A Customized Regulatory Approach to CMCs

BioPharm International, BioPharm International, February 2022, Volume 35, Issue 2
Pages: 34–36

Build into the chemistry, manufacturing, and control strategy the ability to pivot and be flexible should the course change.

Chemistry, manufacturing, and control (CMC) strategies and requirements vary for different products, including small molecules, large molecules, and gene therapy products. Although approaches to CMC strategies differ, how does this factor in from a regulatory perspective?

BioPharm International interviewed Monica Commerford, head of regulatory affairs, viral vector services, pharma services, Thermo Fisher Scientific; Jesse Bishop, manager, regulatory affairs, viral vector services, pharma services, Thermo Fisher Scientific; Bram Lardée, client relationship manager product lifecycle management, ProPharma Group; Peder Edin, managing consultant, RA CMC EU, ProPharma Group; Roland Gustafsson, subject matter expert, quality, ProPharma Group; and Khanh Ngo Courtney, PhD, senior director, biologics, Element. These experts dive into key considerations for CMCs, audits, fast-track designations, and how a one-size-approach doesn’t fit all.

Key differences for CMC requirements

BioPharm: CMC requirements vary for different products, including small molecules, large molecules, and gene therapy products. What are some of the key differences, and what are the best ways to approach each?

Lardée (ProPharma Group): Small-molecule active pharmaceutical ingredients are more robust and resistant against microbial contamination. Generally, small molecules are administered orally and, therefore, formulated accordingly into solid oral dosage forms, suitable for exposure to the harsh conditions in the gastrointestinal tract. Large molecules and gene therapy products are biological products that contain complex proteins or whole cells. These products must retain their structure and modification and are typically dosed via injection or infusion in a clinical setting. The best way to approach each category of products is to acknowledge these differences and combine the similarities in disciplines independent of drug product or process type.

Courtney (Element): CMC for large molecules, particularly gene therapy, is much more complex than for small molecules—specifically when it comes to the measurement of potency and process-related impurities. For a small molecule, U/HPLC [high and ultra-high-performance liquid chromatography] to show purity is sufficient as a measurement of strength and potency. The next level in complexity is a large molecule, such as a recombinant enzyme. To show potency, U/HPLC is not sufficient, but requires an in vitro enzymatic activity and an in vitro cellular potency assay to show in vitro mechanism of action. For gene therapies, showing an in vitro mechanism of action is more complex and cumbersome as the assay must be able to demonstrate viral transduction followed by a cellular response. Demonstrating the clearance of process-related impurities is also more difficult for advanced therapeutics because there are more starting materials, complex upstream processes, and complex purification steps.

Commerford (Thermo Fisher Scientific): We have to remember that cell and gene therapy products still fall under regulations and licensure requirements for biologics in the United States. Therefore, CMC requirements would be similar for cell and gene therapy products as they would for the more traditional biologics (i.e., monoclonal antibodies). However, the licensure regulations in the United States are different than what is needed to approve small molecules (as small molecules and their manufacturing processes are not licensed).

Key considerations for quality

BioPharm: From a quality/regulatory perspective, what are key considerations for CMCs?

Courtney (Element): Stage-gating CMC activities by appropriateness is one of the key considerations for CMCs. Another key consideration is identifying critical quality attributes of the drug substance and drug product as early as possible in product development so that robust methods could be developed to monitor the quality of the product as the process is being developed. A third key consideration is to build into the strategy the ability to pivot and flexibility to change course based on clinical data or business decisions.

Edin (ProPharma Group): The CMC sections in a product dossier should indicate that the drug product is produced with a consistent quality throughout the development process and throughout the period the product is marketed to guarantee the safety and efficacy profile of the medicinal product. To demonstrate that the manufacturer is in sufficient control during manufacture of the drug product, all critical steps and parameters need to be evaluated for starting materials and the production processes during the development phase of the product and, subsequently, a quality control plan needs to be put in place. Additionally, the shelf-life and the usability of the final product need to be established. Extensive characterization of the drug substance and drug product are fundamental for any comparability program following any manufacturing changes. Control of impurities is critical, particularly those that are process-related to gene therapy products.

Bishop (Thermo Fisher Scientific): Matching the quality/manufacturing controls and the regulatory requirements to the phase of development is critical here. Clearly, patient safety should never be compromised, but starting with too many controls too early can cripple a program’s forward momentum and lead to delays in getting patients the life-changing therapies they need. When considering regulatory strategy and forward momentum, it’s also important to have a clear understanding of the increasing regulatory requirements through all phases because of the pitfalls that so many programs are experiencing when not looking ahead.

Regulatory roadblocks

BioPharm: What might halt forward motion for CMCs for small molecules, large molecules, and/or gene therapy products in terms of regulatory steps? How can potential roadblocks be avoided?

Bishop (Thermo Fisher Scientific): No matter what the phase, it’s important to start with the end goal, analyze the regulatory requirements to reach that goal, and develop a long-term strategy to meet those requirements throughout the course of the program’s development. Roadblocks arise when you don’t ask the right questions of the regulators at the right time or don’t prepare for increasing requirements over the program’s movement through the phases. How do we avoid these potential roadblocks? Ask questions of the regulators, early and often. Take advantage of those opportunities whenever possible. Also, it’s important to develop checklists of all regulatory requirements in order to arrive at the end of the programs with all requirements met, instead of experiencing program delays due to having to go back to meet a requirement that was not properly planned for.

