WHITEPAPER - A Holistic Approach to Getting the First Batch Right

By: Mark Rauckhorst, Director Supply Chain and Project Management, Vetter Development Service USA. Inc.

Clinical trials are high-visibility milestones for investors, as this is often the first major step toward financial return on what has likely been years of investment into a new drug. Therefore, it is paramount that timelines are carefully forecasted and adhered to in an effort to prevent any costly delays. While timelines and efficiency are highly important when preparing the first clinical trial materials (CTM), quality outshines both as the most important factor. In fact, the FDA most frequently puts investigational new drugs (IND) on clinical trial holds due to the quality of the drug product above anything else.

In this interview, Mark Rauckhorst, director of supply chain and project management at leading, global contract development and manufacturing organization (CDMO) Vetter, will share his expert insights on how an outsource partner and drug developer can establish a holistic approach to get the first CTM batch right.

What steps should a drug developer take before creating the first CTM?

The clinical filling stage is a critical step in progressing from the lab to clinical trials, representing the shift from drug substance to drug product. It’s no surprise that customers are highly protective of their drug substance, having devoted years to developing it on a microscale to reach this stage. To produce a successful first batch on a commercial scale, developers should meticulously prepare and take all necessary steps ahead of time. This transition from lab-scale to large-scale manufacturing introduces new complexities requiring proactive consideration. The clinical fill not only involves producing thousands of vials, but it also sets the precedent for future clinical batches, impacting the timeline for securing additional funding. To adequately prepare for a successful first CTM batch, take the following steps:

Create a proactive plan – A clinical batch can take anywhere from 3-12 months depending on its complexity. A pharmaceutical service provider will share when specific information is needed, but thinking ahead and preparing this information in advance can prevent delays later on. When developing a plan, make sure to consider more than just the CTM – plan to produce extra to account for method development, transport studies, technical runs, and stability testing.

Prepare the product for production – Develop an understanding of how the drug product behaves in a manufacturing environment. This is likely already well known by the developers who have spent ample time getting the drug substance to this point. However, new considerations will arise, including cross-contamination with other products sharing a production site, safety, stability, and more.

Source the right expertise – Manufacturing a CTM batch requires a variety of expertise, so it’s best to recruit a multidisciplinary team which includes analytical, regulatory, process development, project management, quality assurance, and more. This team can be adopted in several ways, whether through internal teams, consultants, or pharmaceutical service providers. Consultants offer highly experienced domain expertise and often provide access to broad networks and guidance on the right outsourcing partner. CDMOs, on the other hand, should be selected based on the drug product’s unique characteristics to provide product-specific expertise and a robust quality track record.

Implement best practices – CTM must adhere to good manufacturing processes (cGMP) which change constantly and require real-time expertise. An expert partner can maintain cGMP across all areas of quality including qualification, validation and documentation. This commitment to best practices will prove its value when it’s time for regulatory authorities to get involved in clinical trials.

Analytical services are an essential part during the execution of drug product development projects

What can a drug developer do to take a quality-first approach?

When collaborating with a manufacturing partner, drug developers should ask questions from the beginning to foster a well-aligned partnership in which all parties share a unified goal. These questions may include:

• What is a realistic timeline for my project?
• What can we expect from regulatory authorities?
• Are there any potential supply chain issues we should be aware of?

This will give a drug developer the information needed to make informed decisions and show the CDMO that efficiency is a priority. Questions should go both ways – a partner will also take this opportunity to learn more about the API and its developer, which sets the tone for open two-way communication throughout the production process. These questions may include:

• Are more experiments needed to identify the right manufacturing process?
• What do you know about your API?
• Is your manufacturing process scalable?

The more these questions are answered before developing the first CTM, the less likely it will be for issues to arise once the process is underway.

Before transferring any drug to a CDMO partner, confirm they can measure all necessary quality standards. By transferring analytical methods and phase-qualified methods, a drug developer can improve the seamlessness of the transfer and avoid any costly mistakes that may delay the clinical trial timeline. In a best-case scenario, a drug developer can pass over the drug product in transfer-ready form to further protect its quality.

What should a drug developer know about its API?

Knowledge is power and the more that’s understood about a biologic before developing the CTM, the less room for risk. Ample data about a drug is likely accumulated during the lab phases, although this knowledge only applies to a small scale. Clinical manufacturing is on a much larger scale, which comes with new perspectives, a new timeline, and, of course, unforeseen risks. This is essentially a drug’s “graduation” from early phase development to clinical – a new level altogether.

Since CTM will eventually support in-human use, many considerations must be taken into account to successfully manufacture a first batch that meets extensive quality standards and requirements. As the process shifts from a scientific focus to a patient focus, considerations may include how the drug will be delivered to patients, whether the formulation is finalized, any relevant sensitivities, and whether stability studies were performed.

Experienced CDMO partner can support with the most suitable packaging option for your product

How can a developer select the optimal container for its drug product?

While standard vials are the most common primary packaging for injectables, they are not the only option. Vials are the right choice when a final dosage form is not yet confirmed, but other considerations should be weighed when selecting a packaging format. When selecting primary packaging, it is helpful to forecast the entire lifecycle of the drug to avoid issues arising later on. Take the time to consider potential patient needs, shipping and transport, and shelf life to effectively weigh all variables when choosing how the drug will be packaged. CDMOs are equipped to help make this decision, so use their expertise as a tool in the decision process by asking questions such as:

• What is the optimal container for the drug product?
• Will an injector be considered?
• Are there any import or export issues to be aware of?
• Will the delivery device incorporate any nonstandard container components?
• Are there special requirements for the excipients?

In many cases, it’s beneficial to move a drug product to a syringe early in the process, but that decision will depend on the answers to these questions. In the right instances, this packaging shift can save on cost and time, reduce loss in commercial production, and increase out-licensing deals.

Aseptic filling of small batches

How can the pharmaceutical company find the right CDMO partner?

This question is simpler than one might expect. Open communication is the key to identifying the ideal pharmaceutical service partner, especially if no consultant will be used to help find this service provider. Ask the following questions and if the answer to all is “yes,” the partner is experienced and suited for the project.

• Can the CDMO safely handle the drug substance?
• Does their quality management system (QMS) meet the developer’s quality assurance expectations?
• Can they perform the proper testing methods?
• Do they have expertise with this substance class?
• Can they source and process the right packaging configuration?
• Do they have available filling slots?
• Do they agree that the timeline is realistic and can they identify any delay risks?

Although this may seem simple, the contracting process takes time, especially when there is no room for compromise. Make sure to develop an understanding of exactly how many and which types of partners will be needed, along with the necessary resources and quality specifications, and use this information as a guide when selecting a service provider.

This process is extensive. What can be anticipated as the overall CTM project flow?

The timeline for CTM batch manufacturing may vary depending on several variables. But when these recommendations are taken into account and planning is done ahead of time, there can be more control later on. Generally, a CTM project flow may range from 6-10 months from kickoff meeting to a completed CTM batch depending on the unique nuances of the drug product.

It is no small feat to get the first CTM batch right, yet it is one of the most important steps in the larger drug development and manufacturing process. With the right planning, an aligned partner, and open communication, drug developers can achieve this milestone on time, on budget, and without jeopardizing quality.