Printed by: 168305-3 Date: 16.04.

2014 GMP MANUAL © Maas & Peither AG

13 Packaging
13.A Packaging material
13.A.1 Responsibilities
13.A.2 Contents
13.A.3 Materials
13.A.4 Protection against counterfeit medicinal products
13.A.5 Packaging material testing
13.A.5.1 Control tests carried out at the supplier
13.A.5.2 Examples
13.A.5.3 Defect evaluation lists
13.A.5.4 Storage
13.A.5.5 Labelling

13.B Packaging process

13.B.1 Packaging medicinal products
13.B.1.1 Packaging in blisters
13.B.1.2 Packaging in PE or glass bottles
13.B.1.3 Other types of packaging (e.g. tubes)
13.B.1.4 The packaging process

13.B.2 Provision of packaging materials

13.B.3 Line clearance
13.B.4 Line setup and line release
13.B.5 Production and in-process controls
13.B.5.1 Control functions
13.B.5.2 Functional tests
13.B.5.3 Checking (partially) packaged goods
13.B.5.4 Handling samples and rejects
13.B.5.5 Organisation of in-process controls

13.B.6 Labelling
13.B.6.1 Variable data
13.B.6.2 Printing
13.B.6.3 Labels
13.B.6.4 Vignettes

13.B.7 Reconciliation
13.B.8 Completion of a packaging process
13.B.9 Measures to protect against counterfeit medicinal products

13.C Qualification of a servo-controlled blister packaging line

13.C.1 Introduction
13.C.2 Qualification in accordance with GAMP 5
13.C.2.1 Basic risk assessment
13.C.2.2 Requirement specification
13.C.2.3 Supplier audit
13.C.2.4 Functional specification
13.C.2.5 Configuration specification
13.C.2.6 Functional risk assessment
13.C.2.7 Configuration test
13.C.2.8 Functional test
13.C.2.9 Requirements test (user requirements)

13.C.3 Example of a functional risk assessment

13.C.3.1 Blister machine
13.C.3.2 Cartoning machine
13.C.3.3 Checkweigher
13.C.3.4 Control systems (blister and cartoning machine)
13.C.3.5 Supply media
13.C.3.6 Ambient conditions

13.C.4 Example of an FMEA risk analysis (extract)

13.C.5 Example of an IQ qualification plan (extract)
13.C.5.1 IQ-02: Checking the validity of the sealing heater calibration certificate

13.C.6 Example of an OQ qualification plan (extract)

13.C.6.1 OQ-03: Functional test: Insufficient temperature of the sealing heater

13.D References
Printed by: 168305-3 Date: 16.04.2014 GMP MANUAL © Maas & Peither AG
13.A Packaging material
Base Dr. Christian Gausepohl

Here you will find answers to the following questions:

■ What are the requirements of packaging materials tests?
■ How can the expenditure be reduced?
■ What must be taken into consideration when handling packaging materials?

The packaging of an item must realise various functions. It is used to wrap up the product and to protect it against physical and chemical influences on
the product. The aim is to retain the specification defined for the active pharmaceutical ingredient over the period of time that was stipulated.
Furthermore, the packaging contains legally prescribed information for the final customer.
Figure 13.A-1 The function of packaging
The function of packaging

■ To avoid leaks, diffusion or permeation

■ To guarantee the stability of the container when it is handled in the normal manner (pressure, ability of tubes to resist tear)
■ To prevent the ingredients within the packaging from being changed.
■ Protection from light, oxygen, contamination, mechanical damage, humidity.
■ Guaranteeing stability

Packaging material can be divided into primary and secondary materials for functional reasons.
Primary packaging materials come into direct contact with the product and as containers, they protect the product. They include jars (sometimes
dyed for UV absorption) and foil (e.g. for tablets, granulates or suppositories). These materials come into contact with the product and are therefore
subject to specific requirements. The process is described as primary packaging. Secondary packaging materials are added after the primary
packaging to provide extra protection (e.g. folding cartons, paper board containers) and to comply with the legal obligation to identify the contents of the
package (e.g. package inserts, folding cartons, brochures, seals). The process is described as secondary packaging. A further distinction can be made
between unprinted and printed packaging materials. Printed packaging materials contain product- and batch-related data. They include printed foils,
tubes, folding cartons, labels, etc.
The EU Guideline definitions do not count packaging materials as starting materials. However, the same requirements as those for starting materials
should apply when handling the packaging material. “The purchase, handling and control of primary and printed packaging materials shall be accorded
attention similar to that given to starting materials.” (5.40 EU GMP Guideline). This is obvious, because it concerns materials which, as primary
packaging materials, can affect the stability of the product directly and can lead to misidentification if an error is made with the labelling. From a
production point of view, separate stages of handling the packaging materials should be defined, e.g. delivery, storage, allocation and processing.

13.A.1 Responsibilities
The responsibilities for handling packaging materials are clearly regulated (see Figure 13.A-2).
Figure 13.A-2 Responsibilities when handling packaging materials
Responsibilities when handling packaging materials

Sales manager ■ Text contents

Head of Quality Control/qualified Person ■ Conformity with specifications

Head of Production ■ Handling of packaging materials

13.A.2 Contents
The contents of the texts on the packaging materials are defined as follows (Figure 13.A-3, Figure 13.A-4 and Figure 13.A-5). The following tables provide
an overview of the legal requirements. Special cases are not included in this overview.
Figure 13.A-3 Labelling elements
Labelling of bulk

■ Name or company name and address of the pharmaceutical entrepreneur

■ Designation of medicinal product
■ Batch designation “b.des.”, manufacturing date if not possible
■ Expiration date
Figure 13.A-4 General elements of labelling
Labelling of finished medicinal products

■ Name and address of the pharmaceutical company

■ Designation of medicinal product
■ Authorisation number “auth. no.”
■ Batch designation “b.des.”, manufacturing date if not possible
■ Dosage form
■ Content according to weight, room content or number of items
■ Type of application
■Active pharmaceutical components according to type and quantity, further components according to type (if stipulated), parenterals or topical
medicinal products, including ophthalmic products, all components according to type
■For genetically modified medicinal products, the active pharmaceutical ingredient and the designation of the genetically modified micro-organism
used or the cell line
■ Expiration date “use by” (month and year)
■ If applicable “prescription” or “for sale in pharmacies only”
■ For samples “sample”
■ Indication that medicinal products should be stored in a place inaccessible to children
■ Precautions for disposal of the medicinal products if required
■ Storage instructions
■ The species of animal used for production of serums; he host system used for production of viral vaccines
■ For homeopathic medicinal products “homeopathic medicinal product”, “Registration no.”

Figure 13.A-5 General elements of package inserts

Elements of package inserts

■ “User information”
■ Designation of medicinal product
■ Active pharmaceutical ingredients according to type and quantity, further ingredients
■ Dosage form
■ Content according to weight, volume or number of items
■ Material or indication group or action
■ Name or company name and address of the pharmaceutical company and the marketing agent
■ Areas of application
■ Contraindications
■ Precautions if required
■ Interactions
■ Warnings
■ Dosage instructions, length of application
■ Advice in the event of incorrect dosages
■ Side effects with countermeasures
■ Period of use
■ For medicinal products made from human blood plasma for fractioning purposes, display the country of manufacture
■ Date of package insert version
■ Authorisation number “auth. no.”

13.A.3 Materials
The selection of the primary packaging material begins in the early stages of the product development. The selection should take into account functional
aspects, e.g. product-specific factors such as hygroscopicity and light sensitivity needed to attain adequate product stability and possible interactions
(see Figure 13.A-6) and incompatibilities, marketing requirements, e.g. with regard to specific foil colours or formats, and legal requirements such as
childproof features. Ideally, the selection should also take into account technical aspects such as processability in order to achieve the most efficient
packaging process possible. The data determined as part of the stability studies directly relate to the qualities of the primary packaging materials used.
A risk evaluation within the change control process will be required if, at a later stage, primary packaging materials are replaced, e.g. due to a change in
the chemical composition of the sealing lacquer or the thickness of the foil, or due to significant changes in the manufacturing process or to the
replacement of plasteizer in plastic bottles.This can then lead to stability studies (Chapter 14.G Stability testing) and/or variations for product
authorisation.
Figure 13.A-6 Examples of interaction between bulk products and primary packaging materials
Examples of interactions

■ Release of compounds from constituents of the packaging material (e.g. softening agents)
■ Release of visible or sub-visible particles
■ Adsorption of product constituents by the packaging material
■
 ■ Degradation of packaging material constituents in contact with the product
■ Manufacturing process interventions on the container (e.g. sterilisation)
■ Chemical reaction between the product and the packaging material

Given that a large variety of different materials count towards the completeness of the packaging materials used (containers, stoppers, printed packaging
materials, etc.), they make up a non-homogenous group. Very different testing procedures (Figure 13.A-7) are therefore necessary. In addition to the
control tests to check for conformity with legal requirements (pharmacopoeia, data relevant to marketing authorisation, etc.), production-specific
parameters also need to be reviewed. These include, for example, the thermoforming foil shrinkage, dimensional accuracy and precision of the tactile
marks positioning, torsional measurements on tamper-proof closures on bottles, testing the adhesive strength on folding cartons.
Figure 13.A-7 Packaging material groups with typical control tests
(according to Harl)
Packaging materials
groups Test items
A) Primary packaging material
Plastic foils Dimensions, identity (e.g. IR spectrum), abrasion, appearance

Aluminium foils Dimensions, identity (e.g. IR spectrum), texts, appearance

Composite foils Dimensions, identity (e.g. IR spectrum), texts, appearance

Tubing glass Dimensions, light transmittance, wall thickness, filling volume, hydrolytic resistance, breaking load, appearance

Blow-moulded glass Dimensions, light transmittance, wall thickness, filling volume, hydrolytic resistance, appearance

Rubber Dimensions, fragmentation, ash residue, identity (e.g. IR spectrum), purity (chemical-analytical), appearance

Plastic injection-moulded Dimensions, bellows elasticity, dosage volume, metering accuracy, identity (e.g. IR spectrum), breaking resistance of
components yield lines, appearance

Plastic hollow blown Dimensions, filling volume, weight, identity (e.g. IR spectrum), tightness under excess pressure, internal pressure
components resistance, residue drainage capacity, stability of content, imprinting, appearance,

Plastic stoppers Dimensions, identity (e.g. IR spectrum), appearance

Dry capsules Dimensions, microbial count, residual moisture, appearance

Crimping cap Dimensions, sheet thickness, appearance

Other (e.g. tinplate Dimensions, identity (e.g. IR spectrum), printing, fluid thickness, weight, filling volume, appearance
containers, polyethylene
bags)
B) Secondary packaging material
Labels Dimensions, material quality, code testing, printing, abrasion resistance, luminescence, appearance

Package inserts Dimensions, material quality, code testing, printing, luminescence, appearance

Folding cartons Dimensions, material quality, code testing, printing, appearance

Other Dimensions, identity (e.g. IR spectrum), printing, weight, moisture uptake, appearance
(e.g. dry bags, banding foils)

“Outdated or obsolete primary packaging material or printed packaging material should be destroyed and this disposal recorded.” (5.43 EU GMP
Guideline). This means that only the up-to-date, authorised versions should be kept as stock in the warehouse. If packaging material is produced with
changes that are not for legal reasons (e.g. to the colour), the use by dates can be utilised for this. In any case, a mixture of versions should be avoided
(e.g. by using different tube versions in one packaging order). A regular comparison of the current specifications and/or versions with current stocks is
necessary. Due to the different materials handling and stock management systems which exist in the company there are a variety of solutions to
guarantee that the correct versions are used. A specific packaging material, such as a packaging insert, normally has a specific part number which is
then modified for different versions. This makes it possible for a status check (in quarantine, approved, rejected) to also be conducted at this level.

13.A.4 Protection against counterfeit medicinal products

Due to the recent increase in occurrences of counterfeit medicinal products, measures to protect against such falsifications have become necessary. In
addition to organisational measures aimed at preventing misappropriation during the distribution and packaging processes, there are also different
technologies available in the field of packaging materials to protect the originality of the product. Some examples for solid products are listed below (see
Figure 13.A-8).
Figure 13.A-8 Security technologies for packaging of solid products
Examples of security technologies for packaging of solid products

Marking materials ■ Integration into printing

■ Machine detection
■Hidden features
 e.g. magnetic pigments

Printing technologies ■ Micro writing

■ Line screen
■ Data matrix code
■ Hatch markings

Holograms ■ Strip holograms

■ Moving effect
■ Self-verifying hologram
■ Guided holograms

Printing colours ■ Integration in print image

■ Machine detection
■Hidden features
e.g. fluorescent colours

13.A.5 Packaging material testing

13.A.5.1 Control tests carried out at the supplier
A variety of special methods are necessary in the field of primary packaging materials (e.g. elastomers analysis), in order to check that the quality
conforms to the specifications. The time and expense devoted to the equipment and organisation required for these checks can be too much for small
companies. Other systems must therefore be set up to ensure that the duty to conduct these checks is complied with. The acceptance of the primary
packaging material supplier's certificate of analysis is a simple way to reduce the extent of checks needed to the minimum of an identity test. The
precise sequence for this must be specified during the supplier qualification and the contractual delimitation of responsibilities (see Chapter 17
Contractors and Suppliers). The level of quality required can be sufficiently guaranteed if comprehensive control tests are conducted (during current
production and also final inspections). The sampling plan should be drawn up in accordance with the Supplementary EU GMP Guideline for sampling of
starting materials and packaging materials (Figure 13.A-9).
Figure 13.A-9 Aspects of analysis (in accordance with the
Supplementary EU GMP Guideline for sampling of starting
materials and packaging materials)
Aspects of control tests for packaging materials

■ Quantities retained
■ Quality required
■ Type of material (primary/secondary, printed/unprinted)
■ Production method
■ Reviewed knowledge of the supplier's QA system
■ Extent of sampling based on statistics

