PHARMACEUTICAL PREMISES:

SANITATION, ENVIRONMENTAL
CONTROL, UTILITIES AND
MAINTENANCE OF STERILE AREA,
CONTROL OF CONTAMINATION
CURRENT GOOD
MANUFACTURING PRACTICES
(CGMP)
cGMP is a set of regulations published by the US Food and Drug
Administration (FDA).
 Most national and international agencies regulating pharma industries have
similar guidelines or regulations.
 cGMP regulations cover many aspects: organization and personnel, building
and facilities, equipment, control of components, production controls,
packaging and labelling controls , laboratory controls, sanitation,
environmental control, etc.
 In this presentation, we will discuss the aspects like:
 Sanitation
 Environmental Control
 Utilities of Sterile Area
 Maintenance of Sterile Area
 Control of Contamination
SANITATION
 Any building used in the manufacture, processing, packing or holding of a
drug product shall be maintained in a clean and sanitary condition.
 Any such building shall be free of infestation by rodents, birds, insects, and
other vermin ( other than laboratory animals).
 There shall be written procedures assigning responsibility for sanitation and
describing in sufficient detail the cleaning schedules, methods, equipment and
materials to be used in cleaning the buildings and facilities; such written
procedures shall be allowed.
 There shall be written procedures for use of suitable rodenticides, insecticides,
fungicides, fumigating agents, and cleaning and sanitizing agents.
 Written procedures shall be designed and followed.
 Rodenticides, insecticides and fungicides shall not be used unless registered
and used in accordance to the Federal Insecticide, Fungicide and Rodenticide
Act.
 Sanitation procedures shall apply to work performed by contractors or
temporary employees as well as by full time workers during their ordinary
course of operations.
WASHING AND TOILET
FACILITIES
 Adequate washing facilities shall be provided, including hot and cold water,
soap or detergent, air driers or single-service towels, and clean toilet facilities
easily accessible to working areas.
 In addition to GMP regulations, occupational safety and health administration
(OSHA) regulations impact on washing and toilet facilities.
 These require toilet rooms to be separate for each sex except where individual
locked toilet rooms are available and also define the minimum number of
water closets based on the number of users.
ENVIRONMENTAL CONTROL
 Environmental control of pharmaceutical cleanrooms is essential to the
manufacture of a quality product.
 Control of such conditions as airborne particulate, microorganisms,
temperature, humidity, differential pressure, airflow, air velocity and personnel
is crucial to protect the product from contamination.
 Therefore, the design, validation and ongoing monitoring of a cleanroom
HVAC system are necessary to assure the quality and safety of a
pharmaceutical product.
 The manufacturing environment is critical for product quality due to following
factors:
1. Light
2. Temperature
3. Humidity
4. Air movement
5. Microbial Contamination
6. Particulate contamination
 Uncontrolled environment can lead to product degradation.
WHAT ARE CONTAMINANTS?
 Contaminants are
 Substances other than products manufactured
 Foreign products
 Particulate Matter
 Micro-organisms
 Endotoxins
 Cross-contamination is a particular case of contamination.
 CROSS CONTAMINATION
 Contamination of a starting material, intermediate product, or finished
product with another starting material or product during production is known
as cross-contamination.
 It originates from:
1. Poorly designed air handling systems and dust extraction systems
2. Poorly operated and maintained air handling system and dust extraction
system
3. Inadequate procedures for personnel and equipment
4. Insufficiently cleaned equipment
 Cross-contamination can be minimized by:
1. Personnel procedures
2. Adequate premises
3. Use of closed production systems
4. Adequate, validated cleaning procedures
5. Appropriate levels of protection of product
6. Correct air pressure cascade
 HVAC SYSTEM
 H - Heating
 V - Ventilation
 AC- Air Conditioning
HVAC SYSTEM
 Control air-borne particles, dust and micro-organisms.
