PROCESS DEVELOPMENT AND CLINICAL PRODUCT MANUFACTURING - Risk Management Applications in Pharmaceutical and Biopharmaceutical Manufacturing - page 121

cross-contamination. The table has additional columns relating to failure causes
and, of course, assignment of risk scores using a scale of 1-5 for likelihood of
occurrence, and likelihood of detection and severity, respectively. A risk priority
number (RPN) is calculated by multiplying the occurrence by detection by sever-
ity and then prioritizing the risks by the size of the number obtained. The item
numbering is retained from Table 6.6 so that you can check back and see how
the controls have been ramped up and those that were acceptable for a phase 1
study are no longer accepted for a phase III (one step before commercialization
study).
To conclude this section, it is important to emphasize that there is no sin-
gle risk management tool that is appropriate for assessing the risks involved in
investigational products. The specific risks are product and process related and
are closely tied in with the quality system already existing within a particular
company. Incremental application of GMPs ties in with increased risks asso-
ciated with larger populations using the drug in late-stage trials, although the
safety of a few in early-phase trials cannot be overlooked. More importantly, a
company's knowledge base increases as it moves through the phases of clinical
study, such that some risks designated as “high” in phase 1 are substantially
reduced by phase 3 (e.g., toxicity profile may now be well understood and found
to be benign). The common thread throughout the development process is risk
identification, development, and implementation of appropriate risk controls, risk
communication (most commonly overlooked or rushed), risk monitoring, and
then event review—deviations and unexpected events that might send you back
for a revision of your initial assessment and implementation of new controls.
Likewise, all these need to be documented with a brief rationale supporting the
decision.
6.7 PRODUCT SPECIFICATION FILE, DEVELOPMENT HISTORY,
AND TECHNOLOGY TRANSFER
The product specification file is defined in Annex 13 of the EU GMPs as “A refer-
ence file containing, or referring to files containing, all the information necessary
to draft the detailed written instructions on processing, packaging, quality control
testing, batch release and shipping of an investigational medicinal product.”
The annex requires the following information at a minimum to be available
or referenced in the product specification file:
• specifications and analytical methods for starting materials, packaging mate-
rials;
• intermediate, bulk, and finished products;
• manufacturing methods;
• in-process testing and methods;
• approved label copy;