Ohayou Gozaimasu. This week the term/phrase specific to Japan, the doctor would like to introduce to the readers is: “Watashi no namae wa Chief Impalable Officer (CIO)” For those of you moderately fluent in Japanese, the phrase is: 私の名前は Chief Impalable Officer. The literal translation is “My name is Chief Impalable Officer.” This response should be used along with a slight bow as the CIO introduces him or herself to PMDA prior to the commencement of a PMDA inspection.

One element of Ministerial Ordinance 169 (MO 169), Dr. D has grown to love is having of multiple types of devices covered in on succinct regulation versus in multiple documents much like the EU and the MDD, IVDD, and AIMDD. Enough acronyms for you? It makes life so much simpler for the quality and regulatory folks. On another note, the doctor received an email from one of my readers. This individual was not enjoying Dr. D’s attempts at levity. The doctor sends his apologies; however, a little “taradiddle” (look-it-up) is good for the soul. Besides, who doesn’t like seeing the CIO sweat a little bit when presented with a ceremonial sword?

Ministerial Ordinance Number 169 (2004)
Chapter 4 – Manufacturing Control and Quality Control in Manufacturing Sites of Biological-origin Medical Device, etc. Manufacturers, etc.
(Infrastructure of Manufacturing Sites of Manufacturers, etc. of Specified Biological-origin Medical Devices, etc.)
Article 73
The manufacturer, etc. of the products concerned with the medical devices which correspond to the specified biological-origin products specified in Paragraph 10 of Article 2 of Law (hereinafter referred to as “specified biological-origin medical devices, etc.”), the medical devices designated by Minister of Health, Labor 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 “specified biological-origin medical devices, etc.”) (hereinafter collectively referred to as “specified biological-origin medical device, etc. manufacturers, etc.”) shall meet the following requirements in addition to those specified in Paragraphs 1 and 2 of Article 24 and Paragraph 3 of Article 44.

1. To be ensured that the facilities for supplying the distilled water, etc. necessary for manufacturing the products are provided with the structure necessary for preventing contamination of the distilled water, etc. with foreign particulate matter or microorganisms,
2. To be ensured that the work areas meet the following requirements, 

a. Being ensured that the work rooms or controlled work areas, among the work areas, are provided with the buildings and facilities for maintaining the degree of cleanliness according to the manufacturing process,

b. Being ensured that the work rooms for the drying operations or sterilizing operations for the cleaned containers are exclusively used for such operations, with the proviso that this provision shall not apply in case where the cleaned containers could not be contaminated,

c. Being provided with the following facilities in the rooms distinctly segregated from other rooms, with the proviso that this provision shall not apply in case where such facilities are verified not to be necessary for the manufacturing of the products according to the type, manufacturing procedure, etc. of such products,

(i) The facilities for storing the microorganisms,

(ii) The facilities for keeping the animals for utilizing in the manufacturing or testing after inoculation with the microorganisms,

(iii) The facilities for treating the animals for utilizing in the manufacturing or testing,

(iv) The facilities for inoculating the microorganisms into the culture media, etc.,

(v) The facilities for cultivating the microorganisms,

(vi) The facilities for collecting, inactivating, sterilizing, etc., the cultured microorganisms, and

(vii) The facilities for disinfecting the equipment and instruments used in the manufacturing and testing.

d. Being ensured that the surfaces of the ceilings, walls and floors of the rooms provided with the facilities specified in preceding c.(ii) to (iv) and (vi) are the structure which can be easily cleaned and allow disinfection, and

e. Being ensured that the rooms provided with the facilities specified in preceding c. (iv) and (vi) meet the following requirements.

(i) Being aseptic rooms, with the proviso that this provision shall not apply in case where such work rooms are provided with the facilities which have functions to allow that the aseptic operations are conducted without hindrance according to the type, manufacturing procedure, etc. of the products, and

(ii) Being ensured that the aseptic rooms specified in preceding (i) are provided with the adjourning anterooms exclusively used for the rooms so that the rooms are routinely accessible only through such anterooms, and not being placed the entrances of the anterooms, and not being placed the entrances of the anterooms directly leading to the outside.

(3) To be ensured that the work areas for the products concerned with the cell/tissue-based medical devices meet the following requirements, and

a. Being ensured that the areas for receiving and processing the materials, storing the products, etc. are segregated from other areas for manufacturing the products, and

b. Being provided the areas for receiving and processing the materials, storing the products, etc. with the buildings and facilities necessary for conducting such operations.

(4) To be ensured that the areas for manufacturing the products using human blood or plasma as the materials are distinctly segregated from other areas and provided with the facilities and equipment exclusively used for such manufacturing, with the proviso that this provision shