Change is inevitable, continuous, and reportable to the FDA when we are talking about approved human or animal drugs. Specifically, this article seeks to discuss some of the challenges caused by changes, and some thoughts on reporting changes, for branded or generic drugs approved for human use under a New Drug Applications (NDA) or Abbreviated New Drug Applications (ANDA), respectively.

Recently at a conference sponsored by the Association of Affordable Medicines (AAM), speakers from FDA’s Office of Generic Drugs presented that the top two categories of post-approval supplements submitted for ANDAs were related to manufacturing site and manufacturing process; the next three categories of change were also related to manufacturing (i.e., changes to specifications, testing, container/closure, and composition).¹ It is not a far stretch to assume that manufacturing changes similarly represent a large portion of the supplements received by the Office of New Drugs. In fact, the first two sections of FDA’s Guidance, Changes to an Approved NDA or ANDA,² address manufacturing changes and how to report them and more recently FDA’s Draft Guidance, Post-approval Changes to Drug Substances,³ also makes significant reference to manufacturing change, so it seems to be a subject of particular importance.

Unfortunately, even the simplest changes can face hurdles. The requirements for some annual reportable changes, such as Residual Solvents compliance with USP and Elemental Impurities compliance with USP , were found to be a challenge for organizations to assess. When big changes come up in a manufacturing organization, having a regulatory resource present to give an initial assessment of how the change may be handled, and what work might be needed to support the eventual filing to the FDA, is important. A little planning can go a long way—supplements that are needed immediately because they impact product release or are gating to production are not an ideal situation for any company to be in. A robust change management system with a required regulatory assessment can often head this off, but an upfront discussion with the Regulatory Department never hurts when change is brewing in a facility.

More importantly, if left out of the conversation, Regulatory may miss the opportunity to devise a more creative post-approval regulatory pathway than can be managed when there is pressure to submit immediately. Outside of combing through the relevant Change Guidances,^2,3,4 Scale-Up and Post-approval Changes (SUPAC) Guidances,^5,6,7 and prior change precedents to see if the specific manufacturing change fits into any obvious category, there are several forward-looking regulatory pathways that can be used to help facilitate and implement significant changes that can have an impact on patient supply. This article considers a few of these options in relation to examples that may occur in a manufacturing facility.

Comparability protocols
If a change is identified well in advance, the use of a comparability protocol may be something to consider. The FDA issued a Draft Guidance, Comparability Protocols for Human Drugs and Biologics: Chemistry, Manufacturing, and Controls Information, on April 2016⁸ which describes the potential application and use of comparability protocols. This might be a regulatory pathway to consider for changes such as future product manufacturing scale-up, equipment changes, specification changes, or container/closure changes. Comparability protocols must be approved by the FDA in advance of the proposed change and may be submitted in either the original NDA or ANDA or after approval via prior-approval supplement. They can be used to facilitate a one-time change or a re-occurring change throughout the product’s lifecycle.

For this to be a viable regulatory pathway for an anticipated future change, sufficient information and data to support the change—any specific studies, risk assessment, control strategy, side-by-side specification comparison, etc.—will need to be available for the FDA’s consideration. One additional benefit of the comparability protocol is that a reduced reporting category may be proposed, such as a Changes Being Effected (CBE) supplement or even via an Annual Report, to provide product specific outcomes or completion of study protocols proposed in the original comparability protocol. Once approved, it will serve as a roadmap for the company and may reduce the overall timelines for the implementation of the change if the FDA agrees to a reduced reporting category. Once submitted and approved, the comparability protocol must be managed and any modifications to the change that may impact the approved conditions of the comparability protocol will need to be submitted to the FDA; if the change to the comparability protocol is significant, it may need to be submitted as another prior-approval supplement or as a CBE-30 supplement as discussed in the FDA’s Draft Guidance.

Additionally, comparability protocols may also be submitted in relation to the same change that may impact multiple applications, also identified as a grouped supplement. In this case, a lead product (or lead supplement) would be chosen to submit the prior approval comparability protocol prospectively and upon execution of the change, the grouped supplement would be submitted to report the change for multiple applications. A big consideration here is whether the change being contemplated is complex or has the potential to have a significant impact on product quality; if not, the effort and resources needed to submit a proper comparability protocol may ultimately not be worth it. In this case, it is more likely that a comparability protocol will only serve to define the pathway of change and that the FDA may still want to evaluate the change under a prior-approval supplement before implementation. 

Grouped supplements
The use of a grouped supplement is a little more simplistic than a comparability protocol and is a good way to consolidate submission of the same change that affects multiple applications. The rough definition of a grouped supplement in FDA’s MAPP 5015.6 Rev.1 is two or more supplements submitted by the same applicant that are reviewed and processed together for an identical change.

