GMP manufacturing of clinical batches
Risk assessments should be performed before initiating GMP manufacturing to ensure that product quality will be met. The CMO
is responsible if it chooses to go ahead with GMP production when the risk of batch failure is high. Reasons for anticipated
failure can include a lack of process robustness, insufficient process knowledge, and analytics' undemonstrated fitness for
purpose. At this point, additional development activities must be discussed to avoid overpromising. Finally, both parties
should agree on the product specifications in accordance with regulatory requirements as well as the procedures and the method
of production before starting GMP manufacturing. Target production yields and the customer's needs to supply the clinic should
be in good agreement with development data or process history upon normal operating conditions.
Following the risk assessment, the process is transferred to the GMP manufacturing facility. The technical transfer should
never be jeopardized. The CMO is responsible for allocating all resources necessary so that the technology transfer is successfully
achieved. The technology transfer should be documented, and the sponsor should be informed of the transfer's completion and
any issues encountered. Likewise, the quality system in place must ensure the following points during the production of the
- The GMP personnel are adequately trained
- Equipment is qualified
- Operations are traced, recorded, and checked
- No cross-contamination occurs in a multiproduct facility.
Conflict resolution in GMP manufacturing of clinical-phase biologics
Outsourcing biologics manufacturing is costly, and dealing with conflicts that involve financial arbitration is always challenging.
This statement is particularly true when GMP batch quality specifications are not met or production yields are not achieved
(see Figure 2). Identifying financial responsibilities in these situations is often stressful and contentious. Senior management
and appropriate decision-makers for both parties should immediately be informed of the issues and should take time reaching
their conclusions following a thorough investigation. The investigation should be structured and systematically documented
and should address the following technical and quality questions:
Figure 2. Conflict resolution protocol
- Are the people trained in all affected operations?
- Is the equipment qualified?
- Are there any major or critical deviations in the method of production?
- Is the process robust or validated?
- Are critical steps identified or operating ranges well defined?
- Is the issue related to cleaning or cleaning validation?
- Are release specifications accurate with respect to product knowledge?
- Was an out-of-specification investigation opened by the quality-control laboratory?
- Is the out-of-specification root- cause assignable to a laboratory error?
- Are in-process controls as expected with respect to historical data?
This investigation should allow the development of a rationale for discussing the financial responsibility of both parties.
In every case, successful conflict resolution depends on the quality of the investigation at the CMO and the sponsor's understanding
of the issue and root cause. Videoconference or face-to-face meetings are helpful in clarifying perceptions and promoting
dialogue between the sponsor and the CMO. Generally, good conflict resolution, supported by facts and documented evidence,
should benefit both parties and strengthen the partnership.