Did you know that the FDA has issued more than 600 manufacturing citations over the past five years? That’s more than 600 setbacks, 600 delays, and 600 additional costs for the companies developing the products impacted by these citations.
Manufacturing-related challenges like these can happen at any point in the product life cycle, but their risks and impact are particularly acute during the pivot to clinical development. When drug developers are producing their earliest clinical batches, regulatory setbacks for quality issues can have a doubly painful cost: both valuable time in the clinic and irreplaceable trial funding.
So, how can you and your team avoid a painful blow like this? It’s essential to take the time to establish manufacturing processes that comply with current good manufacturing practices (cGMPs) – starting from the very first batches of clinical trial material (CTM).
Why cGMPs matter for early-stage drug products
For an injectable medication, the transition from preclinical to clinical development already adds many new procedural, logistic, and regulatory factors to your product development program. At this critical pivot point, cGMPs can feel like a daunting additional layer of complexity; drug developers often wonder if they’re worth the investment in time and funds.
Rest assured that they are essential, even in the earliest stages of your product’s development. cGMPs are more than simply manufacturing best practices: they set the quality and safety standards that a drug product must meet to be approved for in-human use, making them essential to any new product’s path to the clinic. Aligning with these principles is a regulatory expectation for any authority tasked with ensuring that investigational medicinal products are safe enough to be evaluated in the clinic.
“Follow cGMPs,” however, is far more easily said than done. By their nature, cGMPs are an ever-evolving set of standards. As “current” implies, these guidelines are continually adapted to new chemical, biological, and technological advances. So how do you know when and where to start aligning with these principles?
“When” is relatively simple: as early as possible, starting with the first drug product batches you produce for both your regulatory submissions and your CTM. By integrating best practices early on, you’ll lay strong, strategic groundwork not only for your first regulatory submissions, but also for many downstream evolutions of your manufacturing processes.
“Where” is a more complex question – one that’s always best to discuss with your CDMO, an essential partner who can help you understand both the cGMPs that are most important to your product and how to develop manufacturing processes that are compliant by design. For most injectable medications, however, it’s typically most important to start with three core components of cGMP compliance: qualification, validation, and documentation.
cGMP-compliant clinical trial manufacturing: 3 core components to consider
As he discusses in-depth in our new clinical manufacturing video series, Dr. Gerhard Reuter, Qualified Person at Vetter, has helped numerous drug developers navigate the complexity of establishing manufacturing processes that systematize compliance with cGMPs.
With his extensive experience, Dr. Reuter has found that there are a few key functions companies need to focus on when they’re developing an injectable drug product – especially when they’re planning to fill their crucial first batches of CTM. As these companies pivot from lab to clinic, they’re taking their first few steps on a much longer journey of compliance. And, as Dr. Reuter explains, there are typically three key components that they should consider from the very start:
Establishing the right combination of drug substance, trained manufacturing experts, and state-of-the-art equipment is a vital first step in cGMP compliance. At the very beginning of your CTM project, your CDMO will begin to evaluate which technology and team will be the best match for your molecule.
“Qualifying” that molecule on specific equipment involves detailed assessment of specific filling machinery, sterilization equipment, container types, tubing, and much more – each one of them managed by manufacturing experts with deep, relevant experience in both the technology and the type of substance it will be used to fill. Qualifying your product – with the specific combination of equipment and expertise that will be used to fill it – is a fundamental step as you monitor each drop from API handoff to product release.
The second essential component of a cGMP-compliant CTM batch is manufacturing processes that have been shown to consistently result in identical drug product – the exact same molecule, components, concentration, viscosity, and more – for every unit, every time.
To achieve this kind of validation, your CDMO must account for many different facets of the process used to fill your product: for example, validating the specific filter(s) selected for your product, locking in specific testing methods for multiple points in the process, and conducting media runs to test and verify all these facets before filling your actual CTM.
It's important to note that these critical steps in the validation process often require some amount of drug substance above and beyond what’s needed to produce your CTM. Be sure to account for that requirement in your batch size calculations.
Ultimately, your manufacturing processes will be submitted to regulatory authorities responsible for approving your product for in-human use. And those regulators will expect your processes to be documented in detail – including how they were developed, why they’re appropriate for your molecule, and how you verify that they consistently produce an identical, high-quality drug product that’s safe enough for in-human evaluation.
As Dr. Reuter and his team like to observe: if it isn’t written down, it simply didn’t happen! You need detailed records on how your processes were developed, how they evolved during the development cycle and why, and a rationale for those process pivots. These details will form critical components of your regulatory submissions to the FDA, EMA, or other similar authorities – all of whom will expect to see a documented thought process for how you and your CDMO arrived at your approach to manufacturing your product.
An experienced CDMO will factor in detailed documentation steps as part of their Standard Operating Procedure (SOP). Be prepared for the time those steps will require to support your product’s alignment with cGMP.
Take the time to get it right
These three components are critical to any strategy for producing a cGMP compliant CTM batch and are required for subsequent commercial manufacturing. But they’re ultimately just a starting point for what should be a truly comprehensive approach to implementing manufacturing best practices as early as possible in the development of your injectable drug product.
Each of these components demands specific expertise and its own carefully planned approach, but they all share one critical requirement: time. Qualifying equipment and manufacturing teams, developing and validating processes, and documenting every step along the way – all these activities must be accounted for in your timelines to confirm that your final project outputs are cGMP compliant.
Building in that time is worth it. As those 600 companies found out when they received citations, planning for cGMP compliance is the smart route to saving time, money, and headaches in a critically important period of your product’s evolution.
Did you find this CDMO Insights post helpful? Dr. Gerhard Reuter, Qualified Person, speaks in-depth on cGMP-compliance in a how-to video on the Vetter Video Hub. Sign up today to stream this feature and more – including insights on planning your clinical batch, and strategizing product stability.