 Maintain room pressure (delta P)
 Maintain space moisture ( Relative Humidity)
 Maintain space temperature
COMPONENTS OF HVAC
SYSTEM
 Local heating systems:
Heat source, distributors, and Portable electric heaters, built-in electric
resistance heaters, infrared heaters and wood stoves.
 Local cooling systems:
Air circulation devices such as paddle or desk fan.
 Local ventilating systems
 Local air-conditioning systems
DEMERITS OF HVAC SYSTEM
 HVAC cannot clean up the surfaces of a contaminated places, room or
equipment.
 HVAC cannot compensate for workers who do not follow procedures.
HVAC TECHNIQUES
 Air filtration including “High Efficiency Particulate Air” filters (HEPA filters)
 Directional flow of air
 Pressure relationships within and between adjacent spaces
 Humidification ( used mostly in winter in cold climate), dehumidification
(mostly in summer)
 Heating and cooling to maintain constant temperature.
AIR FILTRATION
 The low particulate counts in classified rooms are achieved by continuous
recirculation of room air with HEPA filters in the recirculation loop.
 The cleaner the room needs to be, the higher recirculation rate required.
 The degree of recirculation is commonly expressed as number of room air
changes per hour (air flow rate divided by room volume).
 Guidelines for required number of air changes:
o 240-480 changes/hr for Class A rooms
o 60-90 changes/hr for Class B rooms
o 20-40 changes/hr for Class C rooms
 These numbers are not regulations, just guidelines. They vary in different
sources.
 Actual number of particles observed depends on activity level- people present,
dust generating operations etc. Easier to achieve low particulates in static (no
activity) than in dynamic conditions.
AIR PRESSURIZATION
 In general, rooms of higher class (cleanest) have positive air pressure as
compared to adjacent spaces.
 Air locks are used to separate clean process rooms from corridors and adjacent
rooms.
 Air locks and gowning rooms are normally negatively pressurized compared to
the process room and positively to corridor.
 Exception can be made in case the product or its component is hazardous (i.e.
live virus), in which case containment consideration may require clean room to
be negatively pressurized.
 In such case, air lock may be made positive to both process room and to the
corridor. This provides both product protection and containment.
 Recommended pressure differential between adjacent areas is 10-15 Pa, as
measured with doors closed.
 When a door opens, pressure differential essentially goes to zero. So air locks
are installed at critical connection points, and the two doors in an air lock are
never opened simultaneously.
 Rooms need to be sealed as tight as possible to enable maintaining required
pressure differential.
AIR QUALITY
MONITORING
• Number of particles per
unit of air volume is tested
during facility
qualification and routinely.
Such testing is done both
“at rest” (no activity) and
during normal operations.
Portable or permanently
installed particle counters
may be used.
CLASSIFICATION OF CLEAN
ROOM
 MONITORING AND TESTING
OF HVAC CLEAN ROOM
 Physical
Air borne particulate matter
HEPA integrity
Air changes/hour
Flow pattern in room
Pressure difference across filter
Temperature and Humidity
 Microbiological
Settling plate
Slit plate
Surface sampling
Parameter Testing frequency
 Particulate monitoring in air  6 monthly
 HEPA filter integrity testing  Yearly
 Air changes rate  6 Monthly
 Air pressure differentials  Daily
 Microbiological monitoring by  Daily
settle plates  Daily
 Temperature and Humidity
UTILITIES OF STERILE AREA
 Aseptic area are generally made in order to prevent contamination.
 Aseptic technique means using practices and procedures to prevent
contamination from pathogens.
 It involves applying the strictest rules to minimize the risk of infection.
 Health care workers use aseptic technique in surgery rooms, clinics, outpatient
care centers and other health care places like pharmaceutical industry.
