Ohayou Gozaimasu. In this edition of Devine Guidance (DG), Dr. D will discuss Chapter One and the “General Provisions” noted in Articles 1 through 3.
Before the doctor dives into Chapter One, Dr. D would like to introduce the term “mutatis mutandis.” In fact, Dr. D will even provide the definition versus having the readers pull out their dictionaries. The term mutatis mutandis has its origins dating back to the 15th century and its roots in Medieval Latin (not pig Latin). According to Merriam-Webster, mutatis mutandis has two definitions:
1. With the necessary changes having been made; and
2.With the respective differences having been considered.
2.With the respective differences having been considered.
So Dr. D, why is this term relevant to this week’s guidance? In Section One of MO 169, mutatis mutandis is referred to 13 times. For you cognoscenti (look-it-up) of medical device regulations and standards, you will quickly ascertain MO 169 is similar in structure and content with those currently employed in the United States and Europe. Go figure!
Ministerial Ordinance Number 169 (2004) – Chapter One “General Provisions”
Section One – General Rules
(Purpose) Article 1 – This Ministerial Ordinance shall provide the standards in accordance with
the provision of Item (4) of Paragraph 2 of Article 14 (including the case where it is applied mutatis mutandis under Paragraph 5 of Article 19-2, and hereinafter referred to as such) of Pharmaceutical Affairs Law (Law No. 145, 1960) (hereinafter referred to as “Law”) which provides that such standards shall be provided by MHLW Ministerial Ordinances.
(Definitions) Article 2 – “Product” throughout this Ministerial Ordinance means the object (including those which have undergone the intermediate process and need to undergo subsequent process to be the (final) products (hereinafter referred to as “intermediate products”)) that has undergone the manufacturing process in the manufacturing site.
2. “Constituent parts, etc.” throughout this Ministerial Ordinance mean the parts, assemblies (limited to those which are used in the products), raw materials, materials, containers, wrappers, labeling (including the package inserts, and hereinafter referred to as such), etc. used in the manufacturing process that constitute parts of the products,as well as the software of the products.
3. “Process agent” throughout this Ministerial Ordinance means the object that is used for the intermediate products in the manufacturing process (excluding those that constitute parts of the products).
4. “Packaging and labeling material” throughout this Ministerial Ordinance means the container, wrapper and labeling among the constituent parts, etc.
5. “Lot” throughout this Ministerial Ordinance means a grouping of the products, process agents or constituent parts, etc. (hereinafter collectively referred to as “products, etc.”) that are manufactured so as to have a uniform quality in a series of the manufacturing process for a certain manufacturing period.
6. “Batch for testing” throughout this Ministerial Ordinance means a lot or another grouping equivalent thereto of the products with a uniform quality.
7. “Controlled unit” throughout this Ministerial Ordinance means a grouping of the packaging and labeling materials that have been verified to be same.
8. “Sterile medical device” throughout this Ministerial Ordinance means a medical device that is sterilized in the manufacturing process.
9. “Validation” throughout this Ministerial Ordinance means to verify and document that the buildings and facilities of the manufacturing site, procedures, processes and other procedures of the manufacturing control and quality control (hereinafter referred to as “manufacturing procedure, etc.”) provide the anticipated results.
10. “Clean area” throughout this Ministerial Ordinance means the place, among those areas where the manufacturing operations are conducted (hereinafter referred to as “work areas”), where the weighing operations for the constituent parts, etc. or the formulating operations are conducted or where the cleaned containers are exposed to the air in the work areas.
11. “Aseptic area” throughout this Ministerial Ordinance means the place, among the work areas, where the aseptic products or constituent parts, etc. or sterilized containers are exposed to the air in the work areas, where the sealing operations for the containers are conducted, or where the aseptic operations including the sterility tests are conducted.
12. “Cell/tissue-based medical device” throughout this Ministerial Ordinance means the medical device composed of human or animal cells or tissue.
