Documentation, responsibilities, and follow-up
Approved written procedures and reports for the PAR/PQR are required or expected by FDA and the EU. The requirement for the
timely completion of corrective actions to address adverse trends is specifically mentioned in the EU and Q7A PQRs. The EU
PQR is the only one that requires a formal system for the ongoing management review of the follow-up actions and their effectiveness.
The EU PQR requires that the QP in the EU (i.e., that individual responsible for batch certification as well as other legal
requirements within the quality system) must ensure, together with the MAH, that the PQR is accurate and performed in a timely
manner. A common misconception in the US is that the QP must personally carry out all the activities for which they are responsible.
That is not true. The QP may delegate certain responsibilities provided she or he has the knowledge that these activities
are being conducted in accordance with both GMP and MA requirements. For example, in the case of the PQR, a practical interpretation
of the QP responsibilities might be that she or he has satisfied herself or himself that there is a robust system in place
to compile the PQR, that the relevant technical agreement or other formal instrument is in place to ensure that all parties
have agreed on their respective responsibilities, and the QP then performs the review and approval of the final PQR. The inclusion
of specific responsibilities for the MAH and not just the manufacturer in the PQR process reinforces the emphasis placed upon
the license holder in the European system.
The US GMP does not specify the responsibility for performing, or ensuring the proper performance of, the PAR. FDA's dosage-form
inspection guide, issued in October 1993, stated that the quality control unit must perform the PAR (15). This statement was
probably more indicative of the requirement to perform a PAR, rather than the actual responsibility for performance by the
quality control unit. In both EU and US drug companies, it is common practice for the quality control unit to perform the
FDA allows the use of a computer to conduct part of the PAR by running a computer program that culls out analytical data from
each batch to conduct a trend analysis (16). FDA does not allow the use of a computer to perform the complete assessment of
the trend data. The preamble to the 1995 GMP revision states that the computer cannot substitute for human judgment and intervention,
and computerized assessments must be monitored by qualified individuals to detect trends (8).
PAR/PQR: A quality systems approach
Industry comments as exemplified by both EFPIA and PDA were supportive of the requirement for a PQR seeing it, for example,
as an "integral part of an effective quality system" (14). Discussions with several EU regulators during the recent 2006 PDA–EMEA
Joint Conference in London highlighted their position that all the requirements contained in the EU PQR represent information
that should be readily available and, in fact, is already being compiled and used by drug companies. There is nothing in the
final version of the PQR requirements that is seen by the regulators to fall outside of the operation of a well-run quality
system. While outside the scope of this article, it is interesting to note that several elements within the recently finalized
FDA Guidance for Industry:Quality Systems Approach to Pharmaceutical CGMP Regulations have parallels in the EU PQR (7). Elements such as system review, examination of inputs (raw materials), process improvements,
data evaluation activities, and addressing discrepancies are common to both the modern quality system described by the FDA
guidance and the EU PQR. The PAR/PQR for the EU or the US should be viewed as an asset within a company's quality system.
The review process should add value to the overall quality of operations, above and beyond just satisfying a regulatory requirement.
The EU PQR requires a review of the adequacy of any other previous product process or equipment corrective actions. This wording
was suggested in comments provided by EFPIA to clarify the intent that this section is referring to the review of corrective
actions from previous PQRs (14). This is a valuable clarification and drives home the importance of not only documenting corrective
and preventive actions but also assuring that these actions are first carried out and then assessed for effectiveness in solving
and preventing further problems—another hallmark of an effective quality system.