Keys To Successful CMC Source Document Preparation For Cell & Gene Therapies

By Steve Kornher, senior consultant, Regulatory CMC, Halloran Consulting Group

Chemistry, manufacturing, and controls (CMC) source documents are the foundation for module 3 of a regulatory submission (Investigational New Drug [IND], Biologics License Application [BLA], as well as CMC amendments to INDs and BLAs). Source documents for module 3 describe process and assay development efforts, addressing critical technical issues associated with the manufacture, testing/characterization, shipment, and stability of both the drug substance (DS) and drug product (DP). These documents chronicle how each of these efforts are executed in compliance with good manufacturing practice (GMP) to support the regulatory submission. Several different types of source documents are essential for the preparation of module 3 for a cell and gene therapy regulatory submission. For example, certificates of analysis and certificates of origin for raw materials and certificates of testing for consumables used in the manufacturing process are source documents that must be provided with the regulatory submission and referenced in module 3.

This article will focus on a class of source documents consisting of study reports for IND-enabling studies. A significant number of these studies are typically required for cell and gene therapy IND submissions. Proper planning and execution of these studies is essential for a successful IND submission.

Scope Of Early-Phase Studies: Sponsor Responsibilities

Cell and gene therapy IND sponsors focus on a wide range of CMC efforts in early development, including process and assay development, drug substance and drug product stability, manufacture and characterization of critical starting materials such as plasmids and cell banks, in-use stability of drug product, compatibility of drug product with the planned clinical delivery system, qualification of release testing methods, excipient selection, and more. Each effort should have a dedicated study protocol and associated report to serve as source documentation for module 3. Examples of two types of critical source documents are discussed in greater detail below.

Raw Materials

It is important, whenever possible, to use raw materials and consumables of the highest quality (compendial or clinical grade) in the GMP manufacturing process. It is not uncommon for research and development (R&D) grade critical raw material to be utilized in process development, including the manufacture of DP for preclinical safety studies. Use of this DP in these studies will require demonstration that the process that manufactured it is comparable to the GMP manufacturing process used to produce clinical grade DP. To address regulatory expectations, comparability is established by head-to-head comparison of the preclinical and GMP drug products using lot release tests and additional characterization methods. Therefore, use of compendial and clinical grade critical raw materials is recommended in these studies despite the additional cost. These raw materials will be used in GMP manufacture of clinical material, so it is important to assess their performance in the manufacturing process as early in clinical development as possible. This assessment should be documented in a study protocol and report that will contribute to the content of the DS manufacturing process development section of module 3.

Methods and Assays

Whenever possible, methods and assays to be used in the testing of GMP manufactured DP should be used during process development. Development of all lot release assays and methods during process development should be documented with protocols and reports. A description of the positive and negative controls and standards used in the assay along with system suitability requirements, sample preparation and sample suitability requirements should be included in the report. If any methods evolve over preclinical and clinical development, then a concise description of how the current method relates to the earlier version of the method should be documented. Assay development protocols and reports are important source documents that will contribute to the module 3 sections pertaining to testing methodology and the qualification of those methods.

The IND sponsor should ensure that all CMC source documents produced during early-phase clinical development provide the rationale underpinning each study design and execution, descriptions of the assays used to generate the study data, a list of the materials and equipment used, tabulated data with graphs and diagrams as needed, a statistical analysis of the data (as appropriate), a discussion of the results, and a conclusion supported by the data presented in the report. Citing studies and data not presented in the report to support study conclusions should be kept to a minimum. Supporting documentation, such as certificates of analysis (CoAs) for the raw materials used in the study and lot release reports for critical starting materials (i.e., plasmids and cell banks), used in the study should be appended to the report. Study reports should always be signed by the author(s).

Responsibility Of Early-Phase Study Report Reviewers

Early-phase study reports should be reviewed, at minimum, by personnel conversant with the technical aspects of the study. A review of the draft report should confirm the following:

• The study was executed as described in the study protocol.
• Data are of sufficient quality to serve as source information.
• Statistical analysis was executed properly.
• The results of the analysis support the study conclusions.

