Chapter 17: Product Trend Requirements

Organizations, no matter what industry they’re in, generate a significant amount of data as a result of running their business. This situation is certainly true of the pharmaceutical industry. Good manufacturing practices (GMP) regulations worldwide require pharmaceutical companies to generate a significant body of data related to all their activities, from the receipt of starting materials through the distribution (and return) of finished products. A large amount of data is generated around the quality of the finished product, both at release for distribution and throughout the established shelf life of the product.

Regulatory agencies around the world recognize that there is value in the data that are generated or obtained (for example, through receipt of returned goods or product complaints) as a result of complying with GMP regulations. It is this acknowledgment, as well as the recognition that it is important to critically assess the “health” of each pharmaceutical product, that resulted in the regulatory requirement for some form of annual assessment. The goals of the annual assessments are to:

• Confirm that the products and associated processes remain in a state of control

• Identify the need for changes to the products or processes

• Recognize opportunities for continuous improvement

Companies that undertake these reviews simply to meet their regulatory obligations may miss out on the opportunities for continuous improvement.

Regulations

The United States Food and Drug Administration (FDA) requirement to conduct an annual product review (APR) is found in 21 CFR 211.180(e). As the name suggests, FDA GMP regulations require that pharmaceutical companies, on an annual basis (or, minimally, one time per year), complete a thorough review of data associated with each pharmaceutical product.

The European requirement to conduct a product quality review (PQR) is found in Chapter 1 of Volume 4, European Union Guidelines to GMP (as well as Chapter 1 of the PIC/S [Pharmaceutical Inspection Convention and the Pharmaceutical Inspection Co-operation Scheme] PE-009-11 PIC/S GMP Guide—Part I, Guide for Medicinal Products). Similarly to the FDA requirement, pharmaceutical companies must, on an annual basis, complete a thorough review of specified data elements. Unlike the FDA GMP requirements, however, this annual assessment must take into account data from previous review periods (previous years). The data elements that must be reviewed differ from the FDA requirements.

Annual Product Reviews

General Requirements

FDA GMP regulations specify that pharmaceutical companies maintain records associated with the production, control, or distribution of each batch of drug product and retain those records for at least one year after the expiration date of the batch (or, in the case of certain over-the-counter [OTC] drug products, three years after distribution of the batch). Additional records related to raw materials, packaging containers, closures, and labeling must be retained according to a similar timeline. The data associated with these records are used for evaluating, at least annually, the quality standards of each drug product.

Under FDA requirements, pharmaceutical companies are required to establish a written procedure for conducting annual evaluations and for ensuring that their procedure is followed as written. Additionally, while not specifically identified in the regulations, firms should document the results of each APR in a written report and submit the reports to senior management for review. The reports typically include summary conclusions on the quality of the product and any corrective/preventive actions initiated and/or completed during the review period. The APR has a strong link to a firm’s corrective and preventive action (CAPA) program, and any identified CAPA items should be tracked appropriately and completed in a timely fashion.

Data Elements

Required. An evaluation of specific data elements, as specified in the FDA GMP regulations, must be included in the APR:

• Representative number of batches, whether approved or rejected

• Product complaints

• Recalls

• Returned or salvaged drug products

• Investigations

Expected. In addition to the required data elements, the FDA has identified, through the issuance of form FDA 483s and other guidance documents, other data elements that they typically expect to see as part of the APR:

• Deviations or nonconformances

• In-process and finished product testing results and a discussion of any adverse trending

• Product stability results and a discussion of any adverse trending

• Changes to processes that occurred during the review period

In the spirit of continuous improvement, additional data elements may need to be included in the review process. Firms should assess all of the data that are gathered throughout their operations and determine what makes the most sense for their particular products and processes.

Product Quality Reviews

General Requirements

European Union (EU) regulations call for regular, periodic, or rolling quality reviews of all licensed medicinal products, including those that are designated as “export only.” The reviews, similarly to FDA requirements, should be conducted and documented annually.

Despite the similarities, there are a number of aspects of the EU regulations that differ from FDA regulations. The primary differences between the EU and FDA requirements related to the quality reviews include:

• EU regulations explicitly require an assessment of the results of the review to determine whether corrective or preventive actions are needed, or whether revalidation is required. FDA likely expects firms to perform this type of analysis, but it is not explicit within the regulations.

• EU regulations require the assessment of current data against data from previous reviews in an attempt to identify adverse trends. FDA does not require firms to look at data from previous review periods. Depending on the number of batches manufactured, however, this type of “prior period” data may be necessary to adequately analyze the data for trends.

• According to EU regulations, quality reviews may be grouped by product type (for example, solid dosage forms, liquid dosage forms, sterile products) where scientifically justified. FDA regulations do not allow products to be grouped; APR must be conducted on individual products.

• EU regulations do not specify a requirement for a written procedure that outlines the PQR process. FDA requirements do explicitly specify that firms adopt a written procedure for the APR process. It is likely best to adopt a written operating procedure that outlines the process for completing these annual product assessments to ensure compliance with expectations of the regulatory agencies involved.

• EU regulations include a number of data elements not required by FDA regulations. It is important to be aware of the differences to ensure compliance with appropriate regulations.

Data Elements Mandated by EU Regulations

Required. An evaluation of the following data elements, as specified in the EU GMP regulations, must be included in the PQR:

• Starting materials, including packaging materials used in the product, with emphasis on those from new sources

• Critical in-process controls and finished product results

• All batches that failed to meet established specification(s) and their respective investigation(s)

• Significant deviations or nonconformances, their respective investigation(s), and the effectiveness of resultant corrective or preventive actions taken

• Changes to processes or analytical methods

• Marketing authorization variations submitted, granted, or refused, including those for export only

• Results of stability programs, and any adverse trends

• Quality-related returns, complaints, and recalls and their respective investigation(s)

• Adequacy of any other previous product, process, or equipment corrective actions

• Post-marketing commitments for new marketing authorizations or variations to marketing authorizations

• Qualification status of relevant equipment and utilities

• Contractual arrangements

Expected. In addition to the required data elements, salvaged products should be included as part of the PQR process.

Additional Considerations

It is important to understand that the use of contractors (for example, contract manufacturers, contract laboratories) does not negate the requirement for the marketing application holder to gather the required data. The application holder is responsible for either ensuring that the contractor completes the APR on their behalf or obtaining the required data from the contractor and completing the annual review on their own. It is critical that the responsibilities for completing the annual reviews be specified in any contracts and/or quality agreements between the contracting parties.