Change control. Demonstration of a robust change control system covering both the sponsor's activities and those of its suppliers provides assurance that future innovation will not undermine patient safety. In-house change control programs and vendor assurance programs are a vital part of the overall control of drug substance quality. The change control mechanism should assess potential changes for their influence on critical quality attributes of the drug substance.

The starting point for the assessment of potential process modifications is the current operating conditions and analytical methods. It is essential to confirm that the analytical techniques are capable of detecting and controlling different impurity profiles that may result from a proposed change (route or process) to the starting material.

Changes to a starting material should be subject to a detailed assessment for the presence of new impurities. Industry and regulatory agencies commonly use a 0.1% threshold for the presence of new impurities in the drug substance to determine equivalence of batches made before and after the change.

Conclusion

To ensure patient safety and obtain regulatory approval, a starting material for a drug substance synthesis must be justified against a set of predefined criteria as outlined by various regulatory authorities. Using a science- and risk-based approach, the authors propose that a global regulatory strategy to justify starting materials can be based on the control of three key themes, namely:

• Process control
• Analytical control
• Change control.

All proposed changes to starting materials and processes must be scientifically assessed using the knowledge gained from the risk-based approach. They should be managed through an appropriate internal change control mechanism that considers the effect of the change on the critical quality attributes. A key factor in this approach is that the sponsor chooses where to set the controls and constraints to ensure a high-quality drug substance while gaining meaningful regulatory flexibility.

By selecting appropriate starting materials for the synthesis of a drug substance, both the needs of patient safety and flexible economic manufacture can be satisfied.

Future challenges

Where a science- and risk-based development has defined a process design space, will global regulatory authorities accept that:

• A robust design space could be used to justify the registration of a shorter synthetic route?
• Movement within the design space is the responsibility of the manufacturer?
• A robust change control mechanism is a key element of such an approach. The interface between GMP inspection and regulatory commitments may become blurred. The roles and responsibilities for reviewers and inspectors may need to be clarified. Examples of questions that may need to be answered include: Where does change control fit into an NDA or MAA? What is the function of a Chemistry, Manufacturing, and Controls Postapproval Manufacturing Plan (CMC-PMP)?

Graham T. Illing, PhD, is a CMC director and group manager of global regulatory affairs at AstraZeneca (Macclesfield, England). Robert J. Timko, PhD,* is a CMC director of global regulatory affairs at AstraZeneca LP, 1800 Concord Pike, PO Box 15437, Wilmington, DE 19850-5437, tel. 302.886.2164, fax 302.886.1557, robert.timko@astrazeneca.com
. Linda Billett is a CMC director of global regulatory affairs at AstraZeneca (Macclesfield).

*To whom all correspondence should be addressed.

Submitted: Jan. 25, 2008. Accepted: Feb. 29, 2008.