On December 7, 2022, FDA’s Center for Biologics Evaluation and Research (CBER) and the Office of Tissues and Advanced Therapies (OTAT) held a town hall to answer questions related to cell therapy and tissue-engineered products chemistry, manufacturing, and controls (CMC). The purpose of these town halls are to discuss topics related to OTAT-regulated products, engage with product development stakeholders, and to provide information to help stakeholders to help advance drug development. The next town hall will focus on the clinical development of gene therapy products for rare diseases in February 2023.
As previously mentioned, sponsors can interact with FDA in the town hall by submitting questions in advance or by asking a question live during the meeting. It is important to keep in mind that this meeting is for general CMC feedback and sponsors are informed that “FDA is not able to comment on or answer questions regarding specific investigational products or drug applications during the town hall.”
In case you do not have time to watch the town hall, we provided a summary of select topics that are discussed below. There was a lot of information on CMC regulatory requirements and pitfalls for cellular therapies and tissue engineered products discussed during the OTAT town hall that are not included in this blog. These topics included the requirements for using irradiated murine cell lines, core blood as a starting material, and fetal bovine serum, FDA’s standards for the development of cell and gene therapies and tissue products, testing requirements for stability, donor eligibility, delivery devices, and for a scaffolding component of a tissue-engineered product.
Common CMC Issues for Phase 1 IND Study
The Agency stated that the most common reason for a clinical hold of a Phase 1 study under an investigational new drug (IND) is related to safety. The reasons for these holds might include not providing sufficient information to describe the manufacturing process, using reagents which are not demonstrated to be of sufficient safety or quality, not conducting donor eligibility or appropriate cell bank testing, insufficient safety testing of the product, insufficient information on the assays to conduct the safety testing, insufficient safety information on delivery device and data demonstrating that the device does not impact the safety or quality of the drug product. The Agency repeatedly stated and strongly recommends sponsors engage with FDA prior to submitting the IND.
Similar to the OTAT town hall meeting in September, potency assay requirements and pitfalls were discussed. The Agency referred to its 2011 FDA Guidance for Industry: Potency Tests for Cellular and Gene Therapy Products during the town hall. As you may know, there are challenges related to developing potency assay(s), and the Alliance for Regenerative Medicine and the American Society of Gene and Cell Therapy recently published a white paper on a workshop held to discuss these challenges. The workshop is also discussed in Cell & Gene here and here.
The Agency recommended that product developers begin designing potency assay(s) early, and developing and evaluating multiple potency assays since not all potency assays can be validated and some potency assays may not fully reflect the biological activity. The Agency stressed that because the ability to measure potency is fundamentally related to product characterization, developers should initiate potency assay development by the way of product characterization during preclinical and early clinical investigation. The potency assay may not be completely defined early in the development, but should become progressively more comprehensive as developers accumulate manufacturing experience, product characterization data and clinical data. For first in human studies, developers need to provide plans for characterization, including a description of the initial critical quality attributes, potency assay development plans during clinical development, and a quality target profile. As the product advances in clinical development, expectations are that the potency test be refined to measure a relevant biological activity of the product. The Agency directly quoted the 2011 FDA Guidance, “if one assay is not sufficient to measure the product attribute(s) that indicates potency, then an alternative approach could be used, such as developing multiple complementary assays that measure different product attributes associated with quality, consistency and stability.” The Agency stated because cellular and tissue-engineered products usually have multiple potentially related critical quality attributes (CQAs), the potency assay strategy could include multiple assays, each of which quantitates a potency-related CQA.
The Agency pointed out that a qualitative potency assay should be accompanied by one or more quantitative assays and cannot be used without a quantitative assay. Although demonstrating accuracy and precision for a qualitative assay could be challenging, the Agency stated that with proper assay design (e.g., sufficient replicates), developers should be able to demonstrate adequate assay consistency. Per the 2011 FDA Guidance, developers should validate the assay prior to conducting a clinical study that will investigate the efficacy for licensure.
For any change, the Agency recommended that developers conduct a risk assessment per ICH Q5E to determine whether there is a potential to affect product quality. This would include an evaluation of the potential for product attributes and process parameters to affect the product quality as they relate to the product safety and efficacy. The goal of the comparability study is to demonstrate a lack of adverse effect on the product quality. The Agency recommended changes in product manufacturing are implemented in the earlier phases of the clinical study to reduce risk to the development program (i.e., before evaluating clinical effectiveness). Depending on the change and at what phase of the clinical study it is made, the Agency expects that a comparability assessment, developmental studies, and risk assessment be conducted to support the change. The developmental studies and the risk assessment should allow sponsors to rank the different product characteristics to determine the type of evaluation that should be performed such that a study can be designed to address the risk(s) identified. The Agency emphasized that release testing alone is not sufficient to assess comparability and that additional characterization testing or in process testing be conducted to demonstrate that there is not adverse effect on product quality.
