Product Annual/Quality Review: US–EU Comparative Analysis and Interpretations - Pharmaceutical Technology

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Product Annual/Quality Review: US–EU Comparative Analysis and Interpretations
There are significant differences between the United States and European Union requirements for the annual review of records related to the manufacturing and control for pharmaceutical products and active pharmaceutical ingredients.

Pharmaceutical Technology
Volume 3, Issue 32

It is interesting to note that a draft revision by the Canadian authorities to their GMP guideline, dated December 2006, includes a new section on PQRs for drug products (11). Canada is a mutual recognition agreement partner with the EU. The draft revision to the Canadian GMP guidance document includes most of the requirements of the EU PQR and, in a number of cases, exact phrases are lifted from the PQR section of the EU GMP Guide. The key differences are the absence in the Canadian PQR of requirements for review of MA variations, postmarketing commitments, and starting materials and packaging materials. Canadian GMPs also do not require the services of the qualified person (QP), and references to the QP in the EU PQR are absent in the Canadian draft revision.

Table V: Summary of review requirements and expectations.
Although there is no similar FDA requirement or expectation to include a review for conformance to the NDA as part of the PAR, FDA made a recommendation that the PAR should help the firm maintain the accuracy and currency of their processes and controls. One specific recommendation for a PAR currency check was to ensure that raw-material specifications match that filed in the most recent NDA submission (12).

Technical agreements are part of the EU PQR as both a requirement for review to ensure that these agreements remain up to date and a necessary document between the marketing authorization holder (MAH) (i.e., the product-license holder) and the manufacturer where these are different parties. The purpose of the technical agreement, in the latter instance, is to define the responsibilities between the two parties in producing and reviewing the PQR. The technical agreement, sometimes referred to as a quality agreement in the US, has a long-standing position within European GMPs and is covered as the main topic of Chapter 7 of the EU GMP guide. Both the EU and the US industry objected to the requirement for a specific technical agreement covering PQR between a MAH and a manufacturer. PDA, in their comments to EMEA, stated that the draft requirement for a technical agreement between a MAH and a manufacturer "exceeded requirements in other markets and added significant administrative burdens with unclear value"(13). The EFPIA pointed out that "a global company may have up to 100 different MAHs either as affiliates to the company or as license holders or agents, and that these firms do not have access to the data or the expertise needed to carry out the review or evaluate the data"(14). The final version of the PQR maintains a requirement for a technical agreement between the various parties involved where the MAH is not the manufacturer. Companies that face inspection by European authorities should be prepared to present these technical agreements and include a section in the PQR to document the review of all GMP technical agreements to ensure that they are up to date. A modular approach, which involves the collective review across a product type, would be well suited to meeting this requirement. The technical agreements should be in place whenever two parties enter into any contract-manufacturing activity. The different sites within the same company that are performing parts of the manufacturing process for APIs or drug products are also expected to have a technical agreement or other formal document in place detailing GMP responsibilities between the sites involved.


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