John Y. Lee is Executive Director (Former FDA Investigator) at Pharmaceutical Compliance Associates, US.

John Y. Lee

In the pharmaceutical industry, a change and deviation management system (CMS) is a central part of the overall quality management system for drug product manufacture — often referred to as the pharmaceutical quality system. In accordance with the ICH Q10 guideline, also supported by the FDA, CMS is one of the four key elements that make up a pharmaceutical quality system (the remaining three elements include process performance and product quality monitoring system; corrective action and preventive action (CAPA) system; management review of process performance and product quality). 

According to the FDA and International Conference on Harmonisation (ICH), a formal CMS should be established to evaluate all changes that could affect the production and control of the drug product, intermediate or API in a pharmaceutical manufacturing company. In addition, some level of CMS is also expected by the FDA for the production of clinical supplies; any changes in the production process and product formulation after the production of the phase III clinical batch must be tightly controlled and carefully evaluated from a product equivalency perspective. Significant process, formulation or equipment changes after the production and use of the phase III clinical batch could result in the performance of lengthy and costly bioequivalency and safety studies, and cause a delay in FDA product approval.  

Although the cGMP regulation for drug products (21 CFR 211) has no direct reference to change control, change control is implied in 211.100(a) and 211.160(a). 211.100(a) requires that changes in production procedures and process controls be reviewed and approved by the appropriate organisation units and the quality control unit. This was a major component of Warning Letters issued by the FDA between 2007 and 2009. 211.160(a) requires a similar review and approval for changes related to laboratory controls, sampling plans, specifications, and analytical test methods. 

The FDA considers change control a very critical GMP compliance issue; therefore it has been one of the main criteria used by the agency in determining their drug inspection depth and coverage, and their decision for follow-up regulatory actions (e.g., Warning Letter issuance). The FDA's strategy for drug inspection and follow-up is evidenced in their systems inspection programme introduced in 2002 for drug product inspection, and in 2006 for API inspection. The FDA compliance programme for drug product inspection (CP7356.002) instructs the FDA investigator to select the comprehensive inspection option when changes have been made that could impact cross-contamination control, or when there had been changes in technology, new facilities or equipment. The FDA compliance programme for API inspection (CP7356.002F) has the same requirements for the performance of a comprehensive inspection, along with additional criteria for changes related to starting materials, intermediates, equipment, facilities, support systems, processing steps, packaging materials or computer software. Both compliance programmes instruct the FDA district office to recommend regulatory actions when there is a pattern of the failure to establish or to follow a CMS. 

Typical major GMP deficiencies related to CMS include: 					

The failure to evaluate FDA filing requirements; i.e., whether to file for a prior approval or changes being effected, or to report the change in the next annual report.

The failure to file changes with the FDA.

The failure to evaluate and/or justify whether equipment/system requalification is needed to support an equipment/system change, and whether process revalidation, stability studies or equivalency studies are required to support a process and/or processing parameter change.

The inadequate review and approval of the change by the quality control unit.

The FDA expects the intimate involvement of the quality control unit in the change control review and approval process, and usually holds the quality control unit responsible for deficiencies regarding change control, which again can be evidenced in several Warning Letters issued in the past years. One example of this FDA expectation was documented in a Warning Letter issued by the FDA in 2003. A company performed a routine replacement of the filling pump pistons, without filing a change request because it was a "like to like" replacement (which has been a typical industry practice). Although the replacement pistons had the same part number as the original pistons, they were slightly longer. This longer dimension caused the pistons to come into contact with the bottom of the filling blocks, resulting in the generation of metal particles, which contaminated the product batches. This metal contamination resulted in the recall of several product batches and the FDA's issuance of a Warning Letter. The Warning Letter stated that: "Prior to changing the filling line pump parts on the…line, the quality control unit failed to properly assess the impact that the change may have on the product. It is the quality control unit's responsibility to review any change to your manufacturing process and to assure the change will not adversely affect the drug product".

When researching the subjects and the number of FDA Warning Letters issued, the pharmaceutical industry has, in the past decade, learned how to comply with change management and change control. Opportunity for improvement though still exists as Warning Letters as described above are still issued on this implied GMP requirement. No specific CMS guidance is mandated for pharmaceutical or clinical supplies companies, which leaves these companies to experiment with various approaches and systems; recent studies reveal that change is still tackled on a plant-specific and even projectbyproject basis, a relatively resourceintensive and impractical approach.

  In addition, change management processes are often still controlled manually, i.e., paperbased, or by a combination of both paperbased and digital CMS (i.e., hybrid) and with a decentralised solution compared with an enterprise-wide, centralised solution. This makes control, visibility and quality control unit action on change control and deviations rigid, if not impossible. 

Paper-based quality management systems are fairly common especially in mid-sized FDA-regulated pharmaceutical companies as well as the clinical supplies industry. While such systems can successfully manage product and process quality, they can significantly increase the risk of GxP and especially GMP non-compliance. They also impede a pharmaceutical manufacturer's ability to implement continuous improvement initiatives in process and products. Finally, paper-based systems can potentially become a bottleneck to fast growth and capitalising on investments. 

Overall, the pharmaceutical and clinical supplies industries still have difficulty in planning and executing GxP, and especially GMP-based change management practices according to their quality manual or equivalent documentation approach. In our opinion, depending on type and size, the number of changes in a pharmaceutical facility can range between 30 and 175 a month; these numbers stress the need for efficient management if randomness is to be removed. Randomness and lack of control exists, which causes non-compliance; approximately 40% of regulatory issues, including warning letters, regulatory inspection observations or compliance observations (CAPA etc.) are attributed to changes.

