Understanding CMC Challenges in Vaccine Development

Author:

Zeb Younes
Head of CMC & Principal Consultant

The COVID-19 pandemic has led to unprecedented public investments, at-risk investment in (clinical) development and manufacturing, and the streamlining of regulatory processes, resulting in rapid, focussed, and collaborative development of COVID-19 vaccines and acceptability of new vaccine platforms.

Moving forward, these experiences and the lessons learned may also be applied for vaccine development in general. With our multidisciplinary team of development experts, Scendea has contributed extensively to (COVID-19) vaccine programs. All aspects in this respect were (and continue to be) supported: regulatory, clinical, nonclinical, and chemistry and controls (CMC)). In this whitepaper we focus on and summarise some of the commonly encountered CMC issues and provide guidance to developers how to avoid these.

Raw/Ancillary/Starting Material Compliance

To support the manufacturing process some of the vaccines require raw/ancillary/starting materials that are non-compendial. 

These materials may be used to consistently yield an active substance or medicinal product of a specified quality in terms of, for example, biological activity, purity/impurity profile, the risk of adventitious agents (bacteria, viruses, etc.) and product stability. The details on the manufacturing process, specifications and stability data for the material may be required for inclusion in the dossiers. Some materials may not compendial or may not have suitable certificates or master files that can be referenced in the regulatory dossiers. In these cases the developer should ensure the material they are using is of the highest quality available and be prepared to provide evidence that this has been assessed and weighed against risks if requested by agencies. 

The impact of the raw material on the quality, safety and efficacy of the product should be evaluated using a risk-based approach. A risk assessment must consider the biological origin and traceability of the raw material, the production steps applied to it, and the ability of the drug product manufacturing process to control or remove the raw material from the final medicinal product. Any risk factor must be evaluated in relation to the clinical benefit/risk of the product. When evaluating the risk posed by the material to the final medicinal product, the patient exposure to residual amounts of raw material with potential harmful effects (e.g. adverse immune reactions) should be considered. 

Potency Assay

Potency method development should be ongoing during development with the aim of ensuring a suitable method is available prior to the pivotal clinical study that is validated prior to full approval. Development and validation of an invitro potency assay that correlates with the mechanism of action may take ~6-12 months or even longer depending on available data and experience. For early development a validated potency assay is not required, however a specific package of in vivo and invitro studies should be conducted to characterise the mechanism of action in support of initiation of the first in human study. Ideally a suitable in vitro potency method should be established. However if timelines do not allow for this and if a suitable in vivo method is available, this may be used until an in vitro method is developed. 

Another option is to present development data in the development dossiers demonstrating one or more in vitro methods that assess different aspects relating to potency are fit for the purposes of characterisation. In these cases it may be acceptable to assign either ‘report results / for information only’ or a very wide acceptance criteria for this method during development.

Storage/Stability/In-use/Transportation

As we saw during the pandemic, rapid vaccine extensive formulation development, leading to drug product formulations that required frozen/cold-chain storage. This is challenging, particularly for global roll-outs for a pandemic situation and results in costly and complex launch plans for cold-chain management. Therefore, developers are advised to ensure alternative storage conditions are evaluated during development and that studies are conducted to ensure the cold-chain can be maintained as required during transit. Where refrigerated formulations are developed, the impact of transportation on product quality must be assessed. It is strongly recommended that the impact of transport related agitation on particle heterogeneity and polydispersity in relation to potency are evaluated as soon as possible in development. In-use preparation stability should also be confirmed to verify the instructions for use conditions/hold time have no detrimental impact to product quality.

Alternative Suppliers, Testing & Manufacturing Sites

To allow for a global roll-out of the vaccine once it is approved, developers are encouraged to establish alternative suppliers of critical reagents/materials, testing sites and manufacturing sites during development. At least a plan should be established to implement these as soon as possible post-approval. If one of the existing sites/suppliers fails, then there may be a critical impact to supply if there are no alternatives. It may take many months to organise any required contractual agreements, technology transfer and qualification.

Comparability

Due to the rapid development of these programs, changes that could impact product quality may be required (such as to container closure/excipients/storage/starting materials). 

If developers intend to embark on rapid vaccine drug development then it is advised that an upfront strategy for evaluating comparability is defined. The strategy should be development stage specific and describe the initial risk assessment that will be conducted, the CQAs that will be evaluated (as part of release, characterisation and stability testing) and number of batches that will be tested. In the event of any residual uncertainty in physicochemical comparability, additional nonclinical studies that will be conducted should also be outlined. For any further uncertainty, then the minimal acceptable clinical bridging studies should be described.

Independent Batch Release

Some agencies will require independent partial/full batch release testing (such as EU and UK). In these cases, developers should account for method transfers to take place prior to approval. Early dialogue with the agencies is recommended here.

Rolling Reviews

Depending on the urgency and risk/benefit profile of the vaccine the agencies may provide additional regulatory support in the form of additional swift scientific advice meetings, rapid assessments and rolling reviews (where for approval, predefined data packages are submitted in discrete phases for review). However, in these cases, developers need to ensure efficient project and resource management to allow them to be ready to adhere to agreed timelines and to respond to agency questions promptly.

Platform Processes & Procedures

In cases where developers can establish platform technology for the antigen delivery/expression, analytical testing and/or manufacture, then the development timelines of the CMC aspects of the vaccine may be further reduced. Such an approach can also allow for an initial parent dossier authorisation that involves a simpler process to introduce specific CMC changes within defined categories. This could be applied in the case of initial vaccine approval followed by updates for variant strains.

For these situations, as discussed above, greater focus should be given to a risk-based approach to CMC development to ensure the highest risks are mitigated and development timelines are met for protection of the population.

To discuss how Scendea can support your vaccine development, get in touch with a member of our team today…