In connection with the Food and Drug Administration’s (FDA) Pharmaceutical Quality Initiative and its risk-based approach to chemistry, manufacturing, and controls (CMC) review, the agency released a draft guidance document on June 24, 2010, regarding CMC postapproval manufacturing changes reportable in annual reports.

After submitting a new drug application (NDA) or an abbreviated new drug application (ANDA) and being granted approval from FDA, new drug applicants still have numerous postmarketing regulatory responsibilities. Each year, within 60 days of the anniversary date of U.S. approval, applicants must submit an annual report which covers such topics as:

– a brief summary of any significant new information from the previous year that might affect the safety, effectiveness, or labeling of the drug product,

– distribution data and information regarding generic drugs,

– current labeling and any changes to such labeling,

– CMC changes,

– nonclinical laboratory studies,

– clinical data,

– the status of postmarketing studies and,

– outstanding regulatory business.

As described in the regulations, all postapproval CMC changes – beyond prior established variations documented in an NDA or ANDA – are broken down into the categories of “major,” “moderate,” or “minor.” Each category of change is associated with different submission and implementation requirements. Major changes must be submitted to FDA for prior approval before the product affected by the change may be distributed by the applicant. Moderate changes must be submitted at least 30 days before distribution, or, in some cases, at the time of distribution. For minor changes, the applicant may proceed with distribution and include the information regarding the minor change in the annual report. Specifically, the regulation specifies that minor changes include “[c]hanges in the drug substance, drug product, production process, quality controls, equipment, or facilities that have a minimal potential to have an adverse effect on the identity, strength, quality, purity, or potency of the drug product as these factors may relate to the safety or effectiveness of the drug product . . . .” For all changes, however, applicants must fulfill their regulatory requirement and assess how they affect product safety and efficacy, and demonstrate these effects through studies, allowing them to best determine whether it would be more appropriate to submit the change via supplement.

The draft guidance document on CMC postapproval manufacturing changes that are reportable in annual reports targets the section of the regulations discussing minor changes to
clarify for industry those FDA has determined “will likely
present minimal potential to have adverse effects on product quality and, therefore, may be reported by applicants in the annual report.”

A Risk-Based Approach

In 2002, FDA announced the Pharmaceutical Current Good Manufacturing Practices for the 21st Century to “enhance and modernize” pharmaceutical products and the manufacturing process. One of the objectives of this initiative was to encourage risk-based approaches to regulation and reporting to ensure that resources are directed appropriately to critical areas. In 2004, FDA released a final report entitled Pharmaceutical Current Good Manufacturing Practices (CGMPs) for the 21st Century–
A Risk-Based Approach. As part of this report, FDA decided that CMC review should be “based on an understanding of product risk and how best to manage this risk.”

The Center for Drug Evaluation and Research (CDER) has internalized this objective by implementing its own risk-based approach for CMC review. As the number of CMC manufacturing supplements for NDAs and ANDAs has grown in recent years, CDER evaluated the CMC postapproval manufacturing supplements they were receiving. During this process, they determined that many of the supplements included changes the agency believed to be of low risk to the quality of the product and, thus, did not need to be submitted by supplement. Accordingly, CDER released a draft guidance document to clarify for companies when they must submit a supplement, and when they may wait to include the information in the annual report.

In the draft guidance document CDER created a list (included as Appendix A in the guidance) of CMC changes they felt may be appropriate for inclusion in the annual report. They encouraged companies submitting supplemental applications to first refer to this list to determine whether the change should be considered for inclusion in the annual report. FDA was quick to highlight, however, that some determinations must be made on a case-by-case basis, so the applicant should not rely solely on the list. Therefore, CDER recommended that companies should still first evaluate whether their proposed change may have an adverse effect on the identity, strength, quality, purity, or potency of the drug product. If a company believes this to be the case, then even if the change is included on the list, the change may still be more appropriately submitted as a supplement. Companies should note they are still required to comply with the CGMP for Finished Pharmaceuticals regulations, including qualifying equipment as suitable for its intended use, assuring validated test methods and ongoing state of control of manufacturing processes, and maintaining appropriate written procedures reviewed and approved by the quality unit.

