A Design Space Verification Protocol for a Small Molecule Drug Substance

Appendix 1

Drug Substance Design Space Process Verification Protocol

The protocol has been modified for illustrative purposes. The name of the drug has been replaced by “XYZ” for proprietary reasons.

This protocol outlines a design space verification procedure for XYZ drug substance. It describes the actions followed to confirm that areas within the design space consistently meet and maintain the desired control strategy when implemented (including any post-approval changes) in a commercial manufacturing facility. The design space verification process is managed and documented in the Site Change Management System.

The design space verification protocol is described in three sections:

• 1. Initial design space verification of the XYZ commercial process

• 2. Change management

• 3. Design space verification specific for XYZ

Initial Design Space Verification of the XYZ Commercial Process

Drug substances manufactured at commercial scale are tightly controlled to a specific area of the design space defined as the NORs. The NORs are based on, for example, the results of design space experimentation, process knowledge, previous experience at pilot and commercial scales (if available), and results of laboratory scale runs. These NORs are chosen to minimize variability, consistently meet the criteria of all the quality attributes as defined by the control strategy, and meet business objectives (such as high yield and low waste).

Procedure: A MBR is prepared which contains detailed instructions that include controls for all the NORs for all critical and non-critical process parameters. The design space is not specifically identified in the MBR, but is maintained (and updated if necessary) in the PQS to support the life cycle knowledge and any potential enhancements to that particular process. The MBR is reviewed and approved using the Site Change Management System within the PQS. This includes verification that the MBR is compliant with the design space, process description, and control strategy as outlined in the regulatory filing.

For XYZ, verification of the design space was initiated at commercial scale with the process NORs during manufacture of clinical and registration stability batches. Verification was concluded by conducting process validation according to a pre-approved process validation protocol prior to release of any commercial material. The process validation protocol verifies that:

• The process operates within the design space, i.e., per the MBR instructions and within the Batch Record NORs.

• The quality attributes for all validation batches are met, maintaining the control strategy, and the data are consistent with the data predicted from the design space developed at laboratory scale.

• The batches are physically and chemically equivalent to previously manufactured batches, for example, clinical trial batches.

• The final drug substance batch is homogenous with respect to chemical and physical quality attributes.

• Deviations, if any, are assessed to ensure no impact on product quality, validation, design space, or control strategy.

After process validation has been completed, commercial scale batches may be manufactured according to the same MBR. The NORs will be monitored through process capability assessments and the Annual Product Review system.

During the manufacture of six XYZ proposed commercial scale batches, a number of parameters inherently have a normal level of variability (albeit small; provided in Table 1 below). Nevertheless, they provide an initial opportunity to confirm small-scale predictions in the manufacturing facility.

Table 1 Examples of commercial scale process parameter ranges for XYZ. This is a high level, illustrative example of three parameters

Change Management

Post-approval changes to process parameter ranges beyond NORs will be managed and documented according to the Site Change Control Procedure that includes re-verification at commercial scale of the proposed new area in the design space. Any proposed change to the manufacturing process within the design space will be evaluated for the impact on the control strategy and the quality of drug substance. This evaluation will be based on scientific understanding of the manufacturing process and will determine appropriate testing to analyze the impact of the proposed change (if necessary through risk assessment). Appropriate testing, or additional testing, may be warranted on the basis of assessment of risk to analyze the impact of the proposed change within the design space and verify that the control strategy is still appropriate to maintain drug substance quality.

Procedure: As increased process knowledge is acquired, or product demand changes, it may become necessary to adjust the NOR within the design space. In such case, the Site Change Control Procedure will be used to assess the relative risk of the change and evaluate the requirements for revalidation of the process.

The change control process will contain the following steps:

• Structured risk assessment will be used to evaluate whether the change impacts the control strategy, i.e., change to a critical process parameter (CPP) or CQA.

• Carry out an evaluation to determine if the new NOR conditions for the process require revalidation (an option for design space verification at scale). This evaluation will take into account the following:

  • Criticality of process parameters impacted

  • Risk of making multiple changes concurrently (if applicable)

  • Extent of movement within design space

  • Potential impact on a CQA

  • Impact of equipment changes on design space

• Carry out laboratory experiments, if deemed necessary, to re-verify that the new area in the design space produces product of appropriate quality.

• Evaluate the need to verify the equivalence of drug substance manufactured after the change through performance in drug product.

• Assess the potential impact of the change on the product stability and/or its degradation pathways.

The MBR is updated to include the change. The MBR is then reviewed and approved using the Site Change Control System. This includes verification that the MBR is compliant with the design space, process description, and control strategy outlined in the regulatory filing.

If deemed necessary by the evaluation described above, the design space is re-verified at scale by conducting process validation according to a pre-approved process validation protocol prior to release of any commercial material manufactured with the revised MBR. The process validation protocol will verify that:

• The process was operated within the design space, i.e., the Batch Record NORs and the data compared back to the data predicted from the design space developed at laboratory scale.

• The quality attributes for all validation batches were met, maintaining the control strategy.

• The batches are equivalent to previously manufactured batches.

• The final drug substance batch is homogenous with respect to chemical and physical quality attributes where the change is considered to have a potential impact on homogeneity.

• Deviations, if any, are assessed to ensure no impact on product quality, validation, design space, or control strategy.

Once process validation has been demonstrated, commercial scale batches will be manufactured according to the revised MBR. The NORs will be monitored through process capability and Annual Product Review systems to routinely verify that the current manufacturing area of the design space remains consistent with the control strategy.

Design Space Verification Specific for XYZ

Moving from one area to another area of higher or unknown risk within the design space would require the design space to be re-verified at commercial scale by conducting process validation, as described in the “Change Management” section (above). This will include verification that the new batches are equivalent to the previously validated process.

When developing the XYZ control strategy, discerning analytical methods were established to collect data for each CQA at multiple points throughout the process. This data provided the linkages between impurities (formation, fate, and/or reduction) in a cumulative manner across the process such that there were multiple options for defining the control strategy for each individual drug substance CQA (impurity). If a CPP for XYZ is moved within the design space to an area of higher or unknown risk, these methods, along with an appropriate sampling plan, will provide additional opportunities for enhanced testing. For example, methods throughout the process are specific for many CQAs regardless of whether that method was chosen as the control point for a particular CQA or not. Based on the structured risk assessment described in the “Change Management”” section, additional monitoring and/or analytical evaluation will be employed to verify the new area of the design space and demonstrate adherence to the control strategy. All verification and validation data are documented and managed within the PQS and available upon request during inspection.

Table 2 outlines a specific, analytical testing plan to execute for each CPP when moving to a new area of the design space with higher or unknown risk. The tests listed with bold font provide additional monitoring opportunities to those defined by the control strategy. Alternate methodologies may be employed during the life cycle of XYZ and would be subject to regulatory action via an update to the control strategy.

Table 2 Control of quality attributes in design space through CPPs. This is a high level, illustrative example of three parameters