2. OUTLINE
INTRODUCTION
COTROL OF MICROBIAL CONTAMINATION
DURING MANUFACTURING
MANUFACTURE OF STERILE PRODUCT
A GUIDE TO CURRENT GOOD
PHARMACEUTICAL PRACTICE
3. Regulatory authorities require that
pharmaceutical products be manufactured
according to the principles of good
manufacturing practice (GMP).
REGULATORY AUTHORITIES INCLUDE:
i. The European Union (EU)
ii. the UK Medicines and Health Care Products
Regulatory Agency (MHRA)
iii. The US Food and Drug Administration (FDA)
4. Products manufactured in the UK for the US
market must satisfy the FDA.
GMP guidelines were first given statutory
authority in the USA and published in the UK in
1971.
IMPORTANCE OF GMP COMPLIANCE
In order to protect patient safety and prevent
financial repercussions, GMP compliance is
essential.
Failure to follow GMP can lead to legal action,
product recalls, license revocation, and bad press.
A previous GMP failure resulted in a significant
vaccination shortage in the USA.
5. Some products, such as injections, must be
sterile.
Oral drugs, need not be sterile but must be free
from pathogens that can be contracted via the
oral route.
The manufacture of sterile products is carried
out in both industry and hospitals.
Batches tend to be much smaller, sometimes
only one item, and the products are stored for a
much shorter time, usually less than 24 hours.
6. IMPORTANT DEFINITIONS:
i: Quality
For the purpose of pharmaceutical products the
term quality is usually taken to mean fitness for
purpose .
Not only must the product have the desired
therapeutic properties, it must also be safe for
administration by the route intended.
ii: Manufacture
Manufacture is the complete cycle of production of
a medical product.
This cycle includes the acquisition of all raw
materials, their processing into a final product,
and subsequent packaging and distribution.
7. iii: Quality assurance ( QA )
It is the total sum of the procedures needed to
ensure the fitness of a pharmaceutical product for
its intended use.
QA incorporates GMP plus other factors.
iv: Good manufacturing practice ( GMP )
GMP is that part of QA which is aimed at
ensuring the product is consistently
manufactured to a quality appropriate for its
intended use and to meet the requirements of the
regulatory authorities.
GMP requires that: (1) the manufacturing process
is fully defined before it begins; and (2) the
necessary facilities are provided.
8. v: Quality control ( QC )
QC is that part of GMP concerned with sampling,
specifications and testing, as well as the
organization, documentation and release
procedures which ensure that the necessary and
relevant tests are carried out, and that materials are
not released for use, nor products released for sale
or supply, until their quality has been judged
satisfactory.
vi: In - process control
This comprises any test on a product, the
environment or the equipment that is used during
the manufacturing process.
An example of this is testing that an autoclave is
functioning correctly.
9. A pharmaceutical product may become contaminated
by a number of means and at several points during
manufacture.
There are several ways in which this risk can be
minimized. These are as follow
i: Risk assessment
GMP is informed by past mistakes and case studies
have been valuable.
Nowadays a manufacturer is expected to demonstrate
to the regulatory authorities that an extensive risk
assessment has been carried out.
10. Risk analysis must comply with ICH 9Q and is underpinned by
a sound understanding of the process and of the microbial
ecology of the environment and ingredients.
Several methods are employed including hazard analysis
critical control points (HACCP), failure mode and effects
analysis (FMEA).
Hazard Analysis Critical Control Points (HACCP)
HACCP has been widely used in the food industry and is
becoming more commonly used in the pharmaceutical
industry. The original HACCP had seven steps:
1: Conduct a hazard analysis and identify preventive measures for
each step of the process.
2: Determine the critical control points.
3: Establish critical limits.
4: Establish a system to monitor the critical control points.
5: Establish the corrective action to be taken when monitoring
indicates that the critical control points are not in a state of control.
6: Establish a system to verify that the HACCP procedure is
working effectively.
7: Establish a record - keeping system.
11. However, HACCP has been modified so that it
can be applied quantitatively not only to
microbiology but also to pyrogens and particles.
Failure Mode and Effects Analysis (FMEA)
FMEA was first used in the engineering industry.
It involves breaking the process down into many
discrete steps.
For each step scales are set for severity, occurrence
and detection.
The scores are multiplied and compared to an
informed score at which risk becomes
unacceptable.