To properly evaluate, approve and implement changes, pharmaceutical and clinical supplies companies (after the production of the phase III clinical batch) should have an effective CMS that ensures continual improvements are undertaken in a timely, prioritised and effective manner while providing a high degree of assurance that no unintended consequences of the change exists (In the absence of FDA guidance on CMS, however, valuable inspiration can be found at a rather untraditional federal agency — The US Occupational Health and Safety Administration using 29 CFR 1910.119, Process Safety Management, a section that offers a useful model for pharmaceutical companies for managing change). 

Table 1: Application of CMS throughout product lifecycle.

The CMS should include the following as appropriate for the stage of the product lifecycle (

Quality risk management should be used to evaluate proposed changes (e.g., using ICH Q9

 ). The level of effort and formality of the evaluation should be commensurate with the level of risk and there should be an assessment to determine whether a change to the regulatory filing is required under regional requirements.

All changes should be properly evaluated. Proposed changes should be evaluated relative to the marketing authorisation, including design space, where established, and/or current product and process understanding. As stated in ICH Q8, movement within the design space is not considered a change (from a regulatory filing perspective). However, from a pharmaceutical quality system standpoint, all changes should be evaluated by a company's CMS.

Proposed changes should be evaluated by expert teams contributing the appropriate expertise and knowledge from relevant areas (e.g., pharmaceutical development, manufacturing, quality, regulatory affairs and medical) to ensure the change is technically justified. Prospective evaluation criteria for a proposed change should be set.

After implementation, an evaluation of the change should be undertaken to confirm the change objectives were achieved and that there was no deleterious impact on product quality.

Regional regulatory submission/approval requirements should be assessed for a proposed change to a marketed product.

The CMS should ensure that the level of documentation and effort is matched to the level of risk associated with the change. Specifically, companies should ensure that the CMS:

is linked (and thus fully integrated) to other quality systems such as CAPA, customer complaints, validation, etc.

includes criteria to evaluate whether changes affect a regulatory filing

includes evaluation criteria for determining if changes are technically justified

contains procedures for confirming and validating that the change has occurred, the objectives were achieved and that there were no unintended consequences

develops a change management tracking system to facilitate effective change control, e.g. on training (training is often not integrated with change).

Significant organisational and cultural barriers should also be addressed. Teams should meet often instead of once a quarter or less, and these teams should use an appropriate set of metrics to track changes and drive process improvements.  

To effectively deal with these basic CMS requirements, life science companies need to be more agile and, as such, have a well-organised, enterprise-wide response to change. Ideally, effective management and structuring of product- and processengineering change can lead to reduced cycle times, quick responses to changing market conditions and increased rates of product innovation. Companies applying an integrated approach to managing change can innovate more quickly, promote compliance with global and regional regulations and better support a profitable, enterprisewide response to innovative and effective production processes as well as customer demand. 

A new paradigm for managing change in an ideal environment is electronic-based CMS; a solution that smoothly complies with the above mentioned requirements and provides a means of bypassing potential barriers and obstacles. 

Digitise and centralise information so that associates can find the organised information they need, when they need it. It should also manage almost any type of file required throughout any of the GxP processes.

Automatically route documents, seek the appropriate approvals/electronic signatures, have incorporated notification and escalation procedures, search for documents and retrieve them.

Provide revision control that is automatic and centralised so that once submitted, documents can be routed and approved quickly and effectively. Change tracking will also be automatic. This will enable annual compliance reviews (CR-cases closed, logbooks reviewed, all complaints properly managed, internal audit reports closed etc.) to be done by a notification report.

Professionals should look for a solution that is customisable to a company's needs and that requires form explanations for changes that are being made.

There has been a significant improvement in change management in the pharmaceutical industry over the last decade. The industry is on the right track and performs relatively better than it did up to 5 years ago when ineffective change management was responsible for the issuance of a significant portion of FDA Warning Letters. 

From a strategic point of view, however, there is still an opportunity for improvement. Fortunately, the changing dynamics of the pharmaceutical industry now reveal a trend towards a new strategic paradigm in favour of electronic, automated and, where applicable, enterprisewide change management systems. The trend is also forecasted for the clinical supplies industry. This approach provides top management, quality executives and engineers with instant access to the status of any change request, i.e., realtime transparency on trivial but formerly timeconsuming details (e.g., who has reviewed the revised document, who is sitting on the approval request and needs to be prompted, and who else needs to review it). The cycle time of review is therefore significantly reduced once the process is automated. Using this new approach also enables outofspecification problems, nonconformance issues and corrective actions to be tracked automatically, allowing users to have full access to details relating to nonconformance issues that have not been resolved or corrective actions that are waiting to be implemented. 

A formal CMS should be established to evaluate changes that affect production and control of a drug product, intermediate or API.

The FDA considers change control a very critical GMP compliance issue, but no specific CMS guidance is mandated for pharmaceutical or clinical supplies companies.

Companies should have an effective CMS that ensures that continual improvements are undertaken quickly, while also providing assurance that no unintended consequences of the change exist.

Articles

Though the pharma industry has improved its change management processes, there are still opportunities for improvement.

Change management: common failures and a checklist for improvement

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 

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). 

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).  

 (EMEA) is the group responsible for coordinating the scientific evaluation of the safety, efficacy, and quality of medicinal products undergoing official review 

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)

 (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.  

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.  

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 

as "Action taken to eliminate the cause of a potential discrepancy or other undesirable situation to prevent such an occurrence."(7) 

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). 

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:  

The PQR topic under review crosses individual product boundaries.

There are established systems with reporting functionality by product type.

The trending is more relevant across product types versus individual products.

The individual product details are not lost during product type reviews.

There is a concentration of product types at a given manufacturing site.

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. 

 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 

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.  

 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 

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 

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). 

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. 

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.