monitoring data is taken into account at the time of batch release. That is, if the limits have been exceeded, the batch must first be rejected and
further investigations must be set up until a safe assessment of the situation is possible.
The monitoring results can also lead to changes in the cleaning or disinfecting processes. The results of changes in other areas (e.g. restructuring
measures, defective transport devices, etc.) only become evident through monitoring, especially in the area of the environment immediately around the
actual production areas. This may mean an increase in the number or frequency of samples carried out in future.
If the particle load is exceeded, changes to facilities, the air flow pattern and air preparation may be necessary (see Chapter 3.G.4 Principles for the
design and planning of air conditioning ventilation systems).
In case of Out of Specification results, measures to be taken should be described in an Out-of Specification (OOS) SOP.
The investigation of OOS Results should include at least the following:
■ Review laboratory analysis performed
■ Perform additional analysis of product
■ Review production documents
■ Review maintenance documents
■ Review sanitation documents
■ Review physical and operational parameters
■ Review personnel monitoring data
The documentation of the results of the investigation should state
■ the problem
■ what was reviewed
■ findings
■ conclusions and recommended corrective actions
Corrective action may include, but is not limited to, the following:
■ Retraining of personnel involved
■ increase the frequency of sampling or number of samples
■ Evaluate the need for increasing the frequency of sanitization
■Perform additional media fill to revalidate the filling environment
■ must demonstrate return to validated state
■ if definable cause, perform one media fill
■ if no definable cause, perform three media fills
All investigations and the decision made regarding the disposition of the affected product have to be documented and should be in accordance with the
written procedure on OOS results.
Summary
Monitoring gives information on the actual hygienic status and thus on the success of the cleaning and disinfecting measures.
Surfaces, personnel, air, utilities and cleansing agents and disinfectants have to be tested. Alert and action limits have to be set, as well as measures
to be taken if they are exceeded.
The monitoring methods must be described accurately.
1EU-GMP-Guide – Annex 1, USP Monograph <1116>, Parenteral Society Technical Monograph 2 on Environmental Contamination Control Practice
11.F GMP in the production process

■ What quality assurance elements are included in production?
■ What aspects must be taken into account to establish GMP in production?
The manufacturing of specification-compliant products depends on the existence of various quality assurance elements. The quality of the individual
elements determines the probability with which manufacturing will be carried out without problems, i.e. within the prescribed limits. Reproducible
production is only feasible given these limits and their mutual interaction. It is the task of the quality assurance system to guarantee this constellation
(Figure 11.F-1).
Figure 11.F-1 Quality assurance elements for pharmaceutical manufacturing
Ideally, quality control of the final product would not be necessary if correct manufacturing could be guaranteed by the environment. However, due to the
many different influencing factors, this only applies in theory. Furthermore, the legislator prescribes final product quality control for pharmaceutical
products. The care with which the surrounding and preliminary influencing factors are managed is responsible for the effort that must be made in the
actual production.
In addition to the elements listed, the aspects shown in Figure 11.F-2 also represent important values for GMP-compliant production.
Figure 11.F-2 GMP aspects in the production process
GMP aspects in the production process
■ Evaluation of the process parameterization regular product review
■ Evaluation of the raw material specifications restriction of specification limits
■Traceability of processes, primary and secondary identifiable via defined code numbers (batch) assignment system
documentation
■ Practicability of the manufacturing instructions ■ evaluation of comprehensibility

■ completeness
■ Qualification level of the staff periodic GMP training and evaluation of personnel through assessments
■ Congruence and practicality of the procedural instructions agreement and practical executability of the requirements
■ Process capability of machines, equipment and processes ■qualified machines and equipment and validation of processes and process
changes
■ maintenance
■ repair
■ calibration
■ Product handling ■definition of in-plant handling of products

■ hold times of intermediate products
■ withdrawal
■ sampling
■ distribution
Self-inspections are an important way of guaranteeing the GMP status within the plant, in this case production. These inspections help uncover
deficiencies and highlight possibilities for optimisation. A permanent target/actual comparison of requirements of the quality assurance system and its
practical implementation helps improve the status. The inspections should be considered as an opportunity to promote the GMP-specific development
process. (See Chapter 18.E Self-inspection.)
Summary
Different quality assurance elements help create a GMP environment in which specification-compliant products can be manufactured. In addition to the
GMP-compliant environment (rooms and facilities), this also includes controlled processes, trained staff and a dense network of instructions and
records.
11.G Weigh-in

■ What requirements are made concerning rooms and balances?
■ What weigh-in principles are possible?
■ What must be taken into account during provision of the starting material, the weigh-in process and provision for production?
The weigh-in process has a significant, quality-determining importance for the manufacture of pharmaceutical products. The aspects described in Figure
11.G-1 must be guaranteed.
Figure 11.G-1 Requirements concerning weigh-in
Requirements concerning weigh-in
■ No impairment of the quality of the starting material

■ Exact compliance with the prescribed formulation
■ Correct documentation
11.G.1 Legal requirements

Rooms
“Weighing of starting materials usually should be carried out in a separate weighing room designed for that use.” (3.13 EU-GMP-Guide, see Chapter
C.4.3 Chapter 3:Premises and Equipment).
This explicit requirement for a weigh-in area reflects the importance of the process. In addition to the requirements regarding layout, surfaces, etc., the
rooms should also be separate from the other rooms in the production area. During the planning phase, the location of the weigh-in process should be
established depending on the defined material and personnel flows. Permanent weigh-in in multi-functional rooms is thus not recommended. This is
understandable, as the weigh-in system must be very precisely defined with balances and processes, in order to prevent cross-contamination, mix-ups
or confusion.
The layout of weigh-in rooms depends on the material flow, the inclusion in zonal concepts and lock orientations.
To prevent dust production, adequate aspiration must be ensured, at least at the open container and at the balance (see example in Figure 11.G-2). This
is important in order to reduce the risk of cross-contamination and to facilitate cleaning (3.14 EU-GMP-Guide, see Chapter C.4.3).
Figure 11.G-2 Dust aspiration for weigh-in in barrels
Balances
Balances and measuring devices must have the appropriate measuring range and required precision (3.40 EU-GMP-Guide). They must be calibrated
regularly and this must be documented (3.41 EU-GMP-Guide). Due to the importance of the initial weight for the subsequent processes and for the
quality of the final product, the checks should be carried out frequently, i.e. in line with the utilisation of the weigh-in area. Usually, daily performance
testing should be carried out, in addition to the calibration to be carried out in longer intervals. For balance faults discovered retrospectively in the course
of the day, the number of critical initial weights can be reduced until the time of the performance test (example: monthly: calibration, daily: performance
test with 3 different weights within the calibration range). Calibrations and performance tests are documented in the log book. (See Chapter 14.E
Calibration in the lab.)
The permissible tolerance must be specified for the respective weighing range, taking into account the measurement inaccuracies, i.e. the tolerated
deviation from the target value.
The equipment and utensils used when handling the raw materials must meet the requirements concerning surfaces in pharmaceutical production. These
must be taken into account when selecting product contact parts, such as scoops (welded seams between handle and pan, rivets, etc., which make
cleaning difficult), dosage systems (dosing augers), (pneumatic) loading systems and couplings (see Figure 11.G-3).
Figure 11.G-3 Unsuitable scoop with rivets and seams
According to the amendment of the Weights and Measures Act in 1992, balances used in production for weigh-in purposes no longer have to be gauged
if regular calibrations ensure that measuring accuracy is guaranteed. However, it can be advisable to gauge the balances in the weigh-in area, in order to
enforce complaints against the vendor regarding underfilling of API containers.
According to 21 CFR 211.01, the batch should be formulated with the intent to provide not less than 100% of the labeled active ingredient (see Chapter
D.1.2). Weighing, measuring or subdividing operations for components should be adequately supervised.
Each container of component dispensed to manufacturing should be examined by a second person for the following verification:
■ Component was released by the Quality Control Unit.
■ The weight is correct as stated in the batch production records.
■ The containers are properly identified
■ Each component that is added to the batch is verified by a second person.
11.G.2 Weigh-in principles

A distinction can be made between
■ product-specific (order-specific) weigh-in of different raw materials
■ raw material-specific weigh-in for different orders.
This selection affects the size of room required. Only the raw materials belonging to the weighing order should be present in the weigh-in room itself.
Besides this, a differentiation is possible between central and local weigh-in (see Figure 11.G-4).
Figure 11.G-4 Weigh-in principles
Weigh-in principles
■ Product-specific Additive, individual
■ Raw-material-specific Individual
■ Central/local
11.G.2.1 Product-specific weigh-in

Additive and individual (separate) weighings are possible for the product-specific procedure, i.e. the starting materials are either successively weighed
one on top of the other or individually in containers. These two types of processing make different demands on the layout conditions of the rooms.
To improve productivity, the entire starting material should be quickly available. However,the advantages of additive weigh-in (space-saving, fewer
containers required, less withdrawal loss, as only one individual container) are contrasted with the disadvantage of a possible weigh-in error. Overdoses
usually lead to destruction of the container content. If the overdose is only slight, an increase in the other materials can be considered for expensive
starting materials. However, this must always be considered in the context of the validated batch sizes. As this is a deviation from the manufacturing
instructions, this change must be approved by the head of production.
Furthermore, the joint weigh-in of APIs and excipients can cause problems in relation to the definition of the date of manufacture or, as a result, the
expiration date and thus the running time of the final product. The appendix to the Note for Guidance on the Manufacture of the Finished Dosage Form,
CPMP/QWP/486/95, Start of Shelf-life of the Finished Dosage Form gives the manufacturing date as the time of combination of the API and excipients.
Weigh-in at the end of the month can therefore lead to a reduction in the running time of the product by one month compared with an individual weigh-in,
if the processing takes place in the next calendar month. A possible remedy is the separate weigh-in of APIs for the additively weighed excipients.
Dimensioning of rooms
Product-specific weigh-in of a large range of starting materials can be carried out in large rooms (depending on the cleanliness grade). In this case,
provision for the weigh-in process in the weigh-in room is order-specific. This requires organisation within the room and of the processes. It is possible to
assign areas within the room, e.g. storage of the starting material containers on one side of the room; then the balances with different weighing ranges
on the other side of the room, separated by a corridor. The hazard of containers of other raw materials becoming contaminated can, in addition to the
spatial orientation, be minimised by specific air supply or air extraction flows (e.g. LF principle, directional aspiration on balances and over open
containers). In this way, the effort for cleaning can also be reduced.
11.G.2.2 Raw material-specific weigh-in
Raw material-specific weigh-in means that one material at a time is weighed for different products or orders. The great advantage of this principle is the
fact that the weigh-in cabin is not contaminated with different materials and cleaning is only necessary when the material changes. The risk of mix-ups is
thereby reduced.
Raw material-specific weigh-in is often applied in combination with automated or semi-automated weigh-in, e.g. for materials which are difficult to handle
due to electrostatic charge (e.g. Aerosil).
For raw material-specific weigh-in, the dimensioning of the weigh-in room is mainly determined by the volume throughput, i.e. the size of the delivery
containers (Big Bags) and the material flow (horizontal or vertical).
Dimensioning of rooms
The weigh-in room should be dimensioned in a way that only the weigh-in process of one material can be executed in it. This reduces the cleaning effort
required. Provision area for the starting materials should be directly in advance of this room, in order to minimise the material flows. If further orders are
held in supply in this provision area, corresponding assurance of the correct assignment must be guaranteed. As the cleanliness grade increases, the
weigh-in room design for smaller rooms (cabins through to LF benches) is simpler in terms of environmental conditions, air flow patterns and monitoring,
compared with large rooms. The use of this room layout is primarily of interest for the processing of a few different starting materials.
11.G.2.3 Central/local weigh-in systems
Central and local weigh-in systems are possible. The optimal solution for the plant is to be viewed according to the spatial circumstances, material flow,
volume throughput and variability of the starting materials. Often, central weigh-in areas are used with supplementary local solutions, i.e. further weigh-in
areas as satellite systems.
A distinction must be made between manual and automatic weigh-in. The use of such a procedure depends on the company-specific requirements.
Often, it is advisable to supplement automatic systems with smaller volume, manual weigh-in.
Figure 11.G-5 Weigh-in procedures
Characteristics of manual and automatic weigh-in procedures
Manual weigh-in ■ High flexibility

■ Low cleaning effort
Automatic weigh-in ■ Large volume throughput

■ Low staff requirements
11.G.2.4 Manual weigh-in

Manual weigh-in is mainly used if there is a high diversity in the materials to be weighed in, as well as a low to average volume throughput. It offers the
advantage of higher flexibility and a lower effort for cleaning.
11.G.2.5 Automatic weigh-in
In principle, automatic systems can be vertically or horizontally organised. Various aspects are important for the selection and operation of an automatic
weigh-in system: In automatic weigh-in systems, the transport, filling, dosing, further transport of starting materials and containers depends on the
degree of mechanisation. There are different dosing principles (mobile balance, weigh-in funnel, etc. as well as direct weigh-in or with preliminary ensiling
or sieving steps). Manual operations are also frequently found in combination with automatic weigh-in processes. Smaller sub-quantities are then dosed
in via the control system. The requirements of the facility design are determined by the type and volume as well as the variety of raw materials. Figure
11.G-6 shows a vertical material weigh-in.
Figure 11.G-6 Schematic illustration of a vertical material weigh-in
In level I, the starting materials are delivered, e.g. in Big Bags, and converted to level II. In level II, additive dosing is carried out via mobile containers
(level II-III) into e.g. containers (level III) that are then incorporated into the production process. The dosing procedure is checked or controlled via a
(mobile) balance in level III. Transitions between cleanliness grades must be taken into account.
Figure 11.G-7 Automatic weigh-in systems
Aspects of automatic weigh-in systems
■ Loading principles (product-based/raw material-based)
■ Weighing principle (differential dosing, subtraction weighing, additional weighing)
■ Dosing systems (precision, dead time, cleaning)
■ Docking systems (dust-tight, force freeness)
To reduce cross-contamination, it is extremely important to prevent dust production. Dust-tight docking systems on containers and aspiration facilities
(ring aspiration) help minimise the risk. Particular attention is to be paid to aspirations and air handling on the dosage units. It must be ensured that
backwards contamination of the dosage units through dust production from the filling process is minimised.
11.G.3 Weigh-in procedure