The control tests carried out when the goods are received at the contract provider shall involve at least an identity test on the packaging material. The
approval will be issued by the head of quality control.
To ensure that the packaging material is not damaged when taking samples upon receipt of the goods, e.g. when removing labels from a roll or when
destroying the seal on bottles, qualified suppliers can send samples taken during the production process together with the packed goods. This has the
advantage of removing the risk of damage and dispensing with the time-consuming sampling that would otherwise be required (repackaging, transports,
etc.). If the supplier takes several samples together following an approved and established sampling plan (one for supplier analysis, one for the contract
provider), the quality evaluations can be directly compared with one another (authenticity of parallel samples). The arrangements made with the supplier
should include specifying the means of transport to be used, so that comparable transport conditions can be obtained for samples and for the delivered
goods (e.g. to avoid the various effects on the thermolabile materials). A simple way to do this is to send the sample together with the goods. To prevent
results from being incorrectly interpreted, both parties will carry out tests in accordance with specifications approved by the contract provider and with
error categories.
The internal testing is normally carried out in the packaging materials laboratory. A variety of testing methods are used here. As part of the stepwise
supplier qualification procedure there are also comparative control tests carried out to evaluate the supplier certificate. The packaging materials
laboratories can be under the organisational control of both the head of production and the head of quality control. The release will always be issued by
the head of quality control.
13.A.5.2 Examples
In addition to complying with pharmacopoeia specifications, the technical requirements must also be reviewed. Examples can be found below.
Package inserts
The dimensions must be checked. The folding on package inserts which have been pre-folded has to be checked. If not, this can lead to huge problems
in the technical handling and also to a loss in productivity. The print quality should also undergo intensive control tests at the printers. The bar code
checks are an important check. In addition to accuracy, the positioning and also the width tolerance of the bar codes are important for the production
process. The luminescence tests in the packaging process must also include suitability testing. In addition, a text analysis can also be necessary.
Since it might be impossible for the laboratory staff to compare texts against an up-to-date master containing a variety of languages and characters,
certain important information (guiding elements) should serve as a test item (e.g. dosages that are also in foreign languages). The ideal solution to this
would be proof reading, in other words, scanning the text and using the computer to compare it with the master. However, this solution is not in operation
everywhere for cost-related reasons.
Labels
In addition to the control tests conducted on the package inserts an adhesiveness test for self-adhesive labels must be included. Holes found in the rolls,
in other words, labels which have become detached from the backing can lead to problems in the production process.
Folding cartons
The legibility of the code found on the folding carton both before and after the carton has been assembled is an important consideration. If the bar code is
placed too close to the break edge, for example, the codes will not be legible later when they arrive at the pharmacy because the unprinted reader zone
is missing. The nature of the folding cartons is a very important consideration from a processability point of view. Fibre orientation and carton
composition, perforation and splice points in addition to the clip functioning and the assembly should be reviewed.
Foils
In addition to the standard control tests (chemical-analytical, physical, visual) process-specific and/or facilities-specific details should also be reviewed.
Behaviour during a thermoforming process, meaning deformation and size increase and/or decreased thickness can be tested using advance
simulations. When specifying tolerances it should be remembered that the combination of different packaging materials (e.g. vials, rubber stoppers,
crimping caps) in the respective limit areas can cause problems in the manufacturing process. This should be considered during development.
13.A.5.3 Defect evaluation lists
When the packaging materials are being inspected upon receipt, representative random samples are taken in so far as this is possible. The sampling is
carried out in accordance with defined and approved sampling plans. The exact sequence and the responsibilities for carrying the sampling out are set
out in the form of organisational instructions. The random sample is evaluated with the help of statistical methods and by classification into defect
categories, according to which the significance of the samples must be critically evaluated, e.g. with regard to their representativeness. There is a
tendency of shifting from random sampling to a 100 % control in the course of the supplier’s packaging materials manufacturing process. However, the
random sample testing has still great importance.
The control tests conducted upon receipt of the goods are carried out with authentic samples (supplier's random sample and/or internal sampling by the
company). Defect definitions and the way that these are classified into categories should be drawn up before evaluation takes place. Acceptable
Quality Limit values (or acceptable quality level) must be specified. These values represent the maximum number of defects that are acceptable
(depending on the size of the random sample). The following table shows that with low AQL values, meaning very strict quality requirements, but with the
same base quantity (e.g. batch size) considerably fewer defects are accepted and/or the number of random samples increases. If the maximum
acceptable number of defects is exceeded, this constitutes an OOS result
The classes of defect with their subdivisions and/or classifications must each be defined individually. This includes summarising categories of over-
critical and critical defect or other subdivisions. Existing defect evaluation lists are frequently adopted for this purpose, e.g. ECV volume: Quality
Assurance of Cosmetic and Pharmaceutical Packaging Material.
Figure 13.A-10 Acceptable quality level in accordance with base
quantity and random sample size for qualitative, non-destructive
testing.
Acceptable quality level
Random
Base quantity sample size 0.1 0.25 0.4 0.6 1.0 2.5

[N] [n] Acceptance number [c]

< 500 80* 1 1 1 1 2 3

501 – 1,200 80 1 1 1 1 2 3

1,201 – 3,200 125 1 1 2 2 3 5

3,201 – 10,000 200 1 1 2 3 4 7

10,001 – 35,000 315 1 2 3 5 6 10

35,001 – 150,000 500 1 3 4 7 9 15

150,001 – 500,000 800 2 4 6 10 1 3 22

> 500,000 1250 3 6 9 14 18 37

*for N < n => N

Figure 13.A-11 Example system for classes of error

Defect
classification AQL values Description Comment

Over-critical defect 0 ■ Endangering human life ■ Packaging material unusable

■ Against legal requirements

Critical defect 0.1–0.65 ■ Changes to the content ■ Packaging material unusable

 Changes to the content Packaging material unusable
■ Endangering the production equipment ■ Complaints from market sources likely

Major defect 1.0–2.5 ■ Likely to cause functional shortcomings ■ Usability gravely damaged
■ Likelihood of consumer complaints ■ Complaints from market sources possible
■ Reduced productivity

Minor defect 4.0–6.5 ■ General reduction in quality ■ Small reduction or no reduction in productivity

A) Over-critical defects
These include defects which endanger human life (such as confusing text errors, lack of sterility) or defects which are against legal requirements (by not
conforming with pharmacopoeia specifications).
B) Critical defects
These include defects where there is a possibility that a patient or consumer could be harmed. They can also result in damage to the production
equipment. These include deformed glass vessels, for example (wedges in the inlet or a leaky closure) or faulty threads on bottles (leaks).
C) Major defects
Major defects are described as such if neither humans nor the product itself is endangered, but the error leads to reduced efficiency during production. A
complaint from market sources is also considered possible. Examples include: Crimping caps with deformations (they cannot be screwed on), folding
cartons which have been pressed down too hard (and cannot be assembled), illegible code marks.
D) Minor defects
These mostly include presentation errors which do not directly affect the quality of the product (e.g. scratches on the surface, slight displacements in
graphic layouts)It is also possible to summarise numbers of single errors within classes of total number of errors. This is a further possibility for a global
evaluation. This can also lead to problems. Changes to the items checked (e.g. by conducting an additional check) increase the likelihood of the material
being rejected. The considered and continuous use of test item-specific AQL values appears to be the more rational method and is equal to a monitoring
system.
The AQL values specified must be re-collected with a view to their use on markets with different quality requirements (e.g. weighing up of minor
presentation defects without damaging the product quality on the Japanese market). Existing error lists and/or categorisation systems are therefore not
transferable without further review and must be critically examined in the individual case.
In principal, a distinction can be made between qualitative control tests whilst retaining the test item and time-consuming, destructive and quantitative
control tests on the other hand. The AQL values for the second group are adapted because the random sample sizes are reduced, or revised downwards.
13.A.5.4 Storage
Packaging materials must be stored under suitable conditions. This means that the quality of the storage rooms must be defined and monitored. The
temperature and humidity should be monitored in order to monitor the retention of these required values. The paper-based packaging materials (package
inserts, folding cartons) are moisture-sensitive.
“Particular attention should be paid to printed materials. They should be stored in adequately secure conditions such as to exclude unauthorised
access.” (5.41 GMP Guideline). This can be achieved in terms of both the rooms and the organisation. The storage can be in segregated storage areas,
which can be achieved by using lockable pallet bays (e.g. inside a grating) or special rooms. In high-bay storage a product can be stored at a great
height and cannot be reached easily (e.g. using a standard ladder). This makes it especially necessary for the warehouse staff using the lifting device to
have authorised access to all the printed packaging materials. This is a possibility for small companies in particular. From the point of view of security,
the use of lockable rooms to which only selected warehouse staff have access is preferable. The aim is to restrict easy access, to only admit defined
people and to control of receipt and delivery packaging materials.
When redeliveries are received from the packaging area, it should be ensured that the packaging material has been sufficiently wrapped (e.g. has each
roll of foil been wrapped, are there any breakages). The redelivery process for partial quantities is only possible for unused quantities of material.
Quantities which contain variable data should be destroyed if possible. If labels, for example, need to be pre-printed, sufficient measures must be taken
to ensure that no cross-mixing or misidentification can take place. This means that in addition to unambiguous labelling, the quantity has also been
sufficiently sealed inside a plastic container, for example. The same requirements as those for the allocation of packaging shall apply to the redelivery
process (see Chapter 13.B Packaging process). The requirement that packaging materials be stacked on pallets must be complied with so that no
damage is caused to the materials.
13.A.5.5 Labelling
“Each delivery or batch of printed or primary packaging material should be given a specific reference number or identification mark.” (5.42 EU GMP
Guideline). This clear obligation to label complies with the requirements for starting materials. Similarly to those requirements, the status checks
(quarantined, released, rejected) can only be conducted physically, e.g. by affixing labels (using different colours as a signal system) or organisationally,
e.g. using a warehouse management system (e.g. by inputting a pallet place number for the requirement) only if the product has the status released.
Each separate container, that is, also each roll of foil must be clearly identifiable (see Chapter 13.B Packaging process).

Summary
The requirements of packaging materials are oriented towards their application. Examples are used to refer to the functional and process-specific
properties.
The delegation of control tests to the packaging material manufacturer is an important means of reducing internal control tests expenditure. In addition,
the possibility of a 100 % control at the supplier is of great importance for quality assurance.
The handling of packaging materials carries high risks due to the danger of cross-contamination and misidentification. Established procedures must be
developed in the areas of storage, labelling and transport among others in order to reduce these risks.
Printed by: 168305-3 Date: 16.04.2014 GMP MANUAL © Maas & Peither AG
13.B Packaging process
Up17 Dr. Christian Gausepohl, Ruven Brandes

Here you will find answers to the following questions:

■ What are the different types of packaging process?
■ What needs to be observed during the provision of packaging materials?
■ What tasks must be carried out prior to the release of the packaging line?
■ What controls must be carried out during the ongoing process?
■ What are the functions of the in-process control?
■ What requirements apply to labelling?
■ How is reconciliation carried out?
■ What measures must be implemented in future to protect against counterfeit medicinal products?

13.B.1 Packaging medicinal products

In the glossary of the EU GMP Guidelines (Chapter C.7), the term packaging is defined as follows: “All operations, including filling and labelling, which a
bulk product has to undergo in order to become a finished product.
Note: Sterile filling would not normally be regarded as part of packaging, the bulk product being the filled, but not finally packaged, primary containers.”
Packaging processes are generally carried out in packaging areas that are physically separate from production, with the exception of on-line packaging.
In these areas, various bulk products are packaged in primary and secondary packaging materials that are frequently different. The differences arise, for
example, from the various packaging sizes or if packaged for different destination countries.
Packaging processes carry a high level of risk due to the large number of factors that can affect quality and safety. The risk factors include the complex
mechanics of the machinery, the range of packaging variants and country-specific designs, the correct application of variable data and the measures
required to protect against counterfeiting.
A fundamental requirement of packaging is to minimise the risk of cross-contamination, mix-up and substitutions (EU GMP Guidelines Part I, Section
5.44, see Chapter C.4.5). This requires, in principle, measures relating to both building structure and organisation (including personnel). The structural
requirements are dealt with in Chapter 3 Premises. The personnel requirements are dealt with in Chapter 2 Personnel.
This chapter focuses mainly on the organisational side of the packaging process and the GMP-relevant aspects of medicinal product safety. A
precondition for a smooth and error-free packaging process is, however, perfect coordination of structural and organisational measures. The better the
structural conditions, the easier it is to organise the entire packaging process. For example, older premises and equipment in an open-plan environment
with very few automatic monitoring devices require greater differentiation in operational organisation and a greater degree of monitoring.
The basic conditions required for packaging are summarised in Figure 13.B-1.
Figure 13.B-1 Basic requirements for packaging
Basic requirements for GMP-compliant packaging

Structural measures Organisational measures

■ Suitable premises ■ Definition of procedures (SOPs)
■ Qualified equipment ■ Assignment of responsibilities
■ Qualified air conditioning and ventilation systems ■ Training of personnel

As already explained, the packaging of bulk product is part of the manufacturing process leading to a proprietary medicinal product. There are different
types of packaging. Figure 13.B-2 provides a basic overview of the different types of packaging.
Figure 13.B-2 Overview of the different types of packaging
Overview of the different types of packaging

Dosage form Example Packaging Labelling

Solid Tablets, Blisters Using folding cartons and preprinted foil (brand name)
dragees,
capsules PE bottles (US market) Using adhesive labels or printed bottles

Powder Pouches/sachets Printed sachets

Screw top jar, Using adhesive labels or printed bottles

PE bottles

Liquid Solutions Glass bottles, Using adhesive labels or printed bottles

(non-sterile) (syrup, drops) drop bottles

Semi-solid Emulsions Glass bottles, Using adhesive labels or printed bottles

plastic bottles

Creams, Tubes (plastic or aluminium) Printed tubes

 Creams, Tubes (plastic or aluminium) Printed tubes
ointments
Tubs, tins or jars with screw tops Using adhesive labels or printed containers

13.B.1.1 Packaging in blisters

Blister packaging is the most widely used type of packaging for tablets, dragees and capsules. It is space-saving, consumer-friendly and economical. Its
greatest advantage, however, is that each single dose can be removed individually in a hygienic way. The packaging can also be made child-resistant by
using special foils and applying cross perforation.
A plastic foil is heated on a deep draw thermoforming machine to make it malleable. The blister cavities are then formed using pressure or vacuum. The
dimensions of the cavities are set to suit the filling product. The tablets or dragees are placed in the cavities using special feeding devices. The filled
blisters then undergo a filling inspection. They are subsequently covered with a printed aluminium foil that is sealed by the application of heat.
Afterwards, the strips are coded (printing of variable data) and punched out. The individual blisters are automatically stacked for further packaging. At the
same time, the folding cartons are coded, controlled (code reader) and stacked in a feed chute. The package leaflets are also controlled and stacked. In
the next step, the blister and package leaflet are placed in the unfolded folding carton which is then closed. The completely filled folding carton (blister
and package leaflet) then moves over a checkweigher. If the folding carton is underweight or overweight, it is ejected.
Other units can be directly connected to the blister packaging line, e.g. batch packaging, heat shrink tunnel and/or cartoner
13.B.1.2 Packaging in PE or glass bottles
When solid, liquid and semi-solid dosage forms are packaged in containers, the filled containers are usually labelled immediately after the filling process.
In the labeller, the batch number, expiry date and security code (e.g. Data Matrix code) are added to the adhesive labels on the carrier strip and
checked. The adhesive label is then transferred from the carrier strip to a label attachment unit. The containers which are round in most cases are moved
to the label attachment unit of the labeller. The labels are then attached to the containers in a rotating movement.
After the label has been attached to the container, the presence of the label on the container is controlled again.
The rest of the process, whereby the labelled primary packages and the package leaflets are packed into folding cartons using cartoning machines, is
practically identical to the method used when packaging blisters. The folding carton is labelled during the cartoning process on the line with a batch
number, expiry date and security code. The package leaflet is identified by a code reader, repeatedly folded automatically and then inserted along with
the package goods into the folding carton which was also previously checked and unfolded automatically. The folding carton is then moved across a
checkweigher where it is checked for completeness.
13.B.1.3 Other types of packaging (e.g. tubes)
Tubes or jars etc. do not have labels attached. The primary packaging is already preprinted. The label is literally already printed on the primary
packaging. Additional packaging in folding cartons with the package leaflet is carried out as described above.

