Microbial Risk in Pharmaceutical Manufacturing and ICH Q9:

Microbial Risk in Pharmaceutical Manufacturing and ICH Q9

1. Dennis E. Guilfoyle, 
2. Richard L. Friedman, 
3. Patricia F. Hughes,
4. David Hussong, 
5. Amy S. Rosenberg and 
6. Kurt Brorson

+Author Affiliations

1. Food and Drug Administration
   Northeast Regional Laboratory
2. Food and Drug Administration
   Center for Drug Evaluation and Research

1. Correspondence author: Kurt Brorson, Food and Drug Administration: Center for Drug Evaluation and Research. journal@pda.org

Pharmaceutical manufacturing generally comprises a complex, multi-step processing system in which significant risks from microbial contamination are presented by diverse sources including raw materials, personnel, equipment, the facility, the environment, and container-closures. A comprehensive and rigorous approach to process design, operational control, and maintenance minimizes contamination risk to the product. A robust program should be in place to identify potential sources of microbiological contamination and to mitigate such risks. The risk management program should incorporate new information as knowledge and understanding regarding potential sources of risk expands. Indeed, as has often been found, subtle changes or anomalies that develop throughout the process lifecycle may introduce significant new microbial hazards that should be identified, evaluated, and appropriately addressed.

ICH Q9 describes important principles of sound quality risk management (QRM) that should be implemented by manufacturers to mitigate microbial hazards. The tools described in ICH Q9 can help manufacturers become aware of emerging microbial risks not only in emphasizing investigations into potential hazards, but in also stressing that risk management is not a “one time” exercise. Rather, “risk management should be an ongoing part of the quality management process” and “the output/results of the risk management process should be reviewed to take into account new knowledge and experience.” Thus, in regard to microbial contamination, manufacturers should monitor microbial profiles of natural raw material sources, and maintain current knowledge of contamination experiences reported by firms at technical conferences or in relevant literature (e.g., new veterinary findings of viral or bacterial risks from source animals). Appropriate measures should then be undertaken to mitigate risk based on such knowledge.

This awareness includes acquiring knowledge of the microorganisms that may enter or grow in the manufacturing process and cause upstream bioburden issues. Examples include viruses in raw materials that amplify in production cell culture, Gram-negative microorganisms that may proliferate at the pre-filtration stage, or downstream bioburden issues including finished product contamination. Recent examples of contamination problems have included bacteria that pass through sterilizing filters (e.g., Leptospira) and viruses present in raw materials (e.g., Vesivirus 2117) that are amplified during cell culture steps. We recommend that firms share these experiences in as open a manner as feasible, as these are public health risks that transcend competitive interests. As knowledge of emerging possible routes of contamination is made available, we also encourage manufacturers to share any appropriate risk mitigation measures that were adopted to better safeguard the product.

With this background, we would like to share the following recommendations regarding microbial risk management:

1. Review available external information from scientific literature, conference presentations, and technical reports from industry organizations that may provide vital information on microbial risks to the process. Where appropriate, mitigation strategies can then be proactively enacted to counter such risks.
2. Use Quality Risk Management (QRM, see ICH Q9) as a key element of your quality system (ICH Q10) to enable sound initial decisions, followed by subsequent continual improvements to design, control, and maintenance to vigilantly prevent microbial risks. Knowledge management is another important element of an effective quality system. Maintaining consistent manufacturing control to prevent contamination requires effective communication between departments, along with effective management of, and learning from, large information streams.
3. Use QRM to define corrective and preventive action (CAPA) plans in response to newly identified sources of contamination risk throughout the lifecycle of the product. ICH Q9 and ICH Q10 are again good references, as they include guidance on performing effective and risk-based investigations and CAPA). A more global response plan may be warranted in some cases to prevent risks to other products and processes.
4. Use appropriate laboratory tests for bacteria, fungi, and viruses. Particularly for viruses, implementation of orthogonal test methods may mitigate detection gaps. Moreover, highly sensitive high-throughput screening methods may be used on a periodic basis to help update the range of routine tests needed as new adventitious agents posing risk are identified.
5. Incorporate an understanding of nonsterile and sterile drug risk assessment. For a sterile drug, contamination with a microorganism is an intolerable risk to the patient. For nonsterile dosage forms, assessing microbial risk is more nuanced, and consideration should be given to the following four elements:
   • Intended use of drug, including understanding of the dosage form and how administered. The route of administration (e.g., oral, topical, nasal, inhaler, injectable.) is an important aspect of microbial risk. For example, for nonsterile topical drugs, this includes understanding the site of application as part of assessing vulnerability to potential for infection. While a nonsterile topical drug should not be applied to a burn or wound, it would be unlikely to pose a hazard to healthy, intact skin.
   • Identity of microorganisms in the product, and “infective dose” (i.e., quantity of a microbe that would lead to pathogenicity). This factor includes understanding of the total microbial count and identity of microbes in the product, as well as whether the latter may be objectionable in view of the product's intended use. Note that the infective dose can vary substantially based on the next factor.
   • Susceptibility of the patient. Knowledge of the nature of the population taking the drug, including whether some patients may be at increased risk, is also significant consideration. Examples of higher risk hosts are those with risk factors such as: chronic disease, shock or trauma, pregnant, immunocompromised, elderly, or very young.
   • Composition of the product. Preservatives are not a substitute for good manufacturing practices and is only intended to mitigate risk from possible incidental contamination during multiple uses. When evaluating this factor, consider whether the product has effective antimicrobial/preservative properties, the product can still support growth of certain organisms, or if it permits stasis of any microbial contamination.

A risk-based assessment incorporating the five recommendations above should be conducted by appropriate technical staff, including microbiology personnel with specialized training in the interpretation of microbiological data. Medical expertise may also be necessary to assess potential patient hazard. A final determination of process consistency and product safety that is both objective and collaborative should be supported by management. Ultimately, by incorporating a lifecycle approach to QRM, the quality system will help prevent surprises and assure the consistent supply of safe and effective medicines.

• © PDA, Inc. 2013

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