B2 - Objectionable Microorganisms in NonSterile Pharmaceutical Drugs Presented by: Thuy Bui An Approach to Microbiological Testing of Raw Materials Utilizing Microbial Growth Potential Assessment Kim Bowers Manager, Quality Science and Technology Pfizer, Andover MA Presented by: Thuy Bui QC Microbiology Manager, Pfizer, Inc. 2 1 B2 - Objectionable Microorganisms in NonSterile Pharmaceutical Drugs Presented by: Thuy Bui 3 4 2 B2 - Objectionable Microorganisms in NonSterile Pharmaceutical Drugs Presented by: Thuy Bui 5 Presentation Outline • Objective • Overview • Microbial Growth Potential • Raw Material Assessments: 2 examples • Considerations for the routine testing laboratory • Summary 6 3 B2 - Objectionable Microorganisms in NonSterile Pharmaceutical Drugs Presented by: Thuy Bui Objective of this presentation • An assessment approach to determine the type of microbial testing required for raw materials. This approach was developed in Andover, and is aligned with the general Pfizer process. • Assessment parameters: – Monograph present? – Is material of natural origin? – Microbial quality attributes: • Microbial growth potential 7 Overview • Raw materials used during biopharmaceutical manufacturing should be assessed for microbiological testing requirements prior to use at the site – EU guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use, Annex 2: Manufacture of Biological active substances and Medicinal Products for Human Use – USP <61>, <1111> • Harmonized with EP, JP 8 4 B2 - Objectionable Microorganisms in NonSterile Pharmaceutical Drugs Presented by: Thuy Bui Overview • Although the microbiological test methods are clearly defined per USP <61>,<62> and <85>, the requirements for determining the type of microbiological testing to perform are not as clearly defined • This can lead to inconsistencies in the approach to microbiological testing. 9 Overview • Pfizer, Andover is a low bioburden biopharmaceutical manufacturing site • The QC Microbiology Laboratory performs both bioburden (total count) and endotoxin testing on raw materials • In most cases, there is no established limit (monograph) for these materials, and the limit is set based on validation data, historical information from the vendor and/or from similar raw materials 10 5 B2 - Objectionable Microorganisms in NonSterile Pharmaceutical Drugs Presented by: Thuy Bui Overview • Pfizer Andover has developed an assessment strategy for determining the requirements for microbial testing by utilizing a system based on the microbial quality attributes of the raw material. • The approach looks at various factors that contribute to microbial growth potential. 11 Determination of Microbial Growth Potential • Microbial growth potential looks at multiple factors including storage, packaging and temperature • Key factors are: • Nutrient availability • Antimicrobial properties • Water activity • pH 12 6 B2 - Objectionable Microorganisms in NonSterile Pharmaceutical Drugs Presented by: Thuy Bui Nutrient Availability The availability of a nutrient source can be difficult to determine. A key factor is whether the raw material is naturally occurring or synthetic/refined Growth Promoting Known to promote Description growth of microorganisms Minimal Nutrients Contains minimal levels of nutrients not as readily utilized for microbial growth No nutrients Contains no organic compounds 13 Antimicrobial Properties • An antimicrobial agent is known to reduce microbial population and/or destroy microorganisms. A reference is required (USP, in-house study, etc.) Antimicrobial Properties Categorization Known Antimicrobial No Undetermined Yes Properties 14 7 B2 - Objectionable Microorganisms in NonSterile Pharmaceutical Drugs Presented by: Thuy Bui Water Activity • Water activity(aw) is the amount of free water in a substance and is associated with microbiological activity. It serves as an indication of potential metabolic activity. As per USP <1112>: Water Activity Microbiological Activity <0.75 Inhibitory <0.60 Growth ceases Solution with < 0.88 Inhibitory to most Category High Moderate Low Liquid with aW of >0.88 0.60-0.88 <0.60 Solid with aW of >0.88 0.75-0.88 <0.75 15 pH • Microbial cells require a physiological pH. A cell’s ability to survive in high or low pH depends on its ability to