Japan’s PMDA post-approval change pilot program will become official and codified into law in 2021, bringing Japan into the fold of developed nations including the U.S. and EU that have a streamlined system for post-approval changes in a pharmaceutical manufacturing context.

The pilot—which began in April 2018—had good industry participation and provided the agency with experience that will be used to make changes from the pilot conditions and help shape the final Act.

At the CASSS CMC Strategy Forum Japan held virtually in December 2020 with significant participation from Japanese regulators and industry representatives, perspectives on PMDA’s Post-Approval Change Management Protocol (PACMP) pilot program were shared.

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Keiko Funato from GlaxoSmithKline K. K. (Japan) reviewed how PMDA’s pilot compares to programs in use by other drug regulatory agencies and PDMA Office of New Drug IV Reviewer and ICH Q12 Implementation Working Group Topic Lead Satomi Yagi provided detail how the version that is proposed to be implemented formally in 2021 differs from the pilot.

[Editor’s Note: Part 1 of this article includes an overview of the pilot program and timelines provided by PMDA’s Futaba Honda and Satomi Yagi.]

Post-Approval Change Processes Compared

GSK’s Funato provided an illustration showing the similarities and differences between Japan, the United States, and Europe in terms of post-approval change systems and comparability protocols (Figure 1).

PACMP Systems in Japan, the United States, and Europe
FIGURE 1 | PACMP/CP Systems in Japan, the U.S., and Europe

In Japan, she explained, items to be approved are contained in Common Technical Document (CTD) section M 1.2. “The contents must be updated as changes take place. They need to meet the partial change or minor change application requirements. However, there is no need for development of the CTD after approval.”

On the other hand, in the West, as a lifecycle document, Module 3 of the CTD is required to be maintained after approval. There are major, moderate, and minor change categories. “As for the mechanism to apply for an approved change plan prior to the change, there is a PACMP in Europe and a Comparability Protocol in the US. In Japan, a PACMP is being piloted. In the West, there is an annual report requirement to report changes. This does not exist in Japan.”

Funato noted that Japan’s Ministry of Health Labor and Welfare (MHLW)—the Ministry through which PDMA reports—and PMDA’s joint conduct of the pilot program provided experiences that will allow consolidation of the criteria for the evaluation of the scope of a change submitted through the program. “They will also confirm the GMP control and the process validation plan. If it is approved, it will be considered either a Minor Change Notification (MCN) or a Partial Change Application (PCA).”

PACMP Pilot Informs Post-Approval Change Regulation

Also speaking at the CASSS forum, PMDA Office of New Drug IV Reviewer and ICH Q12 Implementation Working Group Topic Lead Satomi Yagi addressed how his agency will use information from the PACMP pilot program to codify the program in national legislation.

“To be able to officially introduce PACMP, we have to modify legislation, the Act on Securing Quality, Efficacy and Safety of Products Including Pharmaceuticals and Medical Devices,” he explained. Implementation is planned for some time in 2021.

PMDA and MHLW are working on detailed PACMP regulations for implementation of the updated Act. “Currently, we cannot introduce the detailed Act,” Yagi explained. “But I would like to share as much of our plan as possible” (Figure 2).

Outline of PACMP Based on the Updated Act
FIGURE 2 | Outline of PACMP Based on the Updated Act

A 2-Step PACMP Process

In Step 1, for changes to items related to quality of pharmaceuticals, the Marketing Authorization Holder (MAH) will submit the PACMP to MHLW. The protocol is reviewed and approved by both PMDA and MHLW.

In Step 2, the tests and studies outlined in the protocol are performed. If the results/data generated meet the acceptance criteria in the protocol and any other required conditions are met, the MAH submits a “Notification based on the approved PACMP” to MHLW. The change based on the PACMP may be implemented if no inquiries are received within 40 or 20 business days after submitting the Notification. The 20 to 40 business day timeframe is still under discussion.

PMDA and MHLW are working on detailed PACMP regulations

When the PACMP is submitted and reviewed, a proposed change that may significantly affect the product quality will not be endorsed. In addition, if it is found that a proposed change was out of scope of the system after PACMP review, a retraction may occur. Then a data collection according to the PACMP will be conducted. If a GMP inspection is needed, the application will be submitted and the GMP inspection will take place.

If there is any change, a notification must take place in 40 business days. If the change does not follow the PACMP, suspension of the change may be ordered. If there are any items that PMDA needs to discuss in terms of the submission, it is possible to use the PMDA consultation process.

Major Differences Between the PACMP Pilot and the Proposed Act

Yagi also discussed the major differences between the PACMP pilot program and the proposed PACMP regulations, emphasizing again that the final Act may look different than the draft he shared (Figure 3).

Major Differences: PACMP Pilot vs. PACMP Based on the Updated Act
FIGURE 3 | Major Differences: PACMP Pilot vs. PACMP Based on the Updated Act

During the pilot, checking the protocols was consultation-based. After the revision, it must be submitted to the MHLW.

Regarding scope, in the pilot the scope was prescription drugs, including new drugs and marketed products, biologicals, and chemicals. After the revision it will include OTC drugs and “quasi-drugs” such as cosmetics—products that require MHLW approval.

In the pilot, GMP inspections were performed by PMDA. After the revision, prefectural governments will also participate.

For original submissions, at the present time in the pilot that was not available but will be after the revision.

“For the Step 2 period, with the present program it takes about 3 months,” Yagi said. “But after the revision we anticipate it will take only 40 business days, or 20 business days in special cases. Currently what constitutes a special case is under discussion.”

For the Step 2 reporting categories, in the pilot there were only PCA prior approval and MCN notification categories. But after the revision there will only be prior notification before implementation of the change.

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