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The authors propose that a postapproval management plan can serve as a tool to apply science- and risk-based approaches to the manufacturing process.
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.
(Noel Hendrickson/getty images)
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.
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:
To expand the range of a CIPC, changes would be reported in a similar manner but through a CBE-30 . Table III shows acceptance criteria that could be applied to confirm that the change has not adversely impacted the product.
Table III: Sample drug substance section of the postapproval management plan (acceptance criteria applied to confirm that a change has not adversely impacted the product).
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.
Drug substance X will be packaged in a low-density polyethylene (LDPE) primary liner that is heat-sealed. This primary liner will be placed inside a secondary laminated foil liner. The secondary liner will be heat-sealed. A silica gel desiccant package for moisture absorption will be placed between the primary and the secondary liner. The sealed liners may then be placed in an appropriate container such as a fiber drum, corrugated container, polyethylene drum, or metal drum for shipping and handling.
Table IV: API packaging material protocol.
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.