Devine Guidance

MHLW MO 169 – Chapter 4 – Process Control

By Dr. Christopher Joseph Devine
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Please ensure that the cleanroom/controlled environment has been properly validated and that adequate ongoing monitoring of the operating environment be sustained.

Ohayou Gozaimasu. This week the term/phrase specific to Japan, the doctor would like to introduce to the readers is: “maa-maa desu” For those of you moderately fluent in Japanese, the phrase is: “まあまあです。” The literal translation is “so-so.” If PMDA uses this phrase during an inspection of a device manufacturers’ facility, then chances are “Houston, I think you have a problem.” This holds especially true if the “so-so” is a general comment aimed at the overall assessment of the QMS. So-so would also imply the Chief Impalable Officer (CIO) is not spending enough waking hours on improving the performance of the QMS. Usually, placing pictures of ceremonial swords, in strategic locations within the CIO’s office is all that is necessary to properly motivate the CIO. 
Now granted, working in the medical device industry and specifically quality and regulatory compliance can be a daunting task indeed. In fact, it is not difficult to understand the angst of quality and regulatory professionals due to the often perceived “nomothetic” (look-it-up) nature of regulatory requirements, domestically and abroad. Complying with MO 169 and interfacing with MHLW and PMDA can be challenging; however, Dr. D is here to pave the way with some common-sense guidance and a link for an on-line catalog for ceremonial swords (just kidding.) Enjoy! 
Ministerial Ordinance Number 169 (2004)
Chapter 4 – Manufacturing Control and Quality Control in Manufacturing Sites of Biological-origin Medical Device, etc. Manufacturers, etc.
(Process Control)
Article 75 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 following duties concerned with the process control for such products in accordance with Seihin Hyojun Sho and documented procedure, in addition to the duties specified in preceding Article.
(1) To have the person designated beforehand conduct the following duties according to the details of such duties,
a. Taking necessary actions, in case where the materials or products are inactivated or where microorganisms, etc. contained in the materials or products are inactivated or eliminated, for preventing contamination by the materials or products which have not undergone inactivation or elimination,
b. Conducting continuous measurement of the items necessary for controlling the manufacturing process such as temperature, hydrogen ion index, etc., in case where biochemical technology such as fermentation, etc. is applied to the manufacturing process,
c. Taking necessary actions, in case where the column chromatography apparatuses, etc. are used in the manufacturing process, for preventing contamination of such apparatuses with microorganisms, and to measure endotoxins, where necessary,
d. Taking necessary actions, in case where the culture media are continuously supplied to and the cultured broth is continuously discharged from the tanks, for maintaining the incubation conditions in such incubation tanks during the incubating,
e. Conducting the validation in the following cases and establishing and maintaining records thereof,
(i) The case where the manufacturing of the products concerned with the biological-origin medical device, etc. will newly start at such manufacturing site,
(ii) The case where any change will be made in the manufacturing procedure, etc. which seriously affect the quality of the products, or
(iii) Other cases where it is deemed to be necessary to conduct the validation for appropriate conduct of the manufacturing control and quality control of the products concerned with the biological-origin medical devices, etc.
f. Placing as much restriction as possible on the personnel other than those engaged in the manufacturing operations entering the work areas,
g. Conducting sanitation control of the personnel in accordance with the following requirements,
(i) Placing as much restriction as possible on the personnel entering the clean areas or aseptic areas under operation, and
(ii) Not allowing the personnel engaged in the manufacturing operations to conduct the duties concerned with the control of the utilized animals (excluding those actually utilized in the manufacturing process).
h. Conducting sanitation control of the personnel conducting the duties in the clean areas or aseptic areas in accordance with the following requirements,
(i) Having the personnel engaged in the manufacturing operations wear clothes, work shoes, caps and masks, which have been disinfected,
(ii) Having the personnel undergo medical checkups at intervals not exceeding 6 months in order to verify that they do not suffer from the diseases which could contaminate, with microorganisms, etc., the materials or products, and
(iii) Having the personnel declare of any health condition that could contaminate the products or materials with microorganisms, etc. (including when suffering from a skin or hair infectious disease or a cold, when injured, when showing such symptoms as fever or diarrhea of unknown cause, and hereinafter referred to as such).
i. Constantly keeping the utilized animals (limited to those which are utilized in the manufacturing, and hereinafter referred to as such in this Item (1)) under proper control, and to physically examine the animals when utilizing them so as not to utilize those suffering from communicable diseases nor those otherwise unsuitable for being utilized,
j. Disposing of all the objects contaminated with microorganisms (limited to those contaminated in the manufacturing process) and the animal carcasses so as not jeopardize the public health and hygiene,
k. Establishing and maintaining records of the following items concerned with the handling of the strains of the microorganisms for use in the manufacturing,
(i) The name of the microorganisms and the number assigned to each of containers thereof;
(ii) The date of receipt, and name and address of the person (in case of a corporation, its name and address) who transferred the strains,
(iii) The biological property and date of testing, and
(iv) The status of the passage.
l. Verifying that the raw materials or materials originated in organisms (except plants) that are used in the manufacturing of the products concerned with the biological-origin drugs (hereinafter referred to as “biological-origin raw materials”) are appropriate based on Seihin Hyojun Sho of such products, and to establish and maintain records of the results of the verification, and
m. Maintaining the information that is provided to be recorded under the rules set forth by Minister of Health, Labor and Welfare, or to conclude a contract with the business that collects the origins of the biological-origin raw materials (hereinafter referred to as “biological-origin raw material origins collectors, etc.”) and to ensure that the information is appropriately maintained by such biological-origin raw materials origins collectors, etc., for the period specified in Items (2) and (3) of Article 30, in case where the biological-origin raw materials are used in the manufacturing of the products concerned with the biological-origin drugs, and
(2) To establish and maintain records specified in preceding Item (1) e., l. and m. for each lot.

