Major post-approval changes to pharma manufacturing processes have traditionally taken years to receive regulatory agency approval, independent of whether they improve compliance, implement modern technologies, or drive continual process improvement. The complexity of the approval process is compounded and timelines greatly lengthened for changes involving multiple national agencies.

The ability to make such changes more quickly and efficiently with less governmental oversight has been advocated by industry for many years and agencies have responded with varying degrees of regulatory relief, including from the U.S. FDA, EMA, and ICH. Most recently, Japan’s PMDA established a post-approval change pilot program.

[Related: Looking for information on recent enforcement trends in the Asia-Pacific region? Download our latest report.]

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At the CASSS CMC Strategy Forum Japan, held virtually in December 2020 with significant participation from Japanese regulators and industry representatives, PMDA Office of Cellular and Tissue-based Products Director Futaba Honda provided an update on her agency’s Post-Approval Change Management Protocol (PACMP) pilot program that began in April 2018.

[Editor’s Note: Part 2 of this article reviews the differences between the pilot program and what PMDA intends to implement in 2021 and the differences between the Japanese, U.S., and European post-approval change systems.]

PACMP Pilot Overview

Honda provided an overview of the pilot program and the steps that a company requesting a post-approval change must follow in concert with PMDA.

As part of her high-level overview, she provided a schematic showing the post-approval process before, during, and after the PACMP (Figure 1).

Revision of Procedures for Changing Approved Items Related to Quality of Pharmaceuticals
FIGURE 1 | Revision of Procedures for Changing Approved Items Related to Quality of Pharmaceuticals

She noted that the process depends on a marketing authorization holder (MAH) and PMDA agreeing on the contents of a proposed change to a manufacturing method and on the change category.

The post-approval change management protocol pilot system works as follows.

First, a marketing authorization holder creates a Post Approval Change Management Protocol (PACMP) reflecting the proposed changes to the manufacturing method, including the proposed change category—which is based on how extensive the proposed change is—and the evaluation method, and explains it to the regulatory authority.

Once both parties agree, the MAH conducts the proposed trials and assesses the outcome based on agreed-to evaluation methods. When the results of the trials and assessments meet the criteria described in the PACMP, the changes reflecting those proposed in the PACMP may be made in an expedited manner.

When is a PAC a Minor Change?

In Japan, a “partial change approval” is an application for approval of a major variation, which is equivalent to a major change/prior approval supplement in the United States or a Type II variation in the European Union.  A “minor change” in Japan requires a notification within 30 days after implementation, corresponding to a moderate change/CBE-30, a CBE, or minor annual reportable change in the US, or Type IB or Type IAIN variation in the European Union.

For partial change approval applications or minor change notification by PACMP, records made by PMDA in the PACMP consultation and a statement or written pledge notification that there will be no deviation from the PACMP must be attached to the application.

In the pilot phase, there are three change categories—partial change approval, minor change notification, and something in between the two, which is partial change approval by expedited review and GMP inspection, if needed.

PACMP Pilot Timelines and More Detail

Also speaking at the CASSS forum, PDMA Office of New Drug IV Reviewer and ICH Q12 Implementation Working Group Topic Lead Satomi Yagi discussed the PACMP pilot results based on the agency’s experience and the approval timelines that have been achieved. He noted that prior to implementation PMDA is discussing the results within a task force that includes members of industry and Japan’s Ministry of Health, Labor, and Welfare (MHLW).

PMDA intends to move from the pilot phase to implementation of the PACMP in 2021. It is currently updating its software to work with the new PACMP applications and is “trying to promote understanding of PACMP in Japan and create a mock-up to help with that,” Yagi explained.

The ability to make such changes more quickly and efficiently with less governmental oversight has been advocated by industry for many years

The legal basis for the PACMP pilot is a document titled, “Handling of Changes to Approved Product Information Pertaining to the Quality of Drugs” (PSEHB/PED Notification No. 0309-1 and PSEHB/CND Notification No. 0309-1 dated March 9, 2018, jointly issued by the Director of the Pharmaceutical Evaluation Division and the Director of the Compliance and Narcotics Division, Pharmaceutical Safety and Environmental Health Bureau, MHLW).

PACMP, Yagi said, is intended as “a regulatory tool that provides predictability and transparency in terms of the requirements and studies needed to implement a CMC change as the approved protocol provides an agreement between the MAH and the regulatory authority.”

A Snapshot of the Japan PACMP Process

He provided a schematic of the PACMP process that included more detail on the pilot program and what he termed “median value” timelines (Figure 2).

Overview of PACMP Pilot Program in Japan
FIGURE 2 | Overview of PACMP Pilot Program in Japan

He walked through the process as follows: “At the pre-meeting, a draft of the PACMP document and schedule must be shared by the MAH with PMDA. For the protocols, there is a CMC consultation between the MAH and PMDA. If a GMP consultation is necessary, the process validation plan will need to be confirmed. If the protocol needs to be changed after the consultation, then there will be a follow-up meeting. If the protocol must be changed completely, the process starts back with a new PACMP consultation.”

Depending on the changes made at Step 1, Step 2 will require either a PCA or MCN application. If it is a PCA, it usually takes about three months.

The pilot program started in April 2018. Between then and November 2020, there have been 11 PACMP quality consultations and two GMP consultations that have been implemented. About 80% of those were for biotechnological/biological products and the remaining 20% were for small molecules. The most frequent change was the addition of a new manufacturing site or extension of the shelf life of the product.

[Related: Looking for information on recent enforcement trends in the Asia-Pacific region? Download our latest report.]

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