Building a well-oiled clinical trial supply chain that fulfills the requirements of Phase I and II pharmaceutical clinical trials does not happen by accident. It is universally understood that clinical trial material (CTM) manufacturing demands a commitment to Good Clinical Practice and current Good Manufacturing Practice (cGMP). These guidelines were developed in concert by the scientific community, the pharmaceutical industry, and various government agencies, and ensure that CTM is manufactured as safely and consistently as possible.

While research centers, industry labs, and contract manufacturing organizations (CMOs) have always strived to maintain their own standards of excellence, in recent years the FDA’s oversight of CTM manufacturing has greatly expanded. A nuanced understanding of this evolving regulatory landscape is key to not just meeting any minimum requirements but also exceeding expectations.

Quality by Design (QbD) should be the basis of all clinical trial material manufacturing.

Clinical Trial Material Manufacturing in an Age of Increasing Regulatory Oversight

The concept of QbD was first developed by Dr. Joseph M. Juran in a comprehensive volume he published in 1992. He argued that the overwhelming majority of quality issues in products arose from a shortcoming in their design, and that the quality of a product could and should be built into it from inception. This has been borne out by studies demonstrating that no amount of increased testing of an improperly designed product may improve its quality.

In the context of CTM manufacturing, a high-quality product is defined as a substance or compound that reliably delivers its intended benefit while also being free of contamination. In order to protect the public and ensure cGMP guidelines are maintained, the FDA strongly emphasizes the employment of QbD principles. They apply these across the board, from drug product development and CTM manufacturing to their own regulations.

It has been almost fifteen years since the FDA began requesting chemistry manufacturing control (CMC) information from certain firms as a component of New Drug Applications. They specifically requested this disclosure to confirm that QbD protocols had been followed. Since that time the FDA has increasingly relied on QbD compliance in determining the shape of new regulations.

The fundamental principles of QbD in CTM manufacturing are straightforward: determine the crucial characteristics of a desired product, identify them as a critical quality attribute (CQA), and the employ process design to create a drug product that both includes the critical material attributes (CMAs) and identifies the critical process parameters (CPPs). QbD is as simple as understanding the interplay between the CQAs, CMAs, and CPPs and designing CTM accordingly.

Yet despite the common sense nature of QbD and the many industry issuances on the subject, there remains a great deal of confusion regarding the implementation of pharmaceutical QbD. This is especially true in the context of developing regulations. What does seem certain, though, is that the FDA’s insistence on the QbD imperative will only increase, and CTM manufacturers will do well to adopt and implement these protocols long before the arrival of a strict regulatory prompt.

Proper trial master file (TMF) documentation is more essential to clinical trial material manufacturing than ever before.

Clinical Trial Material Manufacturing in an Age of Increasing Regulatory Oversight

Discussions of CTM manufacturing often revolve around QbD approaches, compounding protocols, and other technical minutiae. One area that does not always receive the same level of attention is trial master file (TMF) documentation and management. Everyone recognizes the paramount importance of accurate record keeping, of course, but too often the paperwork is taken for granted.

This attitude, long overdue for an adjustment, has contributed to certains firms being caught wrong-footed when regulatory inspectors have demanded direct access to their trial master file TMF documentation. Such requests are becoming increasingly common during both clinical study audits and routine inspections. As a result, TMF inspection preparedness ought to be a top priority for any CTM manufacturer.

The most common problem with TMF documentation is that not all firms utilize dedicated electronic systems to manage their files. Relying even partially on paper-based systems is a recipe for confusion, both in terms of in-house performance and status management and in the ability of study teams to accurately access all necessary materials. A specialized eTMF documentation and management system allows for instant, on-site access to everything an inspector might request, as opposed to traditional documentation that may be siloed.

Regardless of whether or not a CTM manufacturer has updated to an eTMF system, certain protocols must be followed in order to meet regulatory compliance. All official records must be made directly available to inspectors upon request, including the complete TMF. Role-based systems are required to have an application in place, audit trails must be in validated systems, and the TMF documentation must be not only complete but also legible and up to date.

Ever-expanding regulations are having a profound impact on the manufacturing of clinical trial material — and that’s a good thing.

While there are certain subsections of any industry who bristle at the prospect of increased regulation, in the field of CTM manufacturing more oversight can only lead to even better cGMP. Whether it is a clarification and codification of QbD principles or a push to smarter, more secure TMF documentation and management, regulatory entities and their inspectors don’t just bear witness to the evolution of the industry, they help shape it.

This is why it is so important to stay abreast of any and all new regulatory developments, be they from the FDA or other government entities, oversight organizations, or individual sponsors. The end result is the adoption of higher standards, which in turn leads to safer, more consistent products. Who wouldn’t want that?