CMC flexibilities in biological medicinal product development: The current EU perspective

In the EU, regulatory CMC flexibilities have been implemented for certain licenced biological medicinal products, focusing on those that target unmet medical needs or are undergoing accelerated assessment, for example, vaccines and therapeutics addressing COVID-19. While the legislative requirements for quality, safety and efficacy still apply, flexible approaches can be taken at critical stages of the product lifecycle, such as postponing some CMC requirements to the post-authorization phase or leveraging of prior knowledge (PrK). 

The European Medicines Agency (EMA) PRIME (priority medicines) scheme provides enhanced support for the development of promising medicines that target unmet medical needs. The EMA published guidance in 2022 (EMA/CHMP/BWP/QWP/IWG/694114/2019) on how flexibilities can be applied in terms of the quality (or CMC) data packages for both PRIME and non-PRIME products that are intended for early access and address an unmet medical need. 

As per this guidance, PrK is a key component in allowing CMC flexibilities. Examples of applying PrK, now formally defined in the recent revision to ICH Q5A guidance, include: 

• Internal platform PrK gained from the production process of one non-PRIME product was presented in support of the proven acceptable ranges (PARs) of another.¹
• Assignment of quality attributes and process parameters as critical was based on extensive platform experience with other products.²

Another example of a flexible approach regarding the manufacture of biologics, outlined in the guidance, is concurrent process validation. In brief, under exceptional circumstances and where a strong benefit–risk balance exists, process performance qualification can be executed concurrently with the commercialization of validation batches. This approach was used during the approval of a pandemic vaccine³ and a gene therapy with orphan status.⁴

Following process changes, comparability between pre- and post-change material is typically demonstrated through comprehensive testing in line with ICHQ5E requirements. However, the above guideline allows the exclusion of certain comparability testing or the delay in the submission of some types of comparability data. The latter approach has been used in the approval of pandemic vaccines⁵ and a vaccine with PRIME designation.⁶ 

A more comprehensive overview of the full range of CMC flexibilities can be found in our article in BioProcess International. This article discusses the full range of flexibilities including the above and: 

• Specification acceptance criteria, where it was allowed to establish these wider than the release data of batches used in clinical studies. 
• Acceptance of stability models for interim shelf life assignment in advance of product-specific data. This approach can avoid delayed patient access and is an example of the application of PrK from structurally similar products and has been used in setting the shelf lives of a pandemic vaccine² and therapy.⁷ 

With COVID-19 now an established and ongoing disease, we believe we may see regulatory authorities apply some of these adaptations to standard CMC approaches to medicines not intended for unmet needs also – if these products are justified to be safe and efficacious, and manufactured consistently. In the short term, such flexibility is likely to be seen for the acceptance of both stability-models and the application of prior knowledge. Guidance on predictive stability modeling will be part of the forthcoming combined ICH Q1A-F, Q5C stability guideline, and clear regulatory acceptance of applying prior knowledge to the evaluation of viral clearance is clearly outlined in the Q5A(R2) guideline which was adopted in November 2023.    

Parexel’s Regulatory Strategy consultants have accumulated significant insight and learnings regarding the application of CMC flexibilities from our work on multiple biological medicinal product development programs. Our experience, with products for unmet medical needs, shows that these flexibilities can accelerate development and timely access for patients to these therapies. Parexel’s biologics CMC consultants are former regulators and seasoned industry experts who bring unique insights into technical and regulatory planning and decision-making. We are committed to helping our clients prepare for and navigate the regulatory aspects of the evolving flexibility in CMC approaches, and in realizing the potential benefits for their development programs.  

References:
¹ https://www.ema.europa.eu/en/documents/assessment-report/mvabea-epar-public-assessment-report_en.pdf

² https://www.ema.europa.eu/en/documents/assessment-report/covid-19-vaccine-janssen-epar-public-assessment-report_en.pdf

³ https://www.ema.europa.eu/en/documents/assessment-report/comirnaty-epar-public-assessment-report_en.pdf

⁴ https://www.ema.europa.eu/en/documents/assessment-report/upstaza-epar-public-assessment-report_en.pdf

⁵ https://www.ema.europa.eu/en/documents/assessment-report/covid-19-vaccine-janssen-epar-public-assessment-report_en.pdf

⁶ https://www.ema.europa.eu/en/documents/assessment-report/vaxzevria-previously-covid-19-vaccine-astrazeneca-epar-public-assessment-report_en.pdf 

⁷ https://www.ema.europa.eu/en/documents/assessment-report/ervebo-epar-public-assessment-report_en.pdf 

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