13.B.1.4 The packaging process

Regardless of the type of packaging, the packaging process is carried out as shown in the flowchart in Figure 13.B-4 and described in the following
chapters.
In this example, the production and in-process control groups are assigned different functions. Deviating organisational forms are possible (see also
Chapter 13.B.5.5 Organisation of in-process controls).
The actual status of a packaging line must be made evident at all times by attaching clearly visible labels (see Figure 13.B-3).
Figure 13.B-3 Labelling of packaging lines
Labelling of packaging lines

■ Setup status
■ Cleaning status
■ Production status
■ Specification of product description, batch number, dosage as applicable, packaging size etc.

Figure 13.B-4 Packaging process flowchart

13.B.2 Provision of packaging materials
Packaging materials may only be released by authorised personnel when a written order is produced for specific quantities which correspond to the
specified requirement. Packaging materials must be commissioned using the appropriate bill of materials from the packaging order. This is used to
request certain types and quantities of materials based on the logistical concept in place. Scheduling is carried out by authorised personnel in a defined
provisioning area (close to the packaging area both physically and in organisational terms). The designation and labelling of the defined area/room
should be unambiguous.
Ideally, the material flow of primary and secondary packaging materials should be segregated. Depending on the cleanliness class, different airlocks
must be passed through during transport. Personnel hygienic measures (e.g. clothing/changing, hand washing) is required here in addition to material
conversions, e.g. changing from wooden pallets to pharma pallets (aluminium or plastic), air showers and the use of compressed air to dedust.
When primary packaging is not cleaned immediately before the packaging process, the outer packaging represents a problem. Cannula, stoppers, rolls
of foil etc. are kept in storage in their outer packaging. This outer packaging must be removed while preventing the dust and dirt contaminating the
packaging or the packaging equipment. A number of different extraction systems can be installed in the conversion and/or provisioning area to meet this
need. The double-wrap system can also be used. This involves, for example, placing a roll of foil into a PE bag (e.g. in a drawstring bag for ease of use).
A second bag is needed to keep dust and dirt away during storage. During conversion, these bags are removed in succession.
A single-order picking method should be observed during commissioning. Different orders should not be simultaneously delivered, unless the orders are
placed in interim storage before the actual commissioning and provisioning. The provisioning area must be large enough for its function and capacity to
prevent mix-ups. It may be advisable to use secured pallets in order to prevent confusion and unauthorised access. This can be done using wire mesh
crates or containers. If the spatial conditions permit, special pre-storage rooms can be added to the individual packaging areas.
The delivered goods should be inspected by packaging personnel before they are placed in the packaging area. This involves comparing the quantities
and identities of each container or roll against the bills of materials for the packaging material orders. Loose printed packaging material that is not in a
closed container should be rejected for safety reasons.

13.B.3 Line clearance

The EU GMP Guidelines Part I state in Chapter 5.45: “Before packaging operations are begun, steps should be taken to ensure that the work area,
packaging lines, printing machines and other equipment are clean and free from any products, materials or documents previously used, if these are not
required for the current operation. The line-clearance should be performed according to an appropriate check-list.“
Please refer to Figure 13.B-5 for an example of an appropriate check list.
Figure 13.B-5 Line clearance check list
Batch packaging record for [product]
 Version 03
Company [name] Line clearance for [machine] valid from [date]

Item no.: [number] Batch no.: [number] Order no.: [number]

Date/
Yes No signature
Production status
■ New setup
■ Campaign manufacture

Room
■ Have all pallets been removed from the room?
■ Have all packaging materials been removed?
■ Have all bulk containers been removed?

Product supply
■Have the product retainers been
■ dismantled?
■ cleaned?
■ checked?

Foils
■ Has the foil feed been emptied?
■ Has the waste foil been removed?
■ Waste bin removed and emptied?

Package leaflets
■Has the leaflet feed been
■ dismantled?
■ checked?

■ Has the folding equipment been emptied?

■ Waste bin removed and emptied?

Folding cartons
■Has the folding carton feed been
■ dismantled?
■ checked?

■ Waste bin removed and emptied?

Assembly lines
■ Transfer assembly lines clear?

Belt weigher
■ Has the collecting tank been emptied?

Bundling machine
■ Emptied?

In-process control samples

■ Have all the samples been removed?

Comments

Conclusion Line clearance completed

Line ready for setting up

This control procedure must be defined in properly authorised packaging instructions. This procedure is referred to as line clearance in the GMP
Guidelines Part I Chapter 4.19. Line clearance is a structured procedure for ensuring that the equipment and work area are free of products, documents
and materials from the previous process that are not required for the next scheduled process, and that the equipment is clean and ready for the next
scheduled process.
An important element in the avoidance of cross-contamination, mix-ups and substitutions during packaging is systematic cleaning of the packaging
line. This involves cleaning up remaining bulk product according to the valid cleaning instructions and removal of loose packaging materials belonging to
the previous batch. The cleaning process and subsequent line inspection have to ensure that neither bulk product (e.g. loose tablets, capsules or bottles)
nor packaging materials (e.g. package leaflets, folding cartons or labels) from the previous packaging process find their way into subsequent packaging
processes. The procedure must be clearly defined in an SOP. The SOP must specify when and to what extent the procedure must be carried out. The
machine-specific guidelines must be clearly formulated to exclude the possibility of staff interpreting them incorrectly. The machine-specific critical parts
can be listed in a check list. Product transfers can only be excluded if this SOP is adhered to in detail. Not only the machine itself, but the
surroundings/room where the utensils, remnants and containers are stored, must be assessed in accordance with the SOP. Samples removed during
the packaging process must also be systematically removed. The process description must state who is responsible for carrying out and checking the
individual steps of the cleaning process. For example, production personnel can be responsible for cleaning and dismantling, persons responsible for the
in-process controls (also frequently referred to as line inspectors) can be responsible for controls and release. The completed check list is enclosed in
the batch documentation of the following product as proof of implementation.

13.B.4 Line setup and line release

After a successful line clearance, the line is prepared for the next packaging order. This is often referred to as setting up the line. All the necessary
components of the packaging order (bulk product and packaging materials) must be prepared at the line and all product-specific machine settings carried
out, e.g. temperature, weight and speed. The setup of the line is checked using a setup report in the form of a check list. An example of this type of
setup report is shown in Figure 13.B-6.
Figure 13.B-6 Setup check list
Batch packaging record for [product]

Version 03
Company [name] Setup report for [machine] valid from [date]

Item no.: Order no.:

[number] Batch no.: [number] [number]

Date/
Yes No signature
Production status
■ New setup
■ Campaign manufacture

Cleaning
■ Was cleaning carried out according to the instructions?

Tools
■ Was the equipment installed in accordance with the SOP?

■ SOP no.:

Shaping tools
■ No water leakage?
■ Are the cavities faultless?

Bulk product feed

■ Is the run-off undamaged?
■ Is the foil feed correct?

Level control
■ Correctly set?

Content control
■ Are all tracks displayed correctly?
■ Have incorrect cycles been removed?

Sealing station
■ Is the temperature correct?
■ Capper check correctly displayed?
■Batch number, expiry date set up according to the SOP? (Make a note of the blister numbers, then
compare them with the numbers entered in the packaging instructions.)

Expiry Batch no.

date

1st blister
2nd blister
3rd blister
4th blister

Packaging instruction specifications

■
 ■ Conformity?
■ Can the labelling be read?
■ Blisters without leakage

Punch
■ Push-through packs undamaged?

Lowering device
■ Correctly placed on the assembly line?

Push-through pack
sorting ■ Is it working correctly?

Blow-off station
■ Are the air nozzles set correctly?
■ Is the retaining flap closing properly?
■ Is the overall function OK?

Congestion controls on
the transfer line ■ Set correctly?

Congestion controls on
the stacking shaft ■ Set correctly?

Adhesive point controls

■ Set correctly?

Stacking shaft
■ Is the depth set correctly?
■ Does the target quantity correspond to the order?
■ Is the count correct?
■ Blister undamaged?

Leaflet
■ Folded correctly in accordance with the order?
■ Can the main text be seen on the outside?
■ Overall function correct?
■ Ready for insertion?
■ Insertion correct?

Folding cartons
■ Package size correct?
■ Overall function correct?
■ Optimal embossing of flaps in embossing station?
■ Are the batch number and expiry date in compliance with the manufacturing instructions?
■Read the number and expiry date from the folding carton and note them down as well as the data
in the instruction!

Expiry Batch no.

date

Folding cartons:

Manufacturing instructions specifications:

■ Can the batch number be read?

■ Can the expiry date be read?
■ Are the side flaps folded correctly?
■ Correct closure?

Code reading
■ Code number on the package leaflet?
■Device setting:
■ Is the read function on page 1 correct?
■ Is the read function on page 2 correct?

■ Code number on the folding carton?

■Device setting:
■
 ■ Is the read function correct?

■ Are faulty packages ejected correctly?

■ Is the luminescence control set correctly?

Transfer to
checkweigher ■ Are the folding cartons leaving the machine free of defects?
■ Are faulty packages ejected correctly?

Checkweigher
■ Is the package interval set correctly?
■ Is the weight set correctly?
■ Are packages with missing leaflets ejected properly?
■ Is the blow-off function set correctly?

General
■ Are the time and registration functions set correctly?
■ Are the control sheets prepared?

Comments:

Conclusion
■ Machine setup complete?
■ Functional tests successfully completed?

Initial sample controls are normally carried out after the machine has been set up, meaning that initial samples are checked from each order by
authorised in-process control personnel.
This involves intensive checks on the packaged goods:
■ Packaging print
■ Batch number
■ Expiry date
■ Additional texts
■ Outer appearance of the packaged bulk product
■ Check of dimensions
■ Checking for leaks

If the values do not conform with the specifications, corrective measures can be taken for the machine where permissible or possible. If after start-up of
the line deviations occur that are outside the specified values, they must be addressed within the framework of deviation management (see Chapter 19.E
Deviations).
The samples produced when the machine was set up should be removed before the packaging process is started and separated as rejected goods in the
same way as during the production process.
The actual releaseof the packaging line for implementation of the respective packaging order is carried out after checking that the machine meets the
technical and order-specific requirements. The general release process should be described in detail in an SOP, while machine and product-specific test
items can be processed using check lists. The tested items are documented. The release is documented in the batch packaging report which is part of
the batch documentation. A sample line release report is shown in Figure 13.B-7.
An additional requirement for line release is unambiguous labellingof the packaging line. This is done by clearly displaying the product description,
batch number and order number on the packaging line.
It is advisable to have the release for production carried out by a group of people who do not interact with production staff to prevent cross-contamination,
mix-ups and substitutions. This group can be made up of personnel who conduct the in-process controls, depending on the type of organisational
system.
Figure 13.B-7 Line release check list
Batch packaging record for [product]

Line release by line inspectors Version 03

Company [name] for [machine] valid from [date]

Item no.: Order no.:

[number] Batch no.: [number] [number]

complies Date/
Type of inspection yes/no signature

The line identification labelling complies with the instruction (SOP 7050).

Line clearance has been completed and documented.

The item number and batch number of the bulk products correspond to the picking order.

The item number and batch number of the foils correspond to the picking order.

Content control: Blisters with missing compressions are ejected (SOP 7053).

The blisters are undamaged (SOP 7055).

The blisters are free from deformation (SOP 7055).

Ejection countercheck: all blisters in a cycle are ejected (machine type I).

The blisters are complete, undamaged and printed, the number of tablets complies with the packaging instructions (SOP 7056).

The leak tightness of the blisters in one cycle complies with SOP 7057.

The variable data on the blisters complies with the packaging instructions.

Perforation: Blisters are free from damage and can be easily separated at the perforated seam (SOP 7059).

The codes on package leaflets and folding cartons comply with the packaging instructions.

The code reader for the package leaflets functions correctly (SOP 7060).

Luminescence control functions correctly (SOP 7061).

The code reader for the folding cartons functions correctly (SOP 7062).

The belt weigher functions correctly (SOP 7065).

The variable data on the folding cartons (if applicable, on the labels) complies with the packaging instructions.

Finished packs are complete and undamaged (SOP 7070).

The number of folding cartons per bundle is correct, the folding cartons are undamaged (SOP 7071).

The vignettes are in the correct position (in accordance with the packaging instructions).

The item numbers and batch numbers of all secondary packaging materials comply with the picking order.

Samples of printed packaging materials were removed (SOP 7080).