12. ii: Environmental Cleanliness and Hygiene
Microorganisms may be transferred to a product from working
surfaces, fixtures and equipment. Pooled stagnant water is a
frequent source of contamination. Thus it is essential that all
working areas are kept clean, dry and tidy. Any cracks where
microorganisms may accumulate must be eliminated.
Fall - out of dust - and droplet - borne microorganisms from the
atmosphere is an obvious route for contamination. ‘ Clean air’ is
therefore a prerequisite during manufacturing processes and the
spread of dust during manufacture or packaging must be
avoided.
Personnel are another source of potential contamination. High
standards of personal hygiene are essential. Operatives should
be free from communicable disease and open lesions on exposed
body surfaces.
To ensure high standards of personal cleanliness, adequate hand
- washing and hand - disinfecting facilities and protective
garments, including headgear and gloves, must be provided.
13. iii: Quality of Starting Materials
Raw materials account for a high proportion of the microorganisms
introduced during the manufacture of pharmaceuticals.
Raw materials which have some non-pathogenic microorganisms
present and this must be considered during risk assessment.
Untreated raw materials that are derived from a natural source
usually support an extensive and varied microflora.
Products from animal sources such as gelatin, desiccated thyroid,
pancreas and cochineal may be contaminated with animal - borne
pathogens.
The use of natural products with a high non-pathogenic microbial
count is possible if a sterilization stage is included either before or
during the manufacturing process.
Such sterilization procedures may include heat treatment,
filtration, irradiation, recrystallization from a bactericidal solvent
such as an alcohol, or for dry products, where compatible, ethylene
oxide gas.
14. iv: Water
Many grades of water are used in pharmaceutical manufacturing.
Water for manufacturing may be potable mains water, water
purified by ion exchange, reverse osmosis or distillation, or water
for injection purposes. Types of water for sterile manufacture
Type Properties Use
Mains (potable) Not sterile. Contains
ions, chlorine
Initial washing if
rinsed with purified
water
Purified water Potable water purified
by distillation, ion
exchange, reverse
osmosis
Not sterile
Washing containers
Water for injections BP Distilled water, free
from pyrogens (some
countries allow
reverse osmosis
Water for injections in
bulk
Final rinse Solutions to
be sterilized
Sterile water for Autoclaved in suitable Sterile solutions
15. v: Quality Control and Documentation
The lower the microbiological count of the starting materials,
the more readily the quality of the product can be controlled.
Microbiological standards should be set for all raw materials as
well as microbial limits for in-process samples and the final
product.
Microbiological quality assurance also covers the validation of
cleaning and disinfectant solutions and the monitoring of the
production environment by microbial counts.
This monitoring should be carried out while normal production
operations are in progress.
Documentation is a vital part of quality assurance.
Details of starting materials, packaging materials, and
intermediate, bulk and finished products should be recorded so
that the history of each batch may be traced.
Distribution records must be kept. This information is of
paramount importance in the event that a defective batch has to
be recalled.
16. vi: Packaging, Storage and Transport
Packaging serves a number of functions; it keeps the
contents in, it should keep contaminants out and is labelled
to permit identification of its contents.
Closure liners of pulpboard or cork, unless specially treated
with a preservative, foil or wax coating, are often a source of
moulds contamination for liquid or semisolid products.
A closure with a plastic flowed-in liner is less prone to
introduce or support microbial growth than one stuck in
with an adhesive, particularly if the latter is based on a
natural product such as casein. Closures can be sterilized by
either formaldehyde or ethylene oxide gas if required.
Injectable and ophthalmic preparations which are
manufactured aseptically but do not receive a sterilization
treatment in their final container the packaging has to be
sterilized.
Dry heat at 170 ° C is often used for vials and ampoules.
17. For production purposes an important distinction
exists between sterile products which have been
terminally sterilized and those which have not.
Terminal sterilization involves the product being
sealed in its container and then sterilized, usually by
heat, but ionizing radiation or, less commonly,
ethylene oxide may be employed. Such a product must
be manufactured in a clean area.
A product which cannot be terminally sterilized is
prepared aseptically from previously sterilized
materials or by sterile filtration; in either case, aseptic
filling is a post - sterilization step. Strict aseptic
conditions are required throughout.
18. Vaccines, consisting of dead microorganisms, microbial extracts
or inactivated viruses may be filed in the same premises as other
sterile medicinal products, so the completeness of killing or
removal of live organisms must be validated before processing.
