The shift from preclinical to clinical development is one of the most important transitions in the early development of any new drug product. Many decisions made during this process can lay the groundwork for both near-term clinical success and long-term lifecycle milestones—from key regulatory submissions to commercial scale-up, competitive differentiation, and beyond. 

For injectable medications, this period is especially critical. When parenteral products pivot from lab to clinic, this step swiftly adds multiple new dimensions to a molecule’s development cycle. Most importantly, the strategic, operational, and compliance demands of the fill-finish process, starting with the very first batches of clinical trial materials (CTM). 

For early-stage drug developers, filling CTM also adds a complex, and time and budget-sensitive manufacturing workflow to the many other logistic and regulatory processes involved in initiating a clinical trial. To keep that critical launch on track, drug developers need a clear, strategic plan for this critical batch of a drug product—one that not only gets CTM to sites as swiftly and efficiently as possible but also ensures that every drop meets quality standards for in-human use. 

Many organizations are looking for an efficient and structured scheme to organize the process. Therefore, Vetter’s team has developed a six-step plan for navigating the transition from benchtop drug substance production to professional manufacturing at a clinical scale—on time and on budget.

Let us take a closer look at each of the six steps in this approach. 

Step 1: Create a proactive plan

Once you’ve decided to take your injectable product to the clinic, start developing a clear, realistic game plan for filling your CTM.

The plan must be comprehensive and detailed, factoring in every potential complication that could impact your team’s ability to file your investigational new drugs (IND) or clinical trial authorization (CTA), release CTM to your sites on time or hit your first patient in (FPI) date. Some key considerations include: 

• Pragmatic timelines. When you map out your project workflows and milestones, factor in the complexity of your product (e.g., molecule type, delivery format) and any development work needed to start filling your CTM.
• Regulatory guidance. Early input from relevant authorities can be invaluable when you’re planning your submissions and building your compliance strategy. Proactively reach out for advice and guidance—especially insights on the quality parameters, testing methods, and submission contents they expect.
• Clinical manufacturing needs. Carefully assess the level of knowledge, resources, and support your team will need to scale up the production of your compound. Focus on their familiarity with cGMP compliance and their ability to extrapolate small-scale study results into clinical-scale manufacturing methods.
• API and formulation. Make sure your team has a detailed understanding of your drug substance and how it is produced, including your formulation, precursors, and excipients—along with any special physical properties or sensitivities your molecule may have.
• Supply chain. Determine what resources you need and the external partner(s) you need to source them. Find out if your product requires any hard-to-obtain components, how you will secure a supply, and if you can expect any logistic hurdles in doing so.

Be honest and realistic when you make this plan. The more you account for early in the process, the more likely you are to avoid costly downstream roadblocks or delays.

Step 2: Select and source your primary packaging and raw materials

For injectable drug products, one of the most significant early manufacturing decisions is your choice of primary packaging. This one upstream decision can have an array of downstream implications for your manufacturing processes, supply chain, and life cycle strategy. 

Drug developers typically have three primary packaging options for a parenteral product candidate:

• Vials. The standard go-to-market starting point for many parenteral medications, vials have well-established manufacturing processes and regulatory pathways. But in a competitive marketplace, their user experience can be a handicap.
• Prefilled syringes. Used on their own or integrated into a delivery device, syringes offer ease of use in exchange for more complex manufacturing processes. Carefully consider which type you choose if you ultimately plan on launching in a delivery device like an autoinjector.
• Cartridges. This may be your format of choice if your product is launching in a delivery device like an autoinjector or pen. These complex formats require significantly more technical and operational planning, as well as expert manufacturing skills.

Going to market in a delivery device is increasingly a priority in today’s fiercely competitive market. If this step will be part of your lifecycle strategy, have that goal in mind when you select your primary packaging. Ask your manufacturing partner how each syringe or cartridge option will impact your future manufacturing options and processes when it’s time to launch in a device. 

Whether you plan to take your product to the clinic in a vial, syringe, or cartridge, you can help keep your project on schedule by proactively identifying exactly what primary packaging components you need and how or where they can be obtained. Avoid costly future project deviations by thoroughly mapping out your primary packaging options and accounting for all sourcing requirements at the start of the clinical manufacturing process.

This is also the time to consult with a manufacturing partner to determine the best ways to obtain the raw materials for your API and packaging. In some cases, components and compounds may be rare, difficult to source, or require long wait times at customs—so make sure you acknowledge those potential complications in your project plan.

Step 3: Finalize all scopes and contracts

For many drug developers, clinical manufacturing expertise is a specialized resource they need to acquire at the outset of a CTM production project. Whether a drug owner lacks that in-house experience, or simply wants to keep their employee focused on core competencies, sourcing the right skillset is often one of the first steps taken to support a clinical fill finish project. 