13. “Donor” throughout this Ministerial Ordinance means the person who donates the cells or tissue that serves as the materials for the cell/tissue-based medical devices (excluding those concerned with the body of a brain-dead person specified in Paragraph 2 of Article 6 of Law on Organ Transplantation (Law No. 104, 1997)).
14. “Donor animal” throughout this Ministerial Ordinance means the animal which provides the cells or tissue that serves as the materials for the cell/tissue-based medical devices.
15. “Input” throughout this Ministerial Ordinance means the information, etc. necessary for the manufacturing control and quality control when conducting a certain process.
16. “Output” throughout this Ministerial Ordinance means the information, etc., that is obtained as a result of a certain process conducted.
17. “Top management” throughout this Ministerial Ordinance means the person or the group of people, including the executive officer who conducts the duties concerned with the manufacturing site, who directs and controls the manufacturing site.
18. “Quality policy” throughout this Ministerial Ordinance means the overall intentions and direction of the manufacturing site related to the quality as formally provided and expressed by the top management in order to ensure the quality of the products.
19. “Quality management system” throughout this Ministerial Ordinance means the management system that the manufacturer and the foreign manufacturer specified in Paragraph 1 of Article 13-3 of Law (hereinafter simply referred to as “foreign manufacturer”) (hereinafter collectively referred to as “manufacturer, etc.”) direct and control the manufacturing site with regard to quality.
20. “Review” throughout this Ministerial Ordinance means the activity undertaken to determine the suitability, adequacy and effectiveness of the subject matter to achieve the established objectives.
21. “Resource” throughout this Ministerial Ordinance means the personal knowledge and skills and technology, facilities and other resource that is utilized for the operations of the manufacturing site.
22. “Infrastructure” throughout this Ministerial Ordinance means the system of the facilities, equipment and services that are necessary for the operations of the manufacturing site.23. “Traceability” throughout this Ministerial Ordinance means the ability to trace the history, application or location of that which is under consideration.24. “Advisory notice” throughout this Ministerial Ordinance means the document that is issued subsequent to the delivery of the products to provide supplement any information or to advise what actions should be taken in use, modification, return or destruction of the products.
(Scope) Article 3 – The marketing authorization holder of the medical devices or in-vitro diagnostic reagents specified in Paragraph 1 of Article 14 of Law, the appointed marketing authorization holder of medical devices or in-vitro diagnostic reagents specified in Paragraph 4 of Article 19-2 of Law or the marketing authorization holder of the designated controlled medical devices specified, etc. in Paragraph 1 of Article 23-2 of Law (hereinafter collectively referred to as “marketing authorization holder, etc.”) shall, in accordance with the provision of Chapter 2 or the provision of Chapter 2 applied mutatis mutandis under Chapter 5, have the manufacturer, etc. conduct the manufacturing control and quality control of the products in the manufacturing site, with the proviso that the manufacturing control and quality control in the manufacturing site of the manufacturer in the category specified in Item (4) of Paragraph 5 of Article 26 of Pharmaceutical Affairs Law Enforcement Regulations (MHW Ministerial Ordinance No.1, 1961) (hereinafter referred to as “Enforcement Regulations”) (hereinafter referred to as “labeling, etc.-category medical device manufacturer”) or the foreign manufacturer in the category specified in Item (4) of Paragraph 4 of Article 36 of Enforcement Regulations (hereinafter referred to as “foreign labeling, etc.-category medical device manufacturer”) (hereinafter collectively referred to as “labeling, etc.-category medical device manufacturer, etc.”), or the manufacturer in the category specified in Item (3) of Paragraph 2 of Article 26 of Enforcement Regulations (hereinafter referred to as “labeling, etc.-category in-vitro diagnostic reagents manufacturer”) or the foreign manufacturer in the category specified in Item (3) of Paragraph 2 of Article 36 of Enforcement Regulations (hereinafter referred to as “foreign labeling, etc.-category in-vitro diagnostic reagents manufacturer”) (hereinafter collectively referred to as “labeling, etc.-category in-vitro diagnostic reagents manufacturer, etc.”) are conducted in accordance with the provision of Chapter 3 or the provision of Chapter 3 applied mutatis mutandis under Chapter 5 may be applied, instead of the provision of Chapter 2 or the provision of Chapter 2 applied mutatis mutandis under Chapter 5.