Release of the packaging line

Release of the packaging line Time:

Date/signature

13.B.5 Production and in-process controls

When the line has been successfully released, the actual packaging process begins. Controls carried out at different levels during this stage ensure the
quality of the finished product:
■ Machine-specific control elements ensure proper control of the manufacturing process (see Chapter 13.B.5.1 Control functions).
■ The function of these control elements must be checked regularly during the packaging process (see Chapter 13.B.5.2 Functional tests).
■In addition, the primary packaged goods and the finished medicinal products are also checked as part of the in-process controls (see Chapter
13.B.5.3 Checking (partially) packaged goods).
All checks are carried out in accordance with the requirements set out in the packaging instructions. They are documented in the batch packaging
record with their results.
The minimum requirements for in-process control tests on the equipment in accordance with the EU GMP Guidelines Part I, Chapter 5.54 are listed in
Figure 13.B-8.
Figure 13.B-8 Requirements for in-process controls during the packaging process
Minimum requirements for in-process control tests on the machine during packaging

■ General appearance of the packages

■ Completeness of packages
■ Use of correct products and packaging materials
■ Printing accuracy
■ Error-free operation of the monitoring devices on the machine

The different tests are normally scheduled, i.e. during the continuous packaging process, tests are carried out and/or samples taken at regular time
intervals. Exact specifications for the frequency, the type of documentation and the responsibility for the individual tests must be defined as part of the
process organisation. This is normally documented in an SOP. When defining the frequencies, the tolerances must also be specified, e.g. every 120
minutes ±15 minutes. This ensures the continuous operation of the machine as well as the availability of personnel. Figure 13.B-9 shows the “In-process
controls” section of a packaging report.
Figure 13.B-9 Example of documentation of in-process control tests
Batch packaging record for [product]

In-process controls: Version 04

Machine: [name] Line inspectors Valid from [date]

Item no.: [no.] Batch no.: [no.] Order no.: [no.]

Test interval: 60 min ±15 min

Test quantity: 5 proprietary medicinal products + 1 seal cycle

Date

Time

Test items complies complies complies complies complies complies complies complies

Vignette positioned correctly Yes Yes Yes Yes Yes Yes Yes Yes

Perforation correct Yes Yes Yes Yes Yes Yes Yes Yes
(SOP 7059)

Bundling correct Yes Yes Yes Yes Yes Yes Yes Yes

Dispatch label positioned correctly, variable data correct Yes Yes Yes Yes Yes Yes Yes Yes

Variable data on folding carton correct and legible Yes Yes Yes Yes Yes Yes Yes Yes

Package leaflet available and undamaged Yes Yes Yes Yes Yes Yes Yes Yes

Blisters undamaged Yes Yes Yes Yes Yes Yes Yes Yes

Variable data on blisters correct and legible Yes Yes Yes Yes Yes Yes Yes Yes

Foil run correct Yes Yes Yes Yes Yes Yes Yes Yes

Blister filling correct Yes Yes Yes Yes Yes Yes Yes Yes

Cavity design correct Yes Yes Yes Yes Yes Yes Yes Yes

Folding carton code reader function correct* Yes – Yes – Yes – Yes –

Package leaflet code reader function correct* Yes – Yes – Yes – Yes –

Luminescence controls correct* Yes – Yes – Yes – Yes –

Deformation ejection controls correct* Yes – Yes – Yes – Yes –

Belt weigher function correct* Yes – Yes – Yes – Yes –

Bundling machine function correct* Yes – Yes – Yes – Yes –

Blister leak tightness complies with* (SOP 7057) Yes – Yes – Yes – Yes –

Checked by/signature

Comments: * Control tests every 120 minutes ±15 min.

13.B.5.1 Control functions

The possibilities for machine-assisted monitoring systems are being constantly increased by technical development. An increase in the speed of the
production process leads to a rise in the requirements placed on the technical control functions. These functions can guarantee the quality of the final
product. A series of optoelectronic control elements such as filling controls, checkweighers, code readers, thermometers, counter units, various
inspection systems etc. are used. These make use of regulation systems (e.g. thermometers), data collecting systems (counters) and also sorting
functions (checkweighers with ejector devices). The control functions must be qualified and calibrated when they are used. Their functionality for critical
elements must be checked during production (functional test).
Filling controls
Filling controls play an important role with regard to GMP compliance and productivity. They are used to monitor the correct filling of the primary
container (e.g. blister cavities) during the actual process. Depending on the technical equipment, presence testing (bulk product available?) and also
qualitative evaluations (bulk product within the tolerances?) can be carried out.
The functionality of these optoelectronic systems is checked as part during qualification and production preparation using the packaging materials and
bulk products. Different parameters can be monitored. Blister packaging lines, for example, are generally checked for double fillings, orientation errors,
fragments or patches. A black and white system is adequate for this function.
More complex systems (colour systems) also make it possible to monitor colour deviations (e.g. differential measurement of colour type, saturation,
intensity) and geometric parameters (differential measurements of surfaces and shape differences.
Error tolerances must be defined. This can lead to a reduction in the number of rejects and production preparation time. This reduction can be achieved
using a knowledge database for general information, e.g. blister segmentation using different cavity diameters, and also using product-related data.
Code reader
Code readers are used at various stages of the packaging process. The packaging materials are checked because the risk of a mix-up and/or the
subsequent risk to the consumer is especially high. These include the package leaflets, the folding cartons and the labels. Different types of barcodes
are used. The tendency is towards increasingly smaller codes, e.g. 2D bar codes which have proven to be very safe due to their high redundancy. They
also offer greater capacity. Systems for monitoring coloured ampoule rings or flip-off coloured caps can also be included in the above. By networking the
central processing units (e.g. line PCs), a simple and safe changeover to the product-dependent packaging material can be carried out. At the same
time, the control activities of the connected code reader can be checked, recorded and stored.
Inspection systems
The function of the inspection systems is to remove defective products before and during the packaging process. They include inspection systems for
detecting suspended solids in solutions, e.g. in injection fluids and liquids.
These devices are generally comprised of the following elements:
■ Sensor
■ Illumination
■ Imaging technology
■ Camera
■ Computer unit
■ Operating and monitor unit

These inspection systems can be used for standard applications such as:
■ Measurement
■ Presence monitoring
■ Completeness control
■ Orientation and position detection
■ Reading of bar and surface code
■ Character recognition

In addition, application-specific inspection systems have been developed and are now widely used:
■ OCR barcode and plain text scanning
■ Surface inspection
■ Colour control
■ Complex image analysis

Both standard and special applications are important when monitoring intermediate and final packaging.
Alongside the actual task and individual components of the inspection system, system integration is also important; i.e. the installation and operation of
inspection systems in the packaging machine. The demands placed on the qualification of these types of systems are extreme.
13.B.5.2 Functional tests
The functionality of the monitoring functions in use must be tested on a regular basis. The intervals between testing must be defined in terms of machine
and product. In addition to maintenance factors and calibration checks, the frequency of the tests must be specified in the packaging instructions and
documented accordingly.
The example of the cartoning machine (after tubes have been filled) illustrates the relationship between control elements, tests and quality attributes (see
Figure 13.B-10).
Figure 13.B-10 Control elements, tests and quality attributes of a cartoning machine (Glamann)
Quality-related
Quality attributes components Quality controls Tests

Completeness of packages ■ Feeds ■ Product enquiries ■ Enquiries functional test

■ Insertion component ■ Code checks ■ Code reader functional test
■ Folding device ■ Checkweigher ■ Checkweigher functional test
■ Tube geometry
■ Tube quality
■ Quality of packaging material

Accuracy of packaging materials ■ Logistics ■ Code checks ■ Code reader functional test
 ■ Supplier

Closure of packs ■ Closure ■ Length measurements ■ Length measurement functional test

■ Quality of packaging material
■ Folding carton geometry

Condition of packaging ■ Machine ■ undamaged ■ visual

■ clean

Correct printed data ■ Logistics ■ visual

■ Data entry
■ Print setup

Ideally, simple and pragmatic solutions should be established for the functional tests to be carried out.
A functional test for code readers can be carried out using a folding carton or package leaflet that is labelled “incorrectly” (e.g. by adding a further bar to
the bar code with a felt-tip pen). An error message should appear on the display panel of the code reader. This also checks the functionality of the
ejector. The ejection control mechanism can be tested by removing the test item before it is ejected. The test item should be marked in a way that
makes it easy to recognise to prevent an accidental mix-up. This can be done, for example, by colouring the edges of the item to ensure that it can be
identified in the feed.
The packaging is usually labelled using a so-called Data Matrix code (2D code). The data of a Data Matrix code is arranged in a very compact way in a
square or rectangular pattern consisting of dots (see Figure 13.B-11). The Data Matrix code contains redundant data so that up to 25% of errors that
may occur can be automatically corrected. This code does not consist of a sequence of bars with different widths as in the case of 1D barcodes. The
layout of dots within the boundary of the matrix and in the matrix grid is scanned. The main advantage compared to the 1D code is that more information
can be placed in a small area. It makes no difference if data or symbols are used. If a Data Matrix code is used, it must be regularly checked. The
quality parameters stipulated in the ISO/IEC 15415 standard are a reliable resource when defining quality acceptance criteria. The methods for
measuring, assessing and classifying 2D symbol features that are used to evaluate the printing quality are specified in the standard. The standard can
also be used to locate possible causes for a reduced printing quality. Error-free readability of these barcodes and symbols is extremely important for
clear identification. A Data Matrix testing device is required for checking if a code is correct or incorrect. Appropriate reading devices for the quality
parameters are now integrated into the camera inspection systems.
Figure 13.B-11 Example of a Data Matrix code

The in-process inspection of belt weighers can be carried out using marked packages of reduced weight. One possibility is to remove the package leaflet
or reduce the filling quantity (e.g. by removing one effervescent tablet from the tube or by removing a blister strip). A check for overfilling is not necessary
with regard to medicinal product safety (exception: filling pressure), but can help detect errors during the filling process. The primary objective of the
check is to monitor the function of the belt weigher; however, the ejector function in combination with the scale is simultaneously checked.
13.B.5.3 Checking (partially) packaged goods
Packaged or partially packaged goods are checked while the machine is running. In addition to specific checks related to the dosage form, e.g. leak
tests on blisters, defect evaluation lists (AQL lists) are used that are similar to those used during the packaging material checks (see Chapter
13.A.5.3 Defect evaluation lists). The defect evaluation lists contain the number of random samples required depending on the size of a particular order.
The types of defect are defined for the individual dosage forms.
An example of a defect classification system for effervescent tablets (filled into tubes) is shown in Figure 13.B-12.
Figure 13.B-12 Defect classes and types for the filling
process for effervescent tablets
Defect class Defect type

over-critical ■ Wrong packaging material

■ Disintegration time OOS
■ Product destroyed

Critical ■ Batch number is missing or illegible

■ Expiry date is missing or illegible
■ Stoppers without drying agents
■ Drying agent not active

Major defect ■ Tube is damaged

■ Tube is not sealed correctly
 ■ The printed text is very difficult to read
■ Filling quantity not correct
■ Effervescent tablets are damaged
■ Batch number only moderately legible
■ Expiration date moderately legible

Minor defect ■ Small stains found on the tube

These classifications must be applied in accordance with company specifications for each dosage form. They must be based on both the legal
specifications and the company quality agreements, that is, the legal minimum requirements must be considered as the absolute minimum threshold.
Many of the defects found during visual inspections rely heavily on interpretation. The difference between “not legible” and “moderately legible”, for
example, depends on the individual interpretation of the persons carrying out the checks. In order to make the evaluation of different features and the
degree of personal interpretation as objective as possible, it is advisable to list examples for the different categories - if possible of defects that are only
just acceptable and errors that are not acceptable. The use of digital images of appropriate samples has many advantages. These “standards” can be
used on different packaging lines or factories and also for training purposes at different locations.
13.B.5.4 Handling samples and rejects
“Products which have been involved in an unusual event should only be reintroduced into the process after special inspection, investigation and approval
by authorised personnel. Detailed record should be kept of this operation.” (EU GMP Guidelines, Part I, Chapter 5.55).
For this reason, packaging materials and finished products which are removed during control tests must not be added to the regular goods except in
cases of control test unit errors. However, this is GMP-critical and must be documented in detail. To ensure that rejects are not reintroduced into the
process, collection containers should be used that cannot be accessed manually. These containers are opened during reconciliation at the latest.
Furthermore, goods that were removed during in-process controls should not be added directly to the accepted goods. During the line clearance
inspection, it must be ensured that samples of previous products taken during IPC have been removed. This is especially important for partially-packaged
goods such as ampoules, tubes and blisters that have to undergo further packaging.
13.B.5.5 Organisation of in-process controls
Various organisational systems are used for in-process control during the packaging process. One possibility is the assignment of functions and
responsibilities to different groups, as shown in Figure 13.B-13. This involves functional tests and routine checks being carried out by production staff
during the actual production process. A start-up control, i.e. a detailed check of the first goods produced for the order as well as the line release is
carried out by a group which reports directly to either the quality control manager or QA to ensure that an independent decision is reached. These
groups, also referred to as line inspectors or monitors (depending on company terminology), can also carry out tests throughout the packaging process,
including functional tests. The responsibilities for the various tests must be clearly specified in each instance to avoid misunderstanding.
An example is shown in Figure 13.B-13.
Figure 13.B-13 Organisation of in-process controls
Responsibilities during in-process controls

Production personnel ■ Operational tests and routine process controls

Line inspectors ■ Release for production, tests on (partially) packaged goods

13.B.6 Labelling
13.B.6.1 Variable data
The batch number and expiration date are referred to as variable data. This data is normally added directly to the respective packaging material as
secondary print during the packaging process. Additional company-related information which sometimes needs to be added as secondary print includes
pricing details, doctors' sample details and warnings. Particular care should be taken when handling pre-printed materials.
Different techniques for applyingvariable data to the product are shown in Figure 13.B-14.
Figure 13.B-14 Variable data application techniques
Labelling techniques

Stamping equipment ■ Stamp printing mechanism

■ Roller printers

Embossing units ■ Without colour

■ Colour-embossing units
■ Heat-embossing units
■ Tampo printing process

Non-contact systems ■ One-jet systems (inkjet printers)

 ■ Multi-jet systems
■ Thermal transfer printers
■ Laser labelling
■ Piezo-electric pulse method

Variable data must meet the following requirements with regard to readability, accuracy and durability.
Readability
Embossing products without using colour is not an ideal solution. It is still used for blister strips and tubes. The use of colour for folding cartons is a
better option. The data should be added in a legible font so that a person with normal vision can read it without a visual aid. The font characters must be
of a sufficient size and there must be a strong contrast with the background colour. A font size of 2 mm (size 8 font) is considered adequate. Guidelines
on font size can also be found in the respective national finished packaging regulations.
Accuracy
The accuracy of the data must be checked before and during the production process. These checks are normally carried out and recorded during the in-
process controls. Visual inspection is still important when the labelling on a product is checked. Automatic detection of the labelling for purposes of
identification is only possible if OCR fonts (plain text/machine-readable) or code symbols (laser-printed) are used. The read result is compared with the
reference symbols that are entered for batches at the beginning of production. If the two results match, the item (e.g. label) is released. Different formats
or fonts should ideally be managed.
Typical functions of plain text control systems are shown in Figure 13.B-15.
Figure 13.B-15 Typical functions of plain text control
systems
Typical functions of plain text control systems

Control of ■ Batch number

■ Expiry date
■ Identification number
■ Proof of origin, etc.

Control objects ■ Tubes

■ Tins
■ Folding cartons
■ Vignettes
■ Labels
■ Package leaflets, etc.

Fault detection in characters ■ Mix-ups

■ Merging or absent
■ Smudging
■ Erosion

Durability
The labelling is acceptable if it is legible and not easily smudged, removed or changed. This normally means that it must be printed. Self-adhesive labels
may only be used if they cannot be removed without causing damage to the surface below.
13.B.6.2 Printing
In addition to printing variable data, complete printing of clichés is possible as well as complete digital printing. A real benefit here is that only unprinted
packaging material is needed. The storage space used for materials decreases provided that the raw foils can be used universally for most of the product
portfolio (identical formats and materials). This means that less obsolete packaging material needs to be destroyed and less waste is produced
(production on demand).
The time taken to equip and convert the equipment for on-line designs can be reduced (print and apply technologies). The printing devices must satisfy
the product requirements, e.g. package leaflets, meaning they must be comparable with those for the packaging materials supplier. It must be ensured
during qualification that a code number (e.g. order number or item number) is correctly assigned to the printed result.
If digital printing systems are used, i.e. the print data and images are generated directly from a file, there are specific requirements for the qualification
and the safeguard of processes and data paths. The time and the person responsible for the print release as well as the use of the print data must be
clearly specified.
13.B.6.3 Labels
If the bulk product is not packaged in blisters, but in other primary containers such as PE or glass bottles, these containers must be labelled after filling
and sealing.
The EU GMP Guidelines state: “Normally, filling and sealing should be followed as quickly as possible by labelling. If it is not the case, appropriate
procedures should be applied to ensure that no mix-ups or mislabelling can occur.“ (EU GMP Guidelines Part I, Chapter 5.49).
All unlabelled containers must be temporarily stored in sealed containers. Great care must be taken when labelling these containers. Before the
containers are introduced into the labelling process, the labels on the outside of the containers as well as the identity of the packaged contents are
visually inspected.
“Special care should be taken when using cut-labels and when over-printing is carried out off-line. Roll-feed labels are normally preferable to cut-labels,
in helping to avoid mix-ups.” (EU GMP Guidelines Part I, Chapter 5.51)
Cut-labels should always be seen as carrying an increased risk. They must be stored and transported in sealed containers.

13.B.6.4 Vignettes
In special cases, vignettes containing pricing information for specific countries, for example, can be attached to the containers. Some of these vignettes
(e.g. Bollini) are consecutively numbered and can be attached to individual folding cartons. The individual vignettes are scanned and automatically
assigned to the relevant bundle prior to banding. After bundling, a bundle label containing the information from the individual vignettes is added.
It must be ensured that unlabelled packages or cut-labels are removed, or at least not added to the undamaged goods in the event of a machine
stoppage. Depending on the degree of automation, measures such as emptying the line using a check list or optoelectronic sensors with ejection
devices are used.

13.B.7 Reconciliation
The EU GMP Guidelines stipulate in Part I, Chapter 4.21(h) that the quantities of all packaging materials and bulk product issued, used, destroyed or
returned to stock and the quantities of obtained product must be documented to provide for a concluding reconciliation.
As was the case during the production stages of the bulk product, the yield must be checked to ensure that it is within the permitted tolerances. The
additional packaging materials supplied are also reconciled so the number of transfer errors can be estimated. The requirement to record the exact
number of packaging components can only be met with great difficulty when the declared quantity is used as a basis, because the underdelivery and
overdelivery of packaging materials by the supplier is not unusual.
The quantity can be determined in one of the following ways:
■Paper and cardboard (folding cartons, labels, package leaflets):
Weighing the paper or cardboard products gives an approximate value with an error tolerance of at least 1% depending on the conditions during
storage. The use of counters for labels and package leaflets, for example makes it possible to compare the actual number used with the yields.
■Rolled and bundled goods (foils, labels on rolls):
In the case of rolled and bundled goods, a reconciliation of the packaging materials as a retrospective evaluation of the packaging process only
gives an approximate result. The possibility of determining the exact amount using a rolling process with a counting unit represents a relatively
critical procedure which can lead to a change in the subsequent rolling behaviour during the actual packaging process.
■Piece goods (bottles, tubes):
Piece goods can, on the other hand, be easily reconciled (e.g. by counting or weighing).

The results must be documented in the batch documentation (for an example, see Figure 13.B-16).
Figure 13.B-16 Example of packaging materials reconciliation
Batch packaging record for [product]

Version 03
Company [name] Packaging materials reconciliation [machine] Valid from [date]

Item no.: Order no.:

[number] Batch no.: [number] [number]
Yield
Package yield Number of full cartons/contents (e.g. 40 per 360 Number of packages in overflow carton (e.g. 1 to 39 Date/
packages) packages) signature

Detection of waste during Folding cartons User information Aluminium foil Labels Date/
packaging signature

Tally sheet

Total quantity

Packaging material Supply quantity Consumption undamaged product* Waste Return delivery quantity Yield Date/
signature

Folding cartons

User information

Aluminium foil

Brochures

Labels

Printed tubes, etc.

Dispatch labels
* Package yields, + total quantity of samples

Deviations outside of the tolerances must be explained:

Up to 5,000 packaging units 85 to 115%

5,001–100,000 packaging units 92.5 to 107.5%
From 100,001 packaging units 95 to 105%
Comments:
The results of the reconciliation comply with the specifications (SOP 7089) yes □ Date/signature
no □

The yields (in %) must be documented with the permitted tolerances. These tolerances are determined within each individual company. Deviations
outside the tolerances must be assessed as part of deviation management. The product is blocked until the exact cause of the deviation has been
determined.
Shortfalls that are detected during reconciliation can be caused by underlying conditions that are not optimal, e.g. unfavourable material routes, lack of
training, losses when setting up etc.
The aim must be to determine the cause(s) of the shortfall(s) and implement appropriate corrective measures to prevent reoccurrence and minimise or
prevent the risk of cross-contamination and mix-ups.

13.B.8 Completion of a packaging process

When a packaging process has been completed, the batch-related printed packaging materials (e.g. labels) are destroyed following reconciliation. This
must be documented. Non batch-related printed packaging materials can be returned to the warehouse or to the packaging materials store (see EU
GMP Guidelines Part I, Chapter 5.57).
These processes must be clearly defined in an SOP. The SOP should state clearly which packaging materials are to be destroyed and which packaging
material is to be returned. In addition, the SOP should specify the return procedure including labelling, packaging, declared quantities and documentation
in the system.

13.B.9 Measures to protect against counterfeit medicinal products

To protect against counterfeit medicinal products, organisational factors must be taken into account along with the possibilities offered by packaging
technology. In addition to the customary measures such as rules governing access to approved, rejected or expired bulk products and packaged
products, a monitored and documented disposal of production waste and the corresponding reconciliation are also important. The pharmaceutical
company is responsible for ensuring that the waste disposal company carries out disposal of the waste properly and professionally, i.e. by qualification
of the waste disposal company (e.g. by audit).
On June 8, 2011 Directive 2011/62/EU of the European Parliament and of the Council was passed amending Directive 2001/83/EC on the Community
code relating to medicinal products for human use, as regards the prevention of the entry into the legal supply chain of falsified medicinal products (the
so-called “falsified medicines directive”)1.
This Directive contains a new stipulation for the manufacturers of medicinal products with regards to the packaging process, the obligatory affixing of
safety features to the packaging.
The affected medicinal product must have unique identification features and an anti-tampering feature affixed directly to the packaging. This Directive
must be transposed into national law by 2013.
The EU Commission still has to provide detailed information on the stipulated safety features. Labelling that has so-called “safety features” is currently
being discussed. These include:
■ Serialised number or seal
■Data Matrix code (still being discussed) if necessary with
■ Item or production number (Global Trade Item Number)
■ PZN (centralized pharmaceutical product number)
■ Individual random number
■ Expiry date
■ Batch number

The purpose of these safety features is the verification of the medicinal product's authenticity and the identification of individual packages. The exact
details of the features listed above as well as the regulations stipulating which prescription medicinal products and non-prescription medicinal products
will be affected by the Directive are still being discussed at this time. Medicinal products which require a prescription are generally going to carry these
features.

Summary
Due to the increase in the level of automation, flexibility and safety requirements, there are stricter requirements for excellent processability of the
packaging materials and specification-compliant packaging of the medicinal product. Every interruption of the packaging process means a loss of
processing time and a considerable quality risk with regard to the danger of mix-ups.
Along with the accurate machinability of packaging materials, the pharmaceutical quality of the overall packaging process of a medicinal product is of
central importance. The machinability of the packaging material can be ensured using established defect evaluation lists during quality control.
Appropriate checks of the packaging process are stipulated in the EU GMP Guidelines to ensure the safety of the process quality. These checks are
based on specifications that affect line-clearance, system release and reconciliation at the end of a packaging process.
In order to monitor quality, the persons responsible for carrying out the initial checks of a packaging process must be specified. These persons should
be independent of the Production department. Production personnel can carry out controls during the ongoing packaging process. Monitoring of the
applied variable data (e.g. on blisters, labels and folding cartons) is very important and must be carried out automatically.
To guarantee the safety of the medicinal product and protect against counterfeits, “safety features” are being introduced.

1 Off. Journal of the EU from 01.07.2011, L174/74

Printed by: 168305-3 Date: 16.04.2014 GMP MANUAL © Maas & Peither AG
13.C Qualification of a servo-controlled blister packaging line
Up17 Rainer Röcker

Here you will find answers to the following questions:

■ Which regulatory requirements must be observed during the qualification of a packaging line?
■ How can the qualification be carried out in accordance with the V-Model described in GAMP 5?
■ How is the functional risk analysis carried out and what are the critical aspects that have to be evaluated?

13.C.1 Introduction
Blister packaging is now widely used in the European pharmaceutical world on account of its many advantages. These include, for example:
■ Protection against mix-up
■ Protection against moisture and mechanical damage
■ Protection against microbial and particulate contamination
■ Application of variable data, including data for tracking and tracing
■ Childproofing is possible

The blisters normally serve as primary packaging for tablets and capsules. In addition, blisters are also used as secondary packaging for syringes,
ampoules, vials and inhalers.
Blisters consist of a deep drawn foil and a covering foil. The materials used for the deep drawn foils include PVC, PVDC, PET and aluminium. Each
material is suitable for a specific application. For example, aluminium foil is a good moisture barrier and protects the product against light. Aluminium foil
with a sealing layer is normally used for the covering foil. Paper foil can also be used for syringes. In this case, the blister packaging does not have to
pass a blue dye test because it is being used as secondary packaging.
25 years ago, blister packaging processes were still very easy to manage. Most of the process actions were of a purely mechanical nature and were still
controlled using relays and electronic components. The current situation is somewhat different.
Industrial PCs combined with programmable logic controllers, controllers for servo drives, camera and printing systems, electronic recording and
signatures and, last but not least, track & trace mean that the blister packaging process is becoming more and more complex. At the present time, the
protection of medicinal products against counterfeiting is presenting the world of packaging with a number of new challenges.
The qualification of this type of equipment is, as a result, quite complex. A proper strategy based on a validation master plan is vital for the success of a
qualification, especially with regard to cost effectiveness and compliance.
The most important regulations and guidelines that must be observed during qualification are shown in Figure 13.C-1.
Figure 13.C-1 Qualification regulations
Qualification regulations

EU GMP Guidelines Annex 11 Computerised Systems (Chapter C.6.11)

EU GMP Guidelines Annex 15 Qualification and Validation (Chapter C.6.15)

EU GMP Guidelines Part III, Quality Risk Management (ICH Q9) (Chapter C.8.2)

21 CFR Part 11 (Chapter D.1.3)

GAMP 5

These machines and the automation systems can be qualified in a cost-effective and compliant manner when the risk-based approach described in ICH
Q9 is used. The latest GAMP 5 also describes a risk-based approach with significant supplier involvement that focuses on the following features:
■ Data integrity
■ Product safety
■ Patient safety

To organise qualification tasks in a cost-effective way, a GMP risk analysis should be carried out and the GAMP 5 software categories to which the
individual systems are assigned must be defined in advance (see Figure 13.C-2). This also affects the supplier evaluation and can be a decisive factor in
deciding if an on-site audit is required.
Figure 13.C-2 Software categories
according to GAMP 5
GAMP 5 software categories

Category 1 Infrastructure software

Category 2 Not used (from GAMP 4)

Category 3 Non-configurable software

Category 4 Configured software

Category 5 Customer-specific software

The following computer-aided systems can be used on a blister packaging line:

■ Servo drives
■ Programmable logic controllers
■ Visualisation
■ SCADA systems
■ Camera systems for filler monitoring
■ OCR camera system for monitoring variable data
■ Foil printing systems
■ Printing systems for variable data

The CSV of the individual systems is not discussed in this chapter. For detailed information on the validation of computer-aided systems, please refer to
Chapter 9 Computer System Validation.
Important aspects of computer-aided systems with regard to suppliers and service suppliers are described in the EU GMP Guidelines, Annex 11,
Chapter 3.

13.C.2 Qualification in accordance with GAMP 5

Figure 13.C-3 shows the typical course of a qualification project based on the V-model described in GAMP 5. The individual steps are described below.
Figure 13.C-3 Course of project based on the V-model (source GAMP 5)

13.C.2.1 Basic risk assessment

Before a requirement specification is created, a basic risk assessment should be carried out to determine and define the basic risks for both company
and process. The question should be asked, for example, whether a plate or rotary sealing machine is better suited to the process and product. The
camera systems, on-line printer, PLC etc. required for the process should be determined during the basic risk assessment. Special camera systems
used for monitoring the filling process and verifying printed data are critical aspects of the overall process. As a matter of principle, a so-called “good
product philosophy” should be in place. This means that when a system component fails, the machine stops and the products that are in the machine
are ejected.
The results of the basic risk assessment must be reflected in the requirement specification.
13.C.2.2 Requirement specification
The requirement specification (also known as user requirement specification/URS) is the basis for the tender and qualification. It is important to invest
sufficient time in this process. At a later phase of the project, it is difficult and/or costly to return to points that were forgotten or not taken into
consideration during this early phase. It should also be kept in mind that the quality of the offer made by a potential machine supplier can only be as
good as the specification requirement. It is, unfortunately, common practice to copy requirement specification documents from previous projects that do
not always match the application in question. This is often difficult for the machine suppliers because they have to comment on every single point.
The requirement specification must include the requirements listed in Figure 13.C-4.
Figure 13.C-4 Contents of a requirement specification (extract)
Contents of a requirement specification (extract)
Machine design
■ An easy-to-clean design incl. a recommendation for cleaning agents
■ Balcony design
 ■ Intended packaging materials, e.g. alu/alu or PVC/alu blisters
■ Foil thickness
■ Foil width
■ GMP requirements
■ Process engineering and mechanics

Products
■Intended products:
This is important for deciding which type of feeding system is required.

