Column - MHLW MO 169 – Chapter 4 – Testing

Ohayou Gozaimasu. For this week, Dr. D is going to change the language lesson up a bit and throw several words at the readers; “jyu, kyu, hati, nana, roku, go, shi, san, ni, ichi.” For those of you moderately fluent in Japanese, the words are: “十, 九, 八, 七, 六, 五, 四, 三, 二, 一.” The literal translation is “10, 9, 8, 7, 6, 5, 4, 3, 2, 1.” If the PMDA inspector commences with a countdown at any point during an inspection, it is time for the Chief Impalable officer (CIO) to do one of two things; (a) start running; or (b) grab the ceremonial sword of the office wall and fall on it. Just kidding folks, but I hope you enjoyed the lesson in Japanese.

On a serious note, the regulatory gods in Japan expect device manufacturers to implement a testing program and actually test medical devices that contain a component of biological origin. What a surprise? Device manufacturers actually have to test their products? Now for device manufactures acting “malafide” (look-it-up), MHLW will soon be sending love letters, accompanied by swords of course, asking that your organization’s devices be pulled from the Japanese marketplace. For the CIO, this would be a very bad thing.

Ministerial Ordinance Number 169 (2004)

Chapter 4 – Manufacturing Control and Quality Control in Manufacturing Sites of Biological-origin Medical Device, etc. Manufacturers, etc.

(Testing)

Article 76 The biological-origin medical device, etc. manufacturer, etc. shall, in case where they manufacture the products concerned with the biological-origin medical devices, etc., control appropriately the duties concerned with the testing of the products concerned with the biological-origin medical devices, etc. in accordance with Seihin Hyojun Sho and the documented procedure, in addition to the duties specified in preceding Article.

(1) To identify appropriately the samples in order to prevent them from being mixed up or cross-contaminated,

(2) To conduct the testing which is important for the quality control and inapplicable to the final products at the appropriate stage of the manufacturing process,

(3) To constantly keep the utilized animals (limited to those utilized in testing, and hereinafter referred to as such in this Item(3)) under proper control, and to physically examine the animals when utilizing them, so as not to utilize those animals suffering from communicable diseases nor those otherwise unsuitable for being utilized,

(4) To dispose of all the objects contaminated with microorganisms (limited to those contaminated in the testing processes) and the animal carcasses so as not to jeopardize the public health and hygiene,

(5) To establish and maintain records of the following items concerned with the handling of the strains of the microorganisms for use in the testing, and

a. The name of the microorganisms and the number assigned to each of containers thereof,

b. The date of receipt, and the name and address of the person (in case of a corporation, its name and address) who transferred the strains,

c. The biological property and the date of the testing, and

d. The status of the passage.

(6) To store a reserve sample in an amount of at least twice of the quantity necessary for the required testing from the products concerned with the specified biological-origin medical devices, etc. specified in Paragraph 10 of Article 10 of Law for each lot (in case where the products are those concerned with the specified biological-origin medical devices which do not constitute a lot, the biological-origin raw materials used in the manufacturing of the products for each manufacturing number of such products corresponding to or for each lot of such biological-origin raw materials) under appropriate conditions for the appropriate period from the date of the manufacturing (in case where the medical devices concerned with the products are the specified biological-origin medical devices, for 10 years plus the shelf life), with the proviso that this provision shall not apply to those products concerned with the specified biological-origin medical devices which do not constitute a lot and of which reserve sample is stored for such period by the biological-origin raw material origins collectors, etc. under a contract concluded between the manufacturer, etc. and such biological-origin raw material origins collectors, etc. For the products concerned with the specified biological-origin medical devices which constitute a lot, after 3 years (for the products of which shelf life shall be displayed and of which shelf life plus 1 year exceeds 3 years, the shelf life of such products plus 1 year) have passed, storage of the biological-origin raw materials used in the manufacturing of such products may be substituted for storage of the products.

2. The biological-origin medical device, etc. manufacturer, etc. shall, in case where they manufacture the products concerned with the cell/tissue-based medical devices, control appropriately the following duties concerned with the testing of the products concerned with the cell/tissue-based medical devices in accordance with Seihin Hyojun Sho and documented procedure, in addition to the duties specified in preceding Paragraph 1.

(1) To have the person designated beforehand conduct the testing of the donor animals upon and after receipt and other necessary duties according to the details of such duties, and

(2) To establish and maintain records of the duties specified in preceding Item (1).

3. The biological-origin medical device, etc. manufacturer, etc. shall maintain the records specified in preceding two Paragraphs 1 and 2 in the manner which allows the series of the records including those of biological-origin raw materials used in the manufacturing and those of the products manufactured using such biological-origin raw materials are verified appropriately.