 Health care professionals commonly use aseptic technique whenthey are:
Handling surgery equipment
Performing dialysis
Handling dialysis catheters
Inserting a chest tube
Performing various surgical techniques
LAYOUT OF STERILE AREA
 Sterile products are produced by:
 Aseptic Processing
 Terminal Sterilization
ASEPTIC PROCESSING
TERMINAL STERILIZATION
MAINTENANCE OF STERILE
AREA
 It includes maintenance of :
a) Personnel
b) Equipments
c) Environment
d) In process control
PERSONNEL TRAINING &
MONITORING
 Clean rooms should remain minimum amount of the personnel.
 It is especially important for an aseptic manufactures .Inspections and
controlling should be done, being outside of clean zones.
 All personnel (including the personnel occupied with clearing and
maintenance service), working in such zones, should have regular training
concerning manufacture of sterile products, including the bases of hygiene and
microbiology.
 It is necessary to pay special attention to instructing and control over the
workers who have not taken such training but it is necessary for them to enter
into a clean room.
 Personal hygiene is also important not to be so professional in the terms of
work but in the form of employee work satisfaction under safety.
QUALIFYING PERSONNEL
AFTER GOWNING
 Microbiological surface sampling of severe locations

1. Glove fingers
2. Face mask
3. Forearm
4. Chest
5. Periodic requalification is necessary.
EQUIPMENT HANDLING
 Critical surfaces:
Surfaces that may come in contact with or directly affect a sterilized product
or its containers or closures. Critical surfaces are rendered sterile prior to the
start of the manufacturing operation, and sterility is maintained throughout
processing.
ENVIRONMENTAL
MONITORING
 In aseptic processing, one of the most important laboratory controls is the
environmental monitoring program.
 Why should an environmental monitoring program cover and how?
All product shifts
Air, floors, walls, equipment surfaces including critical surfaces.
Critical surface sampling should take place at the conclusion of the aseptic
processing operation.
The location of surfaces to be samples, timing, and frequency of sampling
should be specified in writing.
ESTABLISHING AND
MONITORING AN ASEPTIC
ENVIRONMENT
Use clean rooms of various classes to establish an aseptic area.

 Clean rooms use combination of filtration, air exchange and positive pressure
to maintain “clean” environment.
 Lower quality clean areas should not be placed next to high quality areas.
FACILITIES : GENERAL CLEAN
ROOM DESIGN
 HEPA/ULPA filters on ceiling
 Exhaust vents on floors
 Drains in aseptic processing areas are inappropriate.
 Airlocks and interlocking doors to control air balance.
 Seamless and rounded floor to wall junctions
 Readily accessible corners
 Floors, walls, and ceilings constructed of smooth hard surfaces that can be easily
cleaned.
 Limited equipment, fixtures and personnel.
OPEN ISOLATORS
 Require laminar airflow over critical areas.
 Use pressure differential to ensure separation of critical area from external
environment (17.5-50Pa, 0.07-0.20 water gauge)
 Local protection of opening to guard against turbulent airflow and pressure
waves that could compromise critical area.
ISOLATOR
DECONTAMINATION
 Vaporized agents often used:
Glutaraldehyde, formaldehyde, etc.
Use indicator organisms to demonstrate effectiveness of decontamination.
• Should be able to achieve 4-6 log reduction in titer.
• Biological indicator should be placed in multiple, justified locations
throughout the isolator.
• Hard to reach areas (between fingers on gloves) should be addressed.
MATERIALS NOT PERMITTED
IN CLEAN ROOM
 Fibre-shedding materials such as cardboard and paper.
Cardboard packaging must be removed and items placed into non-cardboard
containers.
 Wood ( i.e. wooden pallets)
 Undesignated charts
DISINFECTANTS
&ANTISEPTICS
 Antiseptic: Agent applied to living tissue
 Disinfectant: Agent applied to inanimate surface.
 Examples: glutaraldehyde, formaldehyde, other aldehydes, chlorine releasing
agents, iodine and iodophors, peroxygens and ethylene oxide.