Separate premises are needed for the filing of live or attenuated
vaccines and for the preparation of other products derived from
live organisms.
Non - sterile products and sterile products must not be
processed in the same area.
Clean and Aseptic Areas
i: Design of premises
Sterile production should be carried out in a purpose-built unit
separated from other manufacturing areas and thoroughfares.
The unit should be designed to encourage separation of each
stage of production but should ensure a safe and organized
workflow.
19. ii: Internal surfaces, fittings and floors
Contamination must be prevented.
To this end all surfaces must be smooth and impervious in
order to: (1) prevent accumulation of dust or other
particulate matter; and (2) permit easily repeated cleaning
and disinfection.
Smooth rounded coving should be used where the wall
meets the floor and the ceiling.
Suitable flooring may be provided by welded sheets of
PVC; cracks and open joints which might harbor dirt and
microorganisms must be avoided.
Internal fittings such as cupboards, drawers and shelves
should be kept to a minimum.
Stainless steel or laminated plastic are the preferred
materials for such fittings.
Stainless steel trolleys may be used to transport equipment
and materials within the clean and aseptic areas but must
remain confined to their respective units.
20. iii: Air supply
Filtered air is used to achieve the necessary standards; this should
be maintained at positive pressure throughout a clean or aseptic
area, with the highest pressure in the most critical rooms (aseptic
or clean filling rooms) and a progressive reduction through the
preparation and changing rooms
a minimum pressure differential of 10 kPa is normally required
between each class of room.
A minimum of 20 changes of air per hour is usual in clean and
aseptic rooms. The air inlet points should be situated in or near
the ceiling, with the final filters placed as close as possible to the
point of input to the room.
iv: Changing facilities
Entry to a clean or aseptic area should be through a changing
room fitted with interlocking doors; this design acts as an airlock
to prevent influx of air from the outside.
This route is for personnel only, not for the transfer of materials
and equipment.
21. Staff entering the changing room should already be clad in
the standard factory or hospital protective clothing.
For entry into a clean area, passage through the changing
room should be from a ‘ black ’ to a ‘ grey ’ area, via a
dividing step - over sill.
v: Cleaning and disinfection
A strict, validated disinfection policy is necessary if
microbial contamination is to be kept to a minimum.
Cleaning agents used include alkaline detergents and ionic
and non-ionic surfactants.
A wide range of chemical disinfectants is available.
Clear, soluble phenolic are commonly used for interior
services and fittings. Disinfectants for working surfaces are
alcohols (70% ethanol or isopropanol) or, less commonly,
chlorine - based agents such as hypochlorite's.
Skin may be disinfected with cationic detergents such as
Cetrimide or chlorhexidine, usually formulated with 70%
alcohol to avoid the need for rinsing. Gloved hands may be
disinfected with these detergents or 70% alcohol.
22. vi: Operation
The number of persons involved in sterile manufacture
should be kept to a minimum to avoid the inevitable
turbulence and shedding of particles and organisms
associated with the operatives.
All operations should be undertaken in a controlled and
methodical manner as excessive activity may increase
turbulence and particle shedding.
Ingredients which must be brought into clean areas must
first be transferred to suitable metal or plastic containers.
Containers and closures for use in aseptic manufacture
must, in addition, be sterilized after washing and rinsing in
preparation for aseptic filling.
23. Between 1971 and 1983 the essential features of GMP
were covered in the UK by three editions of the Guide
to Good Pharmaceutical Manufacturing Practice ,
frequently referred to as the ‘ Orange Guide. ’
This guide was prepared by the UK Medicines
Inspectorate in consultation with industrial, hospital,
professional and other interested parties.
The principles of this national guide were subsequently
assimilated into the EC Guide to Good Manufacturing
Practice for Medicinal Products in 1989 and are now
published as Rules and Guidance for Pharmaceutical
Manufacturers and Distributors (2007) by the MHRA.
24. The FDA has published FDA Requirements for
cGMP Compliance (2007) .
Two important publications from the
Pharmaceutical Press are Quality in the
Manufacture of Medicines and Other Health Care
Products (Sharp, 2000 ) and Quality Assurance of
Aseptic Preparation Services (Beaney, 2005 ),
which discusses manufacturing in hospitals.
Compliance with GMP is one of the major factors
considered by the licensing authority when
examining an application for a license to
manufacture under the Medicines Act (1968).
Similar codes exist in the USA and other countries.