All processes from delivery to return must be fixed in written procedures in order to ensure that they can be controlled. The weigh-in process may be
preceded by various processing steps, e.g. sieving steps (as protection or classification sieving).
The main sequence of the weigh-in process is illustrated in Figure 11.G-8.
Figure 11.G-8 Weigh-in sequence
It is important that the dosage factors, which compensate for variable contents of the starting materials (e.g. water content) be compiled when the
starting materials are released. The dosage calculation has to be described in the product dossier. This way of individual conversion is intended to
produce formulation-compliant and specification-compliant quality even with variable quality of raw materials.
11.G.3.1 Allocation of raw materials
This takes place after conversion of the raw material (either from the storage area or areas with a lower cleanliness grade) to a provision area. Here, the
containers are checked for identity, cleanliness and integrity. For product-based weighing, a complete order should be delivered from the storage area if
there are several components. This means that pallets or other delivery forms should be secured individually after picking, e.g. through pallet cages. This
will prevent confusion if containers fall, with subsequent incorrect assignment and unauthorised access.
11.G.3.2 Weigh-in
Only suitable and authorised persons may be involved in the weigh-in process. Reliability is of the utmost importance in this critical area. Competence
can be expressed in the assignment of user rights for the weigh-in systems used.
In principle, a distinction can be made between weigh-in with or without EDP (electronical data processing) support.
Weigh-in without any EDP support should only be used in exceptional cases. The second set of eyes principle applies here, i.e. the activity of the
person carrying out the weighing is checked by a 2nd person. For pharmaceutical practice, this procedure bears a high risk potential through transfer or
reading errors. When composing the weigh-in regulations, this must be accounted for through a high level of clarity (font sizes, line and column spacing,
etc.). Containers must also be identified via a visual control.
EDP supported weigh-in systems reduce the risk in the weigh-in process. The system cannot be used unless it is qualified or validated (see Chapter 9
Computer System Validation). These weigh-in systems can be used in various controlling levels. This can mean simple administration of weigh-in orders
through to complete recording of operating data. EDP support can accomplish a lot of functions, which are listed in Figure 11.G-9.
Figure 11.G-9 EDP supported weigh-in
Aspects of EDP support in a weigh-in system
■ Identification of the user

■ Identification of the container
■ Identification and assignment of containers
■ Control of the release status and expiry date of the raw material
■ dosage calculation
■ Assignment of the appropriate balances
■ Control of the target container (type, cleaning status)
■ Control of the weigh-in process
■User identification Various techniques, e.g. chip cards, barcodes on working clothing, alphanumerical inputs, can be used to guarantee the
authority of the person performing the weigh-in and to acknowledge activity on superordinate systems. Depending on the EDP standard, simple
identification can be sufficient, or an electronic signature might be required.
■Container identification The identification of the container via barcodes, for example, is an additional safety precaution. The barcodes are
usually applied upon receipt of the goods as part of goods acceptance. A status request can be executed by coupling the data with the data from
the warehouse management system, for example. Thus, the batch or container release can be checked at this stage, directly before weigh-in. This
is also possible for the expiry date. Scanning of a container that has not been released, or for which the expiration date has been exceeded, can
accordingly lead to cancellation of the weigh-in process. The differentiation of individual containers is a good way to trace back the properties of an
API batch.
■Assignment of containers Specific containers can be assigned to the weigh-in personnel for weigh-in, e.g. as part of a product-specific
application (dedicated equipment). When recording the operating data, it is advantageous to keep a product history, i.e. traceability of the uses of
containers. The requirement to use only suitable and clean containers can thus be easily and effectively implemented, as the cleanliness status is
available in the system and thus only suitable vessels can be used.
■Balance assignment It is possible to stipulate the balance used for certain weigh-ins (e.g. balance type or balance number). This can be
important for certain weigh-ins, e.g. by stipulating ex-protected rooms, rooms of specific cleanliness grades, weigh-in of raw materials with extreme
bulk densities (e.g. Aerosil). Furthermore it can be assured that only appropriate balances are used (weighing range, precision).
■Checking the weigh-in process The permissible deviations from the target value defined as part of the tolerance definition are directly converted
and controlled. Larger deviations are not accepted. Starting materials that are calculated with dosage factors (e.g. to balance out content
variability, loss on drying, etc.), can either be converted to the necessary required value in the weigh-in system or the requirement from the
superordinate system can be applied. Particular attention must be paid to these points during qualification and validation.
■Different display procedures are used:
- subtractive, i.e. the display of the current difference from the
required value;
- additive, i.e. the total of the partial quantities already weighed in.
■The display of tolerance bars, possibly highlighted in colour (red/green) is a valuable orientation aid for the balance tolerance. A quantity
outside the upper tolerance level, which is taken from the original container, must not be returned to this container.
11.G.3.3 Return
Leftover containers are usually sent to the warehouse via provision. The container must be appropriately and sufficiently sealed, i.e. in terms of tightness
and with no influence on the quality through adhesives that might come into contact with the product. Furthermore, it must be ensured that no product
dust gets onto the exterior of the container. This is of importance for safety at work, but also to prevent dispersion effects and cross-contamination.
Eventually remaining amounts can be transferred into appropriate smaller containers, correct labeling and tightness have to be warranted.
11.G.3.4 Allocation for production
The EU-GMP-Guide permits short-term interim storage in the production area. The weighed starting materials should be processed as quickly as
possible. This is comprehensible, for stability and running time reasons. Care must be taken that the container cannot become dusty, as this could
endanger the product quality during disposition (e.g. when emptying). The requirements of the storage method are the same as those for provision for
weigh-in. Long standing times should, if necessary, only be allowed in the storage area (with sufficient enveloping).
11.G.3.5 Cleaning
Balances and rooms are cleaned after each weigh-in in order to avoid carryover to the next order. The bases of the balance bridges or balance cavities
must also be cleaned regularly as there is an increased risk of microbial contamination here. Cleaning is documented in cleaning records.
Microbiological loads and particle loads must be monitored regularly. Starting materials may have a high microbial count due to their origin and based on
the microbiological limits permitted by the pharmacopoeia (see Chapter 11.E). Therefore, product-specific disinfection methods may be necessary for the
entire room, let alone for the weighing area. All cleaning and disinfection measures are to be codified in the room cleaning records or log books (see
Chapter 11.C.2 Cleaning).
11.G.4 Documentation
Weigh-in is carried out in accordance with the manufacturing instructions. Records of the weigh-in process are required, which document the correct
manner of execution (see example in Figure 11.G-10).
Figure 11.G-10 Example record for product-based, individual weigh-in
Print no. Place of work Weigh-in: FSB Con- 17-51-0 20-2-00 17-51-3 17-51-5
tainer
ID
Bal- 12-23-2 12-23-1 12-23-2 12-23-2

ance
ID
GMP Pharma Work step/ Initial weight/ Date/ 17.03.99/ 17.03.99/ 17.03.99/ 17.03.99/
production stage Granulate Time 10:23 10:37 10:41 11:00
Batch size 460.00 User müller müller müller schmidt
Unit kg kg kg kg
Logo Batch 4563A1 Tare 10.45 1.040 10.34 10.41
ID
Actual 100.10 9.99 75.00 50.07
quan-
tity
Material no. 123456 Batch no. 1 Converted 100.00 10.00 75.00 50.00
target
quantity
Dosage 1.00 1.00 1.00 0.90

factor
Material Granulate test Batch quantity 230,00 target 100.00 10.00 75.00 45.00
designation quan-
tity
Batch 001A5 154b1 147c2 178a8

ID
Order number 4563139 Material 12345 23452 13541 16444
no.
Material Lactose Ethanol Cellulose Potato

desig- starch
nation
Item 1 2 3 4
No.
This means that

■ information on materials,
■ batch IDs,
■ required quantities,
■ actual quantities,
■ possible dosage factors,
■ weigh-in date (possibly time) and
■ the name of the person performing the weigh-in
must be available. In the case of electronic batch recording (see Chapter 19.F Batch Record Review) the paper form can be omitted.
Containers must be labelled. The content must be unambigously identifiable.
Figure 11.G-11 Example of a weigh-in label
When using EDP supported systems, the printout of records and labels is generated by the system. Printers within the weigh-in room must be enclosed
in a housing in order to prevent any mutual influences (dust production/degassing).
Labels should be applied to the containers immediately in order to avoid confusions after completion of one weigh-in process and before another.
Summary
The weigh-in process is a sensitive point in the process chain. The hazard of cross-contamination and confusion must be minimised through structural
and organisational requirements.
A distinction is made between additive (all raw materials for one order in one container) and individual (all raw materials individually) weigh-in. Moreover,
depending on the number of raw materials used in the company, a distinction must be made between order-based or raw material-based weighing.
EDP supported, validated systems offer a high level of security: Only the raw materials clearly specified in the manufacturing instructions and only
released containers can be weighed.
11.H Identification

■ Which requirements apply for the identification of containers, equipment and rooms?
■ How can the identification of the cleaning status of facilities and subsequent documentation in the batch production records be organised?
“At all times during processing, all materials, bulk containers, major items of equipment and where appropriate rooms used should be labelled or
otherwise identified […].” (5.12 EU GMP Guide, see Chapter C.4.5).
This can be achieved through the use of labels or other identification. The declaration of materials, containers and rooms is an essential basic principle
for the prevention of cross-contamination, misidentification and mix-ups (Chapter 11.J Prevention of cross-contamination). The labelling must be carried
out in such a way that it can be easily identified by the observer, i.e. labels should not be below specific minimum sizes. It is recommended that a
uniform layout is used throughout the company. Colours and symbols may be used to achieve a signalling effect – e.g. to provide warnings about
entering rooms where sensitive products are manufactured and specific aspects of pharmacology and work safety apply.
“Labels applied to containers, equipment or premises should be clear, unambiguous and in the company’s agreed format. […]”. (5.13 EU GMP Guide,
see Chapter C.4.5).
This requirement has implications for the legibility of writing (sufficient size and legible) and the appropriate use of material designations (for complex
designations, e.g. when using chemical nomenclatures, abbreviations or number codes).
11.H.1 Handling of labels

Labels are often used for identification. It is also possible to use preprinted cards that can be slotted into mounts on the equipment. It would be
unacceptable simply to place a batch record or the associated manufacturing instructions on a container.
The labelling must be durable, i.e. sufficient adhesion of the glue on the label on the relevant container or vessel materials must be ensured. Temperature
influences must be taken into account depending on the storage area used. At higher temperatures, softening effects have been observed whereas at
lower temperatures, solidification and loss of adhesion were noted. These factors must be taken into account when selecting label types. It must also be
possible to remove labels without leaving a residue, e.g. if they are to be used in the batch documentation.
Also, for cleaning purposes it is important that labels can be completely removed. It may occasionally be beneficial to affix foil to containers beforehand
to which labels are subsequently applied. Labels may therefore be easily removed and included in the batch documentation without causing problems.
The foil can then be removed during the cleaning process. It is recommended that specific areas be designated as labelling areas for containers, vessels
and equipment to make handling more efficient and to minimise the danger of double labelling.
The scope of the labelling depends on the extent of data monitoring or control. The more extensively organised the recording and control of operating
data is, the less effort will be required when creating the labels.
11.H.2 Labelling of starting materials

Companies normally apply their own form of identification to incoming starting materials, usually in the form of self-adhesive labels affixed to each
container. The application of the labels must be durable, i.e. they must be securely affixed. For deliveries of raw materials consisting of a large number of
containers, it is difficult to label individual containers separately. The practise of providing the calculated number of labels loose with the pallet for the
labelling of individual containers as required is not acceptable.
“[…] When fully computerised storage systems are used, all the above information need not necessarily be in a legible form on the label.” (5.29 EU-
GMP-Guide, see Chapter C.4.5).
Ideally, the expiration date should be included on readable labels, but as the running time is normally only assigned during the approval process this is
often not possible. In such cases, the container is labelled anew following approval. If physical approval is carried out by applying status labels (rejected,
quarantine, released), it is certainly practicable to declare the expiration date. Status control via a warehouse management system also makes
monitoring of running times possible even with a random location storage system – as with the random distribution and subsequent booking of pallet
bays.
When starting materials are delivered, order requirements or confirmations are normally compared with the information provided with the goods delivered.
Data already stored in the warehouse management system is the master data to be completed and printed on labels.
Figure 11.H-1 shows an example for the labelling of starting materials. This information is to be attached if visual checks are to be subsequently carried
out.
Figure 11.H-1 Labelling of starting materials
Logo GMP-Pharma
Mat. des. Lactose, anhydrous Supplier Meyer & Müller
Mat. no. 12345 Supplier batch des. AA-124Z4
Batch des. 001A5
Weight 25 kg Storage conditions Room temperature
Container 2/15 Safety instructions none
Date 02.02.2000
11.H.3 Labelling of equipment and containers
11.H.3.1 General
As a matter of principle, all equipment, containers etc. used must be labelled. While this requirement may seem trivial, it needs precise knowledge to be
obtained about the practical implementation of manufacturing processes. It must be possible to clearly identify items, products, partial quantities etc.
promptly. It is unacceptable to attach labels following completion of a production step (e.g. to a container once it has been filled). It must be clear to all
staff involved that when interruptions take place and if these are insufficiently labelled, this could lead to incorrect identification at a later stage. The
significance of personnel training in this area must therefore be emphasised. Inconsistent handling in this regard poses a serious risk of misidentification.
The labelling of an item of equipment that comes into contact with a product must not be completely removed once the end of the relevant manufacturing
step has been reached. It must be ensured that information on the product manufactured is available during cleaning as this may not be carried out by
the same staff or at the same location. Otherwise it is hardly feasible to describe this as product-specific cleaning from the point of view of cleaning
validation. During cleaning, the labels or identification plates must be removed and information attached to the equipment stating that it has been purified.
Labels can be completed by hand or printed out. In either case they must be authenticated by a date and signature. To improve legibility, the printed
option should ideally be chosen. Labels may be printed either directly or in advance. Labels are printed directly either by entering data manually at an
input device or by scanning the relevant containers and equipment/machines with a data recording system. As is the case with written entries, manual
entries for printing purposes must be carefully checked to ensure conformity. Basic mistakes such as inputting numbers in the reverse order must be
avoided.
Labels may be printed in advance in tandem with the compilation of documents (as an integral part of the batch documentation) and then affixed by
personnel at the relevant production level. In so doing, it should be ensured that any potential confusion is eliminated. In addition to signing the labels
when they are attached, the number of labels produced should be known and the number used documented in the batch record for reconciliation
purposes.
The relevant information for the identification of equipment is shown in Figure 11.H-2. An example for labeling of equipment is shown in Figure 11.H-3.
Figure 11.H-2 Identification of equipment
Identification of equipment
■ System (code, unique name, company asset number)

■ Machine (code, unique name, company asset number)
■ Parts (code, unique name, company asset number, designate as dedicated, if applicable)
■ Contents by name and phase of process
■ Containers (compounding, storage)
■ Processing lines
■ Equipment
■ Remove previous batch identification
■ Status (in use, cleaned, to be cleaned, out of service, requires calibration, preventive maintenance, repair, replacement)
Figure 11.H-3 Labelling of equipment
11.H.3.2 Rejection / Quarantine

