Post-approval of CMC changes under FDA, EMA and HSA guidance

Before any drug intended for human use or chemical and biological products can be distributed and utilized, it must undergo approval by regulatory agencies to ensure its safety and efficacy. 

This initial step involves the submission of a new drug application to pertinent regulatory bodies, notably the United States Food and Drug Administration (FDA) for the US market, and other agencies such as the European Medicines Agency (EMA) for the European market, and the Health Sciences Authority (HSA) for the Singapore market. 

However, once the new drug application is approved, there may be changes to the product, production process, quality controls, equipment, facilities, responsible personnel, or labelling. These post-approval changes must also be notified to the regulatory agencies. 

There is an important need to thoroughly assess the effects of the change, to ensure no adverse effects on the identity, strength, quality, purity, or potency of the product quality, as it relates to the safety and effectiveness of a product. In this article, we intend to systemically lay out the different risk-based approaches for post-approval changes across FDA, EMA and HSA.

United States Food and Drug Administration, FDA Under US FDA, the term “Chemistry, Manufacturing, and Controls (CMC) changes” is specifically used for post-approval changes. There are 3 kinds of reporting categories [1]: • Prior Approval Supplement, PAS • Changes Being Effected in 30 Days/Changes Being Effected Supplements, CBE30/CBE • Annual Report, AR

Prior Approval Supplement (PAS) is appropriate for major changes – a substantial potential to have an adverse effect on product quality. A PAS must be approved by the FDA prior to distribution of the product manufactured using the change. 

Changes Being Effected in 30 Days/Changes Being Effected Supplements (CBE30/CBE) are appropriate for moderate changes – a moderate potential to have an adverse effect on product quality. A supplement must be reported to the FDA in at least 30 days prior to distribution of the product made using the change. 

There can be exceptions for a product to be distributed immediately upon receipt of the supplement by the FDA. Annual Report (AR) is appropriate for minor changes – a minimal potential to have an adverse effect on product quality. The changes only need to be documented in an annual report.

A Comparability Protocol (CP) is a good tool to use for PAS changes. A well-written CP could accelerate the timeline of implementation of CMC changes and a product into distribution as well as enable better planning of the product supply chain. Lastly, there are various examples for post-approval CMC changes and the recommended reporting category in the Appendix of the FDA guidance document [1].

European Medicines Agency, EMA The guidelines for EMA originate from International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). There are 2 categories for post-approval of CMC changes and only termed as “Prior approval” and “Notification” [2]. 

Prior approval is for changes of high risk that requires regulatory review and approval prior to implementation and will require a suitably detailed regulatory submission to the regulatory authorities. Notification is for changes of moderate to low risk that does not require prior approval. 

A formal notification of the changes is required to the regulatory authorities within a defined period of time before or after implementation, according to regional requirements in the EU. Like the Comparability Protocol (CP), ICH mentions the use of a Post-approval Change Management Protocol (PACMP). 

This regulatory tool provides predictability and transparency for the requirements and studies needed to implement a post-approval change. It could be used to justify a lower reporting category or a shortened review period.

Health Sciences Authority, HSA Similarly, changes to a product registration throughout its life cycle must be submitted to HSA via a variation application. 

There are 2 types of variation applications [3]: • Major variation application (MAV) • Minor variation application (MIV) 

MAV-1 is for any variation to the approved indication, route of administration, dosing regimen or patient groups. It is also when there is additional clinical information that extends the usage of the product. MAV-2 is for a change in the current approved forensic classification.

For minor variations under MIV-1 (detailed in Appendix 13A [4] and 14A [7]), they require prior approval before the change can be implemented. For minor variations under MIV-2 (Notification) (detailed in Appendix 13B [5] and 14B [8]), they may be implemented within 40 days of submission and upon HSA’s agreement. 

For minor variations under MIV-2 (Do and tell) (detailed in Appendix 13C [6] and 14C [9]), there is only a submission to HSA in 6 months after change implementation, with no prior approval required.

A table below summarises the reporting categories for post-approval changes as a comparison across FDA, EMA and HSA.

Table for Post approval of CMC changes under FDA, EMA and HSA

To give a better sense of the various reporting categories, here are some examples with respect to changes in manufacturing: 

In a Drug Substance Purification Process, an increase in the number of resin cycles or membrane re-use times without an approved protocol would require a PAS under the FDA. However, if a CP were to be submitted, the reporting category can be lowered to an AR. 

A change in the resin or filter supplier with no change in the resin material, operating or performance parameters is recommended to be categorised as a CBE-30 under the FDA [1]. 

For HSA, a change in the manufacturing process of biological products that causes a significant impact on the quality, safety and efficacy of the drug, such as a change in a batch size, would require a MIV-1 variation application [7].

A minor change in the approved manufacturing process that does not require an assessment of comparability, such as duplication of a fermentation train or addition of identical bioreactors, would be categorised as a MIV-2 (Notification) [8]. 

MIV-2 (Do and tell) does not cover for any changes in the manufacturing process of biological products under HSA guidelines [9].

On a final note, regulators are wanting to create less burden, and have provided these guidelines to facilitate applicants to make more informed decisions when reporting and implementing post-approval changes. This initiative is expected to enhance patient outcomes and optimize the supply of medicinal products.

References: 
[1] FDA Guidance for Industry: Chemistry, Manufacturing, and Controls Changes to an Approved Application: Certain Biological Products, June 2021
[2] ICH Harmonised Guideline, Q12, Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management, November 2019 (Adopted by EMA, March 2020)
[3] Health Sciences Authority, Guidance On Therapeutic Product Registration in Singapore, TPB-GN-005-012, Section 22, September 2023
[4] Health Sciences Authority, Guidance On Therapeutic Product Registration in Singapore, Appendix 13A Part A: Checklist on Dossier Requirements for MIV 1 Variation for Chemical Therapeutic Products
[5] Health Sciences Authority, Guidance On Therapeutic Product Registration in Singapore, Appendix 13B Part B: Checklist on Dossier Requirements for MIV-2 (Notification) Variation for Chemical Therapeutic Products
[6] Health Sciences Authority, Guidance On Therapeutic Product Registration in Singapore, Appendix 13C Part C: Checklist on Dossier Requirements for MIV-2 (Do-and-Tell) Variation for Chemical Therapeutic Products
[7] Health Sciences Authority, Guidance On Therapeutic Product Registration in Singapore, Appendix 14A Part A: Checklist on Dossier Requirements for MIV-1 Variation for Biological Therapeutic Products
[8] Health Sciences Authority, Guidance On Therapeutic Product Registration in Singapore, Appendix 14B Part B: Checklist on Dossier Requirements for MIV-2 (Notification) Variation for Biological Therapeutic Products
[9] Health Sciences Authority, Guidance On Therapeutic Product Registration in Singapore, Appendix 14C Part C: Checklist on Dossier Requirements for MIV-2 (Do-and-Tell) Variation for Biological Therapeutic Products

Achieving compliance with post-approval CMC changes is critical. No deviation specializes in streamlining CQV processes, addressing CAPA needs, and implementing digital solutions. Our services range from full risk-based, paperless validations to enhancing existing paper-based systems, ensuring regulatory compliance and operational efficiency.

For tailored solutions to your regulatory challenges, contact us at hello@nodeviation.com or visit www.nodeviation.com for more information.

Let’s enhance your operational efficiency together.

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