Manufacturing CGTs: Should I Use A CDMO?

By Deeona Gaskin and Raj Pai, Sidley Austin LLP

Perhaps unsurprisingly, given FDA’s current regulatory framework, manufacturing issues have become a major challenge for sponsors of cell and gene therapies. Some of the significant cell and gene therapy manufacturing challenges manufacturers have faced include scaling up the manufacturing process. Product and lot-to-lot reproducibility is another important issue that manufacturers have struggled with over time. Anna Kwilas, a CMC reviewer and team lead in CBER, has described some of the additional challenges and agency concerns in this space around material qualification, challenges establishing specifications, and the manufacturing facility, as well as high product variability, qualification of cell banks, stability of cell banks and intermediates, and scale-up.¹

A most pertinent question, then, is: To make or buy your material? Of course, that question has been asked across industries over time as companies gain the option of outsourcing and must weigh whether to make materials in-house or purchase them externally. In the context of cell and gene therapies, this is also an important decision for sponsors of marketing applications that must be considered carefully. Many sponsors will use contract manufacturing organizations (CMOs) or contract development and manufacturing organizations (CDMOs) to produce their cell and gene therapy products to a greater extent than traditional pharmaceutical products. The reason why is tied to the complex nature of these products and the requirements for making them.

Like all drug and biologic products, cell and gene therapies must comply with the good manufacturing practice (cGMP) regulations found in 21 CFR Parts 210, 211, and as applicable, Parts 600 - 680. Therefore, manufacturers need to understand what the critical quality attributes (CQAs) and critical process parameters (CPPs) are for their products. Details regarding the manufacturing process and controls are provided to FDA in the chemical, manufacturing, and controls (CMC) section of a biologics license application (BLA). However, unlike small molecule drug products, cell and gene therapies are manufactured using live, potentially infectious biological products and that creates additional challenges for manufacturing products safely, consistently, and at scale.

FDA uses pre-license inspections (PLI) to evaluate the manufacturing process for cell and gene therapies. Typically, successful PLIs are required prior to approval of a BLA. See 21 CFR §601.20(d) (“A biologics license shall be issued or a biologics license application approved only after inspection of the establishment(s) listed in the biologics license application and upon a determination that the establishment(s) complies with the standards established in the biologics license application and the requirements prescribed in applicable regulations.”) A CBER internal policy explains that “[a] pre-license or pre-approval inspection will generally be necessary for an original application or supplement if any of the following criteria are met: . . . The facility is new (applicant or contract manufacturer), and/or . . . The facility does not have a compliance history.”²

Indeed, one major focus of the Bespoke Gene Therapy Consortium is manufacturing and production, with the goal to “develop a standard set of analytic tests to apply to the manufacture of viral vectors made by consortium researchers.”³

Deficiencies in the manufacturing process can lead to inspectional observations during a PLI and also, potentially, a Complete Response Letter (CRL). Despite the hundreds of INDs, the FDA has reported receiving for cell and gene therapies, less than a dozen cell and gene therapy products are currently approved for marketing in the U.S. And one of the reasons so few cell and gene therapies have been approved is due to cell and gene therapy manufacturing challenges.

Thus, the importance of a robust manufacturing process and facility cannot be overstated. Sponsors of cell and gene therapies must decide whether to make or buy the investigational, and eventually commercial, product. In other words, the sponsor needs to decide whether the sponsor will invest in a manufacturing facility to make these complex products in-house, outsource some of the development and manufacturing work to a third-party manufacturer, or potentially do both. This is a difficult decision, with various factors that need to be weighed. Here are some key questions and considerations.