“Defective equipment should, if possible, be removed from production and quality control areas, or at least be clearly labelled as defective.” (3.44 EU
GMP Guide, see Chapter C.4.3).
Labelling must be carried out in every case to provide a clear visual indication of the equipment's status (see Figure 11.H-4).
Figure 11.H-4 Labelling of rejected equipment
Signalling colours are useful, because it has to be ensured that the equipment is not used for production processes due to lack of knowledge. This
labelling must be durable for equipment that cannot be taken away to be repaired due to the way it has been installed or its size. Where such equipment
is removed from the production area, its use in the period prior to and during transportation must be prevented.
11.H.3.3 Cleaning status
The labelling of the cleaning status is an important prerequisite for the use of production equipment and containers. Only cleaned equipment may be
used. It must be possible through status declaration to differentiate between cleaned equipment and not yet cleaned equipment (see Figure 11.H-5).
Figure 11.H-5 Example of a cleaning label
It is not acceptable simply to assign separate rooms (clean/contaminated), e.g. to deposit a used container in a room labelled contaminated. The
labelling should show the material and batch designation of the previous product – this ensures that the product history can be traced or compiled.
Comprehensive data recording (during the acquisition of operating data) that serves the purposes of a process control system allows information on
previous products to be omitted from labels on the containers and equipment itself. When qualifying the system, it should be ensured that all equipment
and containers can be correctly recorded. For example, this may be achieved by attaching bar codes.
If these are simply glued to the equipment, i.e. there is a possibility that it could get lost or be replaced, a control number should be added as a
minimum requirement in addition to the bar code itself as a counter check option when identifying the object manually (e.g. inventory number). Where the
previous batch is to be documented on the label, the following procedure may be applied by way of example (see Figure 11.H-6).
Figure 11.H-6 Procedure for labelling of the cleaning status (example)
Cleaning label no. 1 is on the equipment before the new production process starts. This contains the necessary data for identification of the previous
batch. As the facility was cleaned before the new start, this is documented on the label. A visual status check is carried out directly before the facility is
reused (condition of the equipment still visually clean, expiry date for purity status not passed). The label is removed and affixed at a defined position in
the batch record. The check is documented. A new label (no. 2) is completed using the data provided in the instruction and attached to the equipment.
Once manufacturing is complete, the cleaning is documented on label no. 2. This guarantees the possibility of product-specific cleaning as information
on the contamination is available.Furthermore, the cleaning of the equipment is testified in the batch record of the following product.
11.H.4 Labelling of rooms

Rooms should be labelled in such a way that their status can be easily identified. It should therefore be clear from outside the room what is being
manufactured at any given point in time or what the cleaning status is. This can be achieved using room cleaning reports, for example (see Chapter
11.C.2 Cleaning). In this case, the product data and cleaning statuses are declared.
The relevant information for a systematic identification of facilities and rooms is given in Figure 11.H-7.
Figure 11.H-7 Identification of
facilities
Facility identification
Identify using unique name or code:

■ Building
■ Floors of each building
■ Rooms on each floor
■ Door of each room
Summary
The obligation to carry out labelling is a fundamental rule as this is the only way to manage and check the correct identification of the relevant status.
Production rooms and equipment must be labelled according to the product and batch being manufactured inside. The cleaning status must also be
visible.
11.I In-process control

■ What are the in-process control tasks?
■ Where should the in-process control group be established in organisational and disciplinary terms?
■ How are the responsibilities regulated?
■ How are in-process controls carried out?
In-process controls (IPC) are checks that are carried out before the manufacturing process is completed. The function of in-process controls is
monitoring and – if necessary – adaptation of the manufacturing process in order to comply with the specifications. This may include control of
equipment and environment, too.
In-process materials should be tested for identity, strength, quality and purity as appropriate and approved or rejected by the Quality Control unit during
the production process. Rejected in-process materials should be identified and controlled under a quarantine system designed to prevent their use in
manufacturing.
Written procedures should be established and followed that describe the In-process controls and tests as specified:
■ Tablet or capsule weight variation,
■ Disintegration time,
■ Content uniformity and homogeneity,
■ Dissolution time and rate,
■ Clarity, completeness or pH of solutions.
In-process controls may be performed in regular intervals during a process step (e.g. tabletting, encapsulation) or at the end of a process step (e.g.
granulation, blending). The objectives of in-process control are both quality control and process control.
11.I.1 Objectives
11.I.1.1 Quality control
This function is performed by documenting production parameters. In a broader sense, this includes the following in-process controls:
■ measured values obtained from process equipment, e.g. temperatures
■ measured values obtained by persons, e.g. times
■ product attributes, e.g. weight, hardness, friability
■ measured values obtained from the room environment, e.g. particle counts
■ tests following completion of intermediate products
The classic interpretation of the term in-process control includes the recording of measured values by members of the in-process control group.
“Finished product assessment should embrace all relevant factors, including […] results of in-process testing, […]” (6.3 EU-GMP-Guide, see Chapter
C.4.6).
The documented in-process data are therefore evaluated by quality control. In accordance with 21 CFR 211.192, in-process results are evaluated by
quality control in the context of batch record review (see Chapter D.1 Code of Federal Regulations). This evaluation is part of the release procedure (see
Chapter 14.J Batch release).
The investigation of intermediate manufacturing steps also falls into the category of in-process controls. An example of this is the homogeneity
investigation carried out on a blend. Normally, such quantitative determinations are the direct responsibility of quality control. In a broader sense, yields
of the various intermediate products are also in-process control values.
11.I.1.2 Process control
During manufacturing and packaging a lot of data are recorded which represent control factors of the manufacturing process. These data may be process
parameters (e.g. outlet air temperature of a fluid bed dryer) or product attributes (e.g. hardness of tablet cores). The results of the measurements may
indicate that a corrective action is required to maintain the process and the product within the specified ranges. The limits within which modifications
may be carried out to match measured values must be determined in advance.
The drying of a granulate is described here as an example. The objective, i.e. the resultant granulate humidity, is determined within the scope of the
manufacturing instructions. If the specified range has not yet been achieved, the normal course of action is to extend the drying time. In this case, it is
irrelevant whether the control is automatic, e.g. by means of online measurement within a fluid bed dryer or manual sampling.
The principle of this control function is shown in Figure 11.I-1.
Figure 11.I-1 Process control by means of in-process controls
11.I.2 Organisation and responsibilities
Precise information about the area of responsibility to which the accomplishment of in-process controls is to be assigned cannot be found in the EU-
GMP-Guide. There is merely the requirement that the procedures have to be authorized by quality control.
“All the in-process controls, including those made in the production area by production personnel, should be performed according to methods approved
by Quality Control and the results recorded.“ (6.18 EU-GMP-Guide, see Chapter C.4.6).
Usually, the tests are carried out by production personnel. This is favourable for organizational and timely reasons, e.g. in a multi-shift operation. The
personnel in the production area referred to here do not have to be directly responsible to the head of production with disciplinary responsibility. On the
basis of organisational instructions and process descriptions, quality control personnel may also carry out the necessary tasks. The head of production
is responsible for carrying out the controls in every case. He or she must ensure that the controls are used as a means of controlling processes in
accordance with the instructions, and that the results are taken into account.
In the case of quality assurance checks, it is recommended from a disciplinary point of view that in-process control personnel are organised
independently of production personnel, i.e. that they report directly to their area manager. This group therefore gains more autonomy in relation to
production personnel. This is necessary as the group must occasionally make decisions to stop or cancel manufacturing steps (see Figure 11.I-2). 21
CFR 211.110(c) states that the responsibility for quality assuring tests lies within the quality control unit (see Chapter D.1.2).
Figure 11.I-2 Example of an organisational structure
The responsibilities and tasks for the in-process control must be clearly laid down in organisational instructions. A number of aspects has to be
considered (Figure 11.I-3)
Figure 11.I-3 Responsibilities
Responsibilities in the context of in-process controls
Task Responsibility
Definition of tests Head of manufacturing
Compilation and approval of the test procedure Head of quality control and Head of manufacturing
Taking samples (mechanical/manual) IPC personnel,

production personnel,
Transportation of the samples to the test laboratory
monitors
Performing tests
Process control information paths Head of manufacturing
Approval of equipment
Measures in the event of deviations
Evaluation of IPC results Quality Control

Quality Assurance / Quality Unit
When deviations occur, or where release analyses of intermediates are carried out outside of production, a method must be defined that prevents
continued processing of the material until the decision or the result is available. Material may be rejected by means of operating data management
whereby the process chain is interrupted. Physical designation of the product affected by means of labelling is recommended.
11.I.3 Carrying out

11.I.3.1 Scope and kind of tests
The in-process control requirements are documented in the manufacturing instructions. For logical reasons, these requirements are compiled together by
development, manufacturing and quality control. The parameters and experiences accumulated during the process validation determine the scope of the
tests as well as the limits. The scope of the tests depends on the extent of process control, i.e. the more reliable the process, the smaller the scope of
the tests. The types of tests carried out depend on the dosage forms being produced.
Physical and attributive features are mainly checked (see Figure 11.I-4).
Figure 11.I-4 Examples of in-process controls
Examples of in-process controls
Physical parameters ■ temperature

■ time
■ pressure
■ weight
■ hardness
■ disintegration time
■ particle size
■ loss on drying
■ viscosity
■ osmolarity
■ pH
Attributive features ■ visible impurity

■ colour
■ completeness
■ integrity
■ fractional part
Physical parameters are checked using only suitable measuring instruments. These instruments are normally calibrated by in-process control personnel.
It may also be advantageous to have measuring instruments in production areas (e.g. balances) calibrated by in-process control personnel.
Operating procedures (SOPs) are used as the basis for the tests together with the manufacturing instructions. The approval of these instructions by
quality control ensures that the test complies with the requirements (normally according to the pharmacopoeia).
The testing of attributive criteria is an important in-process control task. This is particularly of importance in relation to the filling of solutions and solid
dosage forms as well as packaging. AQL lists (AQL = Acceptance Quality Limit) are normally used as the basis for the test procedures/specifications.
(See Chapter 13.A.5 Packaging material testing.)
With many manufacturing operations, release tests are an important in-process control task for starting up equipment or processes.
These are special control loop applications (see Figure 11.I-5).
Figure 11.I-5 Example of approval for tablet production
11.I.3.2 Location
“In-process controls may be carried out within the production area provided they do not carry any risk for the production.” (3.17 EU-GMP-Guide, see
Chapter C.4.3).
This means that particular care must be taken when carrying out sampling or testing. Examples of possible influences of in-process control methods on
production are shown below:
■ Particle measurements (influence on air flow pattern)
■ Direct contact tests (matrix residues on surface)
■ Disintegration tests (influence on room humidity)
■ Leak test on blisters (blue bath with microbial contamination risk)
Tests are therefore normally carried out in a segregated area and not directly at the manufacturing location. To keep equipment expenditure to a
minimum, central in-process control laboratories are occasionally set up to carry out tests relevant to all areas. In these cases, it must be clarified
who is responsible for sampling. Depending on the organisational structure, personnel involved in production, in-process controls or other areas such as
quality assurance (sometimes referred to as monitors) may carry out the sampling. Furthermore, analytical equipment and instruments are protected
from dust by segregating them physically from the manufacturing location.
11.I.3.3 Sampling
Samples can be differentiated according to their representativeness. Non-representative random samples that intentionally provide a snap-shot of the
manufacturing process are used for the purposes of process control. Samples that are generated for the final control are designed as representative
samples. Following this principle, uniform sampling is carried out throughout the entire production (batch).
As a first step, a sampling plan has to be established, which identifies process steps and/or locations for sampling, as well as number and amount of
samples.
When defining the amount to be sampled, statistical criteria should be considered and justified, e.g.
■ Component variability
■ Confidence levels
■ Degree of precision
■ Quantity needed for analysis
■ Reserve amount needed
The sampling plan should also contain precise instructions on the sampling procedure, as listed in Figure 11.I-6.
Figure 11.I-6 Contents of a Sampling Procedure
Contents of a sampling procedure
State type of sample container to be used
Describe collection technique:

■ Prevent contamination of product being sampled,
■ Prevent contamination of sample taken,
■ Aseptic technique if required
Specify sampling utensils:

■ Define type and requirements (clean, sterile, pyrogen free)
Justify any use of composite sample
Describe method for obtaining representative samples
Describe scheme for identifying samples:

■ Name of item
■ Lot number
■ Date taken
■ Sampler’s name
■ Other
11.I.3.4 Testing
Samples are tested to verify conformance with specifications:
■ Identity
■ Component conformity to written specifications
■ Container/Closure conformity to written specifications
■ Examination for contamination
As a result, components, containers or closures will be approved or rejected. The tests to be performed and the methods to be used have to be defined.
A list of specifications has to be established.
Beyond this, procedures for the use of Certificates of Analysis (COA) or Certificate of Conformance have to be established.
11.I.4 Documentation and evaluation of data

When documenting the results of the analysis, care must be taken to ensure that the samples investigated can be assigned to a specific time during the
process or to a specific phase of the process. If the analysis is not carried out directly after sampling, e.g. in the case of central IPC laboratories, the
sampling time (date, time) must be documented in addition to the analysis time.
“Any necessary in-process controls and environmental controls should be carried out and recorded.” (5.38 EU-GMP-Guide, Chapter C.4.5).
This documentation must includea record of the in-process controls, the initials of the person(s) carrying them out, and the results obtained. If problems
or deviations from the manufacturing formula and processing instructions occurred, all relevant information associated with this have to be documented
as well. In case of deviations, the signature of the person who approved the deviation is required (4.17 EU-GMP-Guide, Chapter C.4.4).
It is hereby clearly stated that each deviation from the specifications must be countersigned by Qualified Persons (see Chapter 15.B GMP-compliant
documentation). The head of production is responsible for the deviation procedure.
Figure 11.I-7 shows the information required for documentation of in-process controls.
Figure 11.I-7 Documentation In-process controls
Documentation of in-process controls
Date (poss. time),
Name of person carrying out the test
Results
Description of problems
In case of deviations: ■ Reasons for deviations

■ Measures incl. justification
■ date and name of authorising person
In addition to the numerical compilation of data, a graphical presentation of process control values is recommended. This provides a more simplified
overview that makes it possible for trends to be easily detected at an early stage. The manufacturing of tablets is used for the purposes of the following
example (see Figure 11.I-8).
Figure 11.I-8 In-process control as means of controlling production
Summary
In-process control not only provides a means of controlling production, it also performs a quality assurance function.
The in-process control group personnel may be assigned to production or quality control depending on the relevant company structure. In each case,
autonomy in relation to the production process must be ensured.
The in-process control methods that are part of the manufacturing formula are compiled and validated under the supervision of quality control.
Statistical evaluation and periodic review of in-process data contributes to the general assessment of process performance and product quality.
11.J Prevention of cross-contamination

