PMDA ORANGE LETTER_2026.06

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: June 2026 Title: Management of Expiration Date and Retest Period of API - Preventing Misunderstandings Regarding Retest Related GMP Ministerial Ordinance Clause: Article 3-2, etc. Cases Due to insufficient understanding of the definitions of the expiration date and the retest period APIs, established procedures allowed for the use of APIs even after their expiration date by repeatedly conducting retests on the APIs intended for manufacturing. Background ♦Regarding the storage of APIs, the GMP Ministerial Order requires management under appropriate conditions that do not give impact to quality. ♦For APIs with an "expiration date" specified in the approval document, they can only be used during this valid period and never can be used after their expiration date. On the other hand, for APIs with a specified "retest period", they can be used during the retest period, and even after the retest period has passed, they can be used if they pass a retest immediately prior to use (Refer to GMP Case Studies 1) GMP 21-4). Observations ♦At the manufacturing site, tablets were manufactured using an API with an expiration date specified in the approval document. However, the procedure is specified in a way that allows for the use of API after the expiration date by conducting a retest. ♦Specifically, with the intention of reducing raw material waste and ensuring a stable product supply, the related SOP stipulated: "In principle, APIs that have exceeded...

https://cm-plus.co.jp/en/column/gmp/2026_0803/

Fundamentals of Microbiology [Part 2]

This article is an updated 2026 version of the popular 50-part Japanese series “Microorganisms, Too Embarrassed to Ask Others About!” (いまさら人には聞けない！微生物のお話), previously published on GMP Platform*. Over the next several installments, I will explore a wide range of topics related to microorganisms, from the fundamentals to more in-depth insights that are not widely known even among professionals in the field. Previously... -  Fundamentals of Microbiology [Part 1]   We Live Surrounded by Microorganisms Individual microorganisms are very small and cannot be seen with the naked eye, so we rarely are aware of their existence in daily life. However, unless in a highly controlled environment, microorganisms should be considered to exist everywhere around us. In the air, water, sea, soil, on office desks, on the surface of the skin and mucous membranes, and even in the deep sea, stratosphere, desert sand... Microorganisms exist in almost all conceivable environments.As in the recent news that a large number of microorganisms found in meters underground, microorganisms can exist in places where ordinary animals and plants cannot survive. It is said that there are 1030 bacteria living on Earth, far more than the number of stars in the entire universe, and their weight (in terms of carbon content) is equivalent to the total of all plants on Earth. (https://yusukeokazaki.weebly.com/basic_info.html) It is also said that there are more than 100 trillion microorganisms (mainly bacteria) in our bodies. This is far more than the number of cells (about 37 trillion) that make up the human body. (Source: Hygienic Microbiology Research Center website) Despite this surprising number, these microorganisms are not evenly distributed throughout the body. Microorganisms mainly exist on the body surface and in the digestive tract including the oral cavity. It is said that there are thousands to tens of thousands of microorganisms per 1 cm²...

https://cm-plus.co.jp/en/column/gmp/2026_0804/

Fundamentals of Microbiology [Part 1]

This article is an updated 2026 version of the popular 50-part Japanese series “Microorganisms, Too Embarrassed to Ask Others About!” (いまさら人には聞けない！微生物のお話), previously published on GMP Platform*. Over the next several installments, I will explore a wide range of topics related to microorganisms, from the fundamentals to more in-depth insights that are not widely known even among professionals in the field.   Microorganisms: The Basics of Basics The Earth was born approximately 4.6 billion years ago, and primitive life is said to have appeared about 600 million years after the Earth's birth, that is, about 4 billion years ago. Early life was by no means complex; it is thought to have been single-celled organisms, i.e., microorganisms, that could withstand the severe environment of that time. There are various theories, but humans appeared on Earth several hundred-thousands of years ago. In other words, as living beings on Earth, microorganisms are the senior of humans. Today, the existence of invisible tiny organisms called microorganisms is well understood. It is also well known that they may cause diseases, spoil foods, or produce useful substances through a process called fermentation. Such phenomenon caused by microorganisms has been well known since ancient times. Diseases caused by microorganisms, i.e., infectious diseases, have existed since before the birth of humans, and our ancestors would have experienced battles against such infectious diseases. It is self-evident that food spoils if left unattended, and various processing technologies such as drying and salting have been developed to prevent this spoilage. Alcohol and vinegar are also produced by microbial fermentation, and it is said that they have been known for thousands of years. These have been empirically recognized and passed down, but human beings did not recognize the fact that these phenomena are caused by tiny lives, i.e. microorganisms, until mid-1800s. And microbiology...

https://cm-plus.co.jp/en/column/gmp/2026_0610/

[Indonesia] Seminar – Strategic Synergy Between Pharmaceutical Industry Strategy, Regulatory Compliance, and Engineering Excellence for Global Quality and Competitiveness

