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Designing viral vector manufacturing facilities for cGMP-compliance

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Natasha Rivas, vice president of quality and regulatory, and Jose Cruz, director of vector manufacturing at Genezen, explore the difficulties in ensuring cGMP compliance is achieved throughout viral vector production.

Examining best practice production suite design, they also highlight the key safety considerations needed when manufacturing these new therapeutic tools.

As effective tools in facilitating vector-mediated gene transfer, viral vectors – including gammaretrovirus and lentivirus – are playing an integral role in the advancement of cell and gene therapies (C&GTs). Viral vectors are commonly used in the development of chimeric antigen receptor (CAR) therapies. The growing potential of CAR therapies - particularly in the oncology space - has been realised by the biopharma industry. CAR-T therapies now represent 48% of genetically modified cell therapies in the pipeline, with 98% of these in development for cancer indications.

With the C&GT market predicted to grow between 2021 and 2028 at a compound annual growth rate (CAGR) of 12.4% to reach a value of $13.8 billion, reliance on viral vector development and manufacturers will rise. However, C&GTs are relatively new, meaning safe and regulatory-compliant production of these products currently involves many challenges.

cGMP compliance with ambiguous regulations

Considering the surge in demand for C&GTs, regulations around their development and manufacturing have been relatively slow to manifest in comparison. Consequently, viral vector producers have had to shoulder the responsibility of ensuring that their processes are safe and robust enough to remain compliant with new regulations as they arise.

Conforming to ambiguous regulations written with traditional biologics in mind requires developers and manufacturers to assess how these might apply to viral vector production. Current production processes differ significantly from those typically used for other well-established therapeutics, so it is important for viral vector developers to demonstrate careful consideration of the risks, as well as the application of suitable measures to ensure safety.

Identifying the risks

There are a number of potential risks that are specific to viral vector production. An in-depth understanding of the risks is essential in determining the proper safety measures required to ensure the protection of both the handlers and the patients that will be receiving the final product. Predominantly, these risks are:

Typically, viral vectors will be carefully designed to reduce the health risks associated with potential infection. This includes techniques to ensure that vectors are replication-defective and use self-inactivating (SIN) transfer plasmids.

However, even when working with viral vectors that are replication-defective, there is still the potential for infection to occur and for the target gene to be transfected. Viruses can also become replication-competent if exposed to wild-type viruses. 

Although cell expansion is a common process in the development and manufacturing of many biologics, there are several additional “open processes” involved in viral vector production, which results in handlers being at more risk of coming into contact with biological hazards. These include transfection steps and manual processes involved in harvesting vectors from adherent producer cells grown in 2D culture chambers.

For manufacturers working on multiple viral vector projects concurrently, it is essential to implement measures to prevent cross-contamination, as this could lead to serious risks to patient safety. Steps must also be taken to ensure that there is no contamination of adventitious viruses that could be present throughout production.

Determining the safety measures needed

Determining biosafety levels (BSLs) will help to identify the protective measures needed in a development and manufacturing setting in order to protect workers and the environment. In the US, BSLs have been defined (BSL-1 to BSL-4) by the Centres for Disease Control and Prevention (CDC), with the same levels applicable to the EU, as defined in a directive. Although by default the BSL level for recombinant viruses is BSL-2, BSLs should be determined by risk assessment, as a lower biosafety containment level may suffice for incomplete viruses cultured in vitro.

Different safety measures will be required as projects progress to commercial scale. For example, at early stages of R&D, lower grade materials may be used. These will eventually need to be replaced by higher grade materials for products to safely be used in clinical trials with patients.

Best practice for designing cGMP viral vector production suites

It is important that viral vector production suites are designed with the aim of reducing the identified risks and correlating safety measures needed as projects progress. There are several ways developers can apply best practices when designing their production suites:

In conjunction with appropriate decontamination procedures, production suites should be built to prevent cross-contamination with carefully designed heating, ventilation, and air conditioning (HVAC) systems, and cleanrooms that adhere to set ISO standards. For viral vector production, there will often be a need for ISO 7 (<352,000 PPC [particles per cubic meter] at 0.5 μm) and ISO 8 (<3,520,000 PPC at 0.5 μm) cleanrooms.

By designing HVAC systems whereby air is drawn and exhausted through separate pathways, the appropriate number of air changes can be achieved while minimising the risk of contamination between rooms. This provides flexibility to organisations working on different viral vector projects within the same facility.

In the event of an unplanned release of bioactive materials, for example from bioreactors, production suites should be designed to ensure hazard containment. Isolating and dedicating airflow between different suites helps to ensure that personnel in surrounding areas will be protected from exposure.

Additionally, systems for monitoring room conditions should be used to raise awareness of detrimental changes to airflow, differential pressures across different areas, or temperature fluctuations that could lead to safety risks.

With ambiguous regulations, working with experts that possess a strong understanding of the risks involved in viral vector manufacturing, as well as previous regulatory experience in various therapeutic areas, can ensure the right safety measures are put in place. As regulations evolve, experts in viral vector production will likely be those that can effectively anticipate changes and properly prepare for them.

Preparing for the future

As the C&GT space continues to grow, it can be expected that the regulations and cGMP requirements surrounding viral vector production will continue to evolve. When designing a viral vector production suite, developers must ensure continued compliance with these changes to ensure the safety of both handlers and patients.

With demand for C&GTs continuing to expand, there will likely be an increased reliance on experienced contract development and manufacturing organisations (CDMOs) offering viral vector production services in facilities designed according to best practices. These organisations will offer the additional capacity and capabilities required for cGMP manufacturing, the viral vector expertise and experience needed to anticipate regulatory changes, and the ability to design production suites that can withstand the evolving requirements.

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