■ What are the causes of incidence of cross-contamination?
■ What fundamental measures should be taken to avoid cross-contaminations?
■ What should be observed when manufacturing critical products such as antibiotics, hormones and zytostatics?
Contamination is generally defined as undesired introduction of impurities of a chemical or microbiological nature, or a foreign matter, into or onto a raw
material, intermediate, or API during production, sampling, packing or repacking, storage or transport (EU-GMP-Guide, Part II, see Chapter C.5).
Cross-contamination is defined as contamination of a starting material or of a product by another material or product (EU-GMP-Guide, Part II, see
chapter Chapter C.5).
Thus, cross-contamination is a special case of contamination.
The risk of accidental cross-contamination arises from the uncontrolled release of materials and products in process, from residues on equipment, and
from operators’ clothing. (cf. 5.18 EU-GMP-Guide). Cross-contamination may occur when different materials or products are handled at the same time
but at different locations, or when different materials or products are handled at the same location one after the other.
One of the central aims of the GMP regulations is to minimise these dangers in order to ensure product quality and patient safety. A range of aspects
must be considered in order to achieve this objective.
11.J.1 Causes of cross-contamination

Possible causes of cross-contamination can be summarized as follows:
■ rooms
■ equipment
■ processes
■ personnel
The prevention of cross-contamination should be adressed by means of a risk analysis during the design phase of rooms, HVAC, facilities and
processes.
11.J.1.1 Rooms
To prevent contamination from dust, it is essential to reduce the development or release of dust to a minimum. To this end, closed systems should
mainly be used. This entails e.g. the encapsulation of machines in which open processes are in progress. Each additional item of pipework etc.
increases the amount of cleaning required – a discrepancy which must be evaluated based on a risk analysis.
Aspiration is an additional important measure for preventing the transfer of dust although it must be ensured that exhaust systems themselves do not
become sources of contamination. Care should generally be taken to prevent fluctuations in the existing negative pressure that would cause a reverse
discharge of dust from exhaust systems. Flexible hose systems that are often used must be kept sufficiently clean or be replaced. Monitoring should
include checks on the effectiveness of measures implemented.
The requirement for sufficient space (3.8 EU-GMP-Guide) can certainly be explained in light of the need to prevent the problems mentioned above.
Rooms that are narrow and/or unclearly laid out are not appropriate for effective cleaning or efficient separation of products or containers.
The conversion of materials in a conversion zone normally involves transfer on in-house aluminium or plastic pallets. These should be cleaned after use or
at regular intervals. The condition of the pallets should be checked during cleaning. Pallets with damaged surfaces (e.g. cracks) must be rejected (see
Figure 11.J-1).
Figure 11.J-1 Unsuitable aluminium pallets with cracks
11.J.1.2 Equipment
Cleaning
The most important aspect for prevention of cross-contamination is cleaning validation (see chapter 8 Cleaning validation), because insufficiently
cleaned equipment directly leads to a carry-over of product residues. Equipment should therefore be cleaned according to product-specific, optimised
cleaning procedures, which have been checked by means of cleaning validation (see Chapter 8.B.2 Compilation of cleaning instructions). A fundamental
prerequisite for reproducibility of cleaning processes is the appropriate design of the equipment according to the principles of hygienic design.
Equipment (such as product containers) that is not cleaned directly on-site should be stored provisionally in such a way that the release of dust is
prevented. This may be achieved by designating a room especially for the storage of contaminated equipment that also acts as an anteroom for a
cleaning unit. Ideally, the material routes of cleaned and contaminated equipment should be kept completely separate. A linear material flow should
therefore be ensured (Figure 11.J-2).
Figure 11.J-2 Linear material flow in the cleaning process
Cleaned equipment and containers must be appropriately stored and protected from the accumulation of dust. For small parts, this may be achieved, for
example, by packaging them in polyethylene (PE) bags. Whenever possible, cupboards should be set up outside the rooms in which production takes
place. The use of open shelving for storage must be avoided as there is a risk of dust accumulation.
It is recommended that visual inspections of equipment, machines, containers and rooms be documented prior to use, e.g. on the cleaning label and in
the batch record. Consistent application normally leads to an increased awareness of these requirements amongst staff.
Utensils
More often than not, it is smaller, more insignificant items that can cause contamination, such as adapter sockets for tubes or pipe connections,
scoops, small measuring containers, etc. (see Chapter 11.C.2 Cleaning and Chapter 11.H Identification).
11.J.1.3 Processes
Process-related risks
All individual process steps should be subject to a risk analysis with view to their potential risk of cross-contamination. Processes with open handling of
raw materials, intermediate products or finished products are most critical in this context. Examples for this are weigh-in, sampling, filling and packaging.
This risk can be reduced by use of closed equipment wherever possible.
The check for complete depletion of equipment at the end of each process step as well as the check for cleanliness prior to each processing step are
fundamental requirements for the prevention of cross-contamination. These controls should be part of each manufacturing and packaging instruction.
Packaging processes
In packaging areas, different products are simultaneously packaged in different ways near one another. This makes high demands on rooms, facilities
and the process organisation. The line clearance fulfils an essential prerequisite for the prevention of contamination and mix-ups (see Chapter 13.B.3
Line clearance).
Labelling
The labelling of equipment and containers is extremely important, particularly with respect to the consistent declaration of the cleaning status (see
Chapter 11.H Identification). They must always be labelled before being used in the production process. Start-ups from equipment that are not classified
as acceptable products for safety reasons must be declared to prevent incorrect assignment to acceptable goods.
Waste diposal
Waste must be disposed of as quickly as possible. Production waste must be collected outside the production area. This must be ensured as part of the
organisational process.
11.J.1.4 Personnel
Clothing
The suitability of working clothing is also important for the prevention of cross-contamination. The re-release of particles and dust must be regarded as
critical. Outside pockets are a potential source of danger in every cleanliness grade (see Chapter 11.B.1 Clothing). The transfer of dust due to personnel
movement should be minimised by cleaning rooms and corridors regularly. Dust trap mats at the transition areas between rooms and in locks help
minimise the spread of dust from such rooms and must be cleaned regularly.
The intervals for change of clothing have to be defined with regard to the following aspects:
■ kind of equipment (open/closed)
■ kind of product (dusty/liquid)
■ kind and duration of processes
■ batch size and API content in the formulation
■ clothing material (adsorptive/emittant)
Gloves should always be changed when entering a production room. The effectivity of the clothing concept has to be monitored.
Code of conduct
Training should be carried out on a regular basis to make personnel aware of the consequences of cross-contamination, misidentification and mix-ups.
Regular analysis via discussions on this subject helps pinpoint company-internal weaknesses and allows suitable remedial measures to be taken. (See
Chapter 2.C Training.)
Furtheron, the behaviour in critical situations should be addressed in training sessions. One example for this is shown in Figure 11.J-3.
Figure 11.J-3 Behaviour in critical situations
Emergency spill cleanup procedure
■ Quarantine of area
■ Cleanup of area
■ Quarantine of all product(s) possibly affected
■ Testing of all product(s) possibly affected
■ Follow deviation procedure and documentation requirements for incidents
11.J.2 Measures to prevent cross-contamination

“Measures to prevent cross-contamination and their effectiveness should be checked periodically according to set procedures.” (5.20 EU-GMP-Guide,
see Chapter C.4.5).
Checks of this kind may be carried out as part of the self-inspection (see Chapter 18.E Self-inspection). The check points are then established so that
an evaluation may be carried out for the period concerned.
Measures to prevent cross-contamination may be technical or organisational. Generally, potential causes of cross-contamination have to be identified
and the risk of carry-over has to be reduced. Both from a GMP view and from a safety view, closed facilities are favourable. Individual parts and the
associated assembling and disassembling steps should be minimized. If necessary, tools, equipment, rooms or even entire facilities have to be
dedicated to specific products.
Figure 11.J-4 gives an overview on measures to control the risk of cross-contamination.
Figure 11.J-4 Measures to control the risk of cross-contamination
Measures to control the risk of cross-contamination
■ Evaluation of process steps and material flow

■ Minimization of the number of process steps (process optimization)
■ Minimization of product-contact individual parts
■ closed systems
■ CIP cleaning
■ pressure differential cascades and locks
■ appropriate change intervals for clothing
■ robustness of quality systems (documentation, training, …)
■ dedicated tools, equipment, rooms or facilities
■ periodic review of effectiveness (e.g. by self-inspection)
Containment Facility Designs and Procedures

Containment facility designs and procedures should be established to cover containment requirements for airborne product/active component handled in
a dedicated facility. Monitoring outside of facility is required to verify that containment is working.
The facility design for a non-dedicated facility should take into consideration air flow patterns, maintenance of pressure differentials, dust
removal/filtration, HVAC preventative maintenance and cleaning, material flow patterns, personnel flow patterns and personnel gowning requirements.
The containment procedures for a non-dedicated facility should cover storage and handling of special danger products and APIs, handling of open
containers of APIs, handling of APIs during compounding and handling of spills of product, bulk product and API.
The containment attributes of dedicated and non-dedicated facilities should be validated and documented.
11.J.3 Manufacture of critical products

Specific products should be processed in “dedicated and self contained facilities” (3.6 EU-GMP-Guide). These include “highly sensitising materials (e.g.
penicillins) or biological preparations (e.g. from live micro-organisms)”.
The contamination risk associated with such products implies the need for a dedicated, separate manufacturing site. If this manufacturing site is located
at a company's premises where conventional production is also carried out with similar logistics, it must be ensured that equipment cannot be mixed up.
Separate ventilation systems should exist. At the concept stage, care should be taken to ensure that the air discharge and air intake of separate units
are not located near one another (see Chapter 3.G Heating Ventilation Air Conditioning (HVAC)).
The risk to other products must be regarded as very high. To prevent the dissemination of dust, only copies of the batch records should leave the area
(e.g. via fax), because they are kept near the product. The use of an electronic documentation system is advantageous. (See Chapter 15.C Batch
documentation). If a reasonable possibility exists that a non-penicillin drug product has been exposed to cross-contamination with penicillin, the non-
penicillin drug product should be tested for the presence of penicillin. Such drug product should not be marketed if detectable levels are found when
tested according to specified procedures (According to 21 CFR 211.176, Penicillin Contamination, see Chapter D.1.2).
“[…] certain additional products, such as certain antibiotics, certain hormones, certain cytotoxics, certain highly active drugs and non-medicinal products
should not be conducted in the same facilities.” (3.6 EU-GMP-Guide).
In such instances however it is possible to employ conventional production options during the course of manufacturing campaigns. Special precautions
should be taken. These include the special labelling of manufacturing equipment or rooms in addition to facility-related precautions.
The risk posed by critical processes can be reduced by segregating them either physically or temporally. A cabin enclosure is an effective means of
achieving physical segregation. In this case, the effectiveness of the cabin enclosure measures must be checked during qualification. The area of air-
conditioning technology (air exchange rate, pressure differential, proportion of fresh air to recirculating air (see Chapter 3.G Heating Ventilation Air
Conditioning (HVAC)) is especially relevant. In so-called clean corridors, the corridor in front of the production cabin has a positive pressure in relation
to the cabin which minimises the spread of dust from the cabin. The quality of the corridor (no contaminated equipment or other potential dust sources
present) and efficient performance of the door-closing mechanism (short opening times) are basic requirements (see Chapter 3.D.2 Doors and windows).
The risk of dust being carried out via clothing can be countered by wearing special outer clothing and by cleaning shoes. The use of dedicated equipment
should be anticipated in many cases particularly if the pharmaceutical ingredient is highly potent and the cleaning is classified as critical (e.g. textile
filter bags from fluid bed equipment, tubes that come into contact with products).
Special protective clothing for personnel (in the interests of health and safety at work) should be left in these areas, i.e. a protective suit worn over
normal clothes must be removed in the designated area and not outside of it. The contaminated suits are wrapped up, e.g. in bags, and then removed.
Training has a significant role to play in this regard. Emphasis should be placed on the cleaning of normal clothes prior to leaving the area (e.g. shoe
soles: sole cleaning devices and dust trap mats may prove to be useful). It must be clear to staff that simple oversights (such as the removal of breathing
masks prior to cleaning) may endanger other products being manufactured. Steps must be taken to ensure that protective equipment does not become
contaminated, for example when large quantities of dust are produced. This can be achieved by compartments and cupboards.
“[…] The manufacture of technical poisons, such as pesticides and herbicides, should not be allowed in premises […]” (3.6 EU-GMP-Guide, see
Chapter C.4.3).
As a consequence, pesticides, herbicides etc. must not be manufactured in premises that are used to manufacture medicinal products. General checks
should be carried out to verify whether the manufacture of a given product influences the manufacturing process and overall quality of another product
manufactured nearby. This proximity could be of a physical as well as temporal nature. These rules also apply for the equipment used as well as for the
rooms: “Normally, the production of non-medicinal products should be avoided in areas and with the equipment destined for the production of medicinal
products.” (5.17 EU-GMP-Guide). The manufacturing of food or cosmetics is undoubtedly less critical. In terms of organisation however, this should be
separated from pharmaceutical production.
Summary
Cross-contamination can be prevented by a number of different measures that must be coordinated with one another. One of the main rules to be
observed is the temporal and/or physical segregation of different products during their manufacture and the cleaning of rooms and facilities.
Critical products such as antibiotics, hormones and zytostatics must be manufactured in separate rooms.
11.K Empty Chapter
Up07
The chapter “Deviations” has been moved to Chapter 19.E.
11.L Reworking

■ What is the difference between rework, reprocessing and recovery?
■ What are the prerequisites for reworking?
■ Which aspects have to be considered?
Under the umbrella of rework, there are different terms which will be explained subsequently:
■ Rework
■ Reprocessing
■ Recovery
11.L.1 Definitions
While the terms reprocessing and recovery are defined in the Glossary of the EU-GMP-Guide (see Chapter C.7 Glossary), no definition for rework can be
found there. Within the EU-GMP-Guide, reworking is used as a synonym for reprocessing (see definition below). Nevertheless, there is an explanation for
rework in the WHO-GMP-Guide.
11.L.1.1 Rework
Intermediate, bulk or finished products of a single batch are subjected to a deviant manufacturing process in order to stay in compliance with defined
specifications following a deviation. Rework is an unforeseen event and not covered by the granted authorization (Annex, 4 WHO Technical Report
Series, Glossary).
11.L.1.2 Reprocessing
The reworking of all or part of a batch of product of an unacceptable quality from a defined stage of production so that its quality may be rendered
acceptable by one or more additional operations (EU-GMP-Guide, Glossary, see chapter C.7).
A differentiation has to be made between reprocessing for one processing step (single step repetition) and full reprocessing using the entire
manufacturing process that would include all processing steps.
11.L.1.3 Recovery
The introduction of all or part of previous batches of the required quality into another batch at a defined stage of manufacture (EU-GMP-Guide, see
chapter C.7).
11.L.2 Procedure
11.L.2.1 Reasons for rework/reprocessing
The reworking of products or semi-finished products (bulk) is possible for a number of reasons. There might be failures during the process, which have
been caused by equipment defects or operator mistakes, or unclear documentation that raises doubt on the product quality. Deviations during in-process
control or release testing may also lead to the necessity of reworking. A list of potential reasons for reworking is given in Figure 11.L-1.
Figure 11.L-1 Possible reasons for reworking
Potential reasons for rework or reprocessing
■ Failures in weigh-in (wrong dosage)

