{"id":6563,"date":"2026-09-28T13:54:47","date_gmt":"2026-09-28T04:54:47","guid":{"rendered":"https:\/\/cm-plus.co.jp\/en\/?post_type=column&p=6563"},"modified":"2026-09-28T13:55:29","modified_gmt":"2026-09-28T04:55:29","slug":"2026_0928","status":"publish","type":"column","link":"https:\/\/cm-plus.co.jp\/en\/column\/gmp\/2026_0928\/","title":{"rendered":"GMP WATCH NEWS – A Veteran’s Perspective\uff3b2\uff3d"},"content":{"rendered":"

Paradigm Shifts in Pharmaceutical Quality Systems
\nA Historical Review and Future Perspectives [Part 2]<\/strong><\/span><\/p>\n

Implementation of Process Validation
\n<\/span><\/strong>The concept of validation has its roots in the space technology developed during the U.S. Apollo program (1960s). Launch rockets are single-use. The concept of sampling inspection\u2014where one might say, \u201cLet\u2019s test-launch it; since it worked, we\u2019ll launch it again\u201d\u2014simply does not apply. Therefore, NASA rigorously applied the principles of reliability engineering\u2014the idea that \u201cif the design and manufacturing processes are flawless, the final product must also be flawless\u201d\u2014and established the prototype for the concept of validation.<\/p>\n

FDA officials wondered, \u201cWhy isn\u2019t the same level of precision in quality assurance found in the rocket industry being applied to the pharmaceutical industry, where human lives are at stake?\u201d and introduced the NASA-derived approach of \u201cbuilding quality into the process\u201d into the world of GMP. It can be said that validation is a technology \u201cadapted from the pharmaceutical world to the quality assurance techniques cultivated in NASA\u2019s Apollo program\u2014an environment where failure was not an option.\u201d Understanding this background should help explain why validation places such a strong emphasis on \u201cdocumentation\u201d and \u201cadvance planning.\u201d<\/p>\n

The definition of process validation issued in 1987 was \u201cthe establishment of evidence that provides a high degree of assurance that a process can consistently produce products that meet specified standards and quality characteristics.\u201d But what does \u201cconsistently produce\u201d actually mean? Since the definition provided only a conceptual framework without specifying concrete methods for validating pharmaceutical manufacturing processes, it caused considerable confusion among regulatory authorities and pharmaceutical companies worldwide.<\/p>\n

The FDA must have been quite troubled by this as well; in 1993, the FDA specifically presented \u201cthe successful production of three consecutive batches at actual production scale\u201d as a requirement for completing validation. This became widely recognized within the industry, and the \u201cthree-batch rule\u201d took root worldwide as the \u201cabsolute standard for passing FDA inspections.\u201d Lacking scientific basis, the misconception that \u201cthree successful runs guarantee lifelong security\u201d spread. As a result, companies were unable to respond to fluctuations occurring after market release and were plagued by situations where \u201cdefective products emerged despite validation.\u201d Furthermore, once a process was validated, even the slightest change in procedure required \u201cre-validation,\u201d leading to a perverse situation where production sites hesitated to improve manufacturing methods.<\/p>\n

FDA revised its guidelines on process validation to address this situation as an activity involving the collection and evaluation of necessary data throughout the product lifecycle in 2011. In other words, FDA clarified that process validation is not a one-time activity, such as the successful completion of three consecutive batches, but rather an ongoing process of continuous improvement throughout the lifecycle of a pharmaceutical product.<\/p>\n

That is, process validation is a series of activities that begins with Stage 1: Process Design, proceeds through Stage 2: Process Performance Qualification (PPQ) at actual production scale, and culminates in Stage 3: Ongoing Verification during commercial manufacturing; this means that process validation activities never end as long as the drug remains on the market.
\nProcess validation now consists largely of qualification (Stages 1 and 2); once qualification is complete, the process involves continuing verification while collecting data to improve the process, and is no longer a one-time activity like the previous \u201cthree-batch rule.\u201d\u3000This was indeed a major change that threw the industry into disarray.<\/p>\n