2. The biological-origin medical device, etc. manufacturers, 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 process control for 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 following duties according to the details of the duties, and
a. Taking actions necessary, in case where they handle the cells or tissue collected from the different donors or donor animals, for preventing such cells or tissue from being mixed up or cross-contaminated,
b. Verifying, upon receipt, that the cells or tissue that serve as the raw materials or materials are appropriate, referring to the records of the following items, based on Seihin Hyojun Sho of such products, and establishing and maintaining records of the results of the verification,
(i) The premises where such cells or tissue was collected,
(ii) The date when such cells or tissue was collected,
(iii) In case where such cells or tissue is originated in humans, the conditions of diagnosing by questioning, testing, etc. the donors for the purpose of donor screening (the process to diagnose the donors by questioning, testing, etc. and to judge whether they are sufficiently qualified for donating cells or tissue as the materials of the products concerned with the cell/tissue-based medical devices),
(iv) In case where such cells or tissue is originated in animals, the conditions of receiving the donor animals and the conditions of the testing and keeping control for the donor animals for the purpose of donor screening (the process to test the donor animals and control keeping thereof and to judge whether they are sufficiently qualified for providing cells or tissue as the materials of the products concerned with the cell/tissue-based medical devices),
(v) The course of the collecting operations for such cells or tissue, and
(vi) Other items necessary for ensuring the quality of the products concerned with the cell/tissue-based medical devices, in addition to the items specified in preceding (i) to (v).
c. Taking actions necessary for preventing contamination with microorganisms, etc. in the course of the collection, and to establish records of such actions, in case where the cells or tissue used as the materials are collected from the donor animals,
d. Not allowing the personnel, in case where they are applicable to any of the following cases, to conduct the operations in the clean areas or aseptic areas,
(i) The case where they are in those health conditions which could contaminate the products or materials with microorganisms, etc., or
(ii) The case where they handle the microorganisms, etc. which could contaminate the cells or tissue right before the collecting or processing the cells or tissue.
e. Comprehending the names of the shipping consignee premises, shipping date and lot number, and to establish records thereof,
f. Taking actions necessary for ensuring the quality of the products during the delivery and to establish records of such actions, and
g. To establish records of the keeping control for the donor animals after receipt.
(2) To establish and maintain records specified in preceding Item (1) b., c., f. and g. for each lot, and to establish and maintain records specified in preceding Item (1) e. for each product.

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 that 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
When thinking about Article 75, three words quickly come into the mind of Dr. D, control, control, and more control. Simply stated, all of the work pursued in creating a rock-solid “Seihin Hyojun Sho” (device master file) and scripting procedures will now need to be applied in the pursuit of process control of medical devices containing a component of biological origin. The expectation is that device manufacturers have adequate resources assigned to manage and perform all activities associated with effective process control. If a device manufacturer’s concept of process control is a closed room with an air conditioner humming along, well the doctor believes the CIO is in for a difficult time, and a brief one at that.