■ Raw material (bulk) deviation from specification
■ In-process manufacturing equipment or process deviation
■ Equipment malfunction
■ Operator mistake
■ In process control testing failure
■ Finished product testing failure
■ Packaging issues
■ Returned product
11.L.2.2 Request for rework/reprocessing

Establish a system for request for change (rework or reprocessing) with the following considerations as listed below
■ Mechanism to initiate
■ Statement of rationale/justification
■ Responsibilities: QA/QC, Production, Regulatory, Others
■ Standard forms and records
According to 21 CFR 211.15, written procedures should be established and followed prescribing a system for reprocessing batches that do not conform
to standards or specifications and the steps to be taken to ensure that the reprocessed batches will conform to all established standards, specifications,
and characteristics (see Chapter D.1.2). Reprocessing should not be performed without the review and approval of the quality control unit.
11.L.2.3 Risk assessment
In general, reworking has to be assessed from several points of view: on the one hand, product quality has to be maintained or re-established in order to
ensure the applicability and supply of the product, on the other hand, reworking is associated with costs and effort, and its potential impact on quality,
efficacy and safety has to be evaluated. This may be done by a risk assessment. Relevant aspects to consider are compiled in Figure 11.L-2.
Figure 11.L-2 Risk assessment for reworking
Impact of rework/reprocessing on drug product
■ Patient safety
■ Impact on stability and bioavailability; therapeutic range
■ Impact on drug attributes (i.e., solubility, permeability)
■ Identify testing required
■Determine if process validation is required:
■ Assess against validation master plan criteria
■Consideration of timely aspects:

■ maximum time permitted between initial manufacture and the time of reprocessing
■ time of reprocessing
■ storage conditions during this interval
■ Conformity with submission/market authorization

■ Supply availability/out -of-stock
■ Financial aspects (cost-benefit-analysis)
11.L.2.4 Responsibilities
The responsibilities for QA/QC in relation to reworking or reprocessing activities encompass the following:
■ Identification and segregation (or quarantine) of product until disposition has been completed and verified
■ Assignment of rework or reprocessing to correct functional group
■ Tracking of status until completion
■ Review and approval of all documentation related to rework or reprocessing activity
11.L.2.5 Documentation requirements

Outlined below are some points to consider from a documentation perspective in relation to reworking or reprocessing activities:
■ Rework or reprocessing request
■ Description of methods and materials used to rework or reprocess
■ Identification of personnel who performed rework activities
■ Approval by all appropriate signatories
■ Results of retesting and evaluation performed after rework or reprocessing demonstrating all specifications and requirements are met
■ Amendment of batch records to reflect rework or reprocessing activities performed
11.L.2.6 Regulatory submission requirements

With view to regulatory submissions documentation requirements may be differentiated as follows:
Original and supplemental applications requesting approval of formal reprocessing procedures
■ General rework and/or reprocessing procedure
■ Specific rework or reprocessing procedure
Unexpected rework or reprocessing required

■ Supplemental application for specific rework procedure
In-process single step repetition

■ Infrequent or random occurrence (Report in Annual report)
■ Frequent occurrence: Supplemental application (Amend manufacturing process; Validation of new process)
11.L.3 Rework/Reprocessing of rejected products

Both the EU-GMP-Guide and 21 CFR explicitly permit the reworking of rejected products in exceptional cases (5.62 EU-GMP-Guide, 21 CFR 211.165(f)).
The decision to rework must be based on a risk assessment and requires approval by the responsible persons in manufacturing and quality control, as
well as approval by the Qualified Person. A protocol has to be established which describes the rework activities and defines additional tests of the
well as approval by the Qualified Person. A protocol has to be established which describes the rework activities and defines additional tests of the
finished product, if necessary. Rework itself is carried out and documented according to an authorised manufacturing instruction. Release of the batch
may only occur when all test results are available and show conformity of the product with its specifications. The reworked batch should undergo stability
testing. Rework activities shuld be reported in the Product Quality Review and/or Annual Product Review (see Chapter 19.G Product Quality Review and
Annual Product Review).
Conditions under which rework of rejected products may be carried out are listed in Figure 11.L-3.
Figure 11.L-3 Requirements for rework of rejected products
Rework of rejected products
■ Only in exceptional case

■ Following a risk assessment
■ Carried out in accordance with an authorised manufacturing proce-dure
■ Specifications are complied with
■ Quality of the finished product not impaired
An important question to ask when assessing reworking is whether the current deviation occurs regularly. Deviations should only occur occasionally as
isolated incidences, e.g. due to mechanical defects. Where deviations occur more frequently and /or due to the same reasons, it can be assumed that
the process or process chain is not stable, and revalidation should be considered.
The procedure must be defined in the form of a process instruction that states which functional areas or persons are responsible for the various steps.
Figure 11.L-4 shows an example.
Figure 11.L-4 Sequence of a reworking process
The result of the research is presented in the deviation report in which the order of events and causes are documented . In this example, the results are
compiled by the company's pharmaceutical technology unit. Knowledge about the causes of the deviation allows a proposal for a reworking procedure to
be compiled which in this case is also put forward by the company's pharmaceutical technology unit. The evaluation of the proposal based on the risk
assessment is carried out by the head of quality control with the support of the relevant specialist departments. If the result of the assessment is
positive, manufacturing instructions may be compiled. These must be authorised by persons in the relevant responsible positions. The reworking itself is
then subsequently carried out.
As far as the quality of the finished product is concerned, the evaluation of the risk associated with reworking must sometimes be regarded as critical.
Economic requirements must be considered in relation to quality requirements (see Figure 11.L-5). The decision is to be documented – for example, in
the deviation report together with the reworking proposal. The batch records of the starting batch as well as for the reworked batch must carry a reference
to this report or even include the report to guarantee traceability of the data.
Figure 11.L-5 Economy and quality in the context of reworking
“The quality control department should assess whether a finished product […] must be subjected to additional analyses” (5.64 EU-GMP-Guidee).
This is a consistent approach as the qualitative assessment of a product should be considered separately in such instances. It must be demonstrated
that the reworking procedure does not adversely affect the quality of the product, e.g. as with the effects of heat when crushing solids. The additional
tracing of possible degradation products may subsequently be necessary and should be investigated in a stability study.
Example
The sequence shown in Figure 11.L-4 is illustrated using the following example for the production of solid dosage forms (Figure 11.L-6).
Figure 11.L-6 Example for the reworking of solid dosage forms
Description of the situation Using the set tablet height as the starting point, the tablet hardness was kept at the upper specification limit during
compression. In this case, the tablets were overpressed as a result of the compression force selected, i.e. no additional increase in tablet hardness was
achieved through the application of excess compression force. Formation of cracks in the tablets became apparent as a relaxation effect following a
standing time of approximately 1 hour. The compressed tablets manufactured could not be processed further due to the stability risk. All values
documented (tablet height, tablet hardness, compression forces) were in conformance with the specifications.
Report The initiated failure investigation revealed a connection between raw material specifications (in this case particle sizes) and the required
compression force. Although the specification for the maximum particle size was satisfied, it turned out that the particle size distribution (not part of the
specification) was different to that one observed during development (considerably higher fine-grained fraction, smaller average grain size).
Perspective It was therefore possible to narrow the specification for subsequent batches to achieve regulatory compliance for manufacturing process
values. The tablets were reworked by crushing them and then pressing them once again.
11.L.4 Rework of returned products

According to 21 CFR 211.204, returned drug products should be destroyed unless examination, testing or other investigations prove the drug product
meets appropriate standards of safety, identity, strength, quality or purity. A drug product may be reprocessed provided the subsequent drug product
meets appropriate standards, specifications and characteristics. Records of returned drug products should be maintained.
The decision to rework returned products requires a risk assessment where the following aspects should be considered:
■ Sufficient knowledge about the batch history
■ Sufficient knowledge about the conditions during transportation
■ Type and actual condition of the packaging
■ Time between delivery and return
11.L.5 Rework of products that have not been rejected

“The recovery of all or part of earlier batches which conform to the required quality by incorporation into a batch of the same product […] should be
authorised beforehand. This recovery should be carried out in accordance with a defined procedure […]. The recovery should be recorded.” (5.63 EU-
GMP-Guide).
In this case, batches or parts of the batches are reworked and then used to manufacture further batches. In doing so, the reworked material should be
handled in the same way as a starting material, i.e. determination of release status following quality control, traceability through identification (e.g.
individual material number, batch designation) must be considered. For reprocessing authorised manufacturing instructions must exist in which the
precise allocations of the reprocessed quantities are documented. The reprocessing of these quantities into manufacturing processes must be validated.
Example
The reworking of products that have not been rejected may include the removal of tablets from the blisters and then their repackaging. In this case, the
blisters are initially removed from the folding cartons so that the tablets can then be mechanically pressed out of the blisters. Before the bulk obtained is
packaged, it must undergo a visual inspection prior to approval. This involves testing attributive features such as chipped or broken edges etc. in a larger
random sample as the tablets may be damaged when they are removed from the blisters. If the set limits are exceeded, sorting processes will be
required. The tablets are to be repackaged following approval. In doing so, the usual precautions must be taken to prevent confusion and mix-ups. Due to
the high risk of misidentification, it must be ensured that all the packaging materials of the original batch are gathered up and destroyed to exclude the
possibility of a mix-up (see Chapter 13.B Packaging process). During repackaging, care should be taken to ensure that the expiration date has not
changed. The running time of the product cannot be extended by repackaging.
Summary
Reworking may be carried out for products that have been rejected as well as those that have not been rejected following approval.
The reworked batches are subject to stringent quality controls. It must be demonstrated that reworking has no negative influence on the product
concerned.
11.M Warehouse and logistics

■ What are the requirements for warehouses?
■ How are the responsibilities regulated?
■ How do procedures have to be organised?
11.M.1 Regulatory requirements

It is a general regulatory requirement that the quality of raw materials and finished drug products must not be negatively impacted by storage, e.g. by
degradation, modification or contamination. Moreover, mix-ups have to be avoided.
In order to ensure this, several aspects have to be considered that will be discussed below:
■ Responsibilities
■ Personnel
■ Storage areas
■ Sanitation
■ Material flow
■ Process flow
The European Pharmacopoeia (Pharm. Eur.) states: Medicinal products must be stored in such a way that they are protected against substance loss as
well as a reduction in purity and efficacy. […]. The objective is to avoid contamination, confusion and changes during the storage process which are
beyond the anticipated levels.
The WHO Guide to Good Storage Practice for Pharmaceuticals (Annex 9) (compiled in close collaboration with FIP – Fédération Internationale
Pharmaceutique), hereafter referred to as WHO GSP, acts as a guideline. This replaces the FIP guidelines for good storage practice that are now
roughly 20 years old and describes various aspects of storage.
According to 21 CFR 211.42, written procedures should be established and followed that describe the warehousing of drug products (see Chapter
D.1.2). They should include the quarantine of drug products before release by the quality control unit and storage of drug products under appropriate
conditions of temperature, humidity, and light so that the identity, strength, purity and quality of the drug products are not affected.
According to 21 CFR 211.150, written procedures should be established and followed that decribe the distribution of drug products. They should include
the following:
■A procedure whereby the oldest approved stock of a drug product is distributed first (first in – first out). Deviation from this requirement is permitted
if such deviation is temporary and appropriate.
■ A system by which the distribution of each lot of drug product can be readily determined to facilitate its recall if necessary.
11.M.2 Stock management system

Scope of the system
Warehousing can encompass a wide variety of materials, e.g.
■ Active ingredients
■ Excipients
■ In process materials
■ Labels and labeling
■ Equipment
■ Support systems
Layout requirements
Each of the following activities should be carried out in separate areas in order to prevent mix-ups or contamination:
■ Receipt
■ Sampling
■ Testing
■ Storage (Quarantine, Release, Rejection)
Identification of received goods

A written procedure has to be established that addresses the following items:
■ Decide whether to use computer or paper system
■Define information given in the receipt record:
■
■ Name of item
■ Manufacturer
■ Supplier (if differs from manufacturer)
■ Carrier
■ Date received
■ Manufacturer’s lot number
■ Quantity received
■ Control number
■Establish coding system:

Assign unique control number to lot
■Provide for visual examination of received goods:
■ Labeling (Correct product, properly labeled)
■ Container damage
■ Unbroken integrity seals
■ No apparent contamination
■ State any organoleptic examination required (appearance, feel, odor, other criteria)
■Label product with current status:

■ Quarantined
■ Approved
■ Retested
■ Rejected
Identification of in-process material

If in-process materials are stored, correct identification must be assured through labeling with the following information:
■ Name
■ Batch number
■Phase of process:
■ Processing lines
■ Equipment
■ Removal of previous batch identification
Control of quality status

Written procedures have to be established that describe all aspects which are relevant for the control of the quality status:
■Establish handling practices:
■ Rotation (first in/ first out)
■ Warehouse movement
■ Truck unloading/loading
■ Laboratory samples
■ Contamination prevention
■Define storage conditions (see Chapter 11.M.5 Storage areas and Chapter 11.M.6 Storage conditions):
■ Bagged or boxed components (off of floor, space to permit cleaning)
■ Temperature
■ Relative humidity
■ Light condition
■ Maximum storage time permitted
■ Other environmental factors as appropriate
■ Laboratory samples
■ Maintain an active pest control program (see Chapter 11.M.7 Sanitation and pest control)
■Maintain items in quarantine status (see Chapter 11.M.5.5 Quarantine) when required, such as:
■ Not yet-approved items awaiting sampling, testing, retesting, release by quality control
■ Rejected materials until disposed of properly
Sampling
A written procedure has to be established addressing the following topics:
■ Sample each shipment of each lot
■Define amount to be sampled (Chapter 14.A.2 Sampling plan (instructions))
■Consider and justify statistical criteria: Component variability, Confidence levels, Degree of precision, Past history of supplier, Quantity needed
for analysis, Reserve amount needed
■Define sampling procedure (see Chapter 14.A Sampling)