• What are the timeframes for product development? When are manufacturing facilities needed? It is expensive and time-intensive to build and qualify a manufacturing facility. Expenses and costs are a critical consideration for the make or buy decision, especially for early-stage companies that may have more limited funding, particularly when resources may need to be dedicated to other activities in product development.
• Are there contract manufacturers with experience with similar platforms that can help with development and validation? An experienced cell and gene therapy CDMO could offer multiple benefits for a sponsor, including more efficient development that saves time and subject matter expertise. Some contract manufacturers may also offer a host of regulatory support services.
• Does my company have employees with the necessary skills and experience to oversee in-house manufacturing? The manufacturing process for cell and gene therapies is complex and difficult and it can be hard to find and retain qualified manufacturing personnel. One of the benefits of working with a well-known cell and gene therapy contract manufacturing organization is that they may have valuable experience and expertise that could help sponsors throughout the development process, particularly in anticipating manufacturing issues that could emerge later in the development process.
• If I’m looking to partner with a CDMO, does that potential partner already have experience with manufacturing other drugs or biologics? A less experienced cell and gene therapy CDMO may be riskier as they may not have appropriately qualified personnel or a strong track record with regulatory agencies.
• What is the regulatory history of potential manufacturing partners? It is essential that a sponsor performs due diligence regarding potential cell and gene therapy contract manufacturing organizations and establishes a quality agreement with them. As manufacturing issues can lead to a Complete Response Letter and lack of product approval, a sponsor should carefully select a partner that will be able to successfully pass a pre-license inspection and sustain compliance over time.
• What is the potential size of the commercial market? The terms a CDMO is willing to provide may depend on the financial benefits for the CDMO. Similarly, an investment in an in-house facility may depend on the potential estimated profits.
• How many lines would be needed? Would a contract manufacturer be able to dedicate a manufacturing line? Dedicated lines help reduce many risks, including quality risks (e.g., cross-contamination) and supply risks (e.g., time devoted to other products). Many of the large cell and gene therapy contract manufacturing organizations have multiple customers. Therefore, another consideration for sponsors is how available manufacturing lines and personnel will be for their products and how the contract manufacturing organization prioritizes its customers. Contract manufacturers may also face their own regulatory challenges or requests from the government to prioritize certain customers due to shortage concerns in the market. For example, during the COVID-19 pandemic, the Defense Production Act was used to require certain manufacturers to prioritize products.
• What are the geographic locations under consideration for cell and gene therapy contract manufacturing? The location of the manufacturing facility can have an impact on potential import and export restrictions in other markets, as well as the quality of personnel who may be available to work in the facilities, which could create a downstream supply chain impact.

Ultimately, the key consideration is which choice, make or buy, will reduce and mitigate risks. The answer may be that companies, depending on their unique circumstances, should consider both approaches. A sponsor could develop manufacturing facilities in-house and work with cell and gene therapy contract manufacturing organizations in parallel or at certain phases. Increasingly, having multiple manufacturers for products is a strategically important decision for companies to create and maintain a robust supply chain. Having redundancy in the supply chain may impose some costs for companies on the front end, but will mitigate regulatory risks and provide increased certainty and flexibility going forward, which may provide a significant competitive advantage.

References

1. https://www.casss.org/docs/default-source/cgtp/2020-cgtp-speaker-presentations/kwilas-anna-us-fda-2020.pdf?sfvrsn=6ddcba7e_6
2. https://www.fda.gov/media/108969/download
3. https://www.nih.gov/research-training/accelerating-medicines-partnership-amp/bespoke-gene-therapy-consortium

About The Authors:

Deeona Gaskin is a partner in Sidley Austin LLP's Food, Drug and Medical Device Compliance and Enforcement group. She handles global good clinical practice, current good manufacturing practice, and quality system regulation matters. She also prepares companies for pre-license, pre-approval, for-cause, and bioresearch monitoring inspections, as well as for post-approval surveillance and meetings with the FDA. Gaskin also represents companies in False Claims Act enforcement actions and in internal compliance and government investigations. Formerly, she served as Associate Chief Counsel for Enforcement at the FDA, collaborating with the DOJ on enforcement actions, negotiating consent decrees, and defending the Agency against litigation.

Raj Pai is global leader of Sidley Austin LLP's Food, Drug, and Medical Device Compliance and Enforcement group. He represents global life sciences companies in GMP, QSR, marketing practices, and postmarketing reporting issues. This involves inspection readiness, enforcement action responses, and preparation for regulatory meetings. Additionally, Pai leads internal investigations involving alleged violations of the FD&C Act and False Claims Act for companies, defending them in related civil and criminal proceedings. A former Associate Chief Counsel for Enforcement in FDA's Office of Chief Counsel, Pai was appointed a Special Assistant US Attorney by the DOJ, helping prosecute enforcement actions involving medical products.