2. The marketing authorization holder, etc. of medical devices shall have the manufacturer of the products concerned with the medical devices which correspond to the biological-origin products specified in Paragraph 9 of Article 2 of Law (hereinafter referred to as “biological-origin medical devices”), the medical devices designated by Minister of Health, Labour and Welfare in accordance with the provision of Paragraph 2 of Article 43 of Law, or the cell/tissue-based medical devices (hereinafter collectively referred to as “biological-origin medical devices, etc.”) (hereinafter referred to as “biological-origin medical devices, etc. manufacturer”), and the foreign manufacturer of the products concerned with the biological-origin medical devices, etc. (hereinafter collectively referred to as “biological-origin medical devices, etc. manufacturer, etc.”) conduct the manufacturing control and quality control of the products in the manufacturing site in accordance with the provision of Chapter 4 (limited to Articles 78 and 79 for the manufacturing site that conducts only the labeling, packaging or storing operations) in addition to the provision of Chapter 2.
3. The manufacturer, etc. of medical devices or in-vitro diagnostic reagents shall conduct the manufacturing control and quality control of the products in the manufacturing site specified in Article 96 of Enforcement Regulations in accordance with the provision of Chapter 2 or the provision of Chapter 2 applied mutatis mutandis under Chapter 5, with the proviso that the manufacturing control and quality control in the manufacturing site of the labeling, etc.-category medical device manufacturer, etc. or the labeling, etc.-category in-vitro diagnostic reagents manufacturer, etc. are conducted in accordance with the provision of Chapter 3 or the provision of Chapter 3 applied mutatis mutandis under Chapter 5, instead of the provision of Chapter 2 or the provision of Chapter 2 applied mutatis mutandis under Chapter 5. In addition, the manufacturing control and quality control of the products in the manufacturing site of the biological-origin medical device, etc. manufacturer, etc. shall be conducted in accordance with the provision of Chapter 4 (limited to Articles 78 and 79 for the manufacturing site that conducts only the labeling, packaging or storing operations) in addition to the provision of Chapter 2.
4. The manufacturer of the products concerned with the medical devices or drugs (limited to in-vitro diagnostic reagents, and referred to as such in this Paragraph 4) for the export specified in Paragraph 1 of Article 80 of Law shall conduct the manufacturing control and quality control of the products in the manufacturing site in accordance with the provision of Chapter 2 or the provision of Chapter 2 applied mutatis mutandis under Chapter 5, with the proviso that the labeling, etc.-category medical device manufacturer or the labeling, etc.-category in-vitro diagnostic reagents manufacturer conducts the manufacturing control and quality control of the products concerned with the medical devices or in-vitro diagnostic reagents for the export in accordance with the provision of Chapter 3 or the provision of Chapter 3 applied mutatis mutandis under Chapter 5, instead of the provision of Chapter 2 or the provision of Chapter 2 applied mutatis mutandis under Chapter 5. In addition, the manufacturing control and quality control of the products concerned with the medical devices for the export specified in same Article of Law in the manufacturing site of the biological-origin medical devices, etc. manufacturer shall be conducted in accordance with the provision of Chapter 4 (limited to Articles 78 and 79 for the manufacturing site that conducts only the labeling, packaging or storing operations) in addition to the provision of Chapter 2.