CMC Postapproval Manufacturing Changes Reportable in Annual Reports

The list contained in the draft guidance document grouped changes into six categories:

1)components and composition,

2)manufacturing sites,

3)manufacturing process,

4)specifications,

5)container/closure system,

6)miscellaneous.

While a summary of these groups is discussed below, applicants are encouraged to review the draft guidance document for additional details and exceptions.

The types of changes included in the “Components and Composition” section include: eliminating or reducing overages from the manufacturing batch formula used to compensate for manufacturing losses, changes in the coating formulation for immediate-release solid dosage forms if the material and quantity have been approved in another product and do not alter release, and new suppliers of inactive ingredients if it has minimal effect on performance of the product.

The second section of the list discusses “Manufacturing Sites.” Types of changes described in this section include: facility modification that does not affect a product manufacturing area, sterility, quality, or specifications, adding barriers to prevent routine in-process human intervention in a filling or compounding area, and manufacturing an additional drug product in an approved multiple product area producing other products within certain confines.

The “Manufacturing Process” section includes: several specific process changes: a scale change of pooled or separated batches to perform the next step in the manufacturing process if several other requirements are still met, replacement of equipment with the same design and operating principle that does not affect the process methodology or in-process control limits (with the exception of equipment used in aseptic processing), the addition of a duplicate process chain or unit process with no change in in-process control limits or product specifications, changing a reprocessing protocol for refiltrations to control bioburden because of integrity test failures, reduction of open handling steps if there is an improvement with no change to the process, changes to filtration process parameters within currently validated parameters, and, for sterile drug products, a change from a qualified sterilization chamber to another of the same design and operating principle for container/closure preparation with various limitations.

The fourth section, “Specifications,” includes: addition of a specification for existing excipients, a change to a drug substance or drug product to comply with the official compendia within certain limitations, a change in the approved analytical procedure within specified confines, replacement of a nonspecific identity test with a discriminating identity test that includes a change in acceptance criteria, addition of an in-process test, replacement of blend uniformity and in-process homogeneity tests, revision of tablet hardness if there is no significant change is the dissolution profile, elimination of an in-process disintegration test where a dissolution test is required for release, deletion of the homogeneity test as a routine test from the application; addition of a test for packaging material to provide increased assurance of quality, and a tightening of an existing acceptance criterion.

The “Container/Closure System” section of the list includes items such as: a change in the container/closure system for the storage of a nonsterile drug substance, use of a contract manufacturing organization for the washing of a drug product stopper within enumerated confines, a change in glass supplier without a change in glass type or coating and without a change in container/closure dimensions (for parenteral drug products), and changes to a crimp cap with several limitations. For solid oral dosage forms, elimination of bottle dunnage, and a change in type of desiccant to another equivalent desiccant previously used in another approved product are also included in this section.

The last section covers “Miscellaneous Changes” and includes changes such as: extension of expiry based on real-time stability data from pilot scale batches following an approved stability protocol, reduction of expiration dating for a drug product for reasons other than stability failures, and, if a dissolution test is performed, elimination of a nonstability indicating test for identity or hardness from an approved stability protocol. For changes in an application that are consistent in scope and requirements with changes previously approved in a bundled supplement, the same applicant can add similar drug products.

If a company has questions regarding whether a specific change requires a supplement or may be included in the annual report, CDER directs them to the appropriate review division in the Office of New Drug Quality Assessment (ONDQA), Office of Generic Drugs (OGD), or New Drug Microbiology Staff (OPS-NDMS). If an applicant decides to include CMC changes in the annual report and not by supplement, the report should be written in such a way as to allow CDER to determine whether the appropriate reporting category has been used.
If a change is submitted inappropriately in an annual report, the applicant will be notified and additional information may be requested.

Colleen Heisey is a partner in the Washington, D.C. office of Hunton & Williams LLP (hunton.com) in the firm’s Food and Drug Practice. She can be reached at cheisey@hunton.com.