Whether that means hiring consultants or partnering with a contract development and manufacturing organization (CDMO), it is important to ensure that all contractors, suppliers, and service providers are aligned with your team’s expectations and responsibilities. When working with multiple partners, it is vital to have everyone moving in lockstep, with a clear understanding of expectations, deliverables, and due dates. 

This includes planning ahead for audits that may involve both internal and third-party teams. As drug developers ramp up to clinical trials, regulatory authorities routinely request opportunities to inspect manufacturing facilities, examine fill finish processes, and assess both internal and external teams’ compliance. Book the necessary resources in advance to avoid future manufacturing delays. An unanticipated audit can throw your entire launch plan off course, pushing back crucial deadlines and adding unexpected costs. 

Step 4: Implement good development best practices

The clinical manufacturing project you complete for your current trial may be the first of many fill-finish requirements for your product starting with batches of CTM and scaling all the way to future commercial production. As you start planning your current, clinical-phase project, do not think of it as a one-off jumpstart for your trial. In many ways, today’s clinical batches lay the groundwork for tomorrow’s go-to-market filling runs.

To know your project will set you—or future licensing partners—up for success, confirm that your fill finish strategy includes a robust process development approach, data capture and sharing methods, and standardized knowledge transfer procedures. Here, you want to make sure to align your production processes with relevant guidelines (ICH) to support the quality and transferability of your outputs. Effective, consistent implementation of these guidelines will streamline both your CTM project and future transition to commercial filling facilities. 

The start of your clinical manufacturing project is also the time to embed quality-by-design best practices into your product by defining Critical Quality Attributes (CQAs) and Critical Process Parameters (CPPs). This is an area where an expert CDMO can be particularly helpful.

Step 5: Align with cGMP across your teams and partners

Before your clinical manufacturing project gets started, take the time to make sure all of your internal and outsourced teams are aligned on the manufacturing practices they need to follow. Keep in mind that producing CTM involves far more than simply creating a larger volume of your drug substance. Current Good Manufacturing Practice (cGMP) guidelines call for a number of steps that require additional time and product to ensure your clinical batch is fully compliant. 

One key consideration is batch size. When you calculate the amount of CTM you need to support your trial—and the amount of API you need to create that batch—make sure you factor in the numerous other steps, activities, and tasks that will also require some amount of product. Some of these include: 

• Technical runs. These preparatory steps will likely require some amount of product to test and optimize your manufacturing processes.
• Destructive sampling. Small amounts of the product may need to be earmarked for lab tests and other quality checks that will render the material clinically unusable.
• Rejected product. Quality oversight of a clinical batch typically results in some amount of product that falls out of specification and needs to be discarded. 
• Line losses. Even with state-of-the-art aseptic manufacturing equipment, some trace amounts of product will potentially be lost during the fill finish process.

When estimating the size of your clinical batch, make sure you plan for the overage these cGMP considerations may require. Doing so will help ensure that you know exactly how much API your filling run will require and that your project yields enough supply to sustain your clinical trial. 

Here again, a CDMO partner can be a valuable resource as you map out your project timelines, production goals, and compliance requirements. The right group of aseptic manufacturing experts can help you identify a realistic total batch size, dial in your API requirements, and specify the cycle time needed to produce a fully compliant batch of CTM. 

Step 6: Select the right CDMO partner

As the first five steps of this process demonstrate, it takes extensive know-how and considerable experience to plan, manage, and deliver a clinical fill-finish project. For many drug developers, the smartest, most cost-efficient way to source that expertise is to partner with a CDMO.

What should you look for in that partner? They should offer a combination of specialized expertise, rigorous experience, and well-established processes. To find the right CDMO, ask the right questions: 

• Do they offer dedicated expertise in aseptic filling?
• Do they have experience with molecules like yours? 
• Can they safely handle your API? 
• How does their Quality Management System align with the needs and expectations of your quality organization? 
• Do they have available fill slots when you need them? 

If the answer to these questions is “yes,” then you are on your way to identifying a strong partner who can confidently and efficiently deliver the batch you need to launch your clinical trial. 

Follow these six steps, and you will be on your way to success

The fill-finish process is complex, especially in the early stages of a product’s life cycle when there is still much to learn about your molecule. But it is also one you can navigate with confidence when you take the time for proactive planning, map out your project in detail, and—of course—partner with the right expert CDMO. Follow the proven steps outlined here, and you will have moved toward streamlining your product’s first filling runs, protecting that product’s quality and value, and simplifying your path to the clinic. 

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Garath Duffy serves as director of supply chain and project management at Vetter’s clinical manufacturing facility in Rankweil, Austria. He is an expert in transitioning injectable medications from preclinical to clinical development, with extensive experience supporting biotech companies during the early-phase development of a wide range of molecules. As a leader at Vetter Clinical Development Service, he has helped many of these organizations navigate the critical pivot from lab to in-human trials.