The foundations of a quality system have been adopted by all parties to the International Conference on Harmonization (ICH) through ICH Q8 Pharmaceutical Development, Q9 Quality Risk Management, and Q10 Pharmaceutical Quality System (1–3). Several related initiatives have begun to encourage increased use of scientific- and risk-based approaches in postapproval change management. The development of a robust design space, for example, in accordance with ICH Q8, can reduce the number of critical parameters an applicant needs to submit in its marketing authorization application. The US Food and Drug Administration continues to encourage the use of comparability protocols as a mechanism to gain alignment up front on the reporting category and supporting data required for a change. FDA also has announced that it plans to update the postapproval changes guidance to allow for reduced reporting on low-risk changes. And the European Union is in the process of revising its Variations Regulations to incorporate risk-based approaches. Using process analytical technology (PAT) concepts overall can obviate the need for some release testing, thereby also providing flexibility in approach.
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Another tool that is being actively discussed in the US is the Regulatory Agreement, which has come to be known as the CMC Postapproval Management Plan or PMP. A CMC (chemistry, manufacturing, and control)-based PMP would clearly delineate postapproval commitments in a QbD environment. A PMP differentiates changes (e.g., critical process parameters) that should be reviewed by regulatory authorities from those changes (e.g., operational parameters) that are managed by the manufacturer's internal quality systems. A PMP also defines reporting categories and supporting data required for future changes based on risk assessment and scientific knowledge presented in a regulatory submission.
Once approved, a PMP could serve as a source of mutual understanding between applicant, reviewer, and inspector of postapproval commitments and requirements for reporting future changes. Because a PMP can help to reduce hurdles to continuous improvement in pharmaceutical manufacturing, it may thereby open the door to reduced costs, increased efficiency, and improved safety. This article describes the structure, format, and content of a PMP and its application within the FDA and ICH framework.
By demonstrating to the regulatory authority that the applicant understands its process thoroughly by using QbD principles, a scientific rationale that includes change protocols and associated acceptance criteria for future manufacturing changes can be proposed to the regulatory agency. Using risk management principles, the applicant can propose reduced reporting for certain parameter changes on the basis of the parameter changes' impact on critical quality attributes and the applicant's knowledge of those attributes' interaction with other parameters. The regulatory authority will assess the PMP with the application against its own principles of risk management. The agency's approval of the overall package will confirm its agreement that the appropriate balance of science and risk has been applied to the management of postapproval change for the specific application. FDA has spoken of plans for a pilot program for CMC-based PMPs for use with new applications or existing marketed product applications.
There are several formatting options for the PMP. One suggestion is to base the PMP on the Common Technical Document. This option would be familiar for applicants and regulators (see Table I). The PMP could be applied to both drug product and drug substance (e.g., active pharmaceutical ingredient, or API). The PMP can also help clarify the terminology to be used by the applicant and the regulator. Clearly defined regulatory expectations in the PMP will simplify planning for approval timelines and significantly reduce the cost of change implementation in manufacturing or the need to "manage flavors" (i.e., control release of the drug product to the intended market based on when their health authority approves the supplement or amendment). throughout the supply chain. A PMP also would allow quality and technical support personnel to focus on scientific rationale and evaluation of proposed process changes.
Table I: Sample postapproval management plan table of contents for drug substance X (based on a Common Technical Documents chemistry, manufacturing, and control regulatory commitments).
A PMP could be applied, for example, to process parameters for a drug product. In the United States, widening a proven acceptable range for a critical process parameter requires a manufacturer to submit a prior-approval supplement to FDA. The applicant could propose in the PMP the testing and acceptance criteria, based on product knowledge, by which they would demonstrate that the widened range did not negatively affect the product downstream. The applicant could request that this future change, when needed, be submitted as a CBE-30 (see Table II). For example, as shown in Table II, the proven acceptable range for Water Activity is not more than 0.27. If the manufacturer wanted to increase the upper limit to 0.5, they would look to the PMP where it would describe what data would be required and what criteria must be met to expand that range (e.g. no new peaks in drug product related substances and meets final specifications).
Table II: Sample drug product process control section of the postapproval management plan (Common Technical Document Section 3.2.P.3.4—Controls of critical steps and intermediates).
The following sections provide examples of how a PMP may be implemented.