Regulatory Agency Reporting

Once a pharmaceutical product is introduced into commercial distribution, a number of changes or events can trigger a requirement to submit information to the applicable regulatory authorities. These events can be planned (for example, a predetermined change to the product or manufacturing process) or unplanned (for example, failure of a drug product on stability), but, in either case, the burden of responsibility for reporting these events falls to the pharmaceutical manufacturer. Professionals working in a good manufacturing practices (GMP) environment must have an understanding of the types of events (both planned and unplanned) that result in a regulatory reporting obligation and the specific requirements for submitting the required reports. Failure to submit the required reports can result in enforcement action against the firm.

PLANNED CHANGES

It is not uncommon for changes (or variations) to marketing applications/authorizations to be necessary throughout the life cycle of the drug product. Changes resulting from increased technical or process knowledge or additional safety and quality information resulting from consumer experience or post-marketing studies need to be effectively assessed and communicated to the appropriate regulatory agencies for inclusion in the approved application.

In the United States, the Food and Drug Administration (FDA) seeks to provide clarity around the types of changes and the reporting requirements through their guidance document Changes to an Approved NDA or ANDA. In this guidance document, FDA outlines three categories of changes based on their potential to have an adverse effect on the identity, strength, quality, purity, or potency of a drug product (Table 6.1).

In Europe, the marketing authorization holder is required to take into account technical and scientific progress and to submit amendments that incorporate changes (variations) based on that progress. Additionally, marketing authorization holders may wish to alter or improve the drug product, and those changes or variations also require submission of supplements or amendments to their approved application. The regulations in Europe have classified these changes or variations into two categories:

• Minor variations. Type IA (administrative changes or simple changes with no potential impact on the safety of the drug product) and Type IB (other minor changes as specified in Annex I to Commission Regulation 1085/2003)

• Major variations. All changes (other than Type IA or IB) that require approval before the marketing authorization holder can move forward with the change.

EVALUATING POST-MARKETING CHANGES

The holder of the marketing application or authorization is responsible for assessing the effects of any change before distributing a drug product made with the change in place. Drug manufacturers should have a formal change control process in place to identify what needs to be done to complete the assessment and to document the outcome of the assessment process. While the assessment may vary depending on the type of change, some of the typical steps that may be taken to evaluate the impact of a change on the drug product are standard.

Technical Assessment

It is important to evaluate the impact of the change on the manufacturing process, and

any impact on the finished dosage form. This evaluation should pay close attention to the impact of the change on the critical quality attributes (CQA) of the product and the critical processing parameters (CPP) for the drug manufacturing process. The technical assessment should determine the impact on the validated state of the process and determine whether additional validation activities will be necessary to demonstrate that the process remains in a state of control.

Analytical Assessment

First, it is important to determine whether the change has an impact on the approved regulatory specifications. Changes to incoming raw materials or changes in the manufacturing process may have an impact on the ability of the finished product to meet the regulatory specifications identified in the application.

Depending on the type of change proposed, a change to the regulatory specifications might be necessary. A change that requires a change in the approved specifications will almost always require approval by the regulatory agency involved before product made with the change can be distributed.

Second, it may be important to perform additional analytical testing to demonstrate that the change has not, or will not, have an adverse effect on the bioavailability, stability, or any of the chemical, physical, microbiological, and biological properties of the drug product. Providing a scientific argument or data that demonstrate that the product manufactured with the change will maintain an appropriate level of quality over time is often required before making a change.

Equivalence Assessment

It may be prudent, depending on the type of change, to conduct an assessment of product manufactured before the change versus product manufactured after the change to demonstrate that they are equivalent. Simply stated, is the finished drug product made after the change equivalent to the drug product made before the change? Demonstrating in vitro equivalence may be necessary to preclude the need for in vivo studies.

Adverse Effect

The change needs to be evaluated to determine whether the particular change in question has an adverse effect on the identity, strength, quality, purity, or potency of the drug product. While it seems counterintuitive that a company would move forward with a change that has an adverse impact, an application holder may be forced to do so as a result of changes beyond their control. For example, a change made by an active pharmaceutical ingredient (API) supplier may result in a change in the impurity profile for the finished drug product. If the change is necessary for the API supplier, the pharmaceutical company may be forced to move forward with the change to be able to continue to market the product. While these types of situations are rare, they do occur,

and the pharmaceutical company must have systems in place to effectively evaluate these types of changes.