What device manufacturers need to know
Essentially, chapter one (Article 1) establishes the foundation for MO 169 and the requirement to comply, as delineated by the Japanese Pharmaceutical Affairs Law (JPAL) of 1960. Additionally, similar to other regulations and standards, MO 169 (Article 2) contains its own set of terms and definitions. Although many of these terms and definitions are similar to other regulations and standards; Dr. D strongly suggests becoming intimate with the Japanese terms. The expectation is that when corresponding with MHLW or the Pharmaceuticals and Medical Devices Agency (PMDA), device manufacturers employ terms the Japanese are familiar with. What better way to comply and meet expectations than actually using the terms imbedded in MO 169. Go figure. Remember, just like the device markets in the United States, Europe, Canada, Brazil, Australia, etc., their sandbox, their rules.
Article 3, the scope, delineates the essential regulatory-compliance requirements associated with device entry into the Japanese market. For example, under scope the term “Marketing Authorization Holder” (MAH) is introduced. Similar to the EU Authorized Representative, device manufacturers not have a presence in Japan (manufacturing facility or office) must appoint an agent to oversee the device importation process. Device manufactures must contract with a MAH (licensed and approved by MHLW) to perform the duties of the agent. Additionally, the requirements for establishing manufacturing control and quality control for devices covered by MO 169 are established. This includes all manufacturing facilities that produce devices for entry into Japan and their ongoing compliance with MO 169. Now granted, Article 3 contains its own unique form of legalese and regulatory doublespeak with all of the “hereinafter referred to” statements, it is incumbent upon device manufacturers to drill down through Article 3 and understand the context. In short, Article 3 basically states; “device manufacturers shall comply with Chapter 2 (the QMS requirements) and Chapters 3 through 5, as applicable.
What device manufacturers need to do
As Dr. D alluded to in last week’s DG, the doctor recommends: (a) performing a gap analysis between your organization’s QMS and MO 169 requirements; and (b) map the existing QMS to the requirements delineated with MO 169. This is the only sure-fire way to ensure all of the requirements are adequately addressed. There are organizations such as the Emergo Group (no Dr. D is not a paid spokesperson for Emergo) that have extensive experience in Japan as a MAH and can assist with product entry into the extremely lucrative Japanese market. However, a QMS compliant to MO 169 is still a salient requirement. If the plan is to enter a Class III or IV device into Japan, you can expect an eventual visit from PMDA. So pursuing the path of least resistance such as relying on or stating;
- “Our device company is EN ISO 13485:2003 registered;”
- “Our product is contains a CE Mark of Registration;” or
- “Our product is FDA cleared;” is just not going to work.
In fact, PMDA really does not care, although they will be more tactful than Dr. D, when stating their lack of interest in product approvals given outside of Japan. Not wanting to sound like that proverbial broken record but happy to do so, let the good doctor repeat; “Their sandbox, their rules!” With that said, complying with all aspects of MO 169 is the only true path into the Japanese device market.
Takeaways
Chapter one of MO 169 establishes the foundation needed for manufacturers to gain entry into the Japanese market for their products. Complying with all of the requirements delineated throughout MO 169 is not only the expectation, it is mandated by law.
Similar to other device regulations and standards, MO 169 has its own unique set of terms and definitions. Dr. D strongly recommends learning and when communicating with MHLW and PMDA, actually using them, when appropriate. Finally, although your organization’s QMS may be compliant with FDA, European, TGA, or other national regulations, that does not mean it is suitable for Japan. Ensure that your organization’s QMS is mapped to MO 169.
Until the next edition of DG, when the doctor provides guidance on MO 169 – Chapter 2, Section 1 “General Rules” (Article 4), sayonara from Dr. D and best wishes for continued professional success.
References
- Marketing Authorization Holder for Japan. (2012) Emergo Group website. Retrieved June 24, 2012, from http://www.emergogroup.com/services/japan
- Ministerial Ordinance 169. (2004). MHLW ministerial ordinance 169 on standards for manufacturing control and quality control for medical devices and in-vitro diagnostic reagents. Retrieved June 1, 2012, from http://www.pmda.go.jp/english/service/pdf/ministerial/050909betsu3.pdf
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