PT. CMPLUS Consulting Indonesia, will hold a Seminar in Semarang, Central Java with the theme “Strategic Synergy Between Pharmaceutical Industry Strategy, Regulatory Compliance, and Engineering Excellence for Global Quality and Competitiveness” on Thursday, February 12, 2026, at Amarta Ballroom, Grand Candi Hotel, Semarang, Central Java. There will be three (3) sessions and one (1) special session, namely: “Strategic Industry Trends & Local Compliance,” “Project Management for Renovation Project,” “Risk-Based Cleanroom Management & Contamination Control Strategy (CSS),” and “Sustainability: Carbon Neutral.”   Flyer & Agenda 　 　 Please download the brochure for more detailed information. > Download Event Outline Title Strategic Synergy Between Pharmaceutical Industry Strategy, Regulatory Compliance, and Engineering Excellence for Global Quality and Competitiveness Program ·Opening speech Dra. Rustyawati, Mkes, Apt (Mrs) Head of BBPOM Semarang ・Session 1 : Strategic Industry Trends Local Compliance (From Compliance to Competitive Advantage: Strategic Industry Trends and Local Regulatory Readiness) Matheus Kristianto (Mr.) GMP Advisor, PT. CMPlus Consulting Indonesia. ・Session 2: Project Management for Renovation Project Yasuyuki Suga (Mr.) CMPlus Japan ・Session 3: Risk-Based Cleanroom Management & Contamination Control Strategy (CSS) Under BPOM CPOB 2024-2025: From Compliance to Productivity Gains. Ariyono W. Ardi, Apt. MM (Mr.) Associate GMP Expert, PT. CMPlus Consulting Indonesia. ・Special Session: Carbon Neutral Yoshiyuki Inoue (Mr.) PT. CMPlus Consulting Indonesia. Date and Time Thursday, February 12, 2026, 8:30 AM – 2:00 PM Venue AMARTA Ballroom, Grand Candi Hotel, Semarang > Google Map Entry Fee Free Registration Link Registration Form , Deadline for registration is February 5  

https://cm-plus.co.jp/en/news/event/2026_0122/

CM Plus group to speak at ISPE Indonesia Annual Conference 2025

ISPE Indonesia Annual Conference is the annual conference held by ISPE Indonesia Affiliate. This year, it is scheduled on 21, 22 May, 2025, in Jakarta, Indonesia. CM Plus, with PT.CMPLUS CONSULTING INDONESIA, will sponsor as platinum sponsor and make presentation. More information will follow. Here are the details. Presentation Outline Track - Title Project Management of Renovation Projects Table of contents 1. Purpose of Renovation Work 2. Project Management of Renovation Work 3. How to design in order to make Renovation Work easily 4. How to deliver C&Q for Renovation Work 5. Short Introduction of CM Plus Group Presenters Yasuyuki Suga (Mr.) General Manager of CM Plus Corporation (Japan) Director of ISPE Japan Affiliate Leader of Engineering COP in ISPE Japan Affiliate Date and Time Wednesday 21th May, 2025 xx:xx – xx:xx Venue - Conference Outline Title ISPE Indonesia Annual Conference 2025 Date 21-22 May, 2025 Venue Aston Kartika Hotel & Conference Center, Jakarta, Indonesia

https://cm-plus.co.jp/en/news/event/2025_0417/

Pharmaceuticals and Medical Devices

Home/ Services/ Engineering, Project Management/ Sectors/ Pharmaceuticals and Medical Devices SectorsPharmaceuticals and Medical Devices CM Plus responds to clients’ needs with top-level expertise and technical capabilities in the construction of production facilities in the fields of pharmaceuticals, medical devices, and more. From sterile pharmaceuticals to active pharmaceutical ingredients, regenerative medicine, and medical devices, we have been meeting numerous needs since our founding, from the business planning stage to basic design, construction, and IQ/OQ phases.We flexibly respond to client situations, not only for new construction, but also for expansion, relocation, partial renovations, and technology transfer. Sector Details Our services range from pharmaceuticals (sterile pharmaceuticals, oral drugs, active pharmaceutical ingredients, vaccines, biopharmaceuticals, investigational drugs, and diagnostics) to medical devices, regenerative medicine, and cell therapy.We also provide a wide range of services from R&D facilities to clinical trials, pilot plants, and commercial production. Sterile Pharmaceuticals Oral Drugs Medium-Molecule API Large-Molecule (Biopharmaceutical) API Regenerative Medicine (Consultation Service) Features The pharmaceutical and medical device sectors deal with products that directly impact human health, thus requiring stricter quality control than other products. The characteristics of manufacturing facilities include: Compliance with GMP is required (PIC/S, cGMP, EU-GMP, and GMPs of various countries). Advanced environmental control (cleanliness management, temperature and humidity management, room pressure management, pharmaceutical water management, etc.) is necessary. Advanced hazard management (chemical hazards, biohazards), management of hazardous materials, and management of poisons/narcotics may be required. Since the production equipment and the building/architectural facilities need to function as a cohesive unit, complex integrations between them arise. Proper commissioning and qualification (C&Q) based on accurate risk analysis are required. Keys to Success How to Ensure the Success of Construction Projects in the Pharmaceutical and Medical Device Sectors: From the early planning stages, proceed while consciously including GMP compliance and validation at each step by confirming specifications accurately....