correct for the difference between inside and outside the cell (stability of the biochemical properties of the microorganism). Category Solid pH value NA Liquids Neutral 6-8 Moderate 3.5-6 or 810 Extreme <3.5 or >10 16 8 B2 - Objectionable Microorganisms in NonSterile Pharmaceutical Drugs Presented by: Thuy Bui Raw Material Assessment: Example 1 • Description of Raw Material –It is a solid –It is synthetic and highly refined –Has a carbon source –Has no known antimicrobial properties –Has a water activity of 0.38 17 Nutrient Availability & Antimicrobial Properites for Example 1 Material is synthetic, has a carbon source, equates to minimal nutrients Growth Promoting Minimal Nutrients No nutrients Known Antimicrobial No Undetermined Yes Properties 18 9 B2 - Objectionable Microorganisms in NonSterile Pharmaceutical Drugs Presented by: Thuy Bui Water Activity & pH for Example 1 Material is a solid with a water activity of 0.38 Category High Moderate Low Solid with aW of >0.88 0.75-0.88 <0.75 Category Solid pH value NA Liquids Neutral Moderate Extreme 6-8 3.5-6 or 8-10 <3.5 or >10 19 Determination of required testing for Example 1 • Material has minimal nutrients, no antimicrobial properties, low water activity and is a solid • Result = microbial growth potential, requirement for in house microbial testing (bioburden and endotoxin) 20 10 B2 - Objectionable Microorganisms in NonSterile Pharmaceutical Drugs Presented by: Thuy Bui Raw Material Assessment: Example 2 • Description of Raw Material –It is a liquid –It is synthetic and highly refined –Has a carbon source –Has antimicrobial properties –Has a water activity of 0.80 –Has a pH of 3.3 21 Nutrient Availability & Antimicrobial Properties for Example 2 Material is synthetic, has a carbon source, equates to minimal nutrients Growth Promoting Minimal Nutrients No nutrients Material has antimicrobial properties Known Antimicrobial No Undetermined Yes Properties 22 11 B2 - Objectionable Microorganisms in NonSterile Pharmaceutical Drugs Presented by: Thuy Bui Water Activity & pH for Example 2 Material is a liquid with a water activity of 0.80 and a pH of 3.3 Category High Moderate Low Liquid with aW of >0.88 0.60-0.88 <0.60 Category Solid pH value NA Liquids Neutral 6-8 Moderate 3.5-6 or 810 Extreme <3.5 or >10 23 Determination of Required Testing for Example 2 • Material is synthetic, with minimal nutrients, has antimicrobial properties, moderate water activity and low pH • Result = low microbial growth potential, no in house testing required 24 12 B2 - Objectionable Microorganisms in NonSterile Pharmaceutical Drugs Presented by: Thuy Bui Considerations for Routine Testing • During validation, stick with standardized test methods – Start with a standard test such as USP <61>, USP<85> – Add rinses and/or neutralizers as needed, following compendial guidance 25 Considerations for Routine Testing • Simplest test method with clear instructions – i.e. use a standard media (SCDA) even if alternate media might give slightly better recovery • Benefits to streamlined and simple approach: – Right first time – Standardized and quick training – Fits in with Standard work/lean labs approach 26 13 B2 - Objectionable Microorganisms in NonSterile Pharmaceutical Drugs Presented by: Thuy Bui Considerations for Routine Testing • Validation should include rationale for selection of the test method – Understanding of why the validation was done the way it was • Some frequency of periodic review of the limit would be beneficial – Revisit the established limit once a larger data set is available. – Establishment of the limit is preliminary and is based on a small data set, historical information and similar raw materials. 27 Summary • Having a procedure in place to assess microbial testing requirements provides the manufacturing facility and the QC Microbiology laboratory the following benefits: – consistency in approach – justification and rationale for testing – streamlined process to ensure that the appropriate testing is performed 28 14 B2 - Objectionable Microorganisms in NonSterile Pharmaceutical Drugs Presented by: Thuy Bui Acknowledgements • • • • Thuy Bui Lynn Johnson Hilary Chan Quality Science and Technology – Microbiology (Pfizer, Andover, MA) 29 15
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