Process control
Holding and processing times for animal-derived material should be minimized to reduce the likelihood of microbial proliferation. The process qualification studies should include microbial sampling at multiple time points to evaluate the effects of time, temperature, and processing conditions on microbial growth. Routine microbial identification will provide valuable information regarding the types of organisms present in incoming material and throughout the manufacturing process. Processing conditions can then be adjusted to help control the number and types of organisms present during the manufacturing process. Spores and many bacteria can be removed by filtration when filtration or filtration cascade systems are possible. Usually filters with a pore size rating of 0.45 micron or smaller will remove spores and many bacteria from a preparation. Viruses and many toxins are heat labile so a heat treatment should be considered early in process development. Many purification and concentration systems may have antimicrobial effects. The timing and sequence location in the process along with appropriate holding and processing times may serve to optimize the antimicrobial effects of the processes.

Development of process monitoring tests and acceptance criteria should be established during the process development stage.

Facility and equipment controls
Facilities can also be reservoirs for pathogenic agents. Maintaining a facility within CGMP should include but not be limited to:

• Having adequately trained staff
• Using suitable quality water during manufacturing
• Having a facility design that minimizes the risk of cross-contamination
  Providing for proper storage of the ingredient
• Cleaning procedures should include cleaning of facilities and equipment that ensures the removal of all raw materials between batches.
• Designing an effective cleaning program involves setting specific standards, understanding the facility’s microbial environmental isolates, and selecting the right disinfecting agents to inactivate isolates that may be in the product or in the environment.
• Ingredient manufacturers should use sporicidal agents at appropriate intervals in the cleaning schedule to destroy bacterial and fungal spores. References:

FDA Guidance for Industry, 2001, ICH Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients
United States Pharmacopeia (USP) General Information Chapter <1072> Disinfectants and Antiseptics (USP33–NF 28 Reissue, 2010)
Wiley, JM, L Sherwood, and CJ Woolverton, 2008, Prescott, Harley and Klein’s Microbiology, Boston: McGraw-Hill Higher Education.