https://cm-plus.co.jp/en/service/engineering/field/pharma_medical-device/

Sterile Pharmaceutical Manufacturing Facility

Home/ Services/ Engineering, Project Management/ Sectors/ Pharmaceuticals and Medical Devices/ Sterile Pharmaceutical Manufacturing Facility Pharmaceuticals and Medical DevicesSterile Pharmaceutical Manufacturing Facility About Sterile Pharmaceuticals Sterile pharmaceuticals include injectable drugs administered by injection, dialysis agents administered through dialysis, and eye drops administered to the eye. Direct containers in contact with the drug have functions to maintain the quality of the drug and to ensure user convenience. These containers include ampoules, vials, cartridges, infusion bags, pre-filled syringes (PFS), blow-fill-seal (BFS), form-fill-seal (FFS), and plastic containers. Sterile pharmaceuticals are manufactured using either terminal sterilization methods or aseptic processing methods to ensure sterility. When handling various containers such as vials and syringes, the supply form of direct containers called NEST, where pre-washed and sterilized direct containers are set in dedicated cases, is sometimes used. In such cases, devices like filling machines are also dedicated to NEST, but they feature easy container switching. Filled products are packed in single or multiple layers of films or paper, labeled with legally mandated information (such as lot numbers, expiration dates, and GS1 barcodes), and maintain the quality of the product during transportation and prevent errors and ensure convenience during use. Example of a Sterile Pharmaceutical Manufacturing Process The following diagram illustrates the process flow of a vial product using the aseptic method as an example of a sterile pharmaceutical. Example of Process Flow Diagram:Vial Product Using Aseptic Method   Weighing of raw materials, preparation and processes from washing of containers filling/stoppering/sealing, these processes are conducted in a clean room controlled for appropriate particle count, temperature, and humidity to prevent microbial and foreign matter contamination. Particularly, the filling and stoppering processes are performed in grade A cleanliness environments, classified as critical areas. Vials are depyrogenized through a dry heat sterilization tunnel, while rubber stoppers are washed and sterilized using...

https://cm-plus.co.jp/en/service/engineering/field/pharma_medical-device/sterile_medicine/

Oral Drugs Facility

Home/ Services/ Engineering, Project Management/ Sectors/ Pharmaceuticals and Medical Devices/ Oral Drugs Facility Pharmaceuticals and Medical DevicesOral Drugs Facility About Oral Pharmaceuticals There are numerous oral preparations taken by mouth, with representative types including tablets, capsules, granules, and powders. Tablets, in particular, can come in forms such as uncoated tablets, film-coated tablets, and sugar-coated tablets. The primary packaging, which directly contacts with the drug, functions to maintain the quality of the drug and ensure user convenience. This primary packaging includes PTP (Press Through Package) blister packaging, strip packaging, sachet packaging, stick packaging, and bottle packaging. Primary packaging products are further wrapped with single or multiple layers of film or paper, carrying regulatory-required labels (such as batch number, expiration date, GS1 barcodes, etc.) to maintain the quality of the product during transportation and prevent errors and ensure convenience during usage. Example of Manufacturing Process for Oral Pharmaceuticals The following diagram illustrates a process flow chart for a film-coated tablet blister package product as an example of an oral formulation. Process Flow Chart Example: Film-Coated Tablet Blister Packaging   The preparation process and primary packaging process are conducted in a clean room where temperature, humidity, and particulate matter are controlled to prevent microbial and foreign matter contamination into the products. During the preparation process, raw materials and intermediate products for each batch are handled using containers between different process stages. Tablets are engraved or printed with the product name or other information. After they are visually inspected, samples are taken for quality testing. Lots that pass the quality tests proceed to primary PTP packaging and secondary packaging as pillow packaging, cartoning, printing & inspection and cardboard packing. Unlike the preparation process, where between each stage requires manual handling, the packaging process is normally fully automated. Lots that pass the final quality tests...

https://cm-plus.co.jp/en/service/engineering/field/pharma_medical-device/oral_agent/

Medium-Molecule API Manufacturing Facility

Home/ Services/ Engineering, Project Management/ Sectors/ Pharmaceuticals and Medical Devices/ Medium-Molecule API Manufacturing Facility Pharmaceuticals and Medical DevicesMedium-Molecule API Manufacturing Facility Classification Name Low Molecular Weight Medium Molecular Weight High Molecular Weight Molecular Weight ～500 500～2,000 2,000～ Examples Synthetic Organic Pharmaceuticals eptide Pharmaceuticals Nucleic Acid Pharmaceuticals Antibody Drugs Vaccines Main Manufacturing Methods Organic Synthesis Peptide Synthesis Nucleic Acid Synthesis Microbial Culture Animal Cell Culture Medium-Molecule APIs are considered to have a molecular weight of approximately 500 to 2,000. Since the molecular weight of organic synthesis APIs is below 500, and that of APIs produced by microbial or animal cell culture is around 150,000, the former are called Low-Molecule APIs and the latter High-Molecule APIs. The intermediate ones are referred to as middle molecular weight APIs. Medium-Molecule APIs are broadly divided into peptide pharmaceutical APIs and nucleic acid pharmaceutical APIs. Types and Characteristics of Medium-Molecule APIs Peptide Pharmaceutical APIs Peptide pharmaceutical APIs are obtained by synthesizing peptides through solid-phase or liquid-phase reactions that bond 20 types of amino acids. The synthesized peptides need to have the structure of the active sites of proteins that are usually generated in the body. Generally, the peptides are often cyclic to make them less susceptible to degradation and modification. Nucleic Acid Pharmaceutical APIs Nucleic acid pharmaceuticals make use of nucleic acids such as DNA and RNA, which carry genetic information, in medicinal applications. Since nucleic acid pharmaceuticals can be manufactured with synthetic techniques similar to those used for small molecule pharmaceuticals, they can be produced at a lower cost compared to high molecular weight APIs. Moreover, they can target molecules like mRNA and miRNA, which cannot be targeted by either small or high molecular weight pharmaceuticals. Manufacturing Facilities for Middle Molecular Weight APIs ~Key Points in Construction~ Laboratory Scale Facility Adaptation During the drug discovery...

https://cm-plus.co.jp/en/service/engineering/field/pharma_medical-device/medium_molecule_drugs/

Large-Molecule ( Biopharmaceutical ) API Manufacturing Facility

Home/ Services/ Engineering, Project Management/ Sectors/ Pharmaceuticals and Medical Devices/ Large-Molecule API Manufacturing Facility Pharmaceuticals and Medical DevicesLarge-Molecule (Biopharmaceutical) API Manufacturing Facility Classification Name Low Molecular Weight Medium Molecular Weight High Molecular Weight Molecular Weight ～500 500～2,000 2,000～ Examples Synthetic Organic Pharmaceuticals eptide Pharmaceuticals Nucleic Acid Pharmaceuticals Antibody Drugs Vaccines Main Manufacturing Methods Organic Synthesis Peptide Synthesis Nucleic Acid Synthesis Microbial Culture Animal Cell Culture Large-Molecule APIs include mainly microbial culture APIs and animal cell culture APIs. These APIs are produced by combining techniques such as genetic recombination, cell banking, cell culture, extraction, and purification to generate the active protein components. Examples include antibodies, enzymes, hormones, and interferons. It is expected that they will address unmet medical needs, which were difficult to address with small molecule pharmaceuticals. Since these APIs involve handling biological organisms and proteins, ensuring the sterility of manufacturing facilities and managing the biological aspects of environmental conditions are necessary. Types and Characteristics of Large-Molecule APIs Materials Used in Large-Molecule (Biological) Pharmaceuticals and Major Pharmaceuticals   Material Major Pharmaceuticals Host Cells Animal Cells CHO, SP2/0, NS0, Human Cells (HT1080, HEK), etc. Blood Coagulation Factors Erythropoietin Antibodies Lysosomal Enzymes Fc Fusion Proteins Microorganisms E. coli Insulin Growth Hormone Interferon Cytokines Enzymes Insulin Glucagon Human Serum Albumin HPV Vaccine Insect Cells HPV Vaccine Plant Cells Rice, Tobacco, Carrot Recombinant Lactoferrin Influenza Vaccine Recombinant Anti-Ebola Virus Antibody Gaucher Disease Treatment Source Cells Animal Heparin Hyaluronic Acid Plant Medicinal Herb Morphine Aspirin Plasma Immunoglobulin Albumin Blood Coagulation Factors Fibrinogen Antithrombin Haptoglobin Orphan Drugs Microbial Culture APIs Microbial cultures can be divided into those that use naturally occurring microorganisms and those that use genetically modified microorganisms. The latter involve engineering microorganisms such as E. coli and yeast to incorporate genes that code for the desired substances (APIs) and then producing (expressing) these substances...

https://cm-plus.co.jp/en/service/engineering/field/pharma_medical-device/macromolecular_drugs/