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New drug application (NDA) and abbreviated new drug application (ANDA) holders may wish to make changes to their products post-approval, in line with section 506A of the Federal Food, Drug, and Cosmetic Act (the Act) and 21 CFR 314.70.

Apart from specified biotechnology and specific synthetic biological products, the US Food and Drug Administration’s (FDA’s) Guidance for Industry: Changes to an Approved NDA or ANDA provides recommended reporting categories for post-approval changes for drugs, and covers:

• Components and composition;
• Manufacturing sites;
• Specifications;
• Container-closure systems;
• Labeling;
• Miscellaneous changes, and
• Multiple related changes.

The guidance does not provide detailed recommendations regarding the specific information that should be provided by an applicant to assess the effect of post-approval changes on the identity, strength, quality, purity, or potency of a drug product. Rather, the guidance states that consideration should be given to all relevant Center for Drug Evaluation and Research (CDER) guidance for recommendations concerning the information to be submitted to the Agency to support post-approval changes. The most frequently asked questions with reference to the FDA guidance for changes to an approved NDA or ANDA are answered below.

The FDA guidance states that effects of a change to an approved drug product must be assessed prior to distributing a product which has been made with a manufacturing change. In order to meet this requirement, what does the Agency recommend ANDA or NDA holders evaluate?

Conformance to specifications

The effects of a manufacturing change on the identity, strength, quality, purity and potency of the drug product should include a determination that the drug substance intermediates, drug substance, in-process materials, and/or drug product impacted by the manufacturing change conform to approved specifications.

A specification is defined as “a quality standard (i.e., tests, analytical procedures, and acceptance criteria) provided in an approved application to confirm the quality of drug substances, drug products, intermediates, raw materials, reagents, components, in-process materials, container closure systems, and other materials used in the production of a drug substance or drug product” within the guidance.

Per the guidance, acceptance criteria has been defined as “numerical limits, ranges, or other criteria for the tests described (CFR 314.3(b)),” and conformance to specifications means that “the material, when tested according to the analytical procedures listed in the specification, will meet the listed acceptance criteria.”

Additional testing

Along with confirming the product meets specifications, the FDA recommends, when appropriate, further testing be performed to assess whether the identity, strength, quality, purity, or potency of the drug product have been or will be affected. These attributes (identity, strength, quality, purity, and potency) may impact the safety or efficacy of the drug product. Additional testing should evaluate changes in:

• Chemical;
• Physical;
• Microbiological;
• Biological;
• Bioavailability, and/or
• Stability profiles.

The supplementary assessment may involve testing of the post-change drug product, or if appropriate, material directly affected by the change. Multiple factors should be considered, including the type of manufacturing change, type of drug substance and/or drug product, and effect of the change of the quality of the drug product, when deciding whether the post-change drug product or the material directly affected by the change should be analyzed.

Equivalence

Is the drug product which has been made after the change equivalent to the drug product which was made before the change? This is the critical question the FDA is looking to answer when assessing equivalence. It is critical to note that “equivalent” does not necessarily mean “identical”. Rather, equivalence may relate to the preservation of a quality characteristic (e.g., stability) as opposed to the performance of a single test.

Applicants ought to generally assess the extent to which the manufacturing change has affected the identity, strength, quality, purity, and potency of the drug product, according to Agency recommendations. Test results from pre- and post-change material can be compared, thus establishing whether results are equivalent. However, for specific ANDA post-approval changes, the FDA recommends the reference listed drug (RLD) be used for comparison when re-documenting bioequivalence.

Adverse effect

In many instances when manufacturing changes are shown to have an adverse effect on the identity, strength, quality, purity, or potency of a drug product, applicants choose not to implement such manufacturing changes. However, in some cases, applicants do desire to move forward.