Unfortunately, grouped supplements cannot be submitted by more than one applicant.⁹ If there are product-specific changes related to the grouped supplement change, these should be submitted under a separate supplement with reference made in the cover letters of both the grouped supplement and the product-specific supplement to link them together. This was recently recommended by the FDA² and ensures that the FDA is aware of all potentially related changes that could be incorporated into a grouped review. This may be a viable regulatory pathway for implementation of a new line or site change where the initial change has been previously approved under a lead supplement or refurbishing a facility where multiple changes can be consolidated into one supplement and are applicable to multiple applications.

Lead supplement
The use of a lead supplement may be something that could be considered for a manufacturing organization where it may be beneficial to submit the change to one application and then leverage the approval of the initial change in either individual or grouped supplements that are the same as that approved for the lead supplement.^9,10 This may be useful where the original change is considered prior approval, such as adding an aseptic manufacturing line to an existing facility, and once the facility is reviewed, approved, and inspected (as may be required), additional supplements can be filed as CBE-30 supplements to add the now-approved line.

The lead supplement approach may also tie into the use of either of the comparability protocol and/or grouped supplement regulatory strategies discussed previously.⁸ And, if the change arises quickly, and time and resources do not allow for prospective submission of a comparability protocol, then a product-specific prior-approval supplement with a follow up, downgraded grouped supplement—with or without corresponding product specific supplements—all properly referenced and linked—may be the best option. However, as noted in FDA’s Guidance, Prior Approval Supplements Under GDUFA,¹⁰ it is recommended that the use of this regulatory pathway is verified as appropriate with the FDA prior to submission.

It is important to weigh all these considerations carefully including: the complexity of the change, the chances of being able to reduce the reporting category and management of the amount of upfront information needed. This will help give the regulatory staff sufficient time to consider the options before embarking on any particular regulatory pathway to report your manufacturing changes. 

References

1. Schwartz, P.;Okubadejo, O; Post Approval Changes: Best Practices and Strategies; Presented at the Associate of Affordable Medicines GRx+Biosims Conference, Bethesda, MD, November 2019.
2. US Food and Drug Administration. Center for Drug Evaluation and Research. (2004, April). Guidance for Industry, Changes to an Approved NDA or ANDA. Retrieved from https://www.fda.gov/media/71846/download.
3. US Food and Drug Administration. Center for Drug Evaluation and Research. (2018, September). Draft Guidance for Industry, Postapproval Changes to Drug Substances. Retrieved from https://www.fda.gov/media/115733/download
4. US Food and Drug Administration. Center for Drug Evaluation and Research. (2014, March). Guidance for Industry, CMC Postapproval Manufacturing Changes To Be Documented in Annual Reports. Retrieved from https://www.fda.gov/media/79182/download
5. US Food and Drug Administration. Center for Drug Evaluation and Research. (1995, November). Guidance for Industry, Immediate Release Solid Oral Dosage Forms, Scale-Up and Postapproval Changes: Chemistry, Manufacturing, and Controls, In Vitro Dissolution Testing and In Vivo Bioequivalence Documentation.  Retrieved from https://www.fda.gov/media/70949/download
6. US Food and Drug Administration. Center for Drug Evaluation and Research. (1997, September). Guidance for Industry, SUPAC-MR: Modified Release Solid Oral Dosage Forms, Scale-Up and Postapproval Changes: Chemistry, Manufacturing, and Controls; In Vitro Dissolution Testing and In Vivo Bioequivalence Documentation.  Retrieved from https://www.fda.gov/media/70956/download
7. US Food and Drug Administration. Center for Drug Evaluation and Research. (1997, May). Guidance for Industry, Nonsterile Solid Dosage Forms, Scale-Up and Postapproval Changes: Chemistry, Manufacturing, and Controls; In Vitro Release Testing and In Vivo Bioequivalence Documentation.  Retrieved from https://www.fda.gov/media/71141/download
8. US Food and Drug Administration. Center for Drug Evaluation and Research. (2016, April). Draft Guidance for Industry, Comparability Protocols for Human Drugs and Biologics: Chemistry, Manufacturing, and Controls Information.  Retrieved from https://www.fda.gov/media/97148/download
9.  US Food and Drug Administration. Center for Drug Evaluation and Research, Office of Pharmaceutical Quality. (2016, April). Manual of Policies and Procedures 5015.6 Rev.1, Review of Grouped Product Quality Supplements. Retrieved from https://www.fda.gov/media/72531/download.
10. US Food and Drug Administration.  Center for Drug Evaluation and Research and Center for Biologics Evaluation and Research. (2017, October). ANDA Submissions – Prior Approval Supplements Under GDUFA, Revision 1. Retrieved from https://www.fda.gov/media/89263/download

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Amy Schutte
Senior Associate, Lachman Consultant Services

Amy Schutte is a Senior Associate in the Regulatory Practice at Lachman Consultants with nearly 20 years’ experience. She is a pharmaceutical industry professional with specialization in Regulatory Affairs and experience in quality, regulatory compliance, and pharmacovigilance.