By Erica Marchus
Senior Manager Quality & Compliance | BrevisRefero
Success in the biopharmaceutical industry as a drug developer is largely dependent on an effectual partnership between the Sponsor and the Contract Development and Manufacturing Organization (CDMO) contracted to manufacture the Drug Substance or Drug Product. As a Sponsor, it is a requirement that GMP lots manufactured at a CDMO meet all product specifications and are successfully released, assuring the purity, quality, safety, and efficacy of the product. To ensure that GMP lots are successfully released, it is crucial for the Sponsor and their CDMO to establish and maintain a collaborative partnership from initial CDMO contact through to GMP manufacture and lot release.
Initial interactions during the business development phase of the relationship between a Sponsor and their CDMO will establish clear communication channels, define roles and responsibilities, and ensure that both parties share a common understanding of the regulatory requirements and project goals. This article will discuss some of the important aspects of effectively engaging with your CDMO at the pre-manufacture, manufacture, and post-manufacture periods of the partnership.
In the pre-manufacturing period, defined as the timeframe after contract signing with the CDMO but prior to GMP manufacturing of product, the completion of an on-site quality audit of the CDMO is an important first step in aligning quality expectations between the two organizations. In fact, in many cases a quality audit is conducted prior to contract signing to ensure absolute certainty about the CDMO’s quality level and status. This crucial interaction allows a Sponsor to identify areas of potential risk and gaps in the CDMO’s processes and quality systems. By conducting an audit well in advance of manufacture start, the CDMO will have sufficient time to effectively remediate any identified audit observations that could negatively impact the quality or safety of the GMP product which could subsequently prevent its release for use in clinical trials. It is important to bear in mind that the scheduling of GMP audits with CDMOs should take place as early as possible since often, CDMO scheduling availabilities for client audits are booked several months out.
"By conducting an audit well in advance of manufacture start, the CDMO will have sufficient time to effectively remediate the identified audit observations that could negatively impact the quality or safety of the GMP product which could subsequently prevent its release for use in clinical trials."
Another important pre-manufacture activity is establishment of a Quality Agreement between the CDMO and Sponsor to align and define quality and regulatory expectations, party responsibilities, and quality-related communication channels. The Sponsor and CDMO should review and negotiate the terms of the agreement to ensure they align with industry standards and cover all aspects of quality oversight, monitoring, notification, testing, and required documentation.
Lastly, Sponsor participation in review and approval of batch records and product specification in preparation for the start of manufacture is crucial in ensuring the product is manufactured according to expectations and requirements for successful release.
During the manufacturing period the Sponsor should consider sending a Person-In-Plant (PIP) to the manufacturing facility to observe the process, report on activities and outcomes, and be present should immediate Sponsor decisions need to be taken to prevent process or product failure. Typically, the PIP is either a Sponsor employee, or more frequently, an external third-party manufacturing or quality consultant that participates during the CDMO manufacturing activities to support, observe, and give feedback to all stakeholders. Any CDMO worth contracting with will expect a PIP request as the program nears GMP manufacturing.
" It is essential for the Sponsor to have a clear understanding of the CDMO’s deviation and excursion procedures and to ensure that they are aligned with regulatory requirements, and that the investigation and resolution pathway are understood. "
The management of deviations or excursions is another important consideration that may occur during manufacturing. In the event of a deviation or excursion, the Sponsor and CDMO must work together to assess the impact on the product's quality and implement corrective actions to prevent future occurrences. It is essential for the Sponsor to have a clear understanding of the CDMO’s deviation and excursion procedures and to ensure that they are aligned with regulatory requirements, and that the investigation and resolution pathway are understood.
Expected turnaround time from the end of manufacture to product release is an important topic for the Sponsor to discuss with their CDMO as this can often take upwards of several months. Once the product has been manufactured and placed in quarantine storage, another important opportunity for the Sponsor to ensure a successful lot release is in the review and approval of the Certificate of Analysis (CoA), executed batch records, and other relevant manufacturing documents. These documents, comprising the batch release packet, provide a comprehensive overview of the product's manufacture, testing, and quality attributes and confirms that it meets all specified requirements. The Sponsor should carefully review the CoA and supporting manufacturing and quality control testing documentation to ensure accuracy and completeness before giving the CDMO the approval to disposition the lot as released. In certain cases, the Sponsor’s review can result in observations that require the CDMO’s clarification, and taken together with the CDMO’s review process provides a comprehensive lot release package.
Finally, the Sponsor should actively participate with the CDMO during the packaging and labeling process to ensure that the products presentation is acceptable according to regulatory requirements, project specifications, and Sponsor’s needs. This includes verifying the accuracy of labeling text, determining whether multiple language translations are required, ensuring that the product is correctly packaged and labeled, and performing any required quality control checks and post-activity reconciliation of product and labels.
" By establishing clear communication channels, defining roles and responsibilities, and working collaboratively through the entire manufacturing process, a Sponsor can increase the likelihood of their product meeting specifications and regulatory requirements. "
In conclusion, as the Sponsor is ultimately responsible for the purity, quality, safety, and efficacy of product released for use in clinical trials, an effective engagement with the CDMO is vital to ensure successful release of a GMP clinical lot. By establishing clear communication channels, defining roles and responsibilities, and working collaboratively through the entire manufacturing process, a Sponsor can increase the likelihood of their product meeting specifications and regulatory requirements. From pre-manufacture quality audits to post-manufacture batch documentation review, there are numerous engagement opportunities along the manufacturing value chain for a Sponsor to effectively support their CDMO in achieving a successful lot release.
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If you would like a free, no-obligation consultation to talk about your biologic drug development outsourcing, planning, budgeting, or execution then please reach out to us at:
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By Erica Marchus
Senior Manager Quality & Compliance | BrevisRefero