{"id":6421,"date":"2026-08-14T16:12:30","date_gmt":"2026-08-14T07:12:30","guid":{"rendered":"https:\/\/cm-plus.co.jp\/en\/?post_type=column&p=6421"},"modified":"2026-08-16T21:43:50","modified_gmt":"2026-08-16T12:43:50","slug":"2026_0814","status":"publish","type":"column","link":"https:\/\/cm-plus.co.jp\/en\/column\/gmp\/2026_0814\/","title":{"rendered":"PMDA ORANGE LETTER_2026.07"},"content":{"rendered":"

ORANGE LETTER<\/strong><\/span><\/p>\n

To encourage voluntary quality improvements at pharmaceutical manufacturing sites, Japanese regulatory agency PMDA has been publishing anonymized, highly useful findings from its inspections based on Japanese GMP Ministerial Order. These are published in a format known as the “ORANGE Letter” since 2022.<\/p>\n

CM Plus provides abridged English translations of the Orange Letters, for our clients’ reference.<\/p>\n

\n


\nObserved Regulatory Attention\/Notification of GMP Elements LETTER<\/span><\/p>\n

Author: <\/strong>PMDA
\nIssue: July 2026<\/strong>
\nTitle: <\/strong>Airflow Visualization Testing (Smoke Testing) in Aseptic Areas
\nRelated GMP Ministerial Ordinance Clause:<\/strong> Article 24-3<\/p>\n

Cases<\/strong><\/p>\n

Defects in product contamination prevention control were observed. In a smoke test conducted in an aseptic area, the site failed to detect the product contamination risk suggested by the test results, and there were omissions in some of the evaluations.<\/p>\n

Background<\/strong><\/p>\n

\n

\u2666Regarding the production control of sterile pharmaceuticals, the GMP Ministerial Order stipulates that necessary measures be taken to prevent contamination of starting materials, packaging\/labeling materials, and products from contamination, etc. by microorganisms, etc..<\/p>\n

\u2666PIC\/S GMP Guidelines Annex 1 specifies that airflow pattern under all actual operational conditions should be evaluated to confirm that contamination risks from personnel, equipment, etc., are adequately controlled.<\/p>\n<\/div>\n

Observations<\/strong><\/p>\n

\n

\u2666Upon reviewing the video of a smoke test conducted in the aseptic area of a freeze-dried product line, it was observed that air coming into contact with the operator who is transferring the product to the freeze dryer was flowing into the openings of partially stoppered vials. However, the potential risk of this airflow on product sterility had not been evaluated. Furthermore, smoke tests for certain processes had not been conducted.<\/p>\n

\u2666When reviewing the results of environmental monitoring for the aseptic area of the production line, microorganisms suspected to be derived from operators were found. This suggested the possibility that contamination prevention measures in the aseptic area were not functioning sufficiently, indicating a defect in the Contamination Control Strategy (CCS).<\/p>\n

\u2666Interviews at the manufacturing site revealed that because the production line was not used frequently, the site had lowered the priority of introducing a robust barrier system and compliance to the latest regulatory requirements and guidelines.<\/p>\n<\/div>\n

Subsequent Actions<\/strong><\/p>\n

\n

\u2666Based on the results of a newly conducted risk assessment, the contamination risk associated with interventions in the aseptic area was reduced by taking measures such as introducing dedicated jigs for product transfer, installing shielding plates etc.<\/p>\n

\u2666In addition, additional smoke tests, including those for the previously omitted processes, were conducted to confirm the effectiveness of the correction measures. Furthermore, three Aseptic Process Simulations (APS) were planned before the next manufacturing run.<\/p>\n<\/div>\n

Check Points<\/strong><\/p>\n

\n

\u2666Whether the smoke test goes beyond merely “visualizing airflow” and evaluate conditions under actual operational conditions, including personnel interventions and the placement of items?<\/p>\n