Reporting Strategy

The required reporting strategy may differ depending on the type of change. It is critical that the group responsible for determining the regulatory strategy (typically Regulatory Affairs) is made aware of the change(s) early on so that the requirements for submitting the change to the regulatory agency can be evaluated, and the appropriate timing for implementing the change(s) can be determined. It is often through this assessment that the need for additional testing or manufacture of batches made with the change in place is identified.

REGULATORY REPORTING REQUIREMENTS

Planned Changes

Requirements in the United States. For drug products approved in the United States, FDA identifies four reporting categories depending on the classification of the change:

• Prior Approval Supplement (PAS). A PAS is recommended for anything classified as a major change. In the case of a PAS, the company must wait to distribute product made with the change until after they receive approval from FDA on the supplement.

• Supplement—Changes Being Effected in 30 Days (CBE-30). A CBE-30 is recommended for certain types of moderate changes. In the case of a CBE-30, the supplement needs to be submitted to FDA, and the application holder must wait at least 30 days before the distribution of the drug product. If FDA informs the applicant within 30 days of receipt of the supplement that information is missing, or that a PAS is required, distribution of product must be delayed until the missing information is provided or the PAS is approved. If, after review of the CBE-30, FDA disagrees with the change, they may request that the manufacturer cease distribution of the drug products made using the change.

• Supplement—Changes Being Effected (CBE-0). A CBE-0 is recommended for certain types of moderate changes. In the case of a CBE-0, distribution of product manufactured with the change can occur once FDA receives the supplement. Similarly to what can transpire with the CBE-30, if FDA disagrees with the change, they may request that the manufacturer cease distribution of the drug products made using the change.

• Annual reports. The submission of annual reports for marketed drug products covered by an approved application should include the description of minor changes made to the drug product over the time period covered by the annual report. As a reminder, these minor changes those changes that that have a minimal potential to

have an adverse impact on the identity, strength, quality, safety, purity, or potency of the drug product. It is not appropriate to include changes with either a substantial potential or moderate potential for adverse impact in a drug product annual report.

It is important to note that a single change can require more than one change to the approved application. For example, a change in manufacturing site may involve a change in the equipment used to manufacture the product, or a change in the API may involve a change in the processing parameters for the manufacturing process, or necessitate a change in the approved regulatory specifications. For multiple related changes where the recommended reporting category for the individual changes differs, FDA recommends that the submission strategy use the most restrictive of the categories recommended for the individual changes. When the multiple related changes all have the same recommended reporting category, FDA recommends that the submission use the reporting category for the individual changes.

Requirements in Europe. For drug products approved in Europe, a reporting system similar to that of the FDA is used depending on the type of variation (change) to the marketing authorization being proposed. The submission requirements differ depending on the type of variation, as does the ability of the manufacturer to move forward with implementing the change on commercial product. Three types of variations are recognized:

• Type IA variations. The application holder should verify that all the conditions for a type IA notification are met and that all the documentation requirements are complete. Once the type IA notification is received by the applicable member state (reference member state), the clock is started. By day 14, the reference member state is required to notify the applicant regarding the status of the notification, that is, the notification is acknowledged (accepted) or it is not accepted along with the reason for nonacceptance. If it is acknowledged, or if the application holder has not received communication from the reference member state that the notification has not been approved, the application holder may move forward with the change and distribution of product manufactured with the change.

• Type IB variations. Similarly to a type IA notification, the application holder must ensure that all the conditions for the type IB notification are met and that all documentation requirements are complete and included with the notification. In the case of a type IB notification, the clock does not start immediately upon receipt. The reference member state has 10 working days to verify that the requirements for a type IB notification have been met and that all the supporting data are included. After that 10-day period, the reference member state will inform the applicant of the start date. By day 30, after the clock start date, the reference member state will communicate the status of the notification (approval or nonapproval). Again,

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similarly to type IA notifications, if it is acknowledged, or if the application holder has not received communication from the reference member state that the notification has not been approved, the application holder may move forward with the change and distribution of product manufactured with the change.

• Type II variations. These types of variations are typically processed within 60 days of the clock start date; however, the regulations do allow for a reduced or extended assessment period. As with the type IB variations, the reference member state has 10 working days to validate the submission, and they must notify the application holder of the clock start date. Where there is agreement between member states regarding the outcome of the assessment, the reference member state will send a formal approval or refusal letter to the applicant. The application holder must wait until they receive a formal approval letter before implementing the change.

