Making Sense of Regulations

Regulatory requirements protect patients and consumers by ensuring consistent drug safety, quality, and efficacy. For scientists, navigating regulatory minutiae requires significant time, effort, and resources. Because regulatory requirements change as a drug moves through the various clinical trial phases, knowing what to focus on, what resources are available, and who to talk to for advice can prevent a lot of future headaches.

The IND Application

Researchers must receive permission from local regulatory agencies to begin clinical trials. In the United States, this step entails submitting an Investigational New Drug (IND) application to the Food and Drug Administration (FDA). INDs are reviewed based on pre-clinical testing data robustness, manufacturing processes, and investigator qualifications. An IND application should contain robust pre-clinical data on drug candidate absorption, distribution, metabolism, excretion, and toxicity (ADMET), as well as a clearly defined chemistry, manufacture, and control (CMC) section that outlines the drug’s quality, purity, and strength using industry-established metrics. Finally, some pre-clinical study methodologies should be compliant with good laboratory practice (GLP) regulations.

See “Moving into Biological Manufacturing”

The role of the IND application does not end upon being granted permission for a Phase I clinical trial. Rather, it serves as a roadmap for an ongoing process. As the candidate drug moves through clinical trial phases, new information may come in from either internal or external sources that necessitate alterations of existing workflows or plans. If the changes are sufficiently large in scope, a researcher may need to submit an IND amendment (INDA) for permission. Scientists can avoid the need for INDAs to some degree by carefully crafting the initial IND with potential outcomes in mind, being general enough to accommodate for future variations in manufacturing and clinical planning.

Quality by Design

This sort of proactive planning is termed “quality by design” (QbD), which centers on the idea that quality can be designed into a product from the start.¹ QbD stands in contrast to “quality by experimentation,” which discovers quality issues post hoc and fixes them largely through trial and error. QbD seeks to obtain a greater understanding of the product (via critical quality attributes—CQAs), the materials (via critical material attributes—CMAs), and the process (via critical process parameters—CPPs). These elements, along with the relationships between these elements, help scientists create quality target product profiles (QTPP), a prospective summary of the quality characteristics of a drug product that ideally will be achieved.² QbD minimizes risk by identifying and addressing potential issues before production or manufacturing is initiated.¹

Documentation

From pre-clinical to Stage III, it is difficult to overstate the importance of documentation to drug discovery and manufacturing. Accessible and up-to-date documentation is not only necessary for regulatory compliance, but it is a valuable asset for process/product evaluation and decision making. Acquiring, storing, organizing, and recalling documentation is becoming an increasingly digitized process. The same software suites that drive biomanufacturing workflow automation also collate data from multiple instruments to a single central terminal. Automation software can also serve as a repository for process information, such as experimental parameters and environmental settings. Further, many software suites for managing data flow are designed to be compliant with regulations on electronic data handling.

Smoothing the Journey

Navigating regulatory requirements can be tricky, but there are a host of resources available for scientists on the journey to market. A treasure trove of educational resources, such as Cytiva’s eLearning courses or its Fast Trak^TM education and training program, are available either as short but intensive in person courses or remote offerings to be consumed at one’s own pace. These courses cover topics ranging from increasing biomanufacturing efficiency to the ins and outs of GLP, IND, and CMC. Third-party expertise can also cover knowledge gaps. Consultants and regulators can offer valuable advice throughout the regulatory process, highlighting potential issues that may arise during future clinical trial phases with more stringent regulatory thresholds. Finally, it is possible to outsource parts of the workflow to Contract Development and Manufacturing Organizations (CDMOs). CDMOs offer regulatory understanding, process expertise and security, and manufacturing capacity, removing bottlenecks and expediting the drug discovery journey.