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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.
The US Food and Drug Administration proposed a requirement for preparing a written summary for each product in its February 13, 1976 rewriting of the good manufacturing practices (GMPs) for drug products. The purpose for this proposed GMP requirement was to provide reliable procedures for a drug manufacturer to review the quality standards for each drug product. In response to numerous comments from industry objecting to the preparation of written summaries, FDA revised the proposal to allow each company to establish its own procedures for the evaluation of product quality standards, by reviewing the records required by the GMPs on an annual basis. This requirement was published in the September 1978 final current good manufacturing practices (CGMP) regulations for drug products (21 CFR 211.180(e)) and became effective on March 28, 1979 (1). Since its publication, 21 CFR 211.180(e) has been commonly referred to—by FDA and the pharmaceutical industry—as the "product annual review" (PAR) or the "annual product review" (APR).
Table I: Review objectives.
In August 2001, FDA adopted and published the guidance for industry Q7A Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients. This guidance was developed within the Expert Working Group of the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). This guidance was incorporated as Part II of the European Community Guide to GMP (EU GMP Guide) in October 2005. Sections 2.5 and 12.6 of this guidance specify and refer to the performance of a product quality review (PQR) for active ingredients (2).
The European Medicines Agency (EMEA) is the group responsible for coordinating the scientific evaluation of the safety, efficacy, and quality of medicinal products undergoing official review via the centralized or mutual recognition procedures. EMEA also proposes changes in pharmaceutical legislation for approval by the European Commission. The EU GMP Guide is the document that provides the details supporting the principles of GMPs within the EU. In 2004, EMEA made available for public comment a draft revision of the EU GMP Guide proposing, for the first time, a requirement for a PQR. The European Federation of Pharmaceutical Industry Associations (EFPIA), the Parenteral Drug Association (PDA), and other organizations and individual pharmaceutical companies provided comments to this draft revision. The European Commission officially announced the finalized revision to the EU GMP Guide in November 2005 with an effective date of January 2006. Chapter 1 of the GMP Guide now contains a requirement to perform a PQR (3). The European authorities stated that the industry generally should have the requested information available but acknowledged that it would take some time to "develop and establish a system and associated procedures to implement this new requirement"(4). PQRs for 2006 were to cover at least a six-month period with full annual reports required from 2007 onward.
Comparison of regulations and guidance
Tables I–V provide a summary comparing the GMP requirements and guidance for the PAR/PQR among the US GMP (211.180(e)), the EU GMP (section 1.5), and the ICH Q7A (section 2.5). The authors used three terms for this comparison. "Required" means that the review action or item is specifically written in the regulations or guidance. "Expected, not specified" means that the review action or item is expected by the respective authorities but not written in the regulations or guidance. This review "expectation" is based on written guidance contained in other documents from the respective authorities, recurring citations in FDA 483s (the form used by investigators to record observations of noncompliance with CGMPs) and FDA warning letters, or an industry standard that has been recognized by authorities. "Not specified" means that the review action or item is not a current expectation from the respective authorities.
Objectives of the PAR/PQR program
The three required FDA objectives for performing the PAR are to determine the need to make changes in the manufacturing process, the manufacturing controls (e.g., in-process testing and monitoring), and product specifications. Only one of these three required objectives (i.e., to determine the need to make changes to product specifications) is specified in the EU PQR, and none of these FDA objectives is mentioned in the Q7A PQR. The EU PQR has additional required objectives that are not mentioned in either the FDA PAR or in the Q7A PQR. These include the identification of product and process improvements, highlighting trends, and determining the appropriateness of starting material specifications.
Table II: Frequency and procedure for review.
The required and expected GMP objectives are very important to ensure the development of an efficient and compliant PAR/PQR program. The written procedure for the PAR/PQR should specifically refer to the objectives to determine and justify the areas selected for review and the extent of the review. Any area or item that is not relevant to fulfilling the objectives should be excluded from the PAR/PQR.
As an example, the authors have seen FDA 483s criticizing the failure to trend raw-material test results as part of the PAR for a product. To determine whether this is a valid FDA 483 observation or whether raw-material trending should be included, the following should be considered. If the trending of a raw material (e.g., an active ingredient) identifies an adverse trend (e.g., more than 25% of all lots received in the past 12 months were rejected and sent back to the supplier), would this adverse trend cause the company that performed the PAR to change its manufacturing process for the drug product, the manufacturing controls for the drug product, or the final release specifications for the drug product? When the answers are "no" to all three parts of this question, raw-material trending should not be included as part of the PAR because any result from this trending would not be relevant to the objectives of the PAR and would not generate any follow-up action for implementing changes. To avoid confusion, this example is not to suggest that raw-material trending is not needed, but that it should be performed as part of another program (e.g., vendor qualification program) instead of the PAR program. It should be noted that the EU PQR requires the evaluation of the appropriateness of the raw-material specifications.