■ State type of sample container to be used
■Describe collection technique:
Prevent contamination of product being sampled;
Prevent contamination of sample taken; aseptic technique
■Specify sampling utensils:
Define which type (clean, sterile, pyrogen free)
■ Justify any use of composite sample
■Establish system for sample identification:
name of item, lot number, container from which taken, date taken, sampler’s name, other
■ Specify how to mark container sampled
■ Reseal sampled containers
Sampling has to be performed according to a written sample plan and the sampling procedures. During sampling, contamination has to be avoided. For
the number of samples, the following rule applies:
■ All containers if from unqualified supplier (no history of quality);
■ Representative sample if from qualified supplier (have history of quality)
Rejection
Materials that are unsuitable have to be rejected (21 CFR Part 211.87, see chapter Chapter D.1.2). The workflow and the responsibilities have to be
described in a written procedure as follows:
■Establish mechanism to reject components, containers and closures:
Maintain quarantine status; remove from warehouse
■Status identification:
QC unit is responsible for appointing persons who are allowed to change the status labeling on materials, and for the provisions how materials will
be segregated
Warehouse control
The most important aspects to consider when establishing a warehouse control system are summarized in Figure 11.M-1.
Figure 11.M-1 Aspects to consider for warehouse control
System for Warehouse Control
Material identification
Identify each batch received:
■ describe steps,
■ define responsibilities for key activities
Status identification
Identify each lot to show status:
■Status:
Quarantine (hold), Sampled, Released, Rejected, Returned material, Resampled
■Status Label:
On every container in lot, unless whole pallet is used at one time; Label not required if status controlled by validated computer inventory system
Quarantine Status (21 CFR Part 211.82)

■ Material should be held in quarantine until approved or rejected by QC Unit
■ A quarantine status label is required
Inventory control
■ Maintain inventory of all material
Storage conditions
■ Store safely and off the floor
■ Store within labeled temperature and/or humidity requirements (21 CFR Part 211.82)
Material turnover
■ Establish stock rotation controls (21 CFR Part 211.86)
■ Use oldest approved stock first
■ First In First Out (FIFO) inventory system
Release
■ Establish procedures to assure only approved materials are released for use (21 CFR Part 211.87)
11.M.3 Responsibilities
Responsibility for the storage area lies with the head of production (chapter 1 EU GMP Guide). The storage conditions are defined by the head of
production together with the head of quality control. Both are responsible for regular assessment of the storage conditions, e.g. by means of self-
inspection (see Chapter 18.E.1 Purpose of self-inspection).
Besides the before mentioned tasks and responsibilities, a wide range of activities in the context of warehousing has to be assigned to the respective
personnel, e.g.
■ Receiving inspection personnel
■ Storage and warehousing personnel
■ QC personnel
■ QA personnel
■ Cleaning staff
■ Production/technical personnel
■ Engineering
■ Auditors
11.M.4 Personnel
The personnel requirements in the warehouse are such that a sufficient number of appropriately qualified operators must be present to ensure that the
quality assurance guidelines are complied with. Training is required to provide the necessary knowledge for carrying out tasks at the pharmaceutical
warehouse (WHO GSP 3.1, 3.2). All staff should also receive training in hygiene and cleaning (see Chapter 11.B Personnel hygiene) to enable them to
comply with the specifications (WHO GSP 3.3).
Generally, a large number of work steps are carried out manually, such as the application of labels that are subsequently read mechanically. In order to
avoid confusion, a careful and responsible way of working is indispensable.
When assessing a delivery of starting materials, the experience of the operator is of great importance , e.g. to assess the extent to which it was possible
to maintain the necessary cold chain or to detect hidden damage.
As is the case with production personnel, those persons involved with the sampling of open products, must also regularly undergo medical examinations
(see Chapter 2.B.2 Health requirements). Persons who exhibit inflammatory diseases should be excluded from sampling during the infectious period.
In order to reduce impurities brought into the warehouse, normal clothing should be covered, or working clothing provided.
11.M.5 Storage areas

11.M.5.1 Size
The size of the premises for storage and all the tasks to be carried out represents an important basis for assessing the quality of a warehouse and the
storage. Sufficient capacity for a range of different materials and special storage areas must be available. The risk of confusion is always increased by
cramped spaces and low storage bay capacities, such insufficiencies may result in a mixture of different materials or different batches of the same
material being assigned to the same pallet. To avoid confusion these practises must be avoided. The storage of small containers may be hived off from
the standard high-bay storage areas and ranged in special shelving systems. For ease of handling, paternoster systems may be helpful as they allow a
straightforward loading and withdrawal of goods while the materials remain sealed. Tasks such as picking can only be carried out safely if sufficient
space is available. It is essential to have sufficient space, particularly in zones that are highly frequented and serve as circulation areas.
11.M.5.2 Illumination
The lighting in storage areas should be such that all tasks may be carried out correctly and safely (WHO GSP 4.16). This requirement is the only logical
means of identifying storing positions or containers in non-automated warehouses. A sufficient level of illumination is indispensable in areas where
picking work is carried out and in the incoming goods and dispatch areas. An adequate level of illumination is not only necessary to prevent confusion,
but also essential to perform visual checks on the condition of the floor, aisles, pallets, containers, labels, etc.
11.M.5.3 Incoming goods and dispatch
“Receiving and dispatch bays should protect materials and products from the weather. Reception areas should be designed and equipped to allow
containers of incoming materials to be cleaned where necessary before storage.” (3.20 EU GMP Guide).
It is not explicitly stated whether such areas should be located inside or outside a storage building. In some cases, it may be acceptable for the
incoming goods area to be located under a canopy in the open, although factors such as solar radiation and humidity must be taken into account. Goods
are therefore normally received in a designated zone inside the warehouse building. Before the goods are finally stored, general cleaning is normally
required using aspiration or compressed air and the relevant device must be installed beforehand.
The incoming goods and dispatch areas should ideally be separate. If space is short, additional organisational measures will be required to minimise the
risk, such as temporal separation of goods receipt and goods dispatch procedures or the definition of zones within a handling area (either permanent or
using mobile partitions or chain barriers).
Figure 11.M-2 Requirements for incoming goods and dispatch
Regulatory requirements for Incoming Goods and Dispatch
EU GMP Guide WHO GSP 21 CFR
3.20 4.5; 5.3; 5.7; 7 211.80 (a)
11.M.5.4 Sampling
“[…] If sampling is performed in the storage area, it should be conducted in such a way as to prevent contamination or cross-contamination.” (3.22 EU
GMP Guide).
The risk of contamination is always present when carrying out sampling in the warehouse. Laminar-flow boxes in subdivided rooms present a possible
alternative to complete discharge of the material. Depending on the degree of automation, materials are brought into this kind of cabin either via conveyor
belts (integration of LF cabin into linear flow of components) or manually, in an auxiliary room. Only one batch at a time must be placed under the LF for
sampling and be sampled there.
The specific order of events for the entire procedure, i.e. method for changing batches and products, handling of sampling utensils, labelling, cleaning
etc., must be precisely described in SOPs. Personnel must wear protective clothing when carrying out the sampling. Once the sampling itself is
complete, the LF area is to be cleaned in accordance with the specified procedures. It is recommended that a log book is kept for this area.
The organisation of the sampling is determined by the available space and timing of events at the relevant company. This means that the identification of
each container can be carried out, e.g. using NIR, directly under the conditions described above. It is understood that it is also possible to carry out
individual identification at a later date, providing quality control and approval has been carried out correctly. For logical reasons, this is carried out when
the containers are opened (e.g. during initial weighing).
Further information, e.g. on container-based and reduced identity testing, is provided in Chapter 14.A Sampling.
Figure 11.M-3 Requirements for sampling
Regulatory requirements for Sampling
3.22 4.7; 5.10; 5.11 211.80 (a)
11.M.5.5 Quarantine
“Segregated areas should be provided for the storage of rejected, recalled or returned materials or products.” (3.23 EU GMP Guide).
This makes very good sense as it helps prevent unintentional use or confusion. Additional labelling (rejected) is certainly necessary in cases where
100% separation is not possible, e.g. shared use of incoming goods and dispatch areas for regular goods and rejected goods. Access to these areas
must be restricted to authorised persons.
Raw materials
Rejected starting materials should be returned to the supplier or destroyed. The decision-making path must be defined at the outset and documented.
Quality control must be responsibly involved in every case.
If appropriate, downgrading can be carried out, i.e. a starting material whose quality does not conform to the specifications is graded as an inferior-quality
product for other purposes. (Example: deviations in the particle size distribution of citric acid are found during the incoming goods inspection. The
material is then regraded and used to make up cleaning solutions for cleaning the facility.)
Products in process
When a product is rejected during the production process, it must be ensured that it is moved to quarantine. In terms of data handling, it is necessary to
differentiate between storage locations. Ideally, the system settings will be such that when a material is rejected, following the compilation of a transport
order, its storage location will be automatically changed to quarantine.
Products returned from the market
“Products returned from the market and which have left the control of the manufacturer should be destroyed unless without doubt their quality is
satisfactory; […]“ (5.65 EU GMP Guide).
The head of quality control is responsible for the definition of the required quality. A written procedure that describes the analysis criteria must be defined
beforehand. This assessment has to be very critical as the products will not have been monitored by the manufacturer in the meantime. Figure 11.M-4
shows critical aspects in relation to the assessment of goods that are returned from the retail sector.
Figure 11.M-4 Assessing the quality of returned goods
Aspects regarding the quality assessment of returned goods
■ Type of product (dosage form, sensitivity)

■ Storage and transport conditions
■ Remaining running time of product
■ Running time since delivery
■ History of product
■ Quantity
■ Condition of the products following delivery (integrity)
■ Reason for return
Goods that are returned in the form of single packages from pharmacists must generally be regarded as critical. They should be destroyed for safety
reasons.
Larger quantities sent back by wholesalers who have placed incorrect orders (for example) must be evaluated individually. In these cases, the integrity of
bundled packages is an important criterion, especially in the light of counterfeit drugs.
If a delivery is returned from different climate zones, this must be treated with caution as the stability of the product may have been affected. If there is
any doubt about the quality of a product, it must be destroyed.
If a product is reworked, this must be approved by the head of quality control (see Chapter 11.L Reworking).
Procedure
Segregation or quarantine status should be established for:
■ rejected material and product;
■non-conforming material
■ drug product containers and closures
■ raw materials
■ product
■ material or product pending acceptance
Written procedures describing the handling and disposition of returned products have to be established in order to prevent distribution and use of
quarantined material.
First of all, responsibilities have to be assigned to the departments involved:
■ Receiving/Incoming Department
■ Manufacturing/Production Operations
■ Quality Assurance
■ Quality Control
■ Shipping/Distribution
■ Returned Goods
The written procedure should address the following items:

■ Make sure that all raw materials, components, and products are in quarantine status unless accepted and identified as released for use
■Identify personnel responsible for identifying non-conforming or not yet accepted product in all of the listed departments:
Receiving, Manufacturing, Quality Assurance, Quality Control, Others
■Establish method of status identification
■Tag with a label:
by unit; by container (if units are not practical); Color coded (e.g. Green, Yellow, Red)
■Segregate using physical space:
Covered containers; Movement to off-line area (e.g. segregated bin beside work station, top shelf); Color coded containers
■Quarantine:
Document inventory, location, and status (Paper record, Electronic record via computer); Specify handling and storage conditions (Production
area, Warehouse, Laboratory, Other); Restrict access; Clearly designate the quarantine area with signs; Prevent final product distribution prior to
final QA approval
Documentation
Documentation related to quarantined products may encompass e.g.
■ Non-conformance report: Reason for quarantine status or reject, Quantity, Hold status, pending test results, Disposition decision
■ Quality Control Laboratory: Samples, Test results, Out of specification investigation results
■ Production: Batch production record, In-process samples, Status of rejects or rework
■ Quality Assurance: Record disposition with signatures, dates (Ultimate decision, Executed disposition)
■Material Review Board (MRB): Establish when to elevate to MRB; Document meeting minutes and record quantity; Reason for reject or
quarantine status; Evaluation if the failure is lot specific, product specific, product family specific, applicable to all products; Risk/Hazard medical
assessment, if applicable; Ultimate disposition determination (Use as is, Destroy or scrap in compliance with environmental laws and practices &
Use hazardous waste hauler, if applicable, Rework in accordance with validated process, Research use only (non-animal use, non-human use) ,
Return to vendor, Other)
■Obsolete Material: Identify by inventory control system (Vendor or manufacturer lot number and expiration date, Date placed into inventory, Date
placed into production); Verify if item meets specifications (or not)
The handling of returned product has to be documented with signature and dates. It should be described how the material was received (shipping
conditions), how it was stored, where it was quarantined after being returned and what the ultimate disposition will be.
Figure 11.M-5 Requirements for quarantine
Regulatory requirements for quarantine
3.23; 5.61; 8.14 4.2; 4.6; 4.8; 4.13; 5.13 211.42 (c)
211.80 (d)
11.M.5.6 Special storage areas

Highly-active substances
“Highly active materials or products should be stored in safe and secure areas.” (3.24 EU GMP Guide)
The handling of highly-toxic substances, such as zytostatics or narcotic substances as described, must ensure personnel safety and also avoid possible
interference with the other storage areas and therefore materials and products stored. Special requirements exist, such as those contained in the
narcotics regulation and regulations for hazardous goods.
Printed packaging material
“Printed packaging materials are considered critical to the conformity of the medicinal product and special attention should be paid to the safe and
secure storage of these materials.”(3.25 EU GMP Guide).
Closed storage is recommended. A special intermediate store with air-conditioning may be required to condition the packaging material for the packaging
process (see Chapter 13.B Packaging process).
A written procedure for storage of printed packaging material should be established and address the following aspects:
■ Establish who is responsible for transfer of received printed materials to inventory and to production
■Establish control of labels to prevent mix-up
■ Use spatial requirements
■ Restrict access to labeling: Caged area, Keyed access, other
■ Establish environmental controls for temperature, humidity, other

■ Establish inventory control
Figure 11.M-6 Requirements for special storage areas

Regulatory requirements on highly active substances and printed packaging materials

Highly active substances
3.24 4.9 -
Printed packaging materials
3.25 – 211.42 (b)
211.122 (d)
11.M.6 Storage conditions

11.M.6.1 Temperature and humidity
“Storage areas should be designed or adapted to ensure good storage conditions. In particular, they should be clean and dry and maintained within
acceptable temperature limits. […]“ (3.19 EU GMP Guide).
Starting materials, intermediate products and medicinal products must be stored at suitable temperatures and humidities. Consequently, special storage
areas that guarantee the necessary conditions may have to be available, e.g. cold store or storage areas with tightly-controlled humidity limits.
Stability data or periods of use based on established temperature and humidity ranges normally exist for such stored goods. It is imperative to use these
specifications as the nominal values for storage conditions in order to be able to adopt expiration data from suppliers, for example (see Figure 11.M-7
and Figure 11.M-8). The upper limit of 30 °C specified by Good Storage Practice for exceptional cases must be critically examined in the light of
standard specifications for warehouses. The decision as to which specification should be used to store a material therefore can and must be made with
reference to the storage instructions that are based on the stability data (WHO GSP 4.17, see chapter G.1).
Figure 11.M-7 Pharmacopoeial temperature specifications
European Pharmacopoeia USP
Deep frozen -15 to 0 °C freezed –25 to –10 °C
Refrigerator 0 to +6 °C cold +2 to +8 °C
Cold + 6 °C to +15 °C cool +8 to +15 °C
Room temperature +15 °C to 25 °C –
– controlled room temperature +20 to +25 °C
– warm +30 to +40 °C
Figure 11.M-8 GSP temperature specifications