Unplanned Events

Most often, these events relate to product quality issues or failure of the drug product to meet regulatory specifications throughout its intended shelf life. In those situations where the event is unplanned, strict and very tight deadlines exist for providing the reports to the appropriate regulatory agencies. It is critical to understand the reporting requirements specific to the country or countries in which the products are marketed and the deadlines for submission of the initial reports. Once the issue or event is made known to the pharmaceutical manufacturer, the clock starts, and it is incumbent on the individuals responsible for the reporting to act quickly and to gather as much relevant information as possible in a short period of time.

FDA Field Alert Reports. The FDA Field Alert reporting requirements, as outlined in 21 CFR 314.81, first became effective in May 1985. This regulation requires holders of New Drug Applications (NDA) and Abbreviated New Drug Applications (ANDA) to submit information about distributed drug products to their jurisdictional FDA district office within three business days of receipt of the information by the application holder. These reports, unlike the Adverse Drug Experience (ADE) Reports required under 21 CFR 314.80, are required when a manufacturer is made aware of specific quality issues affecting batches of product that remain in commercial distribution.

For example, generation of an out-of-specification (OOS) result for a finished drug product would be considered the type of “information concerning any failure” described in this regulation. Unless the OOS result is found, through investigation, to be invalid within three days, an initial Field Alert Report should be submitted. Follow-up reports are submitted as new information is identified during the investigation; a final Field Alert Report is submitted once the investigation is finalized and closed.

Biologic Product Deviation Reports. Under 21 CFR 600.14, manufacturers of licensed biologic products are required to promptly notifly FDA of deviatons in the

manufacturing of products that may affect their safety, purity, or potency. Manufacturers must report any event, as well as any information relevant to the event, associated with the manufacturing of the biologic product if that event:

• Represents a deviation from GMP, applicable regulations, applicable standards, or established specifications that may affect the safety, purity, or potency of that product or represents an unexpected or unforeseeable event that may affect the safety, purity, or potency of that product

• Occurs in the sponsor’s facility or a facility under contract with the sponsor

• Involves a distributed biologic product

It is important to note that the expectation regarding the decision to report should be based on whether the event has the potential to affect the safety, purity, or potency of a product.

These reports should be submitted as soon as possible to the FDA but, in all cases, no more than 45 calendar days from the date the deviation was first discovered. Like the Field Alert Reports, follow-up reports are required to update the Agency on any actions taken since the initial report. A final report is also required to close these reports.

Rapid Alert Reports. The alert system agreed on in the framework of the mutual recognition agreement (MRA) ensures that batch recalls and other safety measures resulting from quality defects of medicinal products discovered by one party are transmitted to the MRA partner without delay. It is based on the current rapid alert system (RAS) operational in the European Economic Area (EEA) and in the respective MRA partner country (Australia, Canada, Switzerland, and New Zealand). The alert system provides for communication about counterfeiting and fraud. Suspension and withdrawals of manufacturing authorization are communicated through the alert system as well.

The alert is classified from 1 to 3 depending on the expected risk presented to the public or animal health by the defective product. This classification is internationally agreed on for medicinal product recalls (Table 6.2). In the case of class 1 recalls, a rapid alert notification must be sent to all European Economic Area member states, and the Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme (PIC/S), European Directorate for the Quality of Medicines & HealthCare (EDQM), World Health Organization (WHO), FDA, and MRA partners, irrespective of whether the batch was exported to that country. In most cases, class 1 recalls are to patient level; however, this action may not be appropriate if alternative medicines are not available, so that an assessment by the reporter of the overall risk to patients/animals must be conducted. Consideration must be given to the difficulties of communicating to patients since marketing authorization holders may need to arrange press releases and advertising campaigns.

Class 2 rapid alert notifications should be sent only to those EEA member states, and PIC/S, EDQM, WHO, and MRA partners to which it is known, or believed, that the batch has been distributed. In identifying those countries, due consideration should be given to parallel distribution and import arrangements and the free trade between wholesale distributors within the EEA. In the case of parallel imports where there is difficulty in establishing the traceability of batches, consideration should be given to notifying all member states through the RAS.

Class 3 recalls are not notified through the RAS. For class 2 and class 3 recalls, recall to patient level is rarely required as lack of the product may present a greater risk to the patient than continuing treatment. Occasionally, class 2 or class 3 recalls can be accomplished solely at the wholesale level in circumstances such as where stocks are unlikely to be found farther down the supply chain and the level of risk is sufficiently low.