Statutory
requirements ■ GAMP 5
■ FDA 21 CFR Part 211
■ FDA 21 CFR Part 11
■FDA Guidance for Industry Process Validation:
General Principles and Practices
■ EU GMP Guidelines Annex 11
■ EU GMP Guidelines Annex 15

e.g. sealing
station ■ Type of seal (rotary or plate sealing)
■ Proof of temperature distribution on tool
■ Calibration certificate for temperature and pressure
■ Machine stoppage incl. entry in audit trail when temperature limits are exceeded
■ Ejection of products if sealing station is overloaded

Automation
systems ■ Specification of hardware for control and visualisation
■ Software specification
■ Camera systems
■ Printing systems
■ Servo drives
■ Interfaces
■ Bus systems

Calibration
■As a rule, all sensors must be designed in such a way that calibration can be carried out in a medium. For this reason, the
connector cable length must be taken into account.
■ Calibration of the cycle display
■ Calibration of all heating elements
■ Calibration of sealing pressure
■ Calibration of the cooling water display
■ Calibration of the input pressure
■ Calibration of the flowmeter

Services
■ Personnel training
■ Spare parts package
■ 24h service
■ Qualification documentation
■ Implementation of qualification on site

Machine
acceptance ■ Definition and scope of the FAT and SAT

Technical
documentation ■ EC declaration of conformity
■ CE marking
■ List of all media connections
■ Movement document
■ Schematic circuit diagrams
■ Machine installation plan
■ Operating instructions in specified language
■ Pneumatic diagrams
■ Format parts list
■ Exploded views
■ Bills of materials
 ■ Spare parts list
■ Calibration certificate
■ Maintenance and care instructions
■ ISO 9000 certificate
■ Environmental conditions
■ Installation location
■ List of measuring points
■ List of sensors
■ Proof of internal audits
■ List of lubricants with certificate
■ Clearance certification for machine parts having contact with the product
■ Service personnel training certificate
■ Noise level measurement
■ Proof of EMC

13.C.2.3 Supplier audit

Before any decision is made on the choice of supplier, an inspection must be carried out to ensure that QA processes have been defined and
implemented in the company. An ISO 9001 certificate alone is not sufficient. It must also be ensured that the GMP requirements for pharmaceutical
suppliers are being met.
Suppliers of critical machinery must undergo an on-site audit, whereas a postal audit can suffice for suppliers of less critical machinery. A catalogue of
questions when carrying out an audit of either type is extremely helpful.
A selection of typical questions for the audit include:
■ Has the supplier installed a functioning QMS?
■ How is its proper implementation ensured?
■ How are dealings with subcontractors monitored, especially with regard to software development?
■ Is there a documented approach that includes standards, especially for software development?
■ Is there a software development life cycle right up to decommissioning of the machine?
■ Is the acceptance procedure described in enough detail?
■ Are there reference customers?
■ How many machines has the company installed in a pharmaceutical environment to date?

13.C.2.4 Functional specification

In the functional specification, the contractor should comment on every point of the requirement specification. Even when a point is not applicable, it
should be marked N/A. It is important that the numbering of the individual points is identical to the numbering in the requirement specification
(traceability). Ideally, requirements and functional specifications should be presented face to face in a document. This makes it easier to keep
documents up to date during the entire project.
Figure 13.C-5 shows how requirements and functional specifications can be juxtaposed.
Figure 13.C-5 Juxtaposition of requirement specification/functional specification
No. Process owner requirement Supplier statement

10.2.1 Project planning of overall system The overall system is being planned in accordance with the recommendations in GAMP 5.

10.2.4 Installation of the machine The machine will be installed according to the specification. The necessary skilled work has been
delegated to proven specialists.

10.2.5 Initial calibration of all sensors All of the sensors ordered will be supplied after initial calibration and with a valid calibration certificate.

10.2.6 Commissioning the machine After the machine has been installed, it is commissioned.
A SAT is carried out in order to document the quality of installation/commissioning.

10.2.7 Short user training session during As part of qualification, an on-site user training course on the machine for a maximum of 8 persons is
system acceptance prepared and carried out on-site.

13.C.2.5 Configuration specification

The so-called configuration specification, containing information about the individual system components, was introduced in GAMP 5. The configuration
specification replaced the documents that were previously used; the hardware design specification (HDS) and the software design specification (SDS).
The documents can be left as a draft version until the end and all variable data, e.g. software versions, is contained in this document, making the
qualification more flexible and more efficient. There was a time when one had to wait for the document to be released or make changes to documents
that had already been released. This procedure is no longer applicable.
The configuration specification primarily describes the
■ Hardware components
■ Hardware versions
■
 ■ Firmware versions
■ Software versions
■ Sensor type(s)
■ Alarm limit values
■ User profiles

13.C.2.6 Functional risk assessment

The functional risk assessment is carried out based on the functional specification. During the assessment, it is decided which points are GMP-critical
and which measures have to be subsequently taken. The visualisation of the individual process steps including the automation components is very
helpful. Because the blister packaging process has many complex and thermodynamic processes, all the process steps must be examined in detail.
This ensures that no functions or crucial factors are overlooked. An example of a risk assessment is given in Chapter 13.C.3 Example of a functional risk
assessment.
The FMEA method is extremely well suited to carrying out risk assessment of packaging lines. The ICH Q9 provides valuable information on this in
Chapter 5. The degree of severity and probability of occurrence and detectability of each potential error mode is evaluated using a previously defined
scale. Numeric values of 1–3 and 1–5 are normally used. Using an evaluation scale of 1–5, an RPN of 27 (3 × 3 × 3) can, for example, be defined as a
limit value.
Errors with an RPN >27 can then be classified as critical errors that require the specification of risk reduction measures.
■ RPN < limit value: no measure necessary or only necessary in certain cases.
■ RPN ≥ limit value: definition of measures necessary.

A repeat evaluation is carried out taking the defined measures into consideration and results in the new RPN(2). This RPN(2) must always lie below the
critical limit value. If the RPN(2) is too high, measures for reducing risk must be defined until a value below the critical limit value has been achieved. An
example of this procedure is given in Chapter 13.C.4 Example of an FMEA risk analysis (extract).
SOPs, user training courses and especially the test documents of the supplier can be defined as measures along with the functional tests. Previously,
tests often had to be carried out repeatedly. Now, synergies can be used. It often makes sense to formally approve FAT documents and use parts of
them for the qualification or as a reference. A “risk-based approach” combined with an active supplier involvement results in a cost-effective qualification.
This is schematically illustrated in Figure 13.C-6.
Figure 13.C-6 Model for a cost-effective qualification

After a successful Factory Acceptance Test (FAT) at the manufacturer and installation of the machine at the operator, it is advisable to carry out a
comprehensive Site Acceptance Test (SAT). This shows that the machine works in its operating environment and also works properly with machines
that are integrated upstream or downstream.

13.C.2.7 Configuration test

The configuration test (previously known as the installation qualification (IQ)) can then be carried out. It is based on the configuration specification.
Testing typically includes:
■ Scope of delivery of the machine
■ Visual inspection of the technical documentation
■ Installed software versions and backups
■ Hardware configurations
■ Software configurations
■ Media supply as specified
■
 ■ Installation of sensors with designation
■ Calibration certificates, etc.

The tests should verify that the machine has been configured in accordance with the specification.
13.C.2.8 Functional test
The functional test (previously known as the operational qualification (OQ)) also results from the risk analysis and checks the functions against the
functional specification. Testing typically includes:
■ Alarm messages
■ System access
■ User levels
■ Power failure
■ Recovery of data
■ Backup of data
■ Machine stoppages
■ Ejection of blisters
■ Advance warnings
■ Compliance with 21 CFR Part 11-Requirements

13.C.2.9 Requirements test (user requirements)

This test involves checking the user requirements against the requirement specification and is the final step in the V-model. This test ensures that the
system is operating in a reproducible way within the specified limit values. Above all, this involves testing the limit values of all critical parameters that
resulted from the GMP risk analysis. A matrix is used when carrying out the evaluation in order to show the interdependence.
A detailed and comprehensive description of a functional risk analysis is given in the following Chapter 13.C.3 Example of a functional risk assessment.
On this basis, a single critical function is used to show the procedure for implementing an FMEA risk analysis (Chapter 13.C.4). The qualification tests
resulting from this are presented as examples in Chapter 13.C.5 Example of an IQ qualification plan (extract) and Chapter 13.C.6 Example of an OQ
qualification plan (extract).

13.C.3 Example of a functional risk assessment

This chapter describes an example of a functional risk assessment for a blister packaging system. The blister machine, the cartoning machine and the
checkweigher will be dealt with in the order in which they are used during the process. Final packaging systems are generally not GMP-critical. For
these systems, a detailed FAT/SAT should be carried out instead of a qualification. However, the decision should be based on a general risk analysis.
The general functionality of all of the outlined process steps and/or functional units is described. The assessment focuses on the GMP-critical functions.
There is a large number of variants depending on the manufacturer and product. A description of these variants would be beyond the scope of this
document. The qualification must include appropriate test items for all functions or functional elements that are considered GMP-critical.
Based on the functional risk assessment, a more detailed FMEA risk analysis of the critical functions can be carried out. During this risk analysis,
quantitative weighting of the criticality of the identified functions is carried out based on the severity and probability of occurrence and detection of the
potential error. Risk-minimising measures are defined at the same time, and the risk that remains after these measures have been implemented is
determined. In this way, priorities can be set for processing the functional tests. Some of the less critical functions may even be removed from the scope
of qualification. An example of this procedure is presented in Chapter 13.C.4.
13.C.3.1 Blister machine
Thermoforming machine
When the machine is started, the motor begins to unwind the form foil. The unwinding process is continuous and is controlled by sensors. In older
systems, the process is controlled by a dancer control which switches the unwinding system on and off. When the forming foil roll is replaced with a new
one, the foils are usually spliced together with red adhesive tape that is suitable for deep drawing. A special sensor detects the tape and stops the
feeding process (exact feeding positioning only). The affected blister is ejected at the ejector station (Figure 13.C-7).
Figure 13.C-7 Risk assessment of thermoforming machine
GMP-
Risk/possible error critical

Unwinding of If the foil is not unwound continuously, the foil may stretch unevenly. Yes
forming foil:

End of forming foil: If the sensor does not detect the end of the forming foil, the machine continues to run without forming foil. This means No
that no blisters can be produced.

Forming foil splice: If the sensor does not detect the adhesive tape, the blister is filled and not removed from the production process Yes
despite the adhesive tape.

Drive failure: No forming takes place Yes

Heating station
The heating station consists of two coated heated hot plates, one at the top and one at the bottom. The coating is required to ensure the heated foil does
not stick to the plates. The hot plates are equipped with cartridge heaters and PT 100 temperature sensors. The heating output depends on the size and
shape of the plates. The output is controlled using a PID controller which is integrated into the PLC. Its parameters are set using the control unit. Data is
stored on a per-product basis. When a product change takes place, it is only necessary to select the new product (formula). There are normally two
additional sets of parameters: one for operational mode and one for stop mode. This is because more heat is generated when the machine is running.
The PT 100 sensor data is read using analog input boards. Many manufactures have the cartridge heaters and sensors built into the hot plates. For this
reason, calibration of the sensors can be difficult. It doesn't really make sense to order hot plates with calibrated sensors because the calibration cycle
is one year and this period has normally expired before the system starts production.
The hot plates open and close during operation. When the foil stops moving, the hot plates close and the foil is heated. The heating temperature depends
on the type of foil. For PVC foil, it is approximately 120 °C. After the foil has been heated, the hot plates open and the heated foil is transported to the
forming station. In the case of an ALU/ALU constellation (cold forming), the heating station is switched off. The heating station of older systems is driven
by a vertical shaft, more recent systems are equipped with a servo drive (Figure 13.C-8).
Figure 13.C-8 Risk assessment of heating station
GMP-
Risk/possible error critical

Failure/high The specified temperature is exceeded/not reached. The foils either overheat which can lead to small holes or they do not Yes
degree of control get hot enough which means that the required deep drawing depth is not achieved. This can cause products to stick out and
sensor become attached to the sealing foil. Generally, the sensor is monitored.
inaccuracy:

Failure of A failure of cartridge heaters, and especially a failure of a single cartridge heater, can lead to an uneven distribution of heat. Yes
cartridge As a result, the foil does not get hot enough. Depending on which cartridge is affected, the temperature monitoring system
heaters: may or may not detect the failure. Heating current monitoring can be used to ensure proper monitoring.

Exceeding/not The required temperature limit values are stored in the control parameters. If the limits are exceeded or not reached, the Yes
reaching the machine stops. The system can only be restarted when the values are once again within the limits.
temperature
limits:

Drive failure: No forming takes place Yes

Forming station
The forming station has two tools that create the cavities. One of the tools supplies compressed air, the other one forms the product cavities. The tools
are cooled by a closed cooling circuit. The heated foil is drawn into the tools, the plates close, highly compressed air is forced into the tool and presses
the heated foil into the forming tool. When the tool cools, the foil solidifies again and retains the shape required for the products. In the case of alu/alu
cold forming, the foil is formed using a mechanical stamp. The heating station of older systems is driven by a vertical shaft, more recent systems are
equipped with a servo drive (Figure 13.C-9).
Figure 13.C-9 Risk assessment of forming station
GMP-
Risk/possible error critical

Cooling is not set as This can cause creasing or shrinkage of the formed product cavities. Yes
specified:

Compressed air: The compressed air must have a certain degree of purity and must not contain oil residues or moisture which could Yes
contaminate or damage the product.

Drive failure: No forming takes place Yes

Product supply
A vibratory feeder transports the products into the feed through a filling funnel. The vibration is controlled by a fill level sensor. Different types of feeding
systems are used depending on the product. A basic distinction is made between exact feeding positioning (the products are carefully placed in each
individual cavity) and brushed blister feeding (the products are brushed into the cavities). Both systems have advantages and disadvantages. Exact
feeding positioning can be controlled, e.g. in the case of a splice. The feeding of product can be stopped for this area specifically.
It is important that certificates are available for all machine parts having contact with the product. Feeding systems are critical machine parts with regard
to the cleaning validation because the parts have direct contact with the open product. The cleaning agent(s) recommended by the manufacturer must be
included in the cleaning validation (Figure 13.C-10).
Please note: It may happen that products, especially white ones, become discoloured in the storage hopper despite it being made of stainless steel. If
this happens, the hopper should be coated.
Figure 13.C-10 Risk assessment of product feeder
GMP-
Risk/possible error critical

The fill level sensor is not This can lead to underfilling of the feed which results in partially filled blisters. These are detected by the Yes
working properly: filling control device and ejected.
It can also lead to overfilling of the feed. In this case, the products may get broken or damaged, especially
if a brush box feeder is being used.

