Partial change vs minor change in Japan: which route applies

The Japanese approval text decides the route

Japan does not classify changes by a risk table you can read in isolation. It classifies them by what the approval says.

The legal basis is Article 14 of the PMD Act (the Act on Securing Quality, Efficacy and Safety of Products Including Pharmaceuticals and Medical Devices). A holder that wants to change approved matters (承認事項) needs the Minister's approval, except for minor changes defined by MHLW Ordinance, which are notified instead. Prefectural forms cite these provisions as Article 14, paragraph 15 (partial change) and paragraph 16 (minor change). The English translation PMDA hosts still numbers them paragraphs 9 and 10. Amendments moved the numbers, so you will see both.

The Enforcement Regulations (Article 47) define minor by exclusion. A change is not minor if it affects the nature, properties, performance or safety of the product, if it changes how pathogenic agents are inactivated or removed, if it changes dosage or indications, or if it could otherwise affect quality, efficacy or safety.

The practical boundary was drawn earlier, by the MAH. MHLW's guideline of February 10, 2005 (PFSB/ELD Notification 0210001) told applicants to write the manufacturing method column (製造方法欄) so that they themselves distinguish the items subject to partial change from those subject to minor change notification. For prescription drugs and new-active-ingredient OTC drugs, MHLW reorganized that guidance in a notice of September 30, 2024 (Notification 0930-7). We have not read its text, so treat the 2005 wording as the origin of the practice and ask the MAH which version its approval follows. In either case, the same parameter can be a partial-change item in one approval and a minor-change item in another, depending on how the filing was written.

Specifications and test methods (規格及び試験方法) shifted in 2021. From August 1, 2021, MHLW removed the deletion of specification items and changes of specifications from the regulation's list of non-minor changes. A change in that column can now be a minor change notification, provided it cannot affect quality, efficacy or safety. MHLW's notice of July 30, 2021 (PSEHB/PED Notification 0730-6) adds that every change to the column still needs proper change control, including evaluation of analytical performance.

Ask the MAH for an English translation of the manufacturing method and specification columns that name your site, with each item's route marked, before you plan any change.

A partial change waits for approval; a minor change does not

The two routes differ in timing more than in paperwork. One stops you before the change. The other follows it.

A minor change notification is filed after implementation. A PMDA-hosted industry presentation puts the deadline at within 30 days after implementation or shipping, and prefectural forms use the same 30 days. Nothing waits for Tokyo.

A partial change application is filed before implementation, and product for Japan must keep matching the approved text until approval arrives. Trade press reported in 2024 that PMDA described the ordinary procedure as taking half a year to a year from the application date, and PharmaJapan put the median for manufacturing changes at about six months. For your site, that means running the old and the new version side by side for Japan, or building stock before the switch.

Site changes are the case overseas manufacturers meet most. MHLW's table of typical examples lists the addition or change of a drug substance or drug product manufacturing site as a partial change, and the deletion of a site as a minor change. PMDA's guidance for foreign manufacturers lists partial change applications among the events that trigger a GMP compliance inspection of the sites concerned, as the PMDA inspection guide explains. A new foreign site also needs Accreditation of Foreign Manufacturers, which the accreditation guide covers.

The real cost of the wrong route is not the delay. Japan's GMP Ministerial Ordinance, as revised in 2021, makes compliance with approved matters an explicit duty of the site. A change that should have waited for approval, but was applied to Japanese lots, becomes a GMP finding as well as a filing problem.

Put the Japanese partial change on the project plan as its own critical path, with stock or a parallel process to cover six months to a year.

Since 2024, a middle route promises 40 business days

For years Japan had only the two routes. MHLW has since tested two more, both voluntary and both run as pilots under notices.

The first covers moderate-risk changes. MHLW's notice of September 27, 2024 (Notification 0927-4 of its Pharmaceutical Evaluation Division) introduced a procedure for moderate change items (中等度変更事項) in approved prescription drugs. It covers changes to the manufacturing method, to specifications and test methods, and to storage conditions and shelf life. PMDA and MHLW decide on approval within 40 business days of the application. If PMDA sends questions, the applicant has 30 business days to answer, or the case moves to an ordinary partial change.

Two limits matter to foreign sites. MHLW's material on the pilot says that, for now, it covers changes that, as before, need no GMP compliance inspection and no revision of official standards. A site addition normally brings an inspection, so it is unlikely to qualify, and the MAH should confirm with PMDA. PMDA's pilot guidance does describe a document-based conformity check at filing, limited in principle to how the application came about. On the other hand, the Q&A issued with the notice says items that are CBE-30 in the United States or Type IB in the EU, or lower, can be in scope. Trade press reported that PMDA expected to take roughly 15 applications a month during the pilot, first come, first served.