The extent of analytical evaluation needed in comparability studies generally increases with the stage of clinical and product development and should be supported by knowledge of CQA, accumulated manufacturing experience, and further understanding of the mechanism of action. Understanding the impact of manufacturing changes on product quality is essential to determine the risks to product quality and to design the comparability study. It is important to use analytical methods that could detect meaningful differences in product quality. The Agency recommended developers determine the most appropriate process time points to detect the change in the quality attributes, which could entail evaluating the product at multiple stages of manufacturing. It is possible that the comparability study results may not be sufficient to establish product comparability. The sufficiency of comparability evaluation depends on the type of change and a developer’s level of understanding of product quality attributes as predictors of clinical safety and efficacy. The inclusion of additional characterization tests or preclinical studies may be necessary to support comparability. For some products, animal models may be used to demonstrate that the product has the desired biological effect and provide supportive evidence for comparable biological activity of the pre-change and post change product.
The Agency acknowledged that early in development, a complete understanding of appropriate process controls may be limited and that specific controls may be added or refined during the life cycle. However, the initial IND submission should describe and justify the controls that are implemented to ensure adequate quality and manufacturing consistency. The Agency recommended that product be as fully tested as feasible in early stages of development and that specifications should be appropriate to the stage of product development. For example, for early phase clinical studies, assays should be in place to access identity, quality, strength, and purity. In later stages, more detailed product characterization and potency should be provided. The acceptance criteria for release testing should be established and justified based on data from lots used in preclinical or early clinical studies, lots used in demonstration of manufacturing consistency, and stability studies, and relevant product studies. The Agency recognizes few specifications will be finalized and some tests may still be under development; however, for any given stage of the development, the testing plan submitted should be adequate to describe the physical, chemical, or biological characteristics of the drug product necessary to ensure quality and safety. Specifications should be further refined as product development and tightened based on manufacturing experience as clinical development moves forward.
At what point does manufacturing at the clinical site become manufacturing that requires additional final product release testing?
The Agency stated that manufacturing steps conducted at a clinical site considered to be substantial manipulations (e.g., those used to prepare final drug product after its been released) are subject to manufacturing controls and good manufacturing practices. The Agency also recommended not using substantial manipulations at a clinical site for already released final drug product.
How should sponsors handle manufacturing deviations, including product lots that do not meet lot release specifications?
Manufacturing deviations should be investigated to identify the root cause and appropriate corrective actions should be taken to avoid repeat occurrences in the future. The Agency expects that sponsors provide their risk management approach and change control procedures for how to address the risk manufacturing deviations in their IND. Manufacturers who hold a biological license should report manufacturing deviations to the FDA per 21 CFR 600.14. Product should not be released if it does not meet lot release specifications due to the manufacturing deviations. Sponsors may consult with the Agency to release out of specification product if a patient is at significant risk and is conditioned to receive the product.
Is it acceptable to use products manufactured from engineering runs in clinical studies?
The Agency stated that this may be permissible if adequate justification on safety and quality of the batch and whether or not there are differences in the manufacturing process for that engineering run versus the intended clinical run.
If I use GMP grade reagents, isn’t that sufficient to support their safety? What are the general expectations on reagents used to manufacture products under an IND?
The Agency pointed out that just because a reagent is labeled “GMP grade” does not necessarily mean that the reagent was manufactured using good manufacturing practices (GMP). In some cases, a certificate of analysis from the supplier may be sufficient and FDA would not require additional information regarding the reagent. In other cases, the Agency would require additional testing to ensure safety and quality of the GMP grade reagent. The Agency recommended that sponsors follow the requirements under 21 CFR 211.84(d)(2) and conduct an identity test on at least one lot of reagent in addition to maintaining a supplier qualification program that evaluates reagent suppliers. The Agency stated sponsors could qualify use of research grade reagents in an IND, but that sponsors should progress towards using reagents that have been manufactured under GMP conditions. During the town hall on gene therapy CMC, the Agency noted that it does not recommend the use of research use reagents or materials, but that it could be flexible (minute 42 of the recording here).