Two critical objectives that are specified in the EU PQR and Q7A PQR but not included in the FDA PAR are the verification of the consistency of the existing manufacturing process and the determination of the need for the revalidation of the manufacturing process. The procedures for performing a typical PAR/PQR involve the review, analysis, and trending of historical data (i.e., data generated in the past 12 months), which fit the definition of retrospective process validation as defined in FDA's validation guideline and the EU GMP Guide Annex 15 on qualification and validation (5, 6). A PAR/PQR is, therefore, actually an annual retrospective revalidation of the manufacturing process. When performed properly with the incorporation of the required elements of a retrospective process validation, and in the absence of significant process changes, a PAR/PQR may negate or substitute the need for the periodic prospective revalidation (i.e., intensive sampling and testing) of the manufacturing process. This is supported by the following statement in Section 12.6 of Q7A: "Where no significant changes have been made to the system or process, and a quality review confirms that the system or process is consistently producing material meeting its specifications, there is normally no need for revalidation." A similar statement appears in item 44 of the EU GMP Guide Annex 15. To take advantage of the PAR/PQR as the annual retrospective revalidation of the manufacturing process, the company's master validation plan for process validation should reference the PAR/PQR program as the determining factor for the need of a prospective revalidation of the manufacturing process, in the absence of significant changes.
The following are excerpts from FDA's validation guideline and the EU GMP Guide Annex 15 related to retrospective process validation.
In some cases a product may have been on the market without sufficient premarket process validation. In these cases, it may be possible to validate, in some measure, the adequacy of the process by examination of accumulated test data on the product and records of the manufacturing procedures used. Retrospective validation can also be useful to augment initial premarket prospective validation for new products or changed processes. In such cases, preliminary prospective validation should have been sufficient to warrant product marketing. As additional data is gathered on production lots, such data can be used to build confidence in the adequacy of the process.
Validation of such processes should be based on historical data. The steps involved require the preparation of a specific protocol and the reporting of the results of the data review, leading to a conclusion and a recommendation.The source of data for this validation should include, but not be limited to batch processing and packaging records, process control charts, maintenance log books, records of personnel changes, process capability studies, finished product data, including trend cards and storage stability results.
Although not specifically stated in the FDA PAR or the Q7A PQR, and only mentioned briefly in the EU PQR, the PAR/PQR is actually an analysis to identify adverse trends and is one of the tools for preventive action as defined in the corrective and preventive action (CAPA) system. FDA's quality systems guideline defines preventive actions as "Action taken to eliminate the cause of a potential discrepancy or other undesirable situation to prevent such an occurrence."(7)
Frequency and procedures for PAR/PQR
FDA and EU require an annual frequency for the PAR/PQR, which is stated in all three GMP regulations and the guidance document. FDA does not allow the extension of the review frequency beyond an annual basis, regardless of the number of batches produced in the preceding 12-month period. FDA expressed the concern that "Potential problems with product quality standards could go undetected and thereby delay recognition of a need to revise specifications or manufacturing or control procedures"(8).
Table III: Items for PAR/PQR review.
The EU PQR requires that reviews performed in previous periods be taken into account as part of the current review. This has been an expectation of FDA, as indicated by the many FDA 483 observations, despite no mentioning of this in FDA GMPs or other guidance documents. Although this requirement is also not mentioned in the Q7A, the PQR for active pharmaceutical ingredients should include the trending of PQR results from previous periods because this is required by the EU and expected by FDA.
The EU PQR states that "Quality reviews may be grouped by product type (e.g., solid dosage forms, liquid dosage forms, sterile products) where scientifically justified." FDA prohibits the grouping of different products despite their production using similar processes, or any other similar approach, because the uniqueness of each production process and product specification may result in different manufacturing outcomes (9).
The EU PQR allowance for grouping product types opens up the possibility to consolidate the review for a number of drug products and take a "modular approach" to the information gathering and review process. The modular approach involves using currently established systems, to the greatest extent possible, to provide summary data and information across a product type to satisfy the requirements of the PQR. For example, to meet the requirement to review starting and packaging materials, the modular approach involves querying established systems to provide summary data for all raw materials within a product type and then performing a consolidated review, identifying any trends and specific actions for the product type. The same approach could be used for marketing authorization (MA) variations, change control, stability, product returns, complaints and recalls, equipment qualification, and the technical agreement reviews that are required by the EU PQR. The PQR data mining starts with a product type review with individual products highlighted as necessary to support any trends and/or identify any product or process improvements. It is important that this approach is scientifically justified and that this justification is documented. Several criteria that may be relevant in providing such justification include:
PAR/PQR items and areas for review
The FDA PAR specifies six items that are required to be reviewed, the EU PQR specifies 19 items, and the Q7A PQR specifies 11. Four of the six FDA requirements are common to both the EU PQR and Q7A PQR, which are complaints, product recalls, returned products, and investigations. There are eight items that are required by the EU PQR but not specifically stated in either the Q7A PQR or the FDA PAR. These include the review of export-only products, starting materials and packaging materials, MA variations, postmarketing commitments, equipment qualification status, currency of technical agreements, effectiveness of preventive actions to significant nonconformities, and adequacy of previous product process or equipment corrective actions. Additional EU PQR review requirements that are not specifically stated in the FDA PAR are the review for all batches that failed specifications, critical deviations and nonconformities, product stability results, critical in-process controls and test results, changes to analytical methods, and the effectives of corrective actions.
