In the development of a new drug, when do current Good Manufacturing Practices (cGMP) regulations apply? Clinical project teams often struggle with answering this question. In this article, we will discuss the US Food and Drug Administration (FDA) expectations for the application of cGMP to investigational drugs.

FDA Regulations and Guidance

Good manufacturing practice (GMP) is a system for ensuring products are consistently produced and controlled according to quality standards. It is designed to minimize the risks involved in any pharmaceutical production that cannot be eliminated through testing the final product (World Health Organization). The FDA cGMP regulations for drugs are published in Title 21 of the US Code of Federal Regulations, Parts 210 and 211 (21 CFR 210/211). Generally, US law exempts drugs used for Phase I studies from compliance with 21 CFR 210/211; however, it does not exempt:

  • An investigational drug for use in a Phase I study once it is available for use in a Phase II or Phase III study
  • A drug lawfully marketed as a monograph drug or by an FDA approved market application

Additional guidance on cGMP for investigational drugs used in Phase I clinical trials is provided in FDA’s Guidance for Industry Current Good Manufacturing Practice for Phase 1 Investigational Drugs. In this guidance, FDA notes “where applicable, manufacturers are also expected to implement manufacturing controls that reflect product and manufacturing considerations, evolving process and product knowledge, and manufacturing experience.”

According to 21 CFR 210.2(c) the cGMP regulations formally apply for drugs used in Phase II/III studies.

cGMP Implementation

Implementing cGMPs as early as possible in the development of a drug helps protect the safety of clinical trial participants and provides a foundation for a robust quality management system (QMS). Early adoption of quality systems allows for a gradual integration of processes, which is less burdensome on the organization. In addition, early adoption will ensure tighter controls, build a culture of quality, and minimize the risks of noncompliance. This will benefit the organization as it moves toward commercialization and help to assure a successful pre-approval inspection.

Diagram depicting the process of when you should incorporate good manufacturing practices (GMP) into your workflow

To clarify cGMP requirements, FDA has adopted the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines Q8 Pharmaceutical Development, Q9 Quality Risk Management, and Q10 Pharmaceutical Quality System. Sponsor companies should also follow these guidelines in developing a QMS. If the sponsor is also the manufacturer, they will need a QMS addressing all requirements in the cGMPs. If a sponsor outsources the manufacturing of their investigational drug, they are still responsible for ensuring the contracted vendor(s) has a robust QMS with facilities, systems, and processes that are fit for purpose. In this scenario, the sponsor company should also have their own QMS that at a minimum:

  • Addresses management commitment to quality
  • Includes a quality policy
  • Has defined processes for:
    • Resource management, including employee role based and GMP training
    • Internal communication
    • Management review
    • Document, data, and records management
    • Vendor lifecycle management
    • Product lifecycle management

Complying with cGMP throughout the drug development process helps ensure the quality of investigational products, which helps protect clinical trial subject safety and reduces variability due to poor quality. Even if manufacturing has been outsourced, sponsors are still responsible for ensuring cGMP requirements are met.

Need help complying with cGMP? Advarra can provide support for audits, regulatory inspections, staff training, QMS assessment and development, assessment of facilities, systems, and processes, and more. Contact us for assistance with remote or on-site activities.

Back to Blog