\u2666Whether is it confirmed that unidirectional airflow (first air) is maintained and the product is appropriately protected in the aseptic area?<\/p>\n

\u2666When abnormal signals such as existence of microorganism are confirmed, whether comprehensive root cause investigation is conducted, and effective recurrence prevention measures have been taken?<\/p>\n<\/div>\n

Catchword
\nThe purpose is not to shoot an airflow video! Is a clean environment truly maintained? <\/span><\/em><\/strong><\/p>\n

\n

\u2713 In smoke tests in aseptic areas, it is crucial to confirm that unidirectional airflow (first air) is maintained, and the product is protected from contamination risks under actual working conditions, including personnel interventions and the placement of goods. When evaluating test results, it is desirable to conduct an objective and multifaceted evaluation with the involvement of multiple departments, rather than relying solely on the judgment of a specific department or person in charge.<\/p>\n

\u2713 In sterile pharmaceutical production, humans are the greatest source of contamination. Verification results should not be used to justify human intervention; efforts must continuously be made to reduce human intervention in production line with technological progress. If intervention operations are required, more robust contamination prevention measures are necessary.<\/p>\n

\u2713 Product sterility is assured through comprehensive activities, not only sterility testing but also raw material control, operator qualification, maintenance of facilities and equipment, environmental monitoring, validation, APS, etc. Even if there are no immediate issues with the smoke test results, please comprehensively evaluate the results of environmental monitoring, APS, etc., continuously verify the effectiveness of CCS, and continue improvements toward achieving a higher level of sterility assurance.<\/p>\n<\/div>\n

Source: PMDA, \u201cORANGE Letter\u201d (Issue: July 2026)
\nhttps:\/\/www.pmda.go.jp\/files\/000281742.pdf<\/a><\/span><\/p>\n

\n

About GMP Platform<\/strong> (<\/span>https:\/\/www.gmp-platform.com\/<\/a><\/span>)<\/span><\/p>\n

\n
\"\"<\/div>\n
GMP Platform is a free GMP-related information portal established in 2012 and operated by CM Plus Corporation. Built on CM Plus\u2019s founding principle of addressing quality-related issues in life science facilities, the site provides practical, expert-led information for life science manufacturing professionals. With more than 26,000 registered users, GMP Platform introduces the latest GMP-related regulations and trends in Japan, the United States, Europe, and other regions, along with translated and explanatory articles on guidelines, technical articles, seminars, e-learning programs, and books. It is widely used by professionals involved in GMP compliance, quality assurance, and the development of effective quality systems. Please use Google Translate or similar translation tools to read more articles originally published in Japanese.
\n*If you are using Google Chrome, right-click and select “Google Translate” on the article.<\/div>\n<\/div>\n","protected":false},"featured_media":6370,"template":"","columncat":[61],"columntag":[],"keywords":[11],"acf":[],"yoast_head":"\nPMDA ORANGE LETTER_2026.07\uff5cCM Plus<\/title>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/cm-plus.co.jp\/en\/column\/gmp\/2026_0814\/\" \/>\n<meta property=\"og:locale\" content=\"en_US\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"PMDA ORANGE LETTER_2026.07\uff5cCM Plus\" \/>\n<meta property=\"og:description\" content=\"ORANGE LETTER To encourage voluntary quality improvements at pharmaceutical manufacturing sites, Japanese regulatory agency PMDA has been publishing anonymized, highly useful findings from its inspections based on Japanese GMP Ministerial Order. These are published in a format known as the “ORANGE Letter” since 2022. CM Plus provides abridged English translations of the Orange Letters, for our clients’ reference. Observed Regulatory Attention\/Notification of GMP Elements LETTER Author: PMDA Issue: July 2026 Title: Airflow Visualization Testing (Smoke Testing) in Aseptic Areas Related GMP Ministerial Ordinance Clause: Article 24-3 Cases Defects in product contamination prevention control were observed. 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