MOSTLY USED AGENTS
1. Chlorhexidine Gluconate,4%w/v
2. Iodophors
3. Isopropyl alcohol, 70%
4. Hexachlorophene PhisohexR (no longer recommended)
IN PROCESS CONTROLS
1. Sterile filtration:
 Sterilizing grade filters ( 0.22µm pore size or smaller)
 Use of redundant sterilizing filters should be considered.
 Filters should be validated including the use of microbial challenge.
 Materials:
Poly-vinyl-dene-difluoride (PVDF)
Poly-tetra-fluoro -ethylene (PTFE)
Poly-ether-sulfone
Nylon6,6
 Filter validation:
• Factors that affect filter performance:
 Filtration microbial challenge
Challenge should be at least 10^7 organisms/cm^2 of filtration area.
Number of uses
Filtration time limit
Integrity testing
Forward flow
Bubble point
2. Media fills:
 Used to validate the aseptic process.
 Use microbial growth media instead of drug product-any contamination will
result in microbial growth.
MEDIA FILL STUDY DESIGN
 The design of a media fill study should address the following factors:
Any factors associated with longest run that can pose contamination risk
Lyophilization
Aseptic assembly of equipment
Number of personnel and their activities
A representative number of aseptic additions
Shift changes, breaks, gown changes
Aseptic sample collection
Container closure sysytem
STERILITY TESTING
 For each batch of drug product purporting to be sterile and/or pyrogen-free,
there shall be appropriate laboratory testing to determine conformance to such
requirements.
 Sterility can be defined as the freedom from the presence of viable
microorganisms. However, the conditions that guarantee absolute sterility are
usually too harsh for active ingredients, and the definition of sterility for a
medicinal product must be defined in functional terms.
 There are two alternate methods available when conducting sterility tests:
a) The direct inoculation
b) Membrane filtration
DIRECT INOCULATION
MEMBRANE FILTRATION
 Recommended by most pharmacopoeias, the method by which the great
majority of products are examined.
Membrane filter (pore size 0.45µm); any microorganism present being
retained on the surface of the filter. After washing in situ, the filter is divided
aseptically and portions are transferred to suitable culture media which are
then incubated at the appropriate temperature for the required period of time.
Water-soluble solids can be dissolved in suitable diluent and processed. In
this way, oil-soluble products may be dissolved in a suitable solvent, e.g.
isopropyl myristate.
CONTROL OF
CONTAMINATION
 Maintaining sterility and contamination control are important factors in any of
the pharmaceutical industry. Most, if not all chemicals naturally contain some
degree of contamination, however, even low levels of contaminants can be
expensive or possibly hazardous.
 In clean room labs, the unlikely presence of contaminants can call surprise
reactions and deviate from actual results. In drug/medical equipment
manufacturing, contaminants can include toxins that convert a medicine into a
poison, while infected medical devices can transmit pathogens to patients.
 People came to different ways to manufacture contaminant free products,
ranging from sterilization to containment and contamination control,
depending on the degree of sterilization.
 Limiting the contamination leads to various options available in the market.
From laminar air flow, sealed transfer hatches to disposable containment
systems for individual processes. They provide complementary protection
against infection and avoid cross-contamination.
 In the pharmaceutical industry, decontamination is the first step to proceed
further. Everything from laboratory animals to the glassware and processing
equipment should be sterilized.
 All the glasswares are sterilized in the lab with the help of autoclave. Other
options include dry heat sterilizers and chemical vapour sterilizers. HPV
decontamination system involve the release of hydrogen peroxide vapour, a
powerful disinfectant that combats viruses, fungi and bacteria.
 Clean rooms provide an isolated, ventilated area for safe handling of chemicals
and biologicals. They cannot prevent contamination altogether, but help to
keep contamination to a limited level, protecting cleanroom products from
contamination from the environment, safeguarding chemists and researchers
against hazardous chemicals and biologicals in the cleanroom, and sometimes
protecting the environment at major level from hazardous substances and
pathogens.
THANK
YOU