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Does Your CDMO Have Sustainable API and RSM Strategies?

By Scott Martin, Grace FCMS - 

A wide range of factors are reshaping today’s pharmaceutical supply chains. This includes, but is not limited to, a growing pipeline of diverse small molecule products, emerging markets that continue to reshape the industry landscape, and increasing regulatory expectations. Now the world is facing COVID-19, which is driving many pharmaceutical companies to reexamine their supply chain strategies and footprints. Despite these challenges, it is the responsibility of the pharmaceutical innovator to make sure they establish a reliable supply chain that is compliant with global regulatory expectations. A critical part of doing so is having regulatory starting material (RSM) and active pharmaceutical ingredient (API) strategies that ensure continuity of supply throughout the life cycle of a product.

However, if you are working with a CDMO for the development and manufacture of your product, you are reliant on their supply chain. How can you be sure the one you select has appropriate oversight and management of their RSM and API manufacturing supply chain, so you do not experience costly delays that disrupt your timeline and prevent your product from reaching the patients who need it?

Regulatory Expectations for RSM and API

While there are many terms used across the industry to refer to the starting materials of a drug development process, the importance of RSMs remains the same ― they are a key component of the API and make up a significant structural fragment of the API’s chemical structure. And, of course, without the API, you cannot manufacture your drug product. Therefore, both play a crucial role in the success of your program. An unreliable API supplier or API that is not fully cGMP compliant could delay clinical trials or cause you to miss milestones. For some companies, this may just mean revisiting their timeline, which can be frustrating and costly; but for small and emerging companies, this could be catastrophic if funding is dependent on meeting those milestones or potential risk to interruption of ongoing clinical trials. In addition, chemistry can be quite complex as your volume increases. If your CDMO runs into an API issue during manufacturing scale up and makes a real-time decision without communicating with you first, they may move forward with a solution that leads to compromised quality and, ultimately, a wasted batch. This impacts the downstream supply chain for drug product manufacturing and the ability to supply enough material to your clinical program.

CDMO API suppliers often have a high level of responsibility, as the onus is on them to manage the quality attributes of the RSM before it is introduced into API manufacturing as well as compile the GMP documentation necessary to support the regulatory submission. The closer you get to the final product, the more stringent control needs to be. Yet, the regulatory requirements that used to be centered on API manufacturing have now expanded into change control for RSM manufacturing due to the FDA’s ever-increasing expectations for continuous improvement efforts as the industry grows and changes. If a change occurs with the RSM supplier, the CDMO API is responsible for any impact those changes have on the ultimate quality of the API, making change control communication imperative.

While it does not need to be as rigorous for RSM, the level of oversight and responsibility for understanding these changes has increased considerably.

For example, if an impurity is introduced as a result of a change and it shows up during API manufacturing, the API supplier must ensure the analytical methods for assessing RSMs are robust enough to detect the impurity. If not, it could be introduced into the API, causing major issues later, such as adverse effects on the health of the patient taking the drug. The FDA also now expects manufacturers to perform audits of their RSM supplier, which was originally reserved for API suppliers. This goes beyond completing a paper-based questionnaire but rather includes on-site visits by a representative from your company or a third party to confirm the equipment and quality systems are compliant.

Considering the expectations of the FDA and the fallout from undetected impurities, selecting a CDMO with a solid sourcing strategy for RSM and API is essential. In addition, it keeps you on track with your timeline and associated milestones, which can already be difficult given the unpredictability of drug development and the complex system of interacting factors that must align for it to go as planned. A solid RSM and API sourcing strategy also helps control cost and expenses and affords opportunities for future flexibility as the program develops and matures.

The Importance of Strong API and RSM Sourcing Strategies

Although your API and RSM sourcing strategies should be a continuous checkpoint throughout the life cycle of the program, you should set your priorities early and detail which ones are most vital to the success of your program. You can then use this when vetting potential CDMOs to ensure you find the right partner that fits your highest priorities around timeline and cost. It is important they have enough flexibility to adjust quickly as your program matures, which alleviates concerns about any potential disruptions when you are considering changes and the timeline to implement those changes. This is especially critical if you have a program that could potentially qualify for one of the FDA’s expedited approval pathways.