The feed is not properly Products are not being correctly placed in the cavities and/or can break. Yes
positioned.

Non-authorised materials were The products might become contaminated. Certificates must be requested from the manufacturer for all Yes
used: metallic and non-metallic materials.
 Please note: 21 CFR 211 §177 includes a list of these materials.

Camera filling control

The camera filling control (see also Chapter 13.B.5.1) always monitors a specific part of the filled blisters. There are different types of systems which can
be used depending on the product and type of foil. A distinction is made between transmitted and reflected light systems; a combination of both is also
possible. Simple black and white systems only check the product for presence, size and damage. More expensive colour systems also check the
specified product colour. When a blister is checked that meets the specified features, an OK signal is entered in the shift register. All of the blisters that
do not have an OK signal entered are ejected at the ejector station and the ejection counter control checks that the ejector device is functioning
correctly.
The system parameters can be set using the operating station of the machine or the user interface. This involves data being stored on a per-product
basis which means that when a product change takes place, it is only necessary to select the new product (formula). At the beginning of the 2000s,
machines were equipped with new camera systems in order to comply with the requirements specified in 21 CFR Part 11. The camera controls access
to the machine and the audit trail.
A camera system is a computer-aided system. In addition to the risks listed in Figure 13.C-11, all of the risks discussed in Chapter 9 Computer System
Validation must be evaluated.
Figure 13.C-11 Risk assessment of filling control
GMP-
Risk/possible error critical

Filling control is not working or The machine stops and an error message appears; a restart is only possible when the error is resolved. All Yes
crashes during operation: the blisters between filling control and the ejector station are ejected after restart.

The filling control parameters Depending on the tolerances set, blisters that are OK may be ejected (tolerances too narrow) and fragments Yes
are not correct: and/or tablets that are too small may not be detected (tolerances too wide).

Cover foil unwinding

Pre-printed and unprinted cover foil is available. The relevant product labels are printed onto the unprinted foils using in-line printing. Different processes
can be used, e.g. laser printing and cliché printing. The advantage of unprinted foil is that only one type of foil needs to be kept in storage for each foil
width. This greatly reduces the storage costs. Contract manufacturers with a large number of products per machine can really benefit from this.
When using printers, a monitoring system, i.e. a camera, should be used. The printer and camera are part of the computer system validation and should
be treated as such. The system parameters can be set using the operating station of the machine or the user interface. Data is stored on a per-product
basis which means that when a product change takes place, it is only necessary to select the new product (formula).
The cover foil is treated with sealing lacquer and is sealed to the deep drawn foil strip. The foil brake is released for each feed and the foil unwound. Cover
foil unwinding systems are also available with a drive. When a minimum level is exceeded, a warning is displayed but the machine does not stop. The
end of the cover foil is detected by a sensor which results in the machine stopping and an error message being displayed.
The new foil is then installed and the two loose ends are spliced together using red adhesive tape. The splice is detected by a splice detector and the
affected blisters are ejected from the line. A foil stretching device is used on machines with a precise cover foil image position, e.g. contraceptives. It is
controlled by a sensor (Figure 13.C-12).
Figure 13.C-12 Risk assessment of cover foil unwinding
GMP-
Risk/possible error critical

The printer is not working A defective blister is detected by a camera and ejected. If the fault occurs several times, the machine Yes
correctly: stops (serial fault).

The printed image does not match The foil stretching device or the printed image control is not working correctly. The image monitoring Yes
the product cavities: system responds and stops the machine. The blisters are ejected.

The sensor does not detect the The cover foil is missing from some blisters. Yes
end of the cover foil:

The splice is not detected: Blisters with spliced foil remain on the line Yes

Sealing station
There are two basic types of sealing; rotary and plate sealing. Both systems have their advantages depending on the product on the line. The type of
seal directly affects the feeding system. The foil strip is fed continuously during rotary sealing and intermittently during plate sealing. Rotary sealing
normally requires a higher temperature because the sealing time is shorter. This can sometimes have a negative impact on the labelling of the cover foil.
Example of plate sealing: The sealing station consists of a cooled sealing tool and a sealing plate. The knurled sealing plate is fitted with cartridge
heaters and PT 100 temperature sensors. The sealing temperature is approx. 200 °C, depending on the type of machine and the number of cycles. The
heating output depends on the size and shape of the plates. Unlike the heating station, the cartridge heaters and the PT 100 sensors are not moulded
and can be replaced or the sensor can be removed for calibration in an immersion bath. The output is controlled using a PID controller which is integrated
into the PLC. Its parameters are set using the control unit. Data is stored on a per-product basis which means that when a product change takes place,
it is only necessary to select the new product (formula). The PT 100 sensor data is scanned using analog input boards. The heating station of older
systems is driven by a vertical shaft, more recent systems are equipped with a servo drive (Figure 13.C-13).
Figure 13.C-13 Risk assessment of sealing station
GMP-
Risk/possible error critical
Control sensor If the specified temperature is exceeded, the foil overheats which leads to changes to the cover foil. In some cases, the Yes
failure/high degree cover foil is creased which in turn can lead to leaks in the blisters.
of control sensor If the specified temperature is not reached, the cover foil is not properly sealed. This leads to leaking blisters. As a rule,
inaccuracy: the sensor is monitored.

Failure of cartridge The failure of cartridge heaters, and especially the failure of a single cartridge heater, can lead to an uneven distribution of Yes
heaters: heat. This means the cover foil is not sufficiently heated which in turn leads to leaking blisters. Depending on which
cartridge is affected, the temperature monitoring system may or may not detect the failure. Heating current monitoring can
be used to ensure proper monitoring.

Exceeding/not The required temperature limit values are stored in the control parameters. If the limits are exceeded or not reached, the Yes
reaching the machine stops. The system can only be restarted when the values are once again within the limits.
temperature limits:

The temperature If there are major deviations from the tolerance limits, the temperature limits are not observed. This can result in leaking Yes
sensor is not blisters and/or changes to the cover foil.
calibrated:

Sensor wire The temperature control is no longer working. Modern machines stop immediately and an error message is displayed. Yes
breakage:

Sealing pressure Insufficient sealing pressure results in leaking blisters. If the sealing pressure is too high, the blisters are mechanically Yes
outside the damaged.
specification:

Temperature If the temperature distribution is uneven (design error), a uniform seal is not possible which can cause leaking blisters. Yes
distribution on the Request proof from the manufacturer.
sealing plate:

Drive failure: No sealing Yes

Mechanical embossing station

The embossing station is used to emboss variable data, e.g. the batch number and expiry date, on the packaging. There are heated and unheated
embossing stations. In the case of heated embossing stations, the PT 100 sensor must be calibrated. The output is controlled using a PID controller
which is integrated into the PLC. Its parameters are set using the control unit. Data is stored on a per-product basis which means that when a product
change takes place, it is only necessary to select the new product (formula). The PT 100 sensor data is scanned using analog input boards.
The embossing station of older systems is driven by a vertical shaft, more recent systems are equipped with a servo drive.
Modern systems also use printing systems to attach variable data and monitor it using an OCR camera. These systems must be included in the
computer validation and should be handled accordingly (Figure 13.C-14).
Figure 13.C-14 Risk assessment of embossing station
Risk/possible error GMP-critical

Code on incorrect side Yes

Control sensor not calibrated: Code illegible at times Yes

Drive failure: No code Yes

Perforation station
The perforation station is used for perforating blisters that are required for many products. For this purpose, perforation knives are built into the tool. The
perforation station of older systems is driven by a vertical shaft, more recent systems are equipped with a servo drive. There are also heated and
unheated versions of perforation stations. In the case of heated perforation, the PT 100 sensor must be calibrated. The output is controlled using a PID
controller which is integrated into the PLC. Its parameters are set using the control unit. Data is stored on a per-product basis which means that when a
product change takes place, it is only necessary to select the new product (formula). The PT 100 sensor data is scanned using analog input boards
(Figure 13.C-15).
Figure 13.C-15 Risk assessment of perforation station
GMP-
Risk/possible error critical

Perforation in wrong position: If the perforation is carried out too close to the product cavities, it can cause leaking Yes
blisters.

Control sensor not calibrated: Perforation is not deep enough at times. Yes

Perforation knife defect/broken off: Perforation is not deep enough at times. Yes

Perforation knife is dirty (e.g. because of Perforation is not deep enough at times. Modern systems switch off the perforation Yes
adhesive tape residues) station when splices are detected.

Drive failure: No perforation Yes

Punching station
The punching station is used to punch the blisters out of the foil strip. Positioning accuracy is very important during this process. Otherwise, the edges
of the blisters are not wide enough which can lead to leaking blisters and difficulties during further processing of the blisters in the packaging process.
The punching station of older systems is driven by a vertical shaft, more recent systems are equipped with a servo drive (Figure 13.C-16).
Figure 13.C-16 Risk assessment of punching station
GMP-
Risk/possible error critical

Tool is not Leads to residues at the punching location. Can lead to problems during further processing. The residue on the blisters is Yes
sharp: also called “angel's hair”.

Poor May cause leaking blisters Yes

positioning:

Blister ejection
The ejection of blisters which are identified as defective is carried out mechanically or using a compressed air system. There are different systems from
various manufacturers. Correct ejection is monitored by an ejection counter control. If a defective blister is detected that should have been ejected, the
machine stops.
Modern systems divide defective blisters into three categories when ejecting:
■ Empty blisters
■ Partially filled blisters
■ Full blisters

They are ejected into corresponding containers located at the ejector station. The ejector station is controlled by the shift register in the PLC or a
separate device. Sometimes, the integrated shift register in the camera filling control is used. The parameters for the length of shift register, i.e. for the
detection of defective items prior to ejection, are set using visualisation. The parameters are stored for each individual product.
But blisters are not only ejected from the process if they are empty or partially empty. In addition, the following may lead to ejection:
■ Forming foil splice
■ Cover foil splice
■ Forming foil tear control
■ Sealing station overload
■ Coding station overload
■ Perforation station overload
■ Printed image control
■ Cover foil printing
■ Heating station/overheated foil

As a rule, if a system failure (e.g. camera filling control, foil printing) or a power failure occurs, all the products that might be affected are ejected (Figure
13.C-17).
Figure 13.C-17 Risk assessment of bad blister ejection
GMP-
Risk/possible error critical

Blisters are not being correctly ejected: This must be detected by the sensor of the ejection counter control. Yes

Blisters that are identified as defective are This can occur especially in the case of alu/alu combinations. Can only be regulated using Yes
manually fed into the process using the SOPs.
replenishing chute:

The shift register parameters are not correct: Good blisters are being ejected and defective blisters remain on the line. Yes

Foil strip is loaded incorrectly: Good blisters are ejected and defective blisters remain in the process. Must be checked Yes
using appropriate controls. As a rule, sensors are used to monitor the position of the dancer
roller.

Good blister ejection: If a downstream machine stop occurs, the good blisters are ejected into a container. This procedure is not GMP-critical.
Transfer to the downstream machine
Depending on the system used, the blisters are transported to the cartoning machine with the aid of a suction belt, outfeed belt, product chain or other
suitable device.
13.C.3.2 Cartoning machine
In this example, the cartoning machine packages the blister packs and the package leaflet in the folding cartons. The individual steps of this procedure
are monitored by various monitoring systems, e.g. the code reader or the leaflet presence control. There are different processes for packaging blisters in
cartons. Along with the standard way of pushing the blisters and the package leaflet directly into the folding carton, there is also the possibility of first
packaging them in a wallet or pillow pack. This depends on the respective product protection and marketing strategy of the pharmaceutical company.
There are two different types of vertical cartoning machines: machines with continuous folding carton transport and machines with intermittent folding
carton transport. In addition, there are so-called top loaders which are not discussed here.
Unstacking of products/forwarding of blisters to the product chain
There are different methods for forwarding blisters depending on the product (i.e. tablets, syringes, etc.). It must be ensured that the specified number of
blisters is forwarded to the product chain and that they are undamaged. For stacking wheels, it is particularly important to set the correct parameters
(Figure 13.C-18).
Figure 13.C-18 Risk assessment of blister forwarding
GMP-
Risk/possible error critical

Incorrect The number of blisters in the folding carton is pre-set in the user interface. The necessary parameters for each product are Yes
number of stored there. Likely problems are an incorrect number of blisters and/or incorrect mechanical settings.
blisters in the
product chain:

Control of the The number of blisters is checked using a format part connected to a sensor. The format part must be set exactly to the target Yes
number of blister height. When the number is correct, the controller sends a signal to the leaflet machine to provide a leaflet. If the format
blisters in the part is not set correctly, it can happen that a blister is missing and the package leaflet is still provided, or the number of
product chain: blisters is correct and the leaflet is not provided.

Leaflet folding machine

The leaflet folding machine is usually mechanically connected to the cartoning machine and is used for folding package leaflets of different sizes. A
leaflet is removed from the stack of leaflets on the leaflet table using a vacuum suction cup and forwarded to the respective buckle folder. The number of
folds depends on the respective size of the leaflet.
Before the first fold is made, the pharmacode on both sides of the leaflet is checked by a code reader. The sensor heads scan the printed pharmacode. If
the code doesn't match the pre-set code, the product is ejected at the end of the machine. Depending on the type of system, a folding carton is not
removed and/or the product is not inserted into the carton. If an incorrect code is detected several times, the machine stops and an error message is
displayed indicating a leaflet reading serial error. The code is entered on the control unit of the machine or separately on the evaluation unit of the code
reader. One code is stored for each product. This prevents leaflets for other products entering the process (Figure 13.C-19).
Figure 13.C-19 Risk assessment of leaflet folding machine
GMP-
Risk/possible error critical

Incorrect leaflet code entered: Leaflets are ejected if the code reader functions properly. Yes

Sensor head on code reader incorrectly Leaflets are ejected because an OK signal is expected from the code reader when a leaflet is Yes
set: removed. If this doesn't happen, the respective product is ejected.