In cases where an assessment indicates that a drug product has been adversely affected by a manufacturing change, the FDA recommends changes be submitted in a prior approval supplement irrespective of the recommended reporting category for the change. The following example is provided in regulatory guidance:

A process change recommended for a changes-being-effected-in-30-days supplement may cause the formation of a new degradant which requires qualification and/or identification. However, the applicant’s degradation qualification procedures may indicate there are no safety concerns relating to the new degradant. Nevertheless, the FDA recommends the applicant submit this change in a prior approval supplement with appropriate information to support the continued safety and efficacy of the drug product. The FDA will assess the impact of any adverse effect on the drug product during the review of the prior approval supplement, as this change may impact the safety or effectiveness of the drug product.

An annual report for the addition of time points to the stability protocol or deletion of time points beyond the approved expiration dating period is recommended within the guidance. Is the protocol still considered approved if these changes are made in an annual report?

Yes, if changes such as these are made in an annual report, the stability protocol is still considered to be approved.

How should the addition of a test to an approved stability protocol be reported?

When a test is added, whether it is added to a release specification or a stability protocol, the change should be reported in a Supplement — Changes Being Effected under section VIII.C.2.a of the guidance, which states “An addition to a specification that provides increased assurance that the drug substance or drug product will have the characteristics of identity, strength, purity, or potency that it purports or is represented to possess. For example, adding a new test and associated analytical procedure and acceptance criterion.”

To allow for the use of a company (i.e., secondary) standard in addition to the US Pharmacopeia (USP) standard, how should a revision to an analytical procedure be reported?

It is critical to note laboratory reference standards must comply with cGMP regulations (21 CFR 211.194(c)). Applicants should detail the revision of an analytical procedure allowing the option for the use of a secondary standard in an annual report.

A change (specified change) is planned, and the guidance recommends that the change be reported in a supplemental application. However, the data generated indicate that this change does not adversely affect the identity, strength, quality, purity, and potency of the product. Can this change be reported in an annual report?

No, because recommended reporting categories are based on the potential for the change to adversely affect the identity, strength, quality, purity, or potency of the drug product. This is a result of the direct correlation between these factors and their impact on the safety or effectiveness of the drug product.

Although CDER expects that, in the applicant’s judgement, most of the data and information presented to support a supplemental change will demonstrate that the change does not adversely affect the product, the FDA will evaluate the completeness of the data and provided information. The Agency will then make a determination as to whether the conclusion of the applicant (i.e., there is no adverse effect) is appropriate prior to granting approval for such a change.

If an intermediate or starting material is also a drug substance, do the recommendations regarding reporting site changes for intermediates or drug substances apply?

The guidance on intermediates would apply if a drug substance is used as an intermediate in a drug substance manufacturing process. However, this assumes the material has been properly classified as an intermediate (defined in the guidance as “a material that is produced during steps of the synthesis of a drug substance and undergoes further molecular change before it becomes a drug substance”). Usually, CDER does not consider a drug substance to be a starting material.

If a manufacturing change is planned that can be reported in the annual report, should the data to support the change be included in the annual report?

Yes. After the manufacturing change is implemented, that information should be included in the next annual report. Additionally, the information to support the change must be generated prior to distributing the product made with the change, as stated in section 506A(b) of the Act. Specifically, “a drug made with a manufacturing change (whether a major manufacturing change or otherwise) may be distributed only if, before distribution of the drug as so made, the holder involved validated the effects of the change on the identity, strength, quality, purity, and potency of the drug as the identity, strength, quality, purity, and potency may relate to the safety or effectiveness of the drug.”

How can a CRO/CDMO support holders of approved NDAs or ANDAs looking to make post-approval changes to their drug products?

Element’s team of consultative, industry-leading scientists can help generate the necessary data to support an application to change an approved NDA or ANDA. Our scientists are up to date with regulatory requirements and industry guidance, and can provide exceptional insight into the necessary testing and data needed to submit to the FDA to obtain approval for changes to approved NDAs or ANDAs.