For programs with a high demand, a single-source RSM supplier may not be the best option. To safeguard your supply chain and possibly secure the best pricing, it may make more sense to use multiple raw material suppliers, although this is not something you would likely consider until closer to commercialization. Your CDMO should have a robust vendor approval process for adding new suppliers when appropriate. No matter how many RSM suppliers you have, an open communication pathway between them and your API supplier is important, as it can help with any changes that may occur during API and RSM process development. For example, Grace Fine Chemical Manufacturing Services’ (FCMS)success as a manufacturer of high-quality APIs for a wide range of custom and generic products is due to the expertise and proximity of its sites in South Haven, Michigan, and Tyrone, Pennsylvania. The South Haven facility, which is FDA registered and cGMP compliant, produces custom APIs and advanced intermediates. Our Tyrone facility produces the RSMs used in the manufacture of APIs by Grace FCMS and other suppliers under ISO-9000. The expertise of its R&D, analytical services, engineering, and quality teams combined with clear and open lines of communication gives Grace FCMS the ability to identify and control impurities early during API development and process scale-up as well as speed to market.

Predetermined acceptance criteria help manage the quality of incoming RSMs, and the integration between the two sites facilitates problem solving should the analytical methods used to identify impurities detect an issue. It also allows for cross-functional collaboration during process optimization, as samples can be sent from South Haven to Tyrone to determine how those development samples respond during API manufacturing. This prevents any surprises during API manufacturing should changes occur to the RSMs. Maintaining internal domestic supply is essential, as differing time zones and potential language barriers can create complications in some partnerships. Even before the global pandemic hit the U.S., Janet Woodcock, director of the U.S. Food and Drug Administration’s Center for Drug Evaluation and Research, spoke before a House of Representatives subcommittee about the growth of Chinese facilities supplying API to the U.S. market.1 At the time, 13 percent of the U.S. API supply came from a facility in China.2 This makes the industry extremely vulnerable should that supply become compromised for any reason, especially as the impact of COVID-19 on pharmaceutical supply chains is still not fully known.

Is Your CDMO a Fit for Today and Beyond?

As you consider other factors about your CDMO, such as its expertise, equipment, and scale-up capabilities, make sure to assess whether their team is a cultural fit for your organization. Ask questions about how they handle difficult situations and what the communication structure is. How much they interact with each other as well as transparency will determine whether you will reap the benefits of a true long-term relationship or engage in only a short-term transactional relationship. In addition, if they give the impression that the project manager is your only communication pathway with them, that should be considered a red flag. This implies that you will not have direct communication opportunities with their subject matter experts on a routine basis, such as engineers and process or analytical chemists.

Drug development requires collaboration and brainstorming activities, so you need to be able to openly communicate with everyone involved to come to the best possible conclusion. Giving you access to the resources you need to be successful means they are equally invested in meeting the goals for your program. It is also important to investigate their track record with past customers as well as regulatory authorities and ensure they have secure financial backing. Considering these qualities in the search for your CDMO sets the standard for your organization as well as theirs that you are looking for a collaborator that does not intend to just meet your needs for today but also those well into the future.

  1. FDA. (October 2019). Testimony of Janet Woodcock, M.D., Director of Center for Drug Evaluation and Research, before the House Committee on Engineering and Commerce Subcommittee on Health. Safeguarding Pharmaceutical Supply Chains in a Global Economy. h ttps://www.fda.gov/news-events/congressional-testimony/safeguarding-pharmaceutical-supply-chains-global-e  conomy-10302019
  2. Mullin, Rick. (April 2020). COVID-19 is reshaping the pharmaceutical supply chain. Chemical & Engineering News, Volume 98, Issue 16. Retrieved from https://cen.acs.org/business/outsourcing/COVID-19-reshaping-pharmaceutical-supply/98/i16

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