By Erica Marchus
Senior Manager Quality & Compliance | BrevisRefero
My last article {see link here} discussed the importance of an effectual partnership between the drug developer (Sponsor) and their Contract Development and Manufacturing Organization (CDMO) to ensure a successful and timely manufacture and release of investigational drugs destined for clinical trials. More than six years of my professional career was dedicated to GMP batch record review and product release at a large biopharma CDMO in the United States. During that time, I reviewed and released hundreds of GMP batches destined for use in clinical trials and commercial applications, and undeniably the main objective was ensuring the safety and quality of the product prior to release to the Sponsor. In this article I’ll explain the importance of the Sponsor’s review of their clinical product batch records and present the various aspects that should be considered as part of the review process to ensure the safety and quality of a batch for use in human clinical studies.
Why is Sponsor review and disposition important?
The fundamental goal of investigational drug batch review and disposition by the Sponsor is to ensure the safety, quality, and efficacy of the drug product destined for clinical use. Depending on the CDMO’s internal processes and procedures, the Sponsor may be required to approve the disposition of the batch in conjunction with the disposition by the CDMO, or alternatively, the CDMO may disposition the batch independent and prior to Sponsor review. In either circumstance, the Sponsor retains the important responsibility of ensuring their batch of drug substance and drug product was manufactured in compliance with current Good Manufacturing Practices (cGMP) and that the clinical product can be considered safe and suitable for administration to humans.
"Sponsor retains the important responsibility of ensuring their batch of drug substance and drug product was manufactured in compliance with current Good Manufacturing Practices (cGMP)."
What records make up the batch documentation?
The typical biologics drug manufacture consists of upstream, downstream, and final fill/finish activities, which can also encompass labeling and product distribution. Ancillary to the manufacturing activities are environmental and water monitoring activities and quality control (QC) analyses at various stages (in-process and final analysis) of manufacture. All these manufacturing activities have associated records that make up the batch documentation.
"...it is recommended that the Sponsor create and follow a review checklist, outlining the expected documentation to ensure thorough and consistent reviews are completed on every batch."
Typically, there are statements and certificates that are also provided in conjunction with batch release. These can include the Certificate of Analysis (CoA), Transmissible Spongiform Encephalopathy (TSE) Statement, Melamine Statement, Certificate of Compliance (CoC), among other types of documents. Because of the variety of documents that make up the complete batch documentation, it is recommended that the Sponsor create and follow a review checklist, outlining the expected documentation to ensure thorough and consistent reviews are completed on every batch.
What does a comprehensive review consist of?
First, it is important that the review is performed by qualified professional(s) with the expertise and training necessary to determine whether the batch is safe and suitable for use in a clinical trial. Ideally the reviewer has a grounded understanding of the manufacturing process and is well-versed in cGMP compliance. This ensures the reviewer can identify discrepancies, non-compliance issues, and inconsistencies within the documentation which could impact the quality, efficacy, and safety of the investigational drug product.
When reviewing the batch documentation provided by the CDMO in support of batch disposition, the Sponsor should focus on several key elements (listed below) to ensure compliance with cGMP, regulatory requirements, and product specification.
Completeness: Ensuring all essential documentation from every aspect of the manufacturing cycle is accounted for, including raw material receipt through batch release, and that all required data entries are made and documented contemporaneously with execution of the activities.
Accuracy: Verifying that the information reported within the records is precise, consistent, and free from errors including double-checking all calculations.
Uniformity: Confirming the consistency of processing parameters, equipment settings and analytical test methods used across different batches.
Data Integrity: Ensuring that the data is reliable, traceable, assessable upon request, and securely stored.
GMP compliance: Verifying conformance to relevant regulations and guidelines governing the various aspects of manufacturing operations such as, but not limited to, cleaning and sanitation, personnel training, production and process controls, equipment maintenance, calibration and validation, and adherence to written procedures.
Adherence to Specifications: Confirming that the material met the pre-defined acceptance criteria outlined in the manufacturing batch records and the final product specification.
Deviation Management: Performing a thorough review of documented deviations, out-of-specification (OOS) results, or non-conformances occurring during the manufacturing process to ensure the justifications and corrective actions taken are sound and the product safety and quality are not impacted as a result.
Change Management: Analyzing modifications implemented during the manufacturing process and ensuring proper authorization, rationale, assessment of impact, and subsequent validation activities were carried out if required.
How should issues noted during review be addressed?
It is important for the Sponsor to document and keep a record of their review of the batch documentation for future reference. As mentioned above, utilizing a review checklist outlining all the essential batch documentation associated with batch manufacture is a valuable tool to ensure all records are accounted for during the review process. In addition to following a checklist, the Sponsor should keep a record of their review in a format that captures at minimum the batch number, the reviewer, the records reviewed, comments noting any non-compliance issues, discrepancies, or inconsistencies identified during the review process, and the CDMO’s responses or actions taken to remediate the issue.
"Sponsor evaluation of the CDMO’s responses and remediations are necessary to ensure they are appropriate and in accordance with cGMP..."
During the review process the Sponsor will likely need to engage with individuals from the CDMO’s manufacturing, QC, and QA teams to obtain responses to review comments and any necessary remediations to the batch documentation. Sponsor evaluation of the CDMO’s responses and remediations are necessary to ensure they are appropriate and in accordance with cGMP ensuring the investigational drug product is safe and of the highest quality for use in clinical trials.
In conclusion, it is crucial that Sponsors complete a timely and comprehensive review of all batch documentation associated with their drug products destined for clinical trials. This review focuses on several key elements ensuring compliance with Good Manufacturing Practices (GMP), regulatory requirements, and client specifications, in turn minimizing potential risks associated with substandard batches.
BrevisRefero Corporation is a collection of biologics drug development CMC experts utilizing its collective 100+ years of experience in advancing our clients outsourcing objectives through its RFP>Navigator® portal to accelerate drug candidates efficiently into clinical trials.
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By Erica Marchus
Senior Manager Quality & Compliance | BrevisRefero