Table IV: Responsibility, documentation, review and approvals, and follow-up.
Selection of product batches for review. FDA revised its GMP in January 1995 to eliminate the requirement for the review of all batches produced in the previous 12 months and to allow the review of a representative number of batches. The preamble to the revised GMP regulations states, however, that the review of all batches would be appropriate when the review of a representative number of batches identifies an adverse trend. The EU and Q7A PQRs do not state that all batches must be reviewed, other than rejected batches, but these two documents also do not specifically allow for the review of representative batches. FDA defined representative batches in the preamble of the GMP revision as batches that exhibited varying manufacturing experiences such as batches that were released, rejected or recalled, batches that were the subject of FDA field alert reporting filings, batches with manufacturing discrepancies, and any batches with outcomes that might indicate the need for change (8). FDA later refined the definition for representative to include each batch that was rejected for a different reason, or a different category of rejection (10).
Marketing authorization, postmarketing commitments, and technical agreements. The review requirements in the EU PQR for MA variations, currency of technical agreements, and the postmarketing commitments do not reflect the typical industry practice for PAR/PQR, and there were industry comments that some of these review requirements appeared to be outside the scope of a PQR. The review requirements for MA and postmarketing commitments reflect the long-standing EU emphasis on license compliance and the heightened global emphasis on drug safety, respectively. The MA or, specifically, the marketing authorization application (MAA) is the product license in the EU comparable to the new drug application (NDA) in the US. During an inspection, it is typical for an EU inspector to question the firm's management about their knowledge and assurance of commitments made in the MA. The site master file (SMF) is another submission document that is often discussed during an inspection, though the SMF is not mentioned in the revised PQR section of the GMP guide. In terms of the review of postmarketing commitments, this is an essential activity, but it is not immediately obvious as to why it is required in the EU PQR. The stated objective of the PQR is "...verifying the consistency of the existing process, the appropriateness of current specifications for both starting materials and finished product to highlight any trends and to identify product and process improvements"(3).
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.
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).
Table V: Summary of review requirements and expectations.
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.
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.
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 PAR/PQR.
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.
Conclusion and recommendations
The EU product quality review (PQR) requires a greater number of items and areas for review compared with either the US product annual review (PAR) or Q7A PQR, and expands the review to include quality systems and registration commitments. Despite this expanded review, it does not incorporate two of the three major FDA objectives for the review. The Q7A PQR is very similar to the EU PQR, although it does not include nearly as many areas and items for review as the EU PQR. The Q7A also does not include any of the three objectives of the FDA PAR.
The expanded review required by the EU PQR may not necessarily require additional time and resources, compared with the FDA PAR review, because the EU PQR allows for the grouping of products together in one review whereas the FDA does not. If a company decides to perform one PAR/PQR to satisfy both FDA and the EU, then, they would need additional resources to perform an expanded review, for each product. Companies that supply the US and EU markets should, therefore, decide on the approach that is the most effective, efficient, and economical before rushing to develop or redevelop their PAR/PQR program.
As with all GMP guidance information, it is always valuable to try to understand the underlying principles to respond in a way that both meets the GMP requirement or expectation and strengthens the quality system with ultimate benefit to the patient. This is a shared goal of both regulators and industry. By presenting some of the background information relevant to the PAR/PQR, comparing it with other well-established reviews and outlining one possible approach (i.e., a modular approach) to meeting the EU PQR requirements, compliance can be achieved from a stronger foundation.
John G. Grazal is senior director of the Global Compliance Management Group at AstraZeneca (Wilmington, DE). John Y. Lee* is executive director at Pharmaceutical Compliance Associates, and a former FDA investigator at New Jersey District, 523 No. Bay Avenue, No. Massapequa, NY 11758, tel: 516.752.0998, fax: 516.752.8931, e-mail: email@example.com.
*To whom all correspondence should be addressed.
Submitted: May 10, 2007. Accepted:Aug. 23, 2007
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3. European Commission, "Medicinal Products for Human and Veterinary Use," in EU Guidelines for GMP, Chapters 1–9, Dec. 2005.
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12. FDA, "Human Drug CGMP Notes," HFD-320, 6 (4) (Dec. 1998).
13. PDA Comments on Addition to Chapter 1 of the EU GMP Guide "Product Quality Review," June 2004.
14. EFPIA Comments on Addition to Chapter 1 of the EU GMP Guide "Product Quality Review," June 2004.
15. FDA, Guide To Inspections Of Dosage Form Drug Manufacturer's —CGMPs (Rockville, MD, Oct. 1993).
16. FDA, "Guide To Inspection Of Computerized Systems In Drug Processing," HFN-320 (Feb. 1983).