Any deviations arising from the execution of the study protocol should be noted and addressed. If a quality assurance (QA) representative is not reviewing the report, consider seeking their advice regarding significant deviations to the study protocol. Depending on the nature of the study, heads of R&D and/or process development should sign the reports. Some of these study reports will be reviewed and signed by a representative from QA. Most of the module 3 sections for a Phase 1 IND will contain information provided by these reports.

Scope Of Late-Phase Studies: Sponsor Responsibilities

By Phase 3 of clinical development, IND sponsors will execute CMC studies critical for the license application, including, but not limited to:

• Validation of the manufacturing process
• Validation of lot release tests
• Process transfer reports (as needed)
• Assay transfer reports (as needed)
• Comparability assessments (as needed)
• Compatibility of drug product with the delivery system to be used in the clinic for licensed product
• In-use DP stability assessment
• Demonstration of cold chain custody for drug product shipments to warehouses and clinical sites
• Demonstration of cold chain custody for critical materials shipped to manufacturing facilities
• Drug substance and drug product stability assessments
• Container/closure integrity assessment
• Qualification of reference standards
• Aseptic process simulations
• Qualification of raw material suppliers
• In-house verification of raw materials lot suitability for use in GMP manufacturing
• Risk assessments (as needed)

Examples of studies that will require input from the contract manufacturer and contract testing labs include, but are not limited to:

• Comparability assessments
• Process transfers
• Assay transfers
• Aseptic process simulations
• Process and assay validations

The form and structure of study protocols and reports will not change significantly during clinical development. Report authoring responsibilities by department will not change significantly from those described earlier. More detailed reviewer responsibilities for late-phase studies are described in the next section. The sponsor, as the contractor’s client, should thoroughly review and comment upon every IND enabling study protocol and report generated by the contractor. If possible, the sponsor should formally approve these documents. The sponsor should request that the quality agreement with the contractor include that stipulation. For IND sponsors responsible for their own manufacturing and testing, the document preparation and review requirements for study protocols and reports still apply.

Responsibility Of Late-Phase Study Report Reviewers

Reviewers of late-phase study reports should ensure that all deviations that arose during execution of each study have been successfully resolved and the associated investigation report or summary, if needed, and any corrective actions arising from the investigation have been approved by the contractor’s QA and the sponsor’s QA organization. Reviewers should confirm the report is clearly written, succinct, and includes all supporting documentation. Data should be presented in an organized and coherent manner. If data analysis utilizes statistical methods, then the choice of method should be described and explained (for example, use of non-parametric statistical methods). All study acceptance criteria and system suitability criteria for the test methods used should be met. All conclusions should be supported by data presented in the study report. Reference to studies and data not included in the report should be minimized. Late-stage study reports should be signed by the study author(s), at least one executive from the contractor and one executive from the sponsor, as well as a representative from each QA organization. All late-stage studies should undergo QA review and approval.

Version Control Of Study Protocols And Reports

Revisions of study protocols and reports should be managed under the change control system of the contractor, the sponsor, or both. Revisions should undergo the same level of formal review and approval and be held to the same quality standards as the original document. A revised report that includes a new study should require a formally reviewed and approved revised study protocol.

Summary

Proper documentation of CMC studies is critical. This information constitutes the sponsor’s institutional CMC memory and represents a significant investment in time and money. It warrants documentation in properly executed, reviewed, and approved reports that will meet FDA expectations. By thoroughly documenting every aspect of the sponsor’s CMC development history, the sponsor will safeguard against the loss of institutional memory that can result from personnel turnover. Thorough documentation will assist the sponsor in its preparations for regulatory CMC information requests. Properly designed and executed study reports will support preparation of module 3 sections far more effectively than lab notebooks.

About The Author:

Steve Kornher has been with the Halloran Consulting Group for three years as a senior consultant, Regulatory CMC. Prior to joining Halloran, he was the executive director of quality systems at Vertex Cell and Gene Therapy. Kornher has over 35 years’ experience in biotechnology, primarily in quality control, quality assurance, and CMC regulatory affairs with an emphasis on cell and gene therapies.