Risk identification and analysis
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.
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.
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.
Risk documentation and communication
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-management 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.
Ted Frank is with Merck & Co; Stephen Brooks, Kristin Murray,* and Steve Reich are with Pfizer; 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
1. T. Frank et al., Pharm. Technol.
35 (7), pp. 72–79.
2. T. Frank et al., Pharm. Technol.
35 (8), pp. 72-75.
3. NIH, Guidelines for Research Involving Recombinant DNA Molecules, Appendix K (May 2011).