WHO Good Storage Practice
Normal storage conditions 15 to 25 °C (up to 30°C in exceptional cases)
Defined storage conditions (in accordance with declaration

on container)
Do not store above 30 °C +2 to + 30 °C
Do not store below 8 °C +8 to + 25 °C
Protect from moisture 60% rel. humidity under normal storage conditions; to be handed to the patient in
moisture-tight containers
Protect from light To be handed to the patient in light-proof containers
11.M.6.2 Monitoring
The suitability of a given storage area must be verified. “[…] storage conditions […] should be […] provided, checked and monitored.“ (3.19 EU GMP
Guide). Temperatures and humidities can be monitored permanently using measuring systems with recording functions, e.g. thermohygrometers with
chart recorder functions, or an EDP system. In Figure 11.M-9, the aspects to be considered when using measuring instruments are listed. Ideally,
these should be coupled with an alarm system that indicates when values are outside the specifications or when alert limits have been reached and/or
initiates control steps. For all measuring systems, it is important to define the data acquisition rate. The requirement for the recording interval (in
minutes) depends on the type of product, the storage location and the anticipated speed at which an objective criterion may change. For example,
temperatures are likely to change more slowly in high-bay storage areas than in refrigerators. If measuring instruments with integrated electronic data
storage (data loggers) are used, the evaluation frequency must be defined according to the amount of memory available. The service life of the batteries
is drastically reduced when data loggers with integrated sensors are used at temperatures below 15 °C. This must always be taken into account when
determining the period during which readings are taken. A simple method of compensating for the resistance to heating of storage goods in refrigerators
is to place the sensor in a liquid. It is understood that this must not interfere with the storage goods.
Measuring instruments must be regularly calibrated (WHO GMP 4.17). The data must be stored as secondary documentation.
Figure 11.M-9 Measuring systems
Aspects of measuring systems
■ Data acquisition rate

■ Memory capacity
■ Internal/external sensor
■ Evaluation frequency
■ Alarm signal function
■ Calibration capacity
The number and positioning of the measuring points must be defined within the scope of the room qualification. To do this, it is necessary to compile a
room profile showing the distribution of temperature and humidity within the room and the suitability of the subsequent measuring points in terms of their
representativeness. A simple way to achieve this is to divide the warehouse up according to a coordinate system. The vertical areas under the roof, in the
middle, and directly above the floor, as well as corridors or exit areas with additional air movements should be checked at various horizontal positions.
Seasonal fluctuations must be taken into account, e.g. to record critical temperature increases in the uppermost shelving compartments. According to
WHO GSP (4.18), temperature sensors should be positioned at the points where fluctuations are the greatest. During these investigations, it must be
assumed that the warehouse is full in order to exclude the influence of the room charge due to e.g. altered air flow. As a result of the profile creation
and/or monitoring, the installation of air-conditioning units or the segregation of storage areas with special air-conditioning may be necessary.
It must be established whether the daily average of temperatures should be used as the actual value and compared with the nominal value or whether
individual peak values should be used. If individual values only deviate by a few Kelvin degrees from the average across a 24-hour period, the daily
average can be used for assessment. The same applies for humidity values. One of the tasks of the room qualification is to show this (see Chapter 3.F
Building services).
11.M.6.3 Deviation handling
A procedure must have been established to deal with deviations from the specifications in which information and decision-making paths are defined. For
example, a similar system for the handling of deviations as used in the production area may be used for obtaining information. This has the advantages of
a higher-level system that automatically involves the decision makers in manufacturing, quality control and quality assurance. In straightforward cases,
infringement of the guidelines for the storage conditions leads to rejection of the material by quality control followed by destruction. This is a decision to
be made in each individual case, taking the temperature and moisture sensitivity of the material into account (e.g. insulin suspensions, suppositories or
hard gelatine capsules). Retesting of the material is one way to preserve the usability of high-priced products or materials and must be specified in
individual cases by the head of quality control (see Chapter 14.H Out-of-specification results).
11.M.7 Sanitation and pest control

Storage areas must be clean and dry. Should these criteria be neglected, the diversity of materials then provides conditions that are ideal for the
nourishment of microorganisms, vermin, animals and insects. Storage areas are usually assigned to the hygienic areas F or G as part of the self-
classification (also taking the other ratings into account). As with the production areas, written sanitation programmes that describe the cleaning
procedures and intervals must exist (see Chapter 11.D Sanitation programme). Sources of contamination should be avoided whenever possible.
Contaminated and defective wooden pallets must be replaced by new or clean wooden, plastic or metal pallets prior to storage, for example. The use of
clean wooden pallets in the warehouse is permissible. However, before being brought into weighing areas or production, the containers must be re-
palletted on plastic or metal pallets. Open containers must be avoided without fail in order to protect the material or product and also to prevent
contamination of the environment. Containers opened for sampling must be properly sealed afterwards. Where doubt exists, return deliveries from the
production area are to be cleaned, e.g. by means of aspiration.
In addition to the usual cleaning, storage areas must be subjected to pest control measures. This is necessary as there is a direct connection from
these areas to the environment and deliveries of raw materials may also carry vermin. One preventative measure is to re-pallet the materials prior to
storage, e.g. in tandem with the identity test of individual containers using NIR. During pest control, the type and quantity of the various species can be
defined using species-specific traps (e.g. pheromone traps). Active prevention can also be achieved (e.g. using UV fly killer lamps) at critical locations
such as exit doors leading into the open air.
The type, the number and positioning of the traps for monitoring purposes should be determined by specialists (biologists/zoologists) as knowledge of
individual species is required. This may be achieved through outsourcing to specialists who will provide a map showing the precise locations of the
various traps. This makes the assessment of pest numbers, species and locations possible. These numerical estimations, carried out at regular intervals
(e.g. monthly or quarterly), are subject to evaluation. It is important to specify that the contract giver always has responsibility for this and that delegation
is not possible. The action to be taken in the event that defined limits are exceeded and trends emerge must therefore be determined at the outset within
the scope of the SOPs (4.26 EU GMP Guide). This could for example be the shortening/extending of intervals, changes in the number of traps as well as
structural changes as preventative measures. The highest priority is to prevent the entry of pests.
Monitoring and evaluation may be carried out by authorised functions, e.g. quality assurance. Responsibility for the area of pest control ultimately lies
with the head of production.
Figure 11.M-10 summarizes the above mentioned activities for establishment of pest control.
Figure 11.M-10 Establishment of pest control
Establishment of pest control
Establish responsibilities
■ Of company personnel: Production, Maintenance, Quality, Others
■ Of Contractors: Exterminators, Sanitation or cleaning staff, Others
■Assign responsibility for activities
■ Provide for training pest control personnel in applicable GMP topics: Include contractors who visit unescorted
■ Reporting signs of pest activity
■ Approving method(s) of control to be used: Pesticides, Traps and baits, Frequency, Reports required
■ Reporting kills
■ Recording location of control measures (traps, bait, etc.)
■ Recording pesticide(s) used
■ Related activities
Establish key tasks

■Eliminate conditions that attract vermin
■ External conditions: Trash accumulation, Food sources, Harborage areas
■Internal conditions: Spillage of potential food sources; Water sources; Containers that allow access by vermin; Accumulation of debris; High
humidity/warm areas;Doors/windows open when not in use; Door/window seals not effective; Other potential avenues of ingress
■ Establish pesticide use procedures
■ Determine primary targets (pests)

■ Use only approved agents
■ Clearly label all agents
■ Store according to label directions: Use secured storage area for concentrates and for sprayers/other application tools
■ Mix concentrates as directed in product labeling: Provide controlled area for mixing
■ Follow approved application procedures
■ Establish application schedule
■Determine any special controls needed: Sealing of area; Removal/protection of surfaces and equipment; Quarantine periods for personnel entry
after application; Other factors
■ Determine placement of bait stations and traps: External areas (outdoors); Internal areas; Rodent control; Avian control; Insect control; Other
■ Establish schedule for checking traps and bait stations
■ Establish means of disposal of carcasses when found
■ Establish means of disposal of feces, nesting material, etc.
■Establish records of pesticide/pest control practices

■ Dates of activities
■ Personnel
■ Compounds used
■
■ Signs of activity noted: Carcasses, Feces, urine stains,, Gnawed or penetrated areas, Defiled materials, Other signs
■Take corrective actions: Remove foreign matter; Assess impact on goods (Product, Raw materials, Components, Others): Perform special
cleaning; Repair or modify structures; Reeducate employees
■ Provide for periodic audit of control system
11.M.8 Material Flow

“All materials and products should be stored under the appropriate conditions established by the manufacturer and in an orderly fashion to permit batch
segregation and stock rotation. “ (5.7 EU GMP Guide).
11.M.8.1 Stock rotation
It is convenient to set up a system that makes the selective allocation of starting material and intermediate product batches possible. A similar rule
applies for the delivery of finished product batches for which an identical or like system is recommended considering the need to control their final
destination. It is in the economic interests of the company to use existing quantities of starting materials as efficiently as possible within their period of
use. This is also a reason why the First-expired-first-out principle (FeFo) is generally used as the basic system for stock rotation (4.12 WHO GSP).
There are of course exceptions – if specific starting materials or intermediate products have to be used in particular batches, e.g. to adjust the specific
contents of final products. As to how this system is to be sustained – this is largely dependent on the manner in which the production facility is
managed or the form of EDP organisation used. For a system-controlled application of starting materials, the batch of a material to be used is specified
by the EDP system. These aspects are always critical elements of the validation of the underlying EDP system (see Chapter 9 Computer System
Validation).
11.M.8.2 Reconciliation
The reconciliation of starting materials and products should be carried out regularly (5.14 WHO GSP). Reconciliation has not only a bookkeeping
function, but also provides additional safeguards. At the latest, once a batch has been used up, the book inventory balance and actual balance should be
compared. If deviations occur that cannot be accounted for by possible fluctuations due for example to weighing tolerances or short-shipments by
suppliers, there is a risk of incorrect usage and therefore a production error. Procedures should be defined at the outset to cater for this eventuality.
When a deviation of this kind occurs, a failure investigation report (see Chapter 19.E.4.3 Phase 3a: Failure investigation) must be compiled (5.15 WHO
GSP).
When a system for reconciliation is set up, the steps listed in Figure 11.M-11 have to be followed.
Figure 11.M-11 Aspects to consider for reconciliation
System for reconciliation
Determine what entities must be reconciled
■ Raw material inventories
■ Component and ingredient inventories
■Coded labels and labeling:
Issued, Used, Destroyed, Attached to batch record, Returned
■Label and labeling inventory:
Received, Used, Returned
■ Packaging components with product-specific information
■ Finished product inventory
■ Clinical supplies
Decide frequency of reconciliation activities

Periodically: Each batch:
■ Raw materials inventory ■ Component ingredients
■ Label inventory ■ In-process yields
■Finished product ■ Bulk final products
inventory ■ Labels and Labeling
■ Packaging components (coded)
Define procedure for reconciliation activities

Responsibility for each How discrepancies are to be handled
type of activity
■ To whom alerts are given
■ Who performs activities ■ Procedure to resolve reconciliation discrepancies
■ Who reviews reports ■Follow up actions for Products affected, Lots affected, Identification of root cause of problem, Steps needed to
correct & Steps needed to prevent reoccurrence
How activities are reported
■ Within batch record
■ Separate reports
Set standards for level of accuracy required

Individual unit: Range (e.g., ±X g, or X kg)
■ Labels ■ Raw material inventory
■Primary labeled ■ In-process yields
containers ■ Bulk final product
■ Primary filled containers ■ Packaging components (non-coded, but with product-specific information)
■Finished product
inventory
11.M.8.3 Storage systems

Materials and products that have quarantine status must be separated from others to avoid them being confused with free goods. To this end, a range of
different organisational forms may be applied at the warehouse depending on the type of warehouse management system used.
A simple classic situation is the physical separation of released and not released materials. Separate storage areas should exist and materials should
be identified with status labels (quarantined/released/rejected). The quarantine areas must be labelled and access allowed only for authorised
individuals.
The random location storage system – as it is generally referred to – does not allow for the physical segregation of released and not released goods.
No special storage areas are designated (e.g. inside high-bay warehouse). Available storing positions are either specified by the system (particularly
where automated systems are used) or reported back to the system following manual storage. Status labels are not required (known as indirect
labelling). The status is administered and controlled using the computer-assisted warehouse management system. It is only possible to call up the
storage bay for a specific material or product via the warehouse management system.
Mixed systems that combine the use of status labels with shared storage are possible (see Figure 11.M-12).
Figure 11.M-12 Comparison of storage systems
Storage system Separate areas Status identification
Classic storage systems + +
Random storage systems o o
Mixed system o +
All procedures and organisation forms must be coordinated with the system to guarantee a sufficient level of safety. If, for example, physical labelling of
the release status has been dispensed with, additional checks must then be performed to ensure that a given material is being used correctly – either by
using the EDP system, or by having the checks carried out by personnel. In addition to the release status, it is also imperative to check the expiration
date prior to use. The WHO GSP (5.18) requires that checks for overdue expiration dates are regularly carried out on stock. As soon as the period of
use for a material has expired, it should be blocked automatically by an EDP system. Restricting the availability of the storage bay in the warehouse
management system is an efficient means of preventing the use of a material that has not been released in a random location storage system. This
method ensures that picking orders processed by warehouse personnel or processed automatically will only include released materials or products.
If no EDP-supported control exists, this function could alternatively be carried out via regularly updated lists, with their processing documented by
responsible warehouse staff and reported back to the head of quality control. In order to check any interim storage of starting materials or intermediate
products once they have left a warehouse, it is important to know their respective storage locations (e.g. by making entries specific to the storage
location). Then, when the shelf-life expires, they can be removed on time before the production process starts. It must be ensured that out-of-date or
expired material cannot be dispatched or processed.
Aspects such as release status and period of use must be graded as fully GMP-relevant and critical, and must be taken into account when validating the
warehouse management system.
11.M.9 Process Flow

