|Email Newsletters from Pharmaceutical Technology and Pharmaceutical Technology Europe|
News from Europe's pharmaceutical manufacturing industry coupled with upcoming events, and exclusive articles and interviews from industry experts.
The Postapproval Management Plan
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.
The following sections provide examples of how a PMP may be implemented.
Critical in-process controls (CIPCs) include tests and measurements performed during production to monitor and, if appropriate,
adjust the manufacturing process to ensure that a drug substance or drug product's critical quality attributes are met. Deletion
of a CIPC is typically reported in a prior approval supplement. Under a PMP, the following protocol would be used to add or
tighten a CIPC or to add additional testing or parameters to the manufacturing process. These changes would be reported in
a company's annual report. For example, the report may present:
A PMP can be used to address packaging. The following is an example of a proposed change to the packaging material for an API. The change could be submitted in an annual report rather than a CBE-30 if the criteria are met. The protocol could allow for reduced data requirements by proposing the use of moisture vapor transmission rates in place of stability data.
The materials of construction of the primary packaging component LDPE liner comply with the requirements of the applicable sections of current federal regulations for indirect food additives, 21 CFR Parts 177, 178, and 182.
The following sample protocol would be used for a change in packaging material, with the change and supporting data provided in an annual report.
For packaging material that is in direct contact with the drug substance:
Six months of accelerated stability data for a minimum of three batches of drug substance X per the following stability protocol: All registered acceptance criteria for the analytical properties studied must be met. A minimum of one batch of drug substance X will be placed on stability at 25 °C and 60% relative humidity (RH) either after or concurrent with the accelerated stability study.
For packaging materials that are not in direct contact with the drug substance:
Option 1: Six months of accelerated stability data for a minimum of three batches of drug substance X as per the following stability protocol: All registered acceptance criteria for the analytical properties studied must be met. A minimum of one batch of drug substance X will be placed on stability at 25 °C and 60% RH either after or concurrent with the accelerated stability study.
Option 2: Data demonstrating that the new packaging and previous packaging design have equivalent or better moisture vapor transmission rates.
An effective PMP is product specific and based on sound scientific knowledge. A PMP also incorporates risk-management principles and results with a more predictable and science-based approach to product life-cycle management. Appropriate identification of the critical parameters and change mechanisms is of paramount importance to achieve the "desired state." The desired state, according to FDA, is: "A maximally efficient, agile, flexible pharmaceutical manufacturing sector that reliably produces high quality drug products without extensive regulatory oversight" (4). Overall, the PMP can reduce hurdles to continuous improvement in pharmaceutical manufacturing, thereby opening the door to reduced costs, increased efficiency, and improved safety.
Paula S. Hudson, R.Ph., RAC*, is a manager of CMC Regulatory Affairs and Denyse D. Baker, P.E., RAC, is a principal regulatory scientist, both at Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, tel.
317.277.6730, fax 317.655.6813, email@example.com
*To whom all correspondence should be addressed.
Submitted: Apr. 30, 2008. Accepted: July 28, 2008.
1. ICH, ICH Q8 Pharmaceutical Development (Geneva, Nov. 10, 2005).
2. ICH, ICH Q9 Quality Risk Management (Geneva, Nov. 9, 2005).
3. ICH, ICH Q10 Pharmaceutical Quality System (Geneva, June 2008).
4. J. Woodcock, MD, "Pharmaceutical Quality in the 21st Century—An Integrated System Approach," presented at AAPS Workshop on Pharmaceutical Quality Assessment—A Science- and Risk-Based CMC Approach in the 21st Century (Bethesda, MD), Oct. 5, 2005.