Edin (ProPharma Group): Old processes that do not meet current regulatory requirements, lack of critical data, and risk assessments might halt forward motion for CMC. Different regulatory requirements in different countries and lack of alignment between different authorities (US vs. EU [European Union] vs. JP [Japan]) could also be a hindrance. Other obstacles, especially for large molecules, could be insufficient comparability data to support any manufacturing changes (site, starting and raw reagents, adherent to suspension cell lines). Finally, it must be emphasized that marketed product[s] must always be supported by representative development data. Changes made in the development process can endanger meeting this requirement, which may result in significant delays and extra work. These roadblocks can be avoided by planning and performing comparability studies with validated analytics, having sufficient retains [retainer samples] of pre-change drug substance and drug product as well as post-change drug substance and drug product, and the ability to perform side-by-side comparability analysis. Necessary changes in the development process should always be evaluated for regulatory impact. The involvement of a regulatory CMC person during development—and even the planning of development—could be very helpful to prevent unnecessary delays.

CMC audits

BioPharm: What do you typically encounter with audits for CMCs?

Courtney (Element): CGMP [current good manufacturing practice] compliance is becoming more rigorous and is being required earlier in the CMC process. Even if methods are not yet validated, they are being required to at least be sufficiently qualified. Furthermore, all software that generate[s] electronic records, such as Empower, OpenLab, or instrument-specific acquisition and analysis software, must be 21 CFR [Code of Federal Regulations] Part 11 compliant—particularly regarding audit trail capability and validated systems (1).

Commerford (Thermo Fisher Scientific): This is often looked at as an afterthought or planned for too late in the product’s development timeline. Manufacturing facilities should be in a continuous state of inspection readiness, particularly once the product application has been submitted to regulators. To prepare, the CMCs should be mock inspected by the appropriate subject matter experts. The goal for any mock inspection should be to ensure that the data [are] accurate, that the data [contain] the appropriate level of quality, that quality-by-design principles are built into the manufacturing process, and that the manufacturing process and site practices are aligned with the submitted application.

Bishop (Thermo Fisher Scientific): This is also the perfect time to look ahead at what questions can be anticipated from the regulators during the review cycle (or perhaps at the next submission) as the inspection for a product application and the review of it are linked. Some of these questions or information requests coming back from the regulators are going to be on a short time clock, and if there hasn’t been some thought and preparation for those questions, the program can be slowed down or halted.

Gustafsson (ProPharma Group): For CMC, we focus our expertise on audits of manufacturing sites, which significantly impacts GMP compliance. An important part of this is to make sure that process validations have been performed according to current standards, that the results are reflected in the master batch record, and that all subsequent changes are handled by a change control system. Furthermore, we encounter a focus on the QA/QC [quality assurance/quality control] release process to ensure that registered critical process parameters and critical quality attributes are within limits before batch release and measured with validated analytical methodology.

Fast-track designation

BioPharm: What can increase the likeliness that companies secure a fast-track designation from FDA or other regulatory bodies for CMCs?

Lardée (ProPharma Group): For fast-track designations, this is dependent on the necessity of the medical indication (unmet need). In addition, having a complete and logical technical storyline and communicating this as early as possible does help in convincing the competent authority. Above all, fulfilling an unmet need is most important.

Commerford (Thermo Fisher Scientific): Regulatory bodies (specifically, FDA) have a specific set of criteria that they consider when discussing (and ultimately agreeing to) a fast-track designation that include[s] the seriousness of the condition and demonstrates the potential to address an unmet medical need (2). For applicants considering this designation, early communication (even as early as the pre-IND [investigational new drug application] meeting) with the regulatory body is needed to discuss plans and approaches. Particularly, the FDA recommends submitting your requests “when the IND is first submitted or any time thereafter before receiving marketing approval of their BLA or NDA” (2).

CMC trends

BioPharm: Do you foresee any trends for CMCs in the near future?

Commerford (Thermo Fisher Scientific): Within the next few years, as more and more cell and gene therapy submissions are moving to the market, we will likely see more strategic guidance from regulators as they are starting to compile the necessary quality and safety data from reviewing a diverse range of applications. This guidance could come in formal ways (e.g., guidance documents, industry meeting responses) or through informal means.

Courtney (Element): Analytics will become more automated. There will be more online data capture, such as metabolic or spent media information in bioreactors, or automated data analysis of downstream processes. Process development will become more platform based and streamlined, especially for similar modalities like specific AAV serotypes.

Lardée (ProPharma Group): Personalized medicines continue to gain, independent of drug product or process type. Furthermore, I do expect an increase and optimization in measurement of biomarkers, not only to decrease hospitalizations, but also in creating awareness for potential health issues and pro-actively deal with these. Finally, I foresee an acceleration in more strict and new standards for Eco+ productions and handling of biopharmaceutical waste streams. More efficient use of medication with further improvement of communication and information to end-users will be an important part of this.


  1. Legal Information Institute, “21 CFR Part 11 – Electronic Records; Electronic Signatures,” law.cornell.edu/cfr/text/21/part-11(March 20, 1997).
  2. FDA, Guidance for Industry: Expedited Programs for Serious Conditions – Drugs and Biologics, fda.gov (May 2014).

About the author

Meg Rivers is a senior editor for Pharmaceutical Technology, Pharmaceutical Technology Europe, and BioPharm International.

Article details

BioPharm International
Volume 35, Number 2
February 2022
Pages: 34–36


When referring to this article, please cite it as M. Rivers, “A Customized Regulatory Approach to CMCs,” BioPharm International 35 (2) 34–36 (2022).