What device manufacturers need to know

Hopefully by now, the frequent readers of Devine Guidance will have figured out the importance the Japanese regulatory authorities place on the Seihin Hyojun Sho (device master file) and the establishment of and adherence to procedures. The testing of medical devices containing a component of biological origin is a salient requirement. The expectation is that testing occurs throughout the entire manufacturing cycle, as appropriate. For device manufacturers to comply with Article 76 of MO 169, they must:

Identify and collect test samples and protect them from being contaminated;
Actually perform testing , as appropriate;
Control the herd baby (animals used for testing must be controlled and monitored for disease, remember mad-cow is a bad thing;
Properly dispose of contaminated objects and animal carcasses (throwing carcasses to the wolves or sharks is frowned down upon);
Keep meticulous records for the handling of microorganisms (name, date of receipt, biological property, date of testing, and pass/fail information); and
Store samples (minimum of two times the quantity needed for testing) under appropriate conditions, for 10-years plus shelf life or 3-years of shelf life – plus 1, depending upon the lot configuration or the material of biological origin.

For medical devices that contain a cell/tissue component, testing of animals must occur beforehand. Once again, creating and retaining impeccable records is extremely important. So is ensuring the Seihin Hyojun Sho reflects the testing requirements. Make sure adequate procedures have been established for the testing of cell/tissue material.

Finally, device manufacturers can expect the Japanese regulatory authorities to examine records associated with the testing of medical devices that comprise of a component of biological origin. These records will be needed to support all regulatory submissions made to PMDA, e.g., Shonins; and be made readily available during facility inspections performed by PMDA.

What device manufacturers need to do

It is time for the old doctor to climb onto his soap box (me thinks the doctor needs a ladder) and preach about the importance of procedures. Because of the special niche associated with combination products (approximately 300 manufacturers of combination products in the United States alone) according to FDA, you can better your last yen “¥” PMDA is going to perform that deep dive into the validity of the procedures employed for testing medical devices containing a component of biological origin. In fact, can you say “Test Method Validation?” Yes, Dr. D knows that no such verbiage can be found in MO 169; however, Article 45 of MO 169 does delineate the regulatory requirements for process validation. Guess what, testing is a process. The doctor’s recommendation is to validate all test methods, regardless of how benign a test may appear. The doctor also recommends using Japanese Industrial Standards (JIS) whenever possible. Using a JIS in support of testing will endear your CIO to the good folks at MHLW and PMDA.

Every single test method employed in support of Article 76 should be governed by a written procedure. Chances are pretty good that the material of biological origin, used in a combination product, is being procured from a supplier (hopefully an approved supplier). It is incumbent upon the manufacturer of the finished medical device to ensure the supplier is testing and maintaining records required by Article 76. Why? What part of written procedures and retention of records is not being understood? Because Dr. D says so! If you do not want to believe the doctor, might I suggest reading Ministerial Ordinance 169 from start to finish.

Article 76 maps nicely to ISO 13485 and 21 CFR, Part 820 requirements (refer to Table 1.0). Testing of medical devices, regardless of the regulatory environment, has always been one of the foundations for ensuring devices are safe and effective in their intended use. Because of the additional risk associated with the combining of a medical device with a component of biological origin, testing becomes extremely important. For the manufacturers of combination products, Dr. D strongly suggests that you have a thorough understanding of your supplier’s policies, procedures, and record retention for controlling components of biological origin.

Table 1.0 – Sample Requirements Matrix
Procedure(s)	Procedure Name(s)	Requirement	21 CFR, Part 820	EN ISO 13485:2012	MHLW MO 169
1249-1 Rev A	Planning of Product Realization	Testing	820.80	7.1	Article 76

Takeaways

For this edition of DG, Dr. D wants the readers to focus on two takeaways. One – if the device manufacturer is also manufacturing the biological-origin component, than they must make sure the test procedures employed are documented (in writing) and the test methods are validated. Please do not dispose of animal carcasses in the Pacific Ocean. Dr. D occasional surfs and too many Great White Sharks in one location is a bad thing. Two – if the device manufacturer is purchasing the component of biological origin, it is imperative the suppliers comply with Article 76. Do not be afraid to audit your suppliers, if resources are not available for performing the audit, give Dr. D a call, Devine Guidance International has the resources.

Until the next edition of DG, when the doctor provides guidance on: MO 169 – Chapter 4 “Manufacturing Control and Quality Control in Manufacturing Sites of Biological-origin Medical Device, etc. Manufacturers, etc.” (Articles 77 Training), sayonara from Dr. D and best wishes for continued professional success.

Note: there are only two articles remaining for MO 169. If you have a topic you would like to see Dr. D cover, please let me know.

References:

Code of Federal Regulation. (2012, April). Title 21 Part 820: Quality system regulation. Washington, D.C.: U. S. Government Printing Office.
Code of Federal Regulation. (2012, April). Title 21 Part 1271: Human cells, tissues, and cellular and tissue-based products. Washington, D.C.: U. S. Government Printing Office.
EN ISO 13485:2012. (2012, February). Medical devices – quality management systems – requirements for regulatory purposes (EN ISO 13485:2012).
Final rule – cGMP requirements for combination products. (2013, January). FDA website. Retrieved January 25, 2013, from https://www.federalregister.gov/articles/2013/01/22/2013-01068/current-good-manufacturing-practice-requirements-for-combination-products
Linguanaut the Japanese phrases and expressions. (2012). Retrieved February 2, 2013, from http://www.linguanaut.com/english_japanese.htm
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
Quality management system inspection of medical devices and in-vitro diagnostics in Japan. (2012). PMDA Website. Retrieved November 30, 2012, from http://www.pmda.go.jp/english/service/pdf/qms.pdf

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