Microbial contamination of pharmaceutical products can be influenced by the environment, materials, formulation, equipment, and personnel involved in production. Good manufacturing practices, hazard analysis, and cleanroom facilities are important to minimize contamination. Strict control of air quality, water sources, packaging, and equipment is necessary, as microorganisms may be introduced from these sources or survive and grow if conditions allow. Proper cleaning and disinfection of equipment, facilities, and raw materials is essential to control microbial contamination in pharmaceutical manufacturing.

1. Microbial contamination

2. The microbiological quality of pharmaceutical
products are influenced by:
• Environment and materials used like:
• Formulation
• Raw materials
• Equipment
• Atmosphere
• Person operating
• Final container

3. Good Manufacturing Practices
• To minimize contamination
• By Study of the ecology of microorganisms
• Hazard Analysis of Critical Control Points (HACCP)
• Its objective is to improve the microbiological safety of the product in
a cost-effective manner

4. Atmosphere
• The type of formulation being prepared determines the
microbiological standard of the air supply required and the hazard it
poses.
• Example: in case of Products for injection and ophthalmic (relating to
the eye) use
• An unsatisfactory air count may lead to the casual contamination of a
few containers and be undetected by the test for sterility.

6. The microbial count of air may be reduced by
• Filtration – (cellulose, glass wool, fibreglass mixtures, etc)
• Chemical disinfection- (propylene glycol, ammonium compounds,
formaldehyde gas, etc)
• Ultraviolet (UV) light
• Most critical aseptic work, requires removal of all particles in excess
of 0.1 μm in size, but for many operations a standard of less than 100
particles per 3.5 litres (1.0 ft3) of 0.5 μm or larger is adequate.

8. Cleanroom

10. Biological Safety Cabinets
• Class I - Personnel and Environmental Protection Only
• Class II - Product, Personnel and Environmental Protection
• Class III - Total Containment Cabinets

11. Water
Two main aspects are involved:
• The quality of the raw water
• Any processing it receives and the distribution system
• Microorganisms indigenous to fresh water
• Bacteria which are introduced as a result of soil erosion, heavy rainfall
and decaying plant matter
• Contamination by sewage

13. Supply water
• Surface water the flora - more abundant and faster-growing
• Deep water source such as a well or spring are comparatively less as it
gets filtered out
• Softened water is often used for washing containers before filling with
liquid or semi-solid preparations and for cooling systems.
• Deionized water is used in pharmaceutical formulations, for washing
containers and plant, and for the preparation of disinfectant
solutions.

14. • Distilled water is often used in the formulation of oral and topical
pharmaceutical preparations and a low bacterial count is desirable.
• Water for such preparations is often stored at 80°C in order to
prevent bacterial growth and the production of pyrogenic substances
which accompany such growth.
• Water produced by reverse osmosis (RO) is forced by an osmotic
pressure through a semi-permeable membrane which acts as a
molecular filter.

15. Distribution system
• If microorganisms colonize a storage vessel, it then acts as a microbial
reservoir and contaminates all water passing through it.
• It is therefore important that the contents of all storage vessels are
tested regularly.

17. Microbial transfer from operators

18. Raw materials
• During the manufacture of pharmaceuticals whatever the means of
prevention of growth or survival by chemical or in-process treatment,
it should be regarded as critical and controlled accordingly.
• Untreated raw materials which are derived from a natural source
usually support an extensive and varied microflora.
• Products from animal sources such as gelatine, desiccated thyroid,
pancreas and cochineal may be contaminated with animal-borne
pathogens.

19. Packaging
• Packaging material
• composition and storage conditions
• Closure liners of pulpboard or cork, unless specially treated with a
preservative, foil or wax coating, are often a source of mould
contamination for liquid or semi-solid products.

20. Equipment
The following points are common to many pieces of plant and serve as a
general guide to reduce the risk of microbial colonization.
1. All equipment should be easy to dismantle and clean.
2. All surfaces which are in contact with the product should be smooth,
continuous and free from pits, with all sharp corners eliminated and
junctions rounded or coved.

21. 3. There should be no inside screw threads and all outside threads
should be readily accessible for cleaning.
4. Coupling nuts on all pipework and valves should be capable of being
taken apart and cleaned.
5. Agitator blades and the shaft should preferably be of one piece and
be accessible for cleaning.

22. 6. Mechanical seals are preferable to packing boxes.
7. Valves should be of a sanitary design, and all contact parts must be
treated during cleaning and sanitation, and a wide variety of plug type
valves are available for general purpose use.

23. 8. All pipelines should slope away from the product source and all process
and storage vessels should be self-draining.
9. If a vacuum exhaust system is used to remove the air or steam from a
vessel, it is necessary to clean and disinfect all fittings regularly.
10. If any filters or straining bags made from natural materials such as
canvas, muslin or paper are used, care must be taken to ensure that they are
cleaned and sterilized regularly to prevent the growth of moulds such as
Cladosporium spp., Stachybotrys spp., and Aureobasidium
(Pullularia)pullulans, which utilize cellulose and would impairthem.