The parameters for the shift register If the parameters are incorrect, products that are identified as defective are not ejected. Yes
distance between the leaflet code reading
and ejection are incorrectly set.

Incorrect settings for leaflet folding: If the leaflets are not folded correctly, mechanical damage can occur that makes proper further Yes
processing difficult or impossible.

Leaflet transfer in the leaflet chain: The folded leaflets are not being transferred properly to the leaflet chain. This can result in folding Yes
cartons without leaflets. A luminescence scanner that is working properly detects the missing
leaflet and ejects the product.

The supply monitoring sensor is not The minimum quantity is undershot and there is no acoustic or optical signal. The stack of leaflets No
working properly or is incorrectly set: is reduced to below the minimum quantity.

The leaflet stack minimum height sensor As a result, leaflets continue to be removed from the stack after the minimum height has been Yes
is not working: reached until there are no more leaflets on the table. However, the leaflets might not be removed
and folded properly if the stack is below the minimum height.

Removal of the folding cartons

When the specified number of blisters and the folded package leaflet are present in the product chain, a vacuum suction cup is used to pull the folding
carton from the magazine. It is opened and placed in the folding carton chain. Then, it is transported to the product insertion unit with the leaflet and
blisters (Figure 13.C-20).
Figure 13.C-20 Risk assessment of folding carton removal
GMP-
Risk/possible error critical

Incorrect folding If the code reader functions properly, the folding cartons are ejected. Yes
carton code
entered:

Sensor head on Folding cartons are ejected because an OK signal is expected from the code reader when a folding carton is removed. If Yes
code reader this doesn't happen, the respective product is ejected. The sensor head scans the printed pharmacode. If the code
incorrectly set: doesn't match the pre-set code, the product is ejected at the end of the machine. If an incorrect code is detected several
times, the machine stops and an error message indicating a folding carton code reading serial error is displayed. The
code is entered on the control unit of the machine or separately on the evaluation unit of the code reader. One code is
stored for each product. This prevents folding cartons for other products getting into the process.

The parameters for If the parameters are incorrect, products that are identified as defective are not ejected. Yes
the shift register
distance between
the folding carton
code reading and
ejection are
incorrectly set.

The supply The minimum quantity is undershot and there is no acoustic or optical signal. The stack of folding cartons is reduced to No
monitoring sensor is below the minimum quantity.
not working properly
or is incorrectly set:

The folding carton As a result, folding cartons continue to be removed from the stack after the minimum height has been reached until there Yes
stack minimum are no more cartons on the table. The folding cartons may not be removed properly if the stack is below the minimum
height sensor is not height.
working:

Product inserter
The product inserter slides the stack of blisters and the leaflet into the folding carton. An insertion guide rail which can also be blocked controls the
process. An insertion tongue prevents the blisters from rising up. If a blister or leaflet is missing beforehand, the inserter is blocked and the products fall
into a special container. The correct mechanical setting of the insertion tongues and inserter is important. Otherwise the blisters or leaflet can be
mechanically damaged (Figure 13.C-21).
Figure 13.C-21 Risk assessment of product insertion
Risk/possible error GMP-critical

Inserter is not set correctly: Can cause damage to the product Yes

The insertion tongue is set too low: Can lead to products being pulled out again. Yes

Control of leaflet presence in the folding carton

After insertion of the blisters and leaflet, the side flaps are closed. The leaflet can be clearly seen through the flap opening. The sensor head responds to
the whitener in the leaflet and thus ensures that the leaflet is present. It is very important that the settings are correct (Figure 13.C-22).
Figure 13.C-22 Risk assessment of the presence check of the package leaflet
GMP-
Risk/possible error critical

Incorrect setting: Folding cartons also contain so-called whiteners. If the settings are incorrect, the folding carton will be detected Yes
instead of the leaflet and an OK signal will be sent to the controller. The missing leaflet will remain undetected.

Incorrect parameters If incorrect parameters are set for the shift register distance between detection and ejection, the product identified as Yes
set for the shift defective will not be ejected.
register.

Folding carton coding

Before the folding carton is closed, a mechanical embossing station embosses the variable data including batch number and expiry date onto the flap.
The embossing station of older systems is driven by a vertical shaft; more recent systems are equipped with a servo drive.
Modern systems also use printing systems to print variable data and monitor the data using an OCR camera. These systems must be included in the
computer system validation and should be treated accordingly (Figure 13.C-23).
Figure 13.C-23 Risk assessment of the folding carton coding
GMP-
Risk/possible error critical

Digits not mounted tightly in the Can lead to digits falling off during operational mode and embossing no longer taking place. Can only be Yes
holder. monitored by an IPC.

Folding carton closure

The sides and flaps are closed using guide rails. Some flaps are glued using a hot glue sealing device. Sensors are used to check that the carton is
properly closed.
Figure 13.C-24 Risk assessment of folding carton
closure
Risk/possible error GMP-critical
The folding carton is not properly closed Yes

Folding carton ejection

The ejection of folding cartons that are identified as defective is carried out mechanically or using a compressed air system. There are different systems
from various manufacturers. Correct ejection is monitored by an ejection counter control. If a folding carton is detected that was not ejected, the machine
stops.
The ejector station is controlled by the shift register in the PLC. Visualisation is used for the detection of defective items prior to ejection. The parameters
are stored for each individual product.
Figure 13.C-25 Risk assessment of folding carton ejection
Risk/possible error GMP-critical

The shift register parameters are not correct: Yes

Folding carton ejection when the downstream machine stops or is congested: If a downstream machine stop occurs, the blisters that have been
identified as good are ejected into a container. This procedure is not GMP-critical.
13.C.3.3 Checkweigher
All folding cartons are subsequently moved across a checkweigher. It is very important that the scale is detached and is not in contact with any of the
upstream or downstream machines. The slightest vibration distorts the weighing result and causes ejection of the product. The scale is a reliable
instrument for detecting missing blisters only. Missing leaflets may or may not be detected depending on package size. In the case of a package
containing 100 tablets, the product tolerance is so great that a missing leaflet weighing 1.5 g will not be detected (Figure 13.C-26).
Figure 13.C-26 Risk assessment of check weigher
GMP-
Risk/possible error critical

Incorrect limit If the limits are set too wide, a missing blister will not be detected. Missing blisters can only result from the insertion process. Yes
values: If the set limits are too narrow, unwanted ejection will occur.

Scale not Leads to distortion of the weighing result Yes

calibrated

13.C.3.4 Control systems (blister and cartoning machine)

The machine is controlled using a Programmable Logic Controller (PLC) and a servo drive. The individual functions depend on the process. For detailed
information on the PLC and the qualification/validation of the PLC, please refer to Chapter 4.C Control and Chapter 9 Computer System Validation.
Visualisation/HMI
Visualisation is used when operating, managing and setting parameters for formulas. Normally, the data is transmitted to the PLC. The individual
functions depend on the process and the PLC. For detailed information on visualisation and its qualification/validation, please refer to Chapter 4.K
Process control systems and Chapter 9 Computer System Validation.
13.C.3.5 Supply media
The following supply media are critical to ensure proper functionality of the packaging machine.

Compressed air supply

The machine requires an adequate supply of compressed air, usually at a pressure of at least 6 bar. If the pressure decreases, the pneumatic devices
may no longer function correctly. For this reason, it is important to calibrate the input pressure indicator.
GMP-critical: Yes
Vacuum supply
The machine requires an adequate vacuum supply. The vacuum can be generated centrally or using vacuum pumps. If the pressure decreases, the
suction devices may no longer function reliably. For this reason, it is important to calibrate the input pressure indicator.
GMP-critical: Yes
Voltage supply
A reliable voltage supply must be provided. This is generally not a problem in industrialised countries. In developing countries, a voltage stabiliser may be
required.
GMP-critical: Yes
Cooling system
It must be ensured that the tools are cooled sufficiently in accordance with the specifications. This applies to both flow and temperature. For this reason,
the flow and temperature indicators must be calibrated.
GMP-critical: Yes
13.C.3.6 Ambient conditions
It must be ensured that the specified ambient conditions are met when the machine is being operated. Temperature and humidity are important factors.
Depending on the product properties, it may be necessary to condition the incoming air in the product feed area (specific temperature and humidity
values that are different from the ambient air, e.g. for moisture-sensitive products). For this reason, the conditions must be monitored and the respective
indicators must be calibrated.

13.C.4 Example of an FMEA risk analysis (extract)

Figure 13.C-27 FMEA risk analysis (RA)
Company/Logo

RA-P100-01 FMEA Risk Analsysis (RA) Version 01

Assessment Assessment
Potential before after
impact measure measure
Component Potential of the Cause of the GxP- Remarks /
No. / function error error error critical S O D RPN Cause Measure S O D RPN2
7. Sealing heater
7.1 Sealing Insufficient Leaking Failure of a Yes 3 2 3 18 The failure of a Installation of a heating current 3 2 1 6
heater sealing blisters, single heating heating element monitor to ensure the
caused by product element at the centre of functionality of the heating
uneven at risk the sealing plate elements
distribution of is not necessarily OQ-01-Test Checking the
sealing detected by the heating current
temperature temperature
sensor

7.2 Sealing Sealing Leaking Temperature Yes 3 3 3 27 The temperature Calibration of the PT100 sensor 3 1 1 3
heater temperature blisters, sensor is not controller is not in the sealing plate.
temperature does not product calibrated receiving the IQ-02 Test Checking the
control reach the set at risk actual value calibration certificate of the
value or measured at the sensor in the sealing heater
exceeds it sealing plate. As and calibration reference
a result, no proper device
control

7.3 Sealing Sealing Leaking The Yes 3 3 3 27 The PID controller Correct PID parameters must 3 1 1 6
heater temperature blisters, parameters of cannot control the be entered for operational and
temperature does not product the PID required sealing stop mode. The individual
control reach the set at risk controller are temperature as parameters must be
value or not set specified determined. In addition, the
exceeds it correctly for upper and lower temperature
the process limits for stopping the system
must be entered correctly.
OQ 03-Test
Monitoring the temperature
of the sealing heater
Legend and evaluation:
S = severity of the failure (1 = low; 2 = medium; 3 = high)
O = occurrence of the failure (1 = low; 2 = medium; 3 = high)
D = detection probability of the failure (1 = high; 2 = medium; 3 = low)
RPN = risk priority number (S x O x D)
RPN2 = risk priority number after risk reduction
Please note: The outlined test items are examples that illustrate the general procedure and only represent an extract from the overall risk analysis.

13.C.5 Example of an IQ qualification plan (extract)

13.C.5.1 IQ-02: Checking the validity of the sealing heater calibration certificate
This check is carried out to ensure that the temperature sensor in the sealing station was calibrated and the result documented. Furthermore, the validity
of the calibration of the reference device and its suitability are checked.

Precondition
The sealing heater was successfully calibrated
Test procedure
■ Visual inspection of the calibration certificate for the sealing heater to ensure compliance with the tolerance limits and the period of validity
■ Comparison of the calibration number on the calibration label of the sensor with the data on the calibration certificate
■ Visual inspection of the calibration certificate for the reference device to ensure compliance with the tolerance limits and the period of validity

Figure 13.C-28 Example of an IQ plan (extract)

Test item Acceptance criterion Met Date Deviation
Yes/No Initials No.
Sealing heater calibration The defined tolerance limits must be complied with.
certificate The calibration validity must be within the calibration cycle.
Calibration label The calibration number on the calibration label as well as the date for the next recalibration must
correspond to the data on the certificate.

Reference device The defined tolerance limits must be complied with.

calibration certificate The calibration validity must be within the calibration cycle.

13.C.6 Example of an OQ qualification plan (extract)

13.C.6.1 OQ-03: Functional test: Insufficient temperature of the sealing heater
This test is carried out to ensure that a drop in the heat sealing temperature below the set tolerance limit of ±5 °C causes the system to stop and
generates an error message.
Preconditions
■ The system is ready for operation
■ There are no error messages on the display
■ The set sealing temperature of 210 °C, for example, has been reached
■ The set tolerance limit is ±5 °C
■ The system is set to operate with empty blisters

Test procedure
■ Start the system
■ Set the set temperature on the display to 216 °C and confirm

The test items and acceptance criteria are listed in the table below.
Figure 13.C-29 Example of an OQ qualification plan (extract)
Met Date Deviation
Test item Acceptance criterion Yes/No Initials No.

Insufficient temperature System stops and error message indicating that the heating sealer temperature is insufficient is
of sealing heater displayed when the permitted tolerance limit is exceeded.

Restart the system The system can only be restarted when the error has been successfully cleared.

Entry in audit trail The error and the timeframe are entered in the audit trail.

Summary
A cost-effective qualification of blister packaging lines that complies with the statutory requirements is possible when the following aspects are taken
into consideration:
■ Supplier evaluation before awarding the project
■ Requirement specification and functional specification in a single document
■ Risk analysis with a focus on GMP-relevant functions
■ Cross-references to the IQ and OQ tests to be carried out
■ Reference to tests previously carried out by the manufacturer
■ Reference to SOPs, e.g. in the case of backup and recovery
■ All variable data in the configuration specification
■ Leave configuration specification in draft version for an extended period
■ Inclusion of the manufacturer's validation documentation in the overall system
Printed by: 168305-3 Date: 16.04.2014 GMP MANUAL © Maas & Peither AG
13.D References
Up17
Regulatory Requirements and Guidelines, Europe
1. EU GMP Guidelines Part I, Basic Requirements for Medicinal Products (Chapter C.4)
■ Chapter 3 Premises and Equipment
■ Chapter 4 Documentation
■ Chapter 5 Production
■ Annex 8: Sampling of Starting and Packaging Materials (Chapter C.6.8)
■ Annex 11: Computerised Systems (Chapter C.6.11)

Regulatory Requirements and Guidelines, USA

2. 21 CFR 211 Current Good Manufacturing Practice for Finished Pharmaceuticals (Chapter D.1.2)
■ Subpart E: Control of Components and Drug Product Containers and Closures
■ Subpart G: Packaging and Labeling Control
■ Subpart J: Records and Reports

ICH-Guidelines (www.ich.org)
3. ICH Q9 Quality Risk Management, 2005 (Chapter E.9)

PIC/S-Guidelines (www.picscheme.org)
4. PIC/S PI 011-3: PIC/S Guidance Good Practices for Computerised Systems in Regulated “GxP” Environments, 2007 (Chapter F.3)
5. PIC/S PI 028-1: Aide-Mémoire GMP Inspection related to packaging, 2009 (Chapter F.7)

ISPE-Guides (www.ispe.org)
6. GAMP 5, Good Automated Manufacturing Practice Guide, ISPE, 2008