Manufacturing controls

Question 1

Atmospheric control essentials for non-sterile product

Answer 1

HVAC
Temperature and RH - Shedding
Containment levels
Minimal exposure - product, materials, equipment, people
Cleaning and disinfection
Good clothing practices

Question 2

Atmospheric control essentials for Sterile manufacture

Answer 2

Manufacture essentials:
HVAC
Temperature and RH - Shedding
Containment levels
Minimal exposure - product, materials, equipment, people
Cleaning and disinfection
Good clothing practices

Additional for sterile manufacture:
Terminal HEPA filters
Room air changes
Adequate pressure differentials
Extensive environmental monitoring
Personal hygiene
Strict adherence to aseptic procedures

Question 3

Laminar Air Flow (LAF)

Answer 3

Laminar Air Flow (LAF) enters the room from the ceiling after passing through terminal High Efficiency Particulate Air filters which remove over 99.9% of particulate larger than 0.3 microns.

Question 4

Compressed Air and Gas Controls

Answer 4

• Compressed gases which come in contact with product should be considered a “component” and controlled as such. For example, a Nitrogen overlay.
• Gases used in manufacturing of sterile product should be sterile filtered.
• Dew point must be controlled to reduce the risk of moisture entering the distribution system.
• The contamination risk from bottled gases, particularly those prepared by fractional distillation of liquid air, is much lower because the method of preparation is itself hostile to microbial survival.

Question 5

Facility Risks and Essential Controls

Answer 5

• Walls and Ceilings – smooth, cleanable surfaces and where painted done so with anti-fungal paint.
• Floor and Drains - floors and drains are the ideal environment for bacteria to multiply in very large numbers with wash bays being a prime source. These areas must be properly segregated including negative pressure to the outside environment, sloping floors to the drains, and cleanable with frequent cleaning. Floors must be level, durable, impervious to water, easy to clean (all joints must be sealed and floor to wall coving present to eliminate hard to clean corners) and maintained/repaired if damage does occur.
• Doors, Windows and Fittings – must be designed to be flush with the walls, made of nonporous and cleanable materials, and piping made of cleanable non-shedding materials. Any insulation must be fully sealed in an appropriate “jacket”.
• Equipment: Equipment should be designed to be easily dismantled and cleaned. Pay attention to gaskets. Product contact surfaces must be smooth and continuous with no inside threads!
• Valves:
  
  • Diaphragm valves should be inspected as the diaphragms can become damaged and leak
  • Butterfly valves should be checked for accumulation of residues
• Ball valves cannot be sanitized effectively Pumps:
  
  • Ensure there are no dead legs
  • Should be dismantled with ease
  • Self-emptying
• Check glands and drives Agitator blades:
  
  • Single piece
  • Cleanable
• Bottom impellers should be avoided Pipelines:
  
  • Welds and joints must be kept to a minimum
  • Internal surfaces should be smooth and polished internally
  • Pipes should be Self-draining
  • NO DEADLEGS
• Cleaning Equipment: Cleaning equipment (brooms, mops, disinfectants, cloths etc.) can provide an ideal environment for the growth of fungi and water-borne bacteria as well as air-borne particles if not non-shedding.
  
  • Disinfectants should be made up daily using water-for-injection or purchased ready to use
  • Inspection of mops and buckets for damage prior to use to ensure there is no shedding
  • Don’t use string mops - ever
  • Mops must be stored dry
• Raw Materials: may be a source of microorganisms especially if they are naturally derived.
  
  • Evaluate and qualify all raw material suppliers
  • Pre-treatment (as required) to reduce excessive bioburdens without damaging the raw material (e.g. gentle steaming, drying, irradiation)
  • Appropriate packaging to prevent moisture ingress, particularly for hygroscopic materials
  • Controlled storage and transportation conditions
  • Testing upon receipt
• Packaging Materials: Cardboard and paper, unless treated in some way, provide a hospitable habitat for microorganisms, particularly molds and Gram-positive bacteria which will proliferate further if they become wet. Packaging materials should have a smooth, impervious surface which is free from crevices, such as glass, cellulose acetates, plastics and metal foils and laminates to ensure a very low surface microbial count. Store packaging materials in a cool, dry place with relative humidity below 60%.

Question 6

Water Risks and Controls

Answer 6

The microbial ecology of water is extremely important in pharmaceutical manufacture because it is used for a variety of purposes during manufacture, including product formulation, washing of equipment and components and cooling. The quality of the water used during manufacture will depend upon:
* The quality of the raw water
* The processing it receives in-house
* The storage and distribution system
The controls for water systems include:
* Excellent design with good recirculation
* Keep potable supply water chlorinated for as long as possible
* Good system of pre-treatment before deionization
* Ensure absence of dead legs
* Pipework
* Surface finish
* Self-draining (sloped)
* Minimal welds
* Aggressive flow rates
* High operating temperatures
* Regular sanitisation of pipework and each unit operation
Key components in the design:
* UV sanitisation lamps in situ
* Carbon beds
* Depth filters
* Deionisation units
* RO membranes
* Storage tanks:
* Self-draining
* Vent filter rated at 0.2µ
* Good operating and maintenance procedures

Question 7

People – The Risks and Essential Controls

Answer 7

Up to 90% of cleanroom isolates originate from humans through:
* Direct contamination
* Indirect Contamination
* Non-sterile dosage forms at greater risk of contamination.
* Consequences of sterile product contamination – much more serious Cleanroom controls for people include:
* Where possible, use of closed Production Systems severely reduce the potential for direct and indirect operator contamination
* Personal hygiene is the single most important means of reducing product contamination by the operator. For example, failure to wash hands after visiting the toilet can lead to contamination of the hands other parts of the body. It is therefore essential that pharmaceutical companies provide them with appropriate training in the importance of personal hygiene and, most importantly, provide them with the facilities to maintain acceptable levels of cleanliness.
* Appropriate, protective clothing (gowning) can reduce or minimize the release of particles from the operator into the production environment. Aseptic colleagues must take care to properly gown in fully contained, integral gowns, booties, hood, gloves and mask which are clean, have been sterilized and are prepared from non-shedding materials. The limit for being in the cleanroom without a gown change is approximately 4 hours before the barrier begins to break down.
* Effective ventilation and airflows