“The operational sequences at the warehouse should be defined in writing. The type and procedure for storage as well as the flow of goods and
information should be described.” (WHO GSP 5.1).
It is recommended that procedures are provided in the form of checklists and are documented. In this way, the working method is standardised as far as
possible. This is explained using the receipt of goods as an example.
11.M.9.1 Receipt
Receipt has an important control function. “For each delivery, the containers should be checked for integrity of package and seal and for
correspondence between the delivery note and the supplier’s labels.“ (5.27 EU-GMP- Guide).
Only products and materials that meet the quality requirements may be used. An operating procedure should exist that describes how receipts should
be checked for tampering and damage. In every case of damage, checks should be carried out to determine the extent to which the contents have been
affected. The loss of a seal (originality closure) as a result of mechanical loading is certainly likely to increase the scope of subsequent tests but this
does not automatically mean that it will be necessary to destroy the material. Containers that have been extensively damaged should not be accepted
and a damage report should be compiled. The decision as to whether damage should be evaluated must be made by quality control. Procedures must be
defined at the outset. In each case, all distinctive features should be documented – this makes retrospective consideration as well as the evaluation of
suppliers and forwarding agencies possible.
The check of the uniformity of the delivery as well as its conformity with the order and delivery documents is specified in the WHO GSP (5.7-5.9). In
addition to the commercial aspect of this check, it has a safety function. If different batches of a material or product are delivered at the same time, it is
recommended that these are separated, e.g. by re-palletting individual containers, to avoid confusion from the outset.
Usually, the labelling of containers is performed manually upon receipt of materials or products. These labels must be compiled carefully (see Chapter
11.H Identification). Ideally, the number of labels is controlled by the warehouse management system. A freely-selectable, uncontrolled number of labels
is not acceptable. However, if it is only possible to adjust the number of labels manually, it must be ensured that superfluous labels are not destroyed
without documented comment. If the number of containers has been calculated incorrectly, this error will become apparent when the labels are applied. If
there are 7 containers and 8 printed labels, the label with the information “8 of 8” will remain unused; this must be corrected either by changing the
container labels directly or by printing them again. Sometimes the printout cannot be repeated directly as some systems are equipped with safeguards
to prevent misuse. Whatever the case, the reason for any action taken must be provided in writing. Manual initiation of routine reprinting must be avoided
whenever possible.
Records of receipts with information on suppliers, the supplier's batch designation and goods receipt data must all be retained as secondary
documentation. It is possible to keep a receipt log book or to generate a similar list with time references using the warehouse management system.
Figure 11.M-13 shows a checklist for processing a receipt.
Figure 11.M-13 Checklist for goods receipt
Analogous to the receipt procedure, all other goods movements must also be described using operating procedures. The flow of components to and from
production may only be carried out according to written procedures or EDP-controlled processes.
11.M.9.2 Identification
An identification procedure is necessary in order to selectively assign a material or product throughout its life cycle in the warehouse, production, and
dispatch areas. One of the objectives of this is to ensure the traceability of starting materials and finished products. Unambiguous identification is
normally achieved using a combination of different code systems. Material numbers are often used. In doing so, it is recommended that certain
material or product groups (raw materials, packaging materials, in-process materials, finished products etc.) are assigned specific number ranges that
can be easily identified. Furthermore, batch numbers and receipt numbers are also used; the latter are of significance if several different receipts of
starting materials from the same supplier batch exist, and if the batch notation system does not provide any means of identifying their chronological
sequence. In a warehouse management system, a receipt number is not required if the two receipts referred to above contain different batch numbers.
The relationship to the supplier batch is established via the system in order to possibly reduce the scope of the incoming goods examination or testing.
Batch numbers
This code number may take different forms and is generally alphanumeric in character. It may contain different information (see Figure 11.M-14). It must
be ensured that these codes are unique and that repetition is not possible, whether coincidental or intentional. These codes may be generated
automatically by an EDP system or manually via a batch book. There must be a set procedure to follow in every case as defined by an operating
procedure. For the EDP-supported version, a reliability check must be carried out as part of the validation.
Figure 11.M-14 Examples of information contained in batch numbers
Information content of batch numbers
■ Supplier
■ Manufacturing company
■ Receipt
■ Stability
■ Manufacturing data
■ National codes
■ Types of packaging materials (e.g. suitable for tropical conditions)
■ Package sizes
Package sizes
■ Raw material batches
When establishing a coding system, the following aspects should be considered:

■ Use unique / distinctive code: Code combination should not repeat for a minimum of 10 years
■ Simple code: Linked to batch only
■ Complex code format which identifies specifics: product, strength , package size, plant, manufacturing date, shift, equipment or line, other factors
■Traceability: Code on the final marketed container must allow total traceability to all production and laboratory operations and all components and
materials used in the product
■ Code must be clearly marked and in a location on packages which is easy to read
Expiration data
The method of application may vary with the level of container (Immediate container, Shipping container):
■ Ink stamp
■ Sticker label
■ Stenciling
■ Online printer
■ Application to label
■ Application to container
Expiration data must be supported by valid stability data. Stability tests have to be performed in accordance with ICH or FDA guidance, which means
that stability indicating methods are required and the same container-closure system as used for the marketed product has to be applied. The stability
testing plan has to account for all related storage conditions (see Chapter 14.G Stability testing).
When labeling products for reconstitution, the label must provide expiration information for both the un-reconstituted product as well as the product after
reconstitution.
Regarding location/placement of expiration date on package, the requirements of 21 CFR 201.17 have to be fulfilled.
For OTC products there is an exemption [21 CFR 211.137(h)]: No expiration date is required for OTC products which have no dosage limitation and
stability data supports at least 3 years.
11.M.9.3 Dispatch and transport
Products should only be dispatched if a written order exists (WHO GSP 7.4). As is the case with the receipt of goods, dispatch is a critical step during
which misidentification must be avoided. The use of checklists is also recommended here. Ideally, the product will be checked at the picking stage using
a bar code scanner. A second person should check and sign the compilation of a dispatch order.
The type of dispatch container to be used should be precisely defined in the instructions. If the correct container has been chosen, this guarantees that
the product will also be protected if it is dispatched to another climatic zone. The labelling of this dispatch container should at least include the
dispatch date, the name and the address of the recipient as well as the product description (name, dosage form, strength, batch number), the quantity
dispatched and the transport and storage conditions (WHO GSP 7.7).
“The distribution records should be readily available […]“ (8.13 EU GMP Guideline). The dispatch documentation must be stored as secondary
documentation and must be available at short notice.
Particular care should be taken when using dry ice in refrigerating chains. In addition to occupational safety measures, it must be ensured that the
product does not come into contact with dry ice (WHO GSP 7.2) to prevent negative consequences, e.g. localised freezing.
The basic requirement that the quality of the starting materials and the finished product must not be adversely affected also of course applies for the area
outside of production and the warehouse: this means that the same specifications for storage temperature and humidity must also be applied for the
delivery of starting materials. The extent to which variables affect the properties and stability of materials is difficult to calculate (such as temperature
peaks on the loading surface of a heavy goods vehicle). It may therefore be advisable in the case of sensitive and highly-priced materials to request the
inclusion of measuring instruments (data loggers) (see Chapter 11.M.6 Storage conditions) that record the conditions in transit: these may then be
evaluated during the incoming goods inspection. The same applies for finished products and for these it should also be ensured in this case that the
necessary temperature and humidity conditions are complied with during transportation to, for example, central distribution warehouses. For overseas
dispatches, e.g. involving sea crossings that last for several weeks, the use of measuring instruments is particularly advisable as the product may also
pass through different climatic zones during the journey and the resulting fluctuations may be considerable. As a rule, as with the selection of suppliers,
qualified forwarding agents or courier services should be used.
For company-internal transportation, e.g. within production or for exchanges between warehouse and production, it should also be observed that these
should take place as intended. To ensure this, written procedures should exist and be documented accordingly irrespective of the existing degree of
automation.
Summary
The requirements for warehouses arise from the need to prevent negative influences on the quality of the stored products. Storage conditions
(temperature and humidity) therefore depend on the properties of the materials and products. Different storage areas are to be assigned to different
purposes, such as goods receipt, sampling, quarantine, highly-active substances, packaging material store and dispatch.
The head of quality control is responsible for defining the storage conditions and the head of production is responsible for compliance with the
specifications.
The unintentional use of products that have not yet been released or have been rejected must be avoided by means of status labelling and physical
segregation or by using a validated warehouse management system.
Procedures such as the receipt of incoming goods or provision of goods for production purposes must be clearly described and documented. For the
purposes of traceability, the documentation must be stored.
Criteria for dispatch and transport conditions should also be established and monitored.
11.N References
Up16
Regulatory requirements Europe
1. EU: Volume 4 – Medicinal Products for Human and Veterinary Use: Good Manufacturing Practice, Part I – Basic Requirements for Medicinal
Products,
http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol4_en.htm
(see Chapter C EU Directives and Guidelines)
Chapter 5 Production
Annex 1 Manufacture of Sterile Medicinal Products
Annex 2 Manufacture of Biological Medicinal Products for Human Use
Annex 3 Manufacture of Radiopharmaceuticals
Annex 4 Manufacture of Veterinary Medicinal Products other than Immunological Veterinary Medicinal Products
Annex 5 Manufacture of Immunological Veterinary Medicinal Products
Annex 6 Manufacture of Medicinal Gases
Annex 7 Manufacture of Herbal Medicinal Products
Annex 9 Manufacture of Liquids, Creams and Ointments
Annex 10 Manufacture of Pressurised Metered Dose Aerosol Preparations for Inhalation
Annex 14 Manufacture of Products derived from Human Blood or Human Plasma
2. Annex to Note for Guidance on the Manufacture of Finished Dosage Forms (CPMP/QWP/486/95): Start of Shelf-life of the Finished Dosage Form,
3/2002
3. Note for Guidance on Declaration of Storage conditions for medicinal Products (CPMP/QWP/609/96Rev2), 12/2003
4. Guide to Control and Monitoring of Storage and Transportation Temperature Conditions for Medicinal Products and Active Substances, Irish
Medicines Board, Edition IND-003, version 01, 03/2006
Regulatory requirements US
5. FDA, 21 CFR Part 211 CGMP for Finished Pharmaceuticals,
www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart =211&showFR=1 (see Chapter D.1.2)
Subpart E: Control of Components and Drug Product Containers and Closures
Subpart F: Production and Process Controls
Subpart G: Packaging and Labeling Operations
Subpart J: Records and Reports
6. Guide to Inspections of Oral Solid Dosage Forms Pre/Post Approval Issues for Development and Validation, 1994 (see Chapter D.5)
7. Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing – Current Good Manufacturing Practice, 2004 (see Chapter D.10)
8. Guidance for Industry: Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production, 2006 (see Chapter D.9)
9. USP 36 <1116> Microbiological Evaluation of Clean Rooms and Other Controlled Environment
10. USP 36 <1079>: Good Storage and Distribution Practices for Drug Products
11. GMP Interpretation Decision Records (Q&A) September 2003, Health Canada / Health Products and Food Branch Inspectorate
ISPE
12. ISPE, Baseline® Guide Vol. 1 Bulk Pharmaceutical Chemicals, 2nd Edition 2007
ISPE, Baseline® Guide Vol. 2 Oral Solid Dosage Forms, 2nd Edition 2009
ISPE, Baseline® Guide Vol. 3 Sterile Manufacturing Facilities, 2nd Edition 2011
ISPE, Baseline® Guide Vol. 6 Biopharmaceutical Manufacturing Facilities, 2004,
www.ispe.org
PDA
13. Technical Report No. 13 Revised, Fundamentals of an Environmental Monitoring Program. In: PDA Journal of Pharmaceutical Science and
Technology, Supplement TR13, 55, Number 5 (2001)
14. PDA, Technical Report Series, www.pda.org
ICH
15. ICH Q10 Pharmaceutical Quality System, 2008 (see Chapter E.10)
WHO
16. WHO TRS 957 (2010), Annex 5: Good distribution practices for pharmaceutical products (see Chapter G.1.3)
17. WHO TRS 908 (2003), Annex 9: Guide to good storage practices for pharmaceuticals (see Chapter G.1.2)
International Standards
18. DIN EN ISO 14644-1 Cleanroom and associated controlled environments - Part 1: Classification of air cleanliness (ISO 14644-1:1999)
Publications
19. Clibbon C.: Evaluation of the Effectiveness of polymeric flooring. In: European Journal of Parenteral Sciences, 7(1): 13–15, 2002
20. Garment System Considerations for Cleanrooms and Other Controlled Environments, IEST-RP-CC-003.3, Institute of Environmental Sciences
and Technologies, Rolling Medows, USA, 2003
21. Mestrandrea L.: Microbiological Monitoring of Environmental Conditions for Nonsterile Pharmaceutical Manufacturing. In: Pharm. Technol. 58–74,
1997
22. Scorer T., Perkin M., Buckley M.: Weighing in the Pharmaceutical Industry, Measurement Good Practice Guide No. 70. National Physical
Laboratory, June 2004

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2014 GMP MANUAL © Maas & Peither AG

11.B Personnel hygiene

11.B.2 Code of Conduct

11.B.3 Hand disinfection

11.C Production hygiene

11.D Sanitation programme

11.E.5 Investigation areas

11.F GMP in the production process

11.G.3 Weigh-in procedure

11.I In-process control

11.I.2 Organisation and responsibilities

11.I.4 Documentation and evaluation of data

11.J Prevention of cross-contamination

11.J.2 Measures to prevent cross-contamination

11.K Empty Chapter

11.L.3 Rework/Reprocessing of rejected products

11.M Warehouse and logistics

11.M.6 Storage conditions

11.M.7 Sanitation and pest control

11.M.9 Process Flow

Here you will find answers to the following questions:

■ EU-GMP Guide Part I

11.A.1 Organisational prerequisites

■ Definition of the material flow

11.A.2 Sources of contamination

11.A.3 Responsibilities and implementation

Jewellery, avoid avoid avoid avoid also for occupational

* Grade for the production of non-sterile dosage forms, packaging

11.B.1.1 Clothing material

■ Particle release (from the fabric)

■ Sufficient coverage (good fit)

Cut of the clothing

Mouth mask/face mask

Special requirements for clean room clothing:

11.B.1.4 Gowning procedure

11.B.2 Code of Conduct

11.B.2.1 Personal hygiene

■ NO eating, drinking or chewing

Policy on the wearing of jewelry

Policy on smoking or eating in facility

11.B.3 Hand disinfection

■ Wet the hands

11.B.4 Health requirements

Here you will find answers to the following questions:

■ Premises and facilities ■ Size, positioning of machines

Non-aqueous preparations for oral use 103 102 Absence of E. coli

Aqueous preparations for oral use 102 101 Absence of E. coli

Rectal use 103 102 –

Oromuscosal use 102 101 Absence of St. aureus

Vaginal use 102 101 Absence of Ps.

TAMC: Total Aerobic Microbial Count

11.C.1 Sources of contamination

11.C.1.1 Premises and facilities

Purchasing ■ Purchase contract lists component and container/closure requirements;

Production ■ Only use tested and approved components

Laboratories ■ Analyze samples of components

QC Unit ■ Provide oversight,

11.C.1.3 Packaging materials

11.C.1.7 Ambient air

For more information on filters see Chapter 3.G.3 Filters.

Here you will find answers to the following questions:

11.D.1 Organisation of room cleaning

11.D.1.1 Hygienic areas