The second pilot sits below the minor change notification. MHLW's notice of February 13, 2025 (Notification 0213-5) lets some parameters already written as minor-change items be reported once a year in an annual report (年次報告), instead of one notification per change. The items are written in an annex to the application, and PMDA settles which ones qualify through review or consultation.

We could not confirm whether the 2025 amendment of the PMD Act turns these pilots into permanent routes, or from when. Ask the MAH which vehicle applies at the time you file.

If a change was CBE-30 or Type IB elsewhere and needs no new GMP inspection, ask the MAH whether it fits the moderate change pilot before accepting a full partial change.

Japan's PACMP: confirm the plan first, then notify

Japan also has a protocol route. You agree the plan before the change, then report the result.

The 2019 amendment of the PMD Act created the confirmation of a change plan (変更計画の確認), in force since August 1, 2021. The Minister confirms in advance a plan that sets out the change, how its effect will be evaluated and the acceptance criteria. When the change is then made as planned, the holder files a notification instead of waiting for a partial change approval. MHLW's handling notice for drugs is dated June 16, 2021 (PSEHB/PED Notification 0616-14). Regenerative medical products have their own notice, applied from the same date. PMDA had run a pilot of the concept from April 2018.

It is the Japanese form of the post-approval change management protocol in ICH Q12 (Step 4, November 2019). The fit is the same as elsewhere. It works for changes you can predict and describe in advance: another site, a scale-up, a second supplier. It does not work for a change you cannot specify yet, and a plan written after the fact is worth nothing.

The cost is front-loaded. Someone has to write the comparability protocol in a form PMDA can confirm, and the MAH files it. If the same change will reach several Japanese products, the effort is easier to justify.

If you already know that a site addition or scale-up is coming for Japanese products, propose a change plan to the MAH now, because confirmation has to come before the change.

What the overseas site owes the MAH

The MAH files every route. Your site supplies what the MAH needs to classify and justify the change, and it lives with the result.

Japan has spent a decade checking whether approvals match what sites actually do. After a manufacturer was found making products differently from its approvals, MHLW had the industry check approvals against actual manufacturing in 2016. An MHLW notice of April 1, 2022 then set procedures for products where self-inspection had found discrepancies. In April 2024 MHLW asked MAHs and manufacturers of generic drugs to check manufacturing and test methods against the approvals. The exercise covered every generic product on the national price list, and industry procedures compared the approval text line by line with product master files and batch records.

Foreign sites are part of that comparison whenever their product is. The Japanese approval is written in Japanese, by the MAH, often years ago. Your batch record is in English and has been through many change controls since. Every gap between the two is either a minor change notification that should have been filed, or a partial change that should have waited.

Most of the remedy sits in the quality agreement. The MAH can only classify a change it hears about in time, with enough detail to match it against the approval text. The GMP Ordinance comparison describes the related duty to inform the MAH under Japan's 2021 GMP revision.

Write into the quality agreement that every change touching a Japanese approval item reaches the MAH before implementation, with the data needed to classify it.

Steps for a change that touches a Japanese approval

Take these in order for each change. Steps 1 and 2 decide which route is even possible.

1. Get the current Japanese approval text for the manufacturing method and specification columns that name your site, in English translation from the MAH, with each item marked as partial-change or minor-change.
2. Map the planned change to those items. Note which items it touches, and whether it adds, changes or deletes a manufacturing site.
3. Send the MAH a change notice before implementation: description, justification, data, and the US and EU categories you filed. Ask the MAH to state the Japanese route in writing.
4. If the route is a partial change, agree the filing date, plan stock or a parallel process for Japanese lots for six months to a year, and prepare for any GMP compliance inspection the application brings.
5. If the change was CBE-30 or Type IB elsewhere and needs no new inspection, ask whether the moderate change pilot is open to it. If it touches a minor-change parameter that recurs, ask about the annual report pilot.
6. If the change is predictable and will recur across Japanese products, ask the MAH to propose a change plan for confirmation before you start.
7. After implementation, confirm the date the MAH filed the minor change notification or received the approval, and file that record with your change control.

The Japanese terms used on forms are listed in the side box, and the glossary has more. If the change affects a drug substance registered in Japan's Master File, read the MF guide, since MF changes reach the MAH through their own route.