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A Risk-Management Case Study.
When a manufacturer produces two or more drug substances in the same manufacturing facility, the facility is considered to be multiproduct. The facility designs, operations, and controls related to the use for multiple products should provide for appropriate measures to prevent cross-contamination between products. These controls include the containment procedures used to prevent the release of hazardous agents within the facility.
There are numerous facility design and operational attributes that may significantly affect the quality of products being manufactured. These attributes include, but are not limited to, area classifications, open versus closed processing, utility-system design, cleaning validation/clean-in-place systems, rules regarding equipment sharing, and critical flows throughout the facility. Facility designs and operations should provide for appropriate segregation of products to prevent cross-contamination. For facilities with multiple products or processes, the impact of potential process or product failures on the other operations in the same facility should be evaluated.
The following case study on facility biocontainment and inactivation is part of a series put together by the Product Quality Research Institute Manufacturing Technical Committee (PQRI–MTC) risk-management working group. The series, available on http://www.pqri.org/publications/index.asp, is meant to advance the understanding and application of the International Conference on Harmonization (ICH) Q9 Quality Risk Management guideline by providing actual examples of risk-management assessments used by the bio/pharmaceutical industry.
In this case study, two existing manufacturing suites were proposed to be remodeled to accommodate and contain manufacturing operations involving bacterial fermentation through viable cells of Streptococcus pneumoniae, a pathogenic Biosafety Level 2 (BL2) organism. These suites were separate manufacturing areas located adjacent to mammalian cell culture manufacturing-processing areas. Regulatory guidance requires BL2-Large Scale (LS) waste and residues to be inactivated prior to exiting the manufacturing area (3). An inactivation autoclave was identified during the initial risk assessment as one of the primary means of inactivation of BL2 waste and process equipment prior to exiting the fermentation suite. The risk-review step in the risk-management process identified that there was only one inactivation autoclave in the fermentation suite and that alternative backup inactivation procedures were desired to maintain continuity of manufacturing operations during autoclave preventive- and corrective-maintenance activities.
This case study describes the evaluation of various backup inactivation procedures for operational feasibility and includes a demonstration of an appropriate level of inactivation of the BL2 waste and equipment.
The risk question developed for the subject case study is: What are the appropriate backup inactivation methods (i.e., procedures) that are operationally feasible and provide an appropriate level of decontamination capability that can be utilized in the fermentation suite to inactivate BL2 waste and equipment when the inactivation autoclave is unavailable?
Selection of a backup inactivation procedure is a precise exercise requiring an objective evaluation of the effectiveness of proposed procedures at inactivating the BL2 organism along with demonstration of consistent execution of these procedures each time they are performed.
Hazards analysis and critical control points (HACCP) is a risk-assessment tool that can be proactively used to identify and implement process controls that consistently and effectively prevent hazards from occurring. HACCP involves evaluation of critical procedural limits and determination of how they will be achieved routinely. Because it is essential that the backup inactivation procedures prevent the release of the BL2 organism outside of the fermentation suite, HACCP was selected as the risk-assessment tool to use to determine the appropriate preventative controls.
For this evaluation, there was only one hazard to consider: the BL2 organism. The HACCP process was significantly streamlined to control for operator safety and the high level of regulatory requirements for pathogenic BL2 organisms. The hazard was always considered to be significant in this case study (see Table I).
Table I: Hazard-analysis worksheet.
As shown in Table I, each proposed inactivation mechanism or procedure was deemed crucial because they were proposed as backups for the primary autoclave inactivation method (which was itself deemed crucial). The evaluation of the effectiveness of the procedures including how they would be controlled to achieve consistency among critical parameters is shown in Table II.
Table II: HACCP plan form for the evaluation of the effectiveness and control of standard operating procedures (SOPs). RTD is resistance temperature detector. EH&S is environmental health and safety.
In this case study, identifying effective backup inactivation methods to compensate for times when the primary inactivation autoclave is unavailable for use reduces the risk of a breach of containment in the facility. Table II demonstrates that the backup procedures identified are effective and can be consistently controlled. Table II also indicates that additional, more detailed procedural controls and more clearly defined functional-area responsibilities are required to maintain proper containment of the BL2 organism. These additional procedural controls are identified in the "recommended actions" column of Table II.
For this case study, the outputs of the risk-assessment process, including recommendations for additional procedural and functional-area controls, were documented in a risk-assessment report. This report became part of the operating history of the manufacturing facility and the associated product. The project team of each functional area affected by the results of the risk assessment reviewed and signed off on the results and recommendations. The project team assumed responsibility for implementing the recommendations that arose from the quality risk-eanagement process.
In the case study presented, it may be appropriate to review the backup procedures as additional detailed procedures are developed. This activity will ensure that the backup procedures are fully effective and controlled in an effort to contain appropriately the BL2 organism.
Steve Reich, Kristin Murray*, and Stephen Brooks are with Pfizer; Ted Frank is with Merck & Co; Ed Sanchez is with Johnson & Johnson; Brian Hasselbalch is with the FDA Center for Drug Evaluation and Research; Kwame Obeng is with Bristol Myers Squibb; and Richard Creekmore is with AstraZeneca. *To whom all correspondence should be addressed, at firstname.lastname@example.org