How much is too little versus too much when developing quality systems and controls for investigational cell and gene therapies?
Increase in Cell & Gene Therapy Development & FDA’s Response
In an official statement in January 2019, Scott Gottlieb, M.D., who was the FDA Commissioner at the time, stated that “the FDA is witnessing a surge of cell and gene therapy products entering early development, evidenced by a large upswing in the number of investigational new drug (IND) applications.” With new therapeutic modalities emerging in the cell and gene space (e.g., CAR-T and gene editing therapies) and their promising outcomes, companies are confronted with the need to quickly develop and test these therapies in clinical trials. Because these emerging therapies introduce biological material into human subjects for phase 1 trials, a scientifically based standard of controls and good manufacturing practices (GMPs) are required to ensure patient safety and assure regulators that clinical supplies conform with the chemistry, manufacturing, and controls (CMC) information submitted in the IND.
As per 21CFR210.2(c), an investigational drug or biological product used in human phase 1 clinical studies is exempt from compliance with the cGMP regulations specified in 21CFR211. However, these clinical trial materials are still subject to the adulteration clauses in the Federal Food, Drug, and Cosmetic (FD&C) Act 501(a)(2)(b) that state that a drug is deemed adulterated if the methods used in, or the facilities or controls used for, its manufacture, processing, packing, or holding do not conform to or are not administered in conformity with cGMP… To help companies comply with the requirements set forth in the FD&C Act, while considering the practical and risk-based exceptions to the 21CFR regulations, FDA published a guidance document for companies that manufacture phase 1 clinical trial materials. This guidance does not apply to “investigational products manufactured for phase 2 and 3 clinical trials (manufacture of such drugs must comply with appropriate sections of 21CFR211)”.
FDA has expressed support for regulatory flexibility for phase 1 manufacturing, reducing the GMP compliance burden during clinical development and facilitating a faster route to early phase clinical studies. The use of phase appropriate GMPs and controls was never intended to provide firms an excuse to save money or cut corners. Rather, FDA’s guidance in applying appropriate GMP controls for producing clinical supplies for phase 1 were disseminated to ensure basic safety and documentation standards are met in the manufacture and testing of phase 1 clinical trial material and to encourage the design of quality into the process. It is expected that enhanced process controls and GMP standards will be employed as the material transitions into later clinical stages.
Applying Regulatory Requirements in Real Life Situations
To illustrate this point, ProPharma Group’s experts recently audited a viral vector manufacturer that was being qualified to manufacture and test viral vectors for phase 1 clinical trials. The manufacturer stated that a production incubator used to expand the cells did not require qualification because the material being produced would only be used to support phase 1 trials. While we strongly support the implementation of risk-based and phase-appropriate approaches to the application of GMPs and manufacturing/testing controls, this rebuttal was surprising since control over temperature and CO2 are critical for optimal cell growth and viability. However, during our review of regulatory guidance and industry publications, we quickly realized there could be different interpretations of the industry’s expectation to qualify critical process equipment. This requirement is outlined in the following guidance documents:
- PDA Technical Report #56 – Application of Phase-Appropriate Quality System and cGMP to the Development of Therapeutic Protein Drug Substance, critical equipment should be qualified for its intended use for phase 1 manufacturing.
- FDA Guidance for Industry – cGMP for Phase 1 Investigational Drugs, the only statement about equipment qualification is that adequate equipment is used for the intended task and that it is properly maintained, calibrated, cleaned, and sanitized at appropriate intervals following written procedures. The guidance does not specifically call out requirements for qualification.
- FDA Guidance for Industry– Chemistry, Manufacturing, and Control Information for Human Gene Therapy Investigational New Products Applications
While this example is specific to equipment qualification, it illustrates a general point about defining controls and GMPs that are appropriate to the manufacturers of phase 1 clinical trial material. The basic components of a Quality Management System (QMS) relevant to phase 1 manufacturing are detailed in the FDA’s guidance document; however, these controls are very broad and are open to interpretation. It is crucial that manufacturers of phase 1 clinical trial material assess potential risks associated with their manufacturing process, facilities, equipment, methods, materials, etc. and the associated impact of these risks on the safety and quality of the material. All significant risks should then be mitigated, and appropriate controls implemented to reduce potential adverse impact for the patients and data generated from the phase 1 study.
The Importance of Quality Assurance in Early-Stage Cell and Gene Therapy Development
In the cell and gene therapy space, many new therapies are being developed in smaller academic and research-based institutes. These institutes often do not have a formal Quality unit, and critical quality functions, such as QMS implementation, batch release, Out-of-Specification (OOS) investigations, and corrective and preventative action (CAPA) programs are performed by designated operations or technical personnel. While the FDA guidance does address this issue that phase 1 clinical trial material manufacturers can perform traditional quality functions with operations and technical staff, it is highly recommended that it is performed in a way that quality control testing and oversight are separated from the manufacturing unit. However, as the therapy advances to phase 2 trials, this Quality function must be performed according to GMP through a formal Quality Assurance program.
By establishing controls and implementing GMPs through a defined quality program that is based upon a documented assessment of risk to the patients undergoing treatment using cell and gene-based therapies, manufacturers of phase 1 clinical supplies can relax some of the systems required for later phase and commercial manufacturing. However, this relaxing of standards should not be considered as a way to cut corners. Remember, these therapeutic treatments could be a life saving measure for patients enrolled in the clinical studies, and safety and efficacy of the treatment material must be the basis for all GMP programs and decisions.
ProPharma Group: Experts in All Cell and Gene Therapy-Related Matters
Are you in the process of developing a cell and gene therapy product? Regardless of where you are in the development lifecycle or what your current needs are, we have the skills, capabilities, and expertise you need on your side. ProPharma Group’s Cell and Gene Therapy Center of Excellence experts can help you with any and all of your cell and gene therapy-related needs. Contact us today to learn more about our full range of cell and gene therapy-related services.
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