Best practices for manufacturing Antibody Drug Conjugates (ADCs)

This is the first in a four-part series about challenges and best practices in developing antibody-drug conjugates, or ADCs.

At present, nearly 100 new ADCs are undergoing clinical studies as they gradually revolutionize cancer treatment through their potential for delivering highly potent payloads to a specific site of action compared to the off-site toxicity observed with conventional systemic chemotherapy agents. The first treatment (Mylotarg) was approved nearly 25 years ago; since then, we have seen an increasing number of ADCs being authorized in the U.S. and Europe. 

The complex composition of ADCs

In short, the treatment consists of a monoclonal antibody, which contributes specificity and a long circulation time; the drug, known as the “payload,” which delivers a cytostatic treatment to the site of action; and the drug linker. The drug linker serves an essential function, enabling the drug to detach and deliver its payload specifically to the targeted tumor. The linker thereby is an important factor in the systemic toxicity of the overall ADC and the therapeutic index of the final product. Moreover, this method involves combining a large molecule (the antibody) with a small molecule (the drug / drug-linker), introducing complexity, whilst the linker itself contributes to the stability profile of the drug substance.

Traditionally, combining these components has been done via conjugation through chemical bonds using a native lysine or cysteine residue on the antibody. More recently, site-specific conjugation has been used to narrow the range of drug-to-antibody ratio and increase the precision of delivering the payload. While a (freeze-dried) powder for solution for injection/infusion is used as a dosage form for a better stability profile, improvements in linker technology and knowledge and stability performances of all components mean that it is becoming technically feasible to develop solutions for injection/infusion which are easier to handle and administer.

For production, the composition of these drugs poses a host of challenges in chemistry, manufacturing, and controls (CMC) management and regulatory approval, related primarily to the mixed modality. One challenge relates to the two different intermediates, which require more points of control and thereby more testing. A second relates to intensified characterization: of the small molecule, the monoclonal antibody, and the drug substance. Third, the overall complexity increases the volume of CMC sections required for Module 3, and how best to present them within M3 can be difficult. 

Regulatory guidelines

While we have clear ICH guidelines for both small and large molecules, there is a degree of ambiguity regarding the control of intermediates. Both the European Medicines Agency (EMA) and U.S. Food and Drug Administration (FDA) have existing guidelines in place that can be applied to ADCs, but as of yet there are no ADC product-specific EMA or FDA CMC guidelines.  European Federation of Pharmaceutical Industries and Associations (EFPIA) has published a draft white paper (K. Bechtold-Peters et al. / Journal of Pharmaceutical Sciences 00 (2023) 1−16) which is a very useful resource that considers the idiosyncrasies of ADCs.

The following recommendations are intended as general considerations for reducing risk in three key areas.

1. Comparability studies

As developers move through clinical phases, scaling up to a commercial process, changes will invariably be introduced to the manufacturing processes of each component. For example, as you move from a single manufacturer and small batches to multiple sites and commercial scale for each component, changes are involved that might necessitate a comparability study. What type of studies will be required? If you have to change an intermediate (e.g. mAb, drug/drug-linker), a regulator’s expectation may be an N + 1 approach such that a comparability study is conducted on both the intermediate, as well as the next step below, the drug conjugate. On the other hand, it could be possible through a comparability assessment to determine that the structure, purity, impurity, and reactivity are sufficiently similar (drug / drug-linker); or the quality attributes are unchanged (mAb). Using this approach it might be possible to justify not carrying out a comparability study additionally at the next level. The EFPIA draft white paper (K. Bechtold-Peters et al. / Journal of Pharmaceutical Sciences 00 (2023) 1−16) presents a number of helpful decision trees.

2. Control strategies

After the intermediates and conjugation step, there will be purification steps that involve, for example, ultra-filtration and possibly an additional chromatography step. These processes remove many of the upstream impurities associated with the small molecule chemical and the monoclonal antibody. Is it therefore necessary to apply a full complement of tests and limits for both the conjugated drug substance and the antibody intermediates given the presence of downstream filtration and chromatography step(s)? It could be argued that such testing does not contribute to the overall quality of the conjugated drug substance. Regulators could be cautious in this regard and an overall risk-based approach will help determine the comparability studies required.

3. Presentation of data in Module

The assessment team involved in reviewing M3 for an ADC will typically include reviewers with either small molecule or biological expertise which could give rise to a siloed regulatory assessment. In this scenario, the small molecule and biological components of the active substance are reviewed in isolation against their respective small molecules / biologicals quality guidelines without an overall collective overview of how they relate to each other. 

Further, regulators prefer three discrete sections related to the monoclonal antibody, the conjugated drug substances, and the drug linker. Presenting three separate sections can be beneficial from the applicant’s perspective in supporting lifecycle maintenance; the drawback is that it lends itself more to the aforementioned siloed assessment. There is a viewpoint that this approach could enable assessment teams to lose sight of the fact that the monoclonal antibody and the drug linkers should be considered intermediates rather than drug substances in their own right.
An alternative way of presenting M3 DS information is to use the section within the drug substance section of Module 3 that addresses the control of intermediates (3.2.S.2.4), including individual S1 sections. This approach places more emphasis on the intermediate nature of the drug / drug-linker and mAb but leads to more complexity in lifecycle maintenance. However, you will feasibly gain a better understanding of your product and processes, and of the impact of changes on critical quality attributes. 

Conclusion

Making these judgments requires strong process and product knowledge, along with a thorough understanding of the individual case and how these recommendations might apply. That said, given the ambiguities in regulatory guidance and the overall complexity of ADCs, we highly recommend frequent communication with regulators via scientific advice procedure. This will help to tease out what pivotal issues such as what comparability studies are required: is there more flexibility to deviate from the available guidance or is a more conservative approach needed for testing and when? Engagement with regulators and consultation with them at critical decision points is essential. Having experts who can offer have a fresh viewpoint by conducting a gap analysis of your data and documentation is a valuable preemptive step before scientific advice. Early action is always beneficial.

How we can help

Parexel Consulting can help throughout the drug development process: gap analysis of development work carried out so far; preparation of M1-M5 documentation for Clinical Trial Applications / Investigational New Drug submissions; Marketing Authorization Applications / Biologics License Applications; as well as scientific advice procedures to de-risk planned strategies. 
Our strong team of commercial strategists, clinicians, former regulators, and market access experts can partner with you to de-risk your drug development and illuminate the path to commercial success. It is an exciting time for the industry, and we look forward to joining you in the journey to bring important innovations to patients. 

Parexel Biotech offers the personal, responsive, and committed approach of a small CRO, with all the benefits of a large CRO.  Our dedicated team of Biotech experts will amplify your team's expertise to help you uncover insights faster to impact patient lives. Connect with us today.

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