In 2008, the FDA issued guidance exempting most Phase 1 investigational drugs from the full scope of Title 21 of the Code of Federal Regulations (CFR) parts 210 and 211. This exemption supports a risk-based framework tailored to the unique scale and purpose of early development, where speed, adaptability and resource efficiency are critical.
Many small pharmaceutical and biotech companies advance one or two investigational products, often with limited funding. For these organizations, this regulatory flexibility serves as a critical facilitator of early development, emphasizes operational readiness and adheres to current Good Manufacturing Practice (cGMP) regulations set by the FDA.
Understanding how to apply these risk-based cGMP principles effectively can significantly reduce development costs and timelines, enabling faster progress to first-in-human trials without compromising safety or quality.
What Is a Phase 1 Investigational Drug Clinical Trial?
21 CFR § 312.21(a) describes a Phase 1 clinical trial as the first time an investigational drug is introduced into humans. These studies are typically small, involving 20 to 80 healthy volunteers or patients and are designed to evaluate how the drug behaves in the body. This phase may also include research on drug metabolism, structure-activity relationships and mechanisms of action.
As Phase 1 trials are exploratory and limited in scale, the FDA recognizes that full commercial manufacturing requirements are not appropriate at this stage. As a result, most Phase 1 investigational drugs are exempt from the detailed regulations outlined in 21 CFR 210.2(c):
Applicability of current good manufacturing practice regulations.
(c) An investigational drug for use in a phase 1 study, as described in § 312.21(a) of this chapter, is subject to the statutory requirements set forth in 21 U.S.C. 351(a)(2)(B). The production of such drug is exempt from compliance with the regulations in part 211 of this chapter.
For pharmaceutical and biotech companies in need of commissioning support for Phase 1 readiness, CAI delivers risk-based commissioning strategies that meet FDA regulations quickly and cost-effectively. Explore CAI’s risk-based commissioning for pharmaceutical manufacturing.
2025 Updates to FDA cGMP Phase 1 Guidance
In January 2025, the FDA released a draft guidance to update expectations under 21 CFR 211.110. While these updates do not apply to Phase 1 investigational drugs, they reflect the FDA’s broader emphasis on science- and risk-based quality management. The updated guidance encourages manufacturers to:
- Use flexible, data-driven control strategies
- Implement in-line or real-time monitoring tools
- Design systems based on a thorough understanding of process risk and product criticality
The flexibility, risk-based controls and data-driven decision-making emphasized in the 2025 draft guidance are foundational principles that guide CAI’s approach. We work with clients to integrate these practices early, helping them establish compliant, efficient systems that scale seamlessly as products move into later phases. This ensures our clients are inspection- and development-ready.
FDA Expectations for cGMPs in the Manufacture of Phase 1 Investigational Drugs
The FDA recommends following the two steps below to establish an appropriate manufacturing environment for Phase 1 investigational drugs:
- Risk assessment: A comprehensive evaluation of the manufacturing setting (i.e., environment, equipment, process, personnel and materials) to identify any potential hazards.
- Ongoing operational readiness: Implement appropriate actions before and during manufacturing to minimize or eliminate the potential hazards identified during the risk assessment.
Beyond general principles, the FDA provides specific guidance on essential quality elements required for early-phase manufacturing. These foundational controls ensure investigational products are manufactured under appropriate oversight while preserving development flexibility.
- Personnel: All personnel should have the education, experience and training (or any combination of the three) to ensure they can perform their assigned functions.
- QC Function: Every manufacturer should have an established written plan that describes the QC responsibilities and functions.
- Facility and Equipment: The facility used should have adequate work areas and proper equipment for the intended task.
- Controls of Components, Containers and Closures: The company should have established written procedures describing the handling, review, acceptance and control of materials.
- Manufacturing and Records: The manufacturer should follow written manufacturing and process control procedures.
- Laboratory Controls: Laboratory tests used in manufacturing should be scientifically sound, suitable and reliable for the specific purpose. The testing should be performed under controlled conditions and follow written procedures.
- Packaging, Labeling and Distributing: The packaging, labeling and distribution operations should follow written procedures. The packaging of the drug should be suitable to protect it from alteration, contamination and damage.
- Record Keeping: Manufacturers should keep complete records relating to the quality and operation of the manufacturing process.
Facility and Equipment Expectations For Phase 1 Investigational Drugs
Among the most critical applications of risk-based thinking is how facility and equipment readiness is managed in early-phase settings. Through a structured risk assessment, manufacturers can identify potential hazards associated with the facility, equipment and process environment. This assessment serves as the basis for determining where commissioning activities are necessary to ensure that systems function reliably and meet performance requirements.
Rather than investing time and resources in full qualification, a well-executed commissioning program provides assurance that equipment can maintain environmental and process manufacturing conditions. This targeted approach aligns with FDA expectations and results in faster startup, reduced cost and greater flexibility in early development.
These practices align directly with how CAI supports early-phase clients in building compliant, flexible systems with a clear pathway to operational readiness. Our commissioning and qualification services are tailored for early-phase environments, ensuring that critical utilities and systems are validated and prepared to support GMP operations. This includes services like environmental monitoring performance qualification (EMPQ) and air handling unit readiness.
By introducing operational excellence principles early in the project, such as defining performance readiness criteria and optimizing workflow efficiency, CAI enables clients to accelerate startup timelines and establish a strong foundation for sustained operational performance and compliance. Learn more about our EMPQ and validation support services.
Partner With CAI to Meet FDA cGMP Guidance in Early-Phase Manufacturing
Companies that embrace a risk-based cGMP framework for Phase 1 manufacturing can meet FDA expectations without compromising agility or efficiency. CAI helps you get there by aligning systems, resources and teams to accelerate development, control costs and protect patient safety. Get in touch.