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

Qualification of equipment and utilities. The EU PQR requires a review of "The qualification status of relevant equipment and utilities, e.g., HVAC, water, compressed gases, etc." While the concept of ensuring that equipment and utilities continue to operate in a qualified state is CGMP in both the EU and US, there is no specific FDA PAR or Q7A PQR requirement to include such a review. This review requirement appears to be another example in which EU authorities are tapping into a current practice being performed under other systems and are now requiring that it be covered in the PQR. For example, a firm may presently control the initial equipment qualification via a master plan, and any need to requalify equipment through the change-control and deviation progams and trend results from the maintenance and calibration programs. One criterion that is often applied when reviewing the essential requirements to support a change is whether equipment requalification, in whole or part, is required. A deviation investigation may also lead to questions about equipment qualification status following an equipment fault or other discrepancy. The preventive maintenance and calibration programs should have been developed in conjunction with equipment qualification (as indicated in the FDA's 1987 validation guideline) and, therefore, directly support the qualified state of equipment in the absence of significant changes.

The underlying theme of the equipment and utilities qualification review in the EU PQR is not to require duplicate information or lists, or the performance of redundant work. The GMP principle is to demonstrate that equipment and utilities remain in their qualified state. The review and trending of relevant information on the robustness of related systems (e.g., change control, deviations, preventive maintenance, and calibration) that are responsible for ensuring equipment and utilities qualification status is one means of satisfying this section of the EU PQR. The CGMP has long required responsible individuals to review information to ensure that systems are functioning and outputs meet acceptance criteria. This is a fundamental principle of system control. Companies should leverage the information that they are currently capturing to demonstrate that equipment and utilities qualification is under control. The modular approach may be applied by consolidating, summarizing, and/or referencing key data from relevant systems to provide internal assurance that equipment and utilities qualification, across a product type, meets the requirements of the EU PQR.

Appropriateness of specifications. The FDA PAR requires a review to determine the need to make changes in product specifications. The EU PQR requires a review for the appropriateness of product as well as starting material specifications. The EU uses the term starting materials to include all raw materials (i.e., any substance used in the production of a medicinal product but excluding packaging materials). The review of starting materials is not specified in the FDA PAR requirements or in the Q7A PQR. In addition to reviewing the appropriateness of the starting material specifications, the EU PQR also requires a more general review of the starting materials and packaging materials. (The EU definition for packaging materials includes any materials used in the packaging of a medicinal product, excluding any outer packaging used for transport or shipping and printed packaging materials.) The EU industry requested the removal of the requirement to include starting and packaging materials in the PQR or the revision of the wording so as to allow a risk-based review based on materials that are "deemed to be critical to the product or where issues have occurred"(14). These industry recommendations were not incorporated exactly into the final version of the EC GMP for PQR, but a concession was made to limit the review of starting and packaging materials to those "especially from new sources." The requirements for this section may also be fulfilled using the modular approach by taking data and information currently being gathered and reported from systems such as change control, laboratory information management, materials receipt and inventory, and deviation management. This information can be summarized and reviewed as a collective "module" for starting materials or packaging materials. Any trends or issues can then be discussed with corrective and preventive actions highlighted for product types or individual products. The PQR should include a specific section within the review for "new source" materials where data and information for this subset of materials are given focused attention.

Recommendations for selecting review areas and items. As discussed under the section on the objectives of the PAR/PQR, the areas and items for the PAR/PQR should be selected only when they fulfill one or more of the specified objectives for the respective PAR/PQR.


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