In other words, PPQ has shifted from the unscientific three-batch-rule to a requirement to demonstrate the necessary number of batches through scientific justification. The primary basis for determining the number of batches is the qualification data accumulated during the Stage 1 development phase and the scale-up phase. Based on this data, we predict \u201cvariability\u201d in commercial production and determine the required number of batches through risk assessment and statistical analysis. There is a stark difference in the level of quality assurance and the persuasiveness during inspections between the old attitude of \u201cWe made three batches because that\u2019s the rule\u201d and the new approach of \u201cAfter statistically calculating variability and evaluating risk, we concluded that three batches are sufficient to demonstrate the reliability of our product.\u201d It can be said that this reflects how deeply the company understands its own processes.<\/p>\n

If process qualification is thorough, a single PPQ may suffice. Ultimately, the essence of process validation lies in process qualification, while PPQ and ongoing verification serve merely to confirm it.<\/p>\n

At the time, I was conducting scale-up studies for a synthetic API. Since I firmly believed that as long as we could determine the scale-up factors for the synthesis process, we would undoubtedly be able to produce the product, I thought the \u201cthree-batch rule\u201d for process validation was unreasonable. At least, for synthetic API processes, I believed that if there was a scientific basis for the process control parameters, verification of a single batch would be sufficient.<\/p>\n

In particular, when the final process step involves purification by recrystallization, I believe that excessive validation is unnecessary because a 100% inspection can be performed to ensure that the crude crystals are completely dissolved and the mixture is homogeneous. Of course, documentation is required by regulations, but as long as there is scientific justification, the PPQ should be straightforward.<\/p>\n

However, the situation is different in the world of pharmaceutical formulation. For example, there is no scientifically validated method for uniformly mixing two powders with different properties. Segregation may occur during mixing, and extending the mixing time does not necessarily result in greater uniformity. Furthermore, there is no scientifically validated sampling method to confirm that the mixture has become uniform. Thus, when a process cannot be fully qualified, simply achieving three consecutive successful batches is insufficient to complete PPQ.<\/p>\n

The number of batches required for PPQ must be determined based on the level of qualification of that process.<\/p>\n

Process validation, which originated in rocket science, caused a sensation in the pharmaceutical industry. However, it ultimately settled into a very ordinary manufacturing activity: qualifying processes, operating them at commercial scale to verify performance, managing them on a daily basis, and making improvements when problems arise.<\/p>\n

While questions regarding analytical method validation or cleaning procedure validation can be answered with a simple \u201cYes\u201d or \u201cNo,\u201d process validation has become a unique case in that the only possible answer is that it is always in progress. For the sake of convenience, I believe most people interpret PPQ as process validation. In any case, it cannot be denied that confusion arose because the FDA changed its definition of process validation from a one-time activity to a continuous activity spanning the entire lifecycle of a drug.<\/p>\n

\n

Author<\/strong><\/p>\n

\n
\"\"<\/div>\n
Akio Nakao, Ph.D.<\/a>
\nNakao started his career in 1976 at Tanabe Seiyaku Co., Ltd. After carrying out research in synthetic organic chemistry and process chemistry (industrialization) at the company, he successively took the positions of quality assurance manager, director and general manager of production, and managing director in charge of management planning. After Tanabe merged with Mitsubishi to become Mitsubishi Tanabe Pharma Corporation, Nakao became Managing Executive Officer and Chief Director of Medicine Manufacturing. Through his experience in dealing with FDA inspections and activities at the Parenteral Drug Association (PDA), Nakao became convinced that GMP is an “exact science.”
\nFinding that his beliefs were reflected in CM Plus Corporation’s enthusiasm for improving GMP education, Nakao joined CM Plus in 2011 as a Director and be promoted as executive vice-president in 2012. Fellow since July 2017.<\/div>\n<\/div>\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":6469,"template":"","columncat":[61],"columntag":[],"keywords":[11],"acf":[],"yoast_head":"\nGMP WATCH NEWS - A Veteran's Perspective\uff3b2\uff3d\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_0928\/\" \/>\n<meta property=\"og:locale\" content=\"en_US\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"GMP WATCH NEWS - A Veteran's Perspective\uff3b2\uff3d\uff5cCM Plus\" \/>\n<meta property=\"og:description\" content=\"Paradigm Shifts in Pharmaceutical Quality Systems A Historical Review and Future Perspectives [Part 2] Implementation of Process Validation The concept of validation has its roots in the space technology developed during the U.S. Apollo program (1960s). 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