As a minimum, the following elements need to be considered when establishing effective process control:
  • Effective contamination control;
  • Continuous monitoring of the environment i.e., temp and RH (extremely important when employing biochemical technology);
  • Preventing the contamination of column chromatography apparatuses, when such equipment is employed in the manufacturing process;
  • Controlling the conditions influencing culture media, when such media is employed;
  • Performing process validation and documenting and approving the validation protocols and reports, in writing;
  • Ensuring controlled areas have restricted access (no manufacturing in the facility hallways or on the shipping docks);
  • Ensuring adequate sanitation controls  are in place in support of maintaining an aseptic area (free of pathogenic micro-organisms);
  • Ensuring a gowning procedure is in place and  employees are dressed appropriately for access into the cleanroom, i.e. no cargo shorts of flip flops (or California casual);
  • Keeping control of the animals employed as part of the manufacturing process (not acceptable to have cows roaming through the clean room);
  • Proper disposal of contaminated material, including the carcasses of animals and employees (just kidding about the animals);
  • Keeping meticulous records for microorganisms employed during manufacturing (name, date of receipt, organization transferring the microorganism, biological properties, date of testing, and the results of the testing);
  • Verification that the “biological-origin raw materials” actually originated from an animal versus a plant or the CIO; and
  • Ensuring that information collected and provided is in accordance with MHLW rules and regulations.
Guess what? The same inherent controls are also required for cell/tissue based medical devices. In the good ole U.S. of A., HCT/P (Human Cellular Tissue Products) has a dedicated regulation under 21 CFR, Part 1271. The doctor highly recommends reading it, as it is considered the quality system regulation for HCT/P. Article 75 of MO 169 has specific requirements dedicated for the control cell/tissue based products such as:
  • Handling cells and tissues in a manner that prevents cross-contamination;
  • Verifying the cell/tissue received are appropriate for use (this information should be collected and documented in the “Seihin Hyojun Sho” (Device Master File);
  • Ensure the required information is collected for cell/tissue (premises where collected, date of collection, for human tissue – the process for determining suitability for use, for animals – condition of the animal and testing employed, and other tools employed to determine the suitability for use of cell/tissue products);
  • Keeping meticulous records so traceability can be made back to donor animals;
  • Keeping aseptic areas employed for manufacturing aseptic (no employee lunch and learns are permitted in the  clean rooms);
  • Maintaining a list of shippers, addresses, dates and lot numbers (as applicable); and
  • Ensuring product quality is sustained during the delivery process.
Finally, just like the EU or the United States, MHLW is big on having device manufacturers that make medical devices that contain a component of biological-origin or cell/tissue component, keeping meticulous record. Nobody wants to see a repeat of the Chinese heparin debacle. Ensuring records, records, and more records are retained and that such records are defendable during a PMDA inspection needs to be the fundamental goal of device manufacturers wishing to enter their products into the Japanese device market.  If accurate and detailed records are not collected and maintained, the CIO’s destiny could result in a meeting of the ceremonial sword.
What device manufacturers need to do
It is Dr. D’s fondest wish that medical device manufacturers are successful in designing and developing medical devices that are safe and effective in their intended use. That said, the doctor is in the mood for some pontification. Dr. D recently had an opportunity to read all about the Poly Implant Prothesis (PIP) debacle and was appalled at what occurred in this manufacturer of breast implants located in France. For years, PIP perpetrated the ultimate fraud. In 2001, in an effort to save money, PIP began employing industrial-grade silicone gel versus medical-grade silicone gel and continued to lie and defraud regulators about the gel being used. When these sub-standard implants began to rupture and women were being diagnosed with breast tumors, the resulting investigation uncovered the dastardly fraud. The executives involved are currently under indictment in France and will have their day in court in 2013. I hope the guillotines are ready. 
So what does this lovely story have to do with Article 75? In short, it is imperative that device manufacturers always do the right thing. Cost, although important, should never influence patient safety. In regards to Article 75, creating and maintain an aseptic environment is extremely important. No short cuts are ever permitted. When establishing the aseptic area (cleanroom or controlled environment) please ensure that the area is properly validated (static and dynamic conditions). Remember, control is so terribly important when dealing with materials of biological-origin or cell/tissue. As Dr. D recalls, mad-cow is still a dreaded disease and HIV and a variety of hepatitis strains impose a serious threat to public health. Testing, control, and records delineating the origin of these materials are critically important in not only manufacturing a device that is safe and effective but protecting the population (in this case Japan) from disease. 
Considering Article 75 relies on many areas of the QMS to be effective, there is not just one functional area that it can be effectively mapped to. That said, the doctor has taken the opportunity to map Article 75 to the basic requirements for process control associated with the QSR and ISO 13485.

 Table 1.0 – Sample Requirements Matrix

Procedure(s)

 Procedure 

Name(s) 

 Requirement 

 21 CFR, Part 820 

 EN ISO 13485:2012 

 MHLW MO 169

1254-1 Rev B

Production & Process Control

Process Control

 820.170

7.5 & 7.5.1

Article 75 

Takeaways

After months of providing guidance and takeaways, for MO 169, the doctor is growing weary. Dr. D cannot place enough emphasis on the importance of process control, the keeping of meticulous records, the control of an aseptic environment for manufacturing, and the availability of a rusty sword for the CIO to fall on. Considering process controls, record keeping and rusty swords are the general expectations Japanese regulators, Dr. D. will leave the readers with just one takeaway, the importance of constructing and maintaining an aseptic manufacturing environment. Please ensure that the cleanroom/controlled environment has been properly validated and that adequate ongoing monitoring of the operating environment be sustained. Employee hygiene, gowning, temperature controls, the  control of RH, particle counts, bioburden testing, cleaning, maintaining of positive pressure, and Hepa filtration are some of the elements required for maintaining an aseptic environment. Please ensure your organization’s procedures address all of the required elements.

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.” (Article 76 – Testing), sayonara from Dr. D and best wishes for continued professional success.

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

References: 

  1. Code of Federal Regulation. (2012, April). Title 21 Part 820: Quality system regulation. Washington, D.C.: U. S. Government Printing Office.
  2. 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.
  3. EN ISO 13485:2012. (2012, February). Medical devices – quality management systems – requirements for regulatory purposes (EN ISO 13485:2012).
  4. Linguanaut the Japanese phrases and expressions. (2012). Retrieved February 2, 2013, from http://www.linguanaut.com/english_japanese.htm
  5. 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
  6. 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

About The Author

Dr. Christopher Joseph Devine, President, Devine Guidance International

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