Japan GMP Ordinance vs 21 CFR 211 and EU GMP: the gaps

Where Japan's ordinance already matches 21 CFR 211 and EU GMP

Almost everywhere. The 2021 revision was written to close the gap with PIC/S.

The ordinance is MHLW Ordinance No. 179 of 2004. MHLW Ordinance No. 90, issued on April 28, 2021, amended it, and the changes took effect on August 1, 2021. PMDA's own lecture material calls it the first revision in about 16 years and gives two aims: harmonization with the PIC/S GMP Guide, and bringing the concepts of ICH Q10 (pharmaceutical quality system) and ICH Q9 (quality risk management) into the ordinance. It applies to foreign sites too. MHLW states that the ordinance covers manufacturing sites outside Japan that make products for the Japanese market.

The new articles read like a PIC/S index. Article 3-3 covers the pharmaceutical quality system and Article 3-4 quality risk management. Article 11-2 covers stability monitoring, Article 11-3 product quality review, Article 11-4 supplier management for raw materials, and Article 11-5 outsourced contractors. Not all of these were new ideas in Japan. Hiroshima Prefecture's lecture material notes that the content of stability monitoring had already been set out in MHLW's enforcement notice for the ordinance. The revision moved it from guidance into binding text.

Your existing system has a counterpart for each. EU GMP covers the product quality review in Chapter 1, ongoing stability in Chapter 6 and outsourced activities in Chapter 7. In the US, 21 CFR 211.166 requires a written stability testing program and 211.180(e) an annual product review.

One new article deserves more attention than the rest. Article 3-2, compliance with approved matters, is where the real work starts.

If your site already meets PIC/S GMP, start the Japan gap check from the Japanese approval text and the MAH relationship, not from the quality system headings.

Article 3-2 makes the Japanese approval part of GMP

Japan wrote compliance with the approval into the GMP text. A gap between your batch record and the Japanese approval is a GMP finding.

PMDA's lecture on the revision says why the article exists: it was added in response to recent illegal manufacturing cases in Japan. The best known is Kobayashi Kako. In February 2021, Fukui Prefecture ordered the generic maker to suspend business for 116 days, a record at the time, after its itraconazole tablets were contaminated with the hypnotic rilmazafone. Reports found that the company had also made products under procedures that differed from the ones in its approvals.

For a foreign site, the risk is quieter than fraud. The Japanese approval is a Japanese-language document filed by the MAH. It may describe your process, parameters and specifications differently from your US or EU dossier, and it is the version a PMDA inspector holds. Under the 2021 enforcement notice, as Nara Prefecture summarizes it, the manufacturing supervisor must have the QA organization manage things so that specifications and manufacturing procedures do not differ from the approved matters.

Japanese approvals also sort every change into one of two filing routes. For applications made from August 1, 2021, MHLW treats a deletion or change of an item in the specifications and test methods as a minor change notification, unless it could affect quality, efficacy or safety, in which case it stays a partial change application. MHLW's examples on the process side follow the same logic. A change to a critical process parameter, such as sterilization conditions, is a partial change. A change to another parameter, such as manufacturing scale, is a minor change. MHLW's July 2021 notice also expects appropriate change control for every item in the specifications and test methods column, including those that need only a notification.

Get a translation of every Japanese approval that names your site, and add its partial change and minor change routes to your change control system as separate triggers.

The quality department needs a separate QA organization

The 2021 enforcement notice calls for two organizations inside the quality department: one for quality assurance and one for testing.

According to Nara Prefecture's summary of the 2021 enforcement notice, the quality department must have an organization responsible for QA work and an organization responsible for testing. We did not find a published rule on how large either organization must be, so read the notice itself before you redraw a small site's chart.

Compare that with your current structure. 21 CFR 211.22 describes a single quality control unit with the authority to approve or reject components, containers, closures, in-process materials, labeling and drug products, including those made under contract. It does not itself say how that unit is divided. Japan's notice names the QA function and the testing function as separate organizations, so be ready to show each one on your chart.

Japan also names a site-level role in the law itself. Domestic sites appoint a manufacturing supervisor (製造管理者), who in principle must be a pharmacist under PMD Act Article 17, paragraph 5. Act No. 37 of 2025 added item 3 to that paragraph, in force since May 1, 2026: where appointing a pharmacist is found to be markedly difficult, a non-pharmacist engineer can serve, and MHLW issued handling notices on February 27, 2026.

Article 17 is written for manufacturers licensed in Japan, but the ordinance reaches abroad. Its Article 3-3 uses "manufacturing supervisor" as one collective term that, for a foreign manufacturer, means the responsible person (責任者) of the accredited site or a person the manufacturer designates in advance. The duties the ordinance gives this role, such as reporting in writing on how the quality system is operating, therefore land on someone at your site. Decide who that is: the responsible person named in your accreditation, or a person you designate.

"Manufacturing supervisor" is also the English used in PMDA's tentative translation of the ordinance and in the Japanese Law Translation version of the PMD Act's enforcement regulation. MHLW's own slides call the head of a site "Responsible Person of Manufacturing Site".

Draw your organization chart the way the ordinance reads it: a QA organization, a testing organization, and a named owner for each duty the ordinance gives the manufacturing supervisor.

Stability monitoring comes with a duty to call the MAH

Article 11-2 makes ongoing stability monitoring a GMP duty and links it to the MAH. When a result is out of specification, or at risk of becoming so, the MAH must hear about it promptly.

The ordinance asks the site to choose the test items most affected by storage, based on an assessment of quality risk. On an out-of-specification (OOS) result or the risk of one, the site must take the necessary measures, including prompt contact with the MAH and providing the information needed for a recall decision. 21 CFR 211.166 and EU GMP Chapter 6 also require ongoing stability programs. What the Japanese text adds is a named first recipient for the call: the MAH.

PMDA's ORANGE Letters show how inspectors apply it. These are anonymized summaries of GMP inspection findings that PMDA has published since fiscal 2022. ORANGE Letter No. 9, dated July 7, 2023, described a drug substance with a 5-year retest period. At 48 months, a related substance in a reprocessed lot had reached the area of its upper limit. Because the result was still within specification, the site had done no investigation and no risk assessment. PMDA's message was that procedures must evaluate signs of abnormal quality, not only check results against limits.

The March 2025 letter went further. At the 6-month and 12-month stability points, potency fell below the lower limit of the approved specification in several retests, and the site judged that variability in the test values meant quality had not changed. PMDA called that series of judgments inappropriate when out-of-specification results or change over time cannot be ruled out with evidence, and warned that product below the desired quality could be distributed. The January 2026 letter described unfavorable trends across several products and test items on which the site took no action, such as assessing whether results could exceed specifications before expiry, and it cited a gap in analytical method validation that undermined stability monitoring.

Write into the quality agreement who at the MAH receives stability OOS and adverse-trend calls, and within what time, because the ordinance makes that call part of GMP.

Release and suppliers: Japan splits control with the MAH

In Japan, your site releases product from the site. The MAH decides whether it goes to market, under a separate ordinance.

That ordinance is the GQP Ordinance (MHLW Ordinance No. 136 of September 22, 2004), which sets quality assurance standards for the MAH and is a condition of its licence. Article 9 covers control of market release. MHLW describes the arrangement in two layers. The manufacturer controls manufacturing itself, and the MAH that entrusts the work also supervises that control. The EU places batch certification with a Qualified Person under Article 51 of Directive 2001/83/EC and EU GMP Annex 16. In the US, the quality control unit approves or rejects drug products under 211.22. In Japan, a further release decision sits with the MAH, under its own ordinance.

For a foreign site, the practical effect is a longer chain. Your QA release is necessary, but the MAH can still hold product. It will ask for the records it needs to decide.

Supplier control follows the same pattern of explicit duties. Under Article 11-4, the QA organization, working from written procedures, sets appropriate specifications for raw materials, evaluates and selects suppliers, and confirms that their manufacturing and quality control are adequate. Article 11-5 adds the management of outsourced contractors. Japan assigns supplier control to the QA organization by name.

Agree with the MAH which batch documents it needs for its market release decision and how fast, so that GQP release does not become the hidden bottleneck in your Japanese supply.

Steps for a Japan gap check

Run these in order. The first step usually finds the most.

1. Collect a translation of every Japanese approval that names your site. Mark which changes the approval routes through a partial change application and which through a minor change notification.
2. Reconcile each approval line by line with your master batch records, specifications and test methods. Treat every difference as a deviation from Article 3-2 until it is resolved through the MAH.
3. Redraw the quality organization chart: a QA organization, a testing organization, and a named owner for each duty the ordinance gives the manufacturing supervisor.
4. Review the stability program for Japanese products. Check that it selects storage-sensitive items by risk, evaluates trends over time, and escalates OOS results and adverse trends to the MAH promptly.
5. Check that supplier management meets Article 11-4 (specifications, supplier evaluation and selection, confirmation of their controls) and that outsourced work is managed under Article 11-5.
6. Update the quality agreement with each MAH: change notification, stability calls, documents for GQP market release, and sharing of PMDA inspection outcomes.
7. Read PMDA's ORANGE Letters as they appear, and work from the current Japanese text of the ordinance. English translations are tentative and can predate the latest amendment.

The PMDA inspection guide covers how PMDA checks all of this at your site. If your stability program needs equipment or software, compare options in the stability testing directory and the LIMS directory. Japanese terms are collected in the glossary.