Cell and Gene Therapies (CGT): 6 Detailed CMC Considerations for IND Submissions

Background

Cell and gene therapies (CGT), often referred to as advanced therapeutic medicinal products (ATMPs), are rapidly emerging as favorable treatments, repeatedly targeting rare, ultra‑rare diseases and fall under regulators’ expedited programs [1]. To date, the FDA has approved 34 cell and gene therapies (CGT) for commercial use [2]. As these therapies continue to develop, the guidance and regulations are still being defined and lack harmonization. In recent years, FDA has adapted and expanded its efforts to support the growth of cell and gene therapies (CGT) submissions [3]. Among many initiatives, such as the PDUFA VII commitment, the FDA now offers a CMC Development and Readiness Pilot (CDRP) program for expedited development for cell and gene therapies (CGT) products meeting an unmet need [3]. Sponsors participating in the CDRP program can benefit from additional CMC‑focused advice from the FDA, which is critical in successful cell and gene therapies (CGT) development given its dynamic regulatory landscape.

Related article: CMC And Quality Enhancements Under PDUFA VII Explained

IND Preparation for Cell and Gene Therapies (CGT)

Due to their unique nature and complexity, cell and gene therapies (CGT) products present their own challenges as development progresses. Even the smallest change to the manufacturing process or manufacturing facility during clinical development may impact product quality and trigger a need for additional comparability studies to ensure the proposed change does not affect the product safety and efficacy.

Related article: Understanding Comparability Studies for Biologics: Why They Matter

Therefore, it is key to begin dialog with the FDA early in the product lifecycle to discuss CMC topics, including any unusual aspects, manufacturing changes, safety concerns, or quality challenges.

It should be noted that Sponsors are not required to complete all CTD sections in the original IND submission. The amount of CMC information to be submitted depends on the phase of investigation and the scope of the clinical investigation proposed (21 CFR 312.23(a)(7)).

However, there are several important CMC areas that require strategic approach prior to submitting IND quality documentation for CGT products and are summarized below. These points should be discussed and added to the appropriate Quality Module 3 IND sections, where applicable.

Section-Specific CMC Considerations

• 3.2.S.2.2 – Manufacturing Process Controls

Process controls will be refined throughout product development. Process controls and parameters need to be defined and included in the IND [4]. Aseptic processing is extremely important in manufacturing these products and should be described. Additionally, it is important to update the IND with new details. Changes and updates to the drug substance (DS) manufacturing process and process controls information should be submitted as an amendment to the IND (21 CFR 312.31(a)(1)) prior to implementation for investigational use in clinical studies [4].

• 3.2.S.2.3 Control of Materials

The FDA recommends using clinical grade or standard grade materials in the manufacturing process, where possible. If the material is not FDA‑licensed or standard grade, additional manufacturing or testing information may be required to evaluate the material [4].

Additionally, the FDA recommends using non-animal‑derived reagents (e.g., serum‑free tissue culture media or recombinant proteases) in manufacturing processes [4]. The use of serum may increase the risk of introducing adventitious agents. Furthermore, serum used during manufacturing may cause batch variation and impact the product quality [4].

• 3.2.S.4.1 and 3.2.P.5.1 – Potency

Potency tests are expected to be part of release specifications for all biological products. The IND should include a description of the potency assay for DS and drug product (DP). The development of potency assays will likely progress and develop during the clinical trial [5]. If a change is made to a material or the manufacturing process, it is important to understand the potential impacts on potency through comparability. As a result, comparability data may need to be submitted.

• 3.2.S.4.2 and 3.2.P.5.2 – Safety Testing and Microbial Control

Cell and gene therapies (CGT) products are not suitable to undergo pharmacopeial methods for thermal sterilization as they are live therapeutics [1]. However, safety testing, such as USP <71> sterility test, USP <61> bioburden, USP <63> mycoplasma, and endotoxin test are an important component of ensuring the safety of the cellular product prior to patient administration and should be included and described in the IND [4].

• 3.2.S.3.2 and 3.2.P.5.5 – Characterization of Impurities

Impurities are not readily defined in guidance for cell and gene therapies (CGT). Impurities may include, but are not limited to proteins, DNA, cell debris, and reagents/components used during manufacture [4]. Impurities must be identified, defined, and characterized by the Sponsor. It is important to include release limits and rationale for process‑related and product‑related impurities, if applicable. Non‑target cell types are also a potential impurity and immunogenic issue. Explanations and risk assessments for impurities should be included [4].

Cell death may introduce cell debris into a process or product. Manufacturing processes may require long times in culture with multiple steps or hold times. During passaging, it is unlikely a cell population has maintained 100% viability. It is important to understand the rate of cell death during manufacturing. Cell death release criteria should be explained and included, if applicable.

• 3.2.S.5 and 3.2.P.6 Reference Standards

Reference standard information must be included with the IND submission. The reference standard may be a standard material or a characterized lot of DS or DP [4]. It is recommended to provide the source, lot number, and expiration date, CoAs for the reference standard, when applicable. Characterization may be challenging if a cell therapy product is autologous. However, sufficient characterization of the reference standard is expected.

Get your Questions Answered

While the cell and gene therapies (CGT) regulatory landscape is constantly evolving and regulators work to gain more knowledge about these therapies, it is the Sponsor’s responsibility to ensure that the IND quality information provides confidence in the product safety and quality. The above snapshot of challenging topics important for inclusion in IND Module 3 for cell and gene therapies (CGT) is just the beginning.

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Authored by:
Cailin Wilson, Medical Writer, Regulatory and Medical Writing &
Margaret Studzinska, Director of CMC and Nonclinical Writing

References:

• Sterility Testing for Cellular Therapies: What Is the Role of the Clinical Microbiology Laboratory? – PMC (nih.gov)
• US FDA. Approved Cellular and Gene Therapy Products. 2023.
• Eglovitch, J.S. FDA describes agency’s initiatives to accommodate growth in cell and gene therapy fields. 2023.
• Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs) | FDA
• Guidance for Industry Potency Tests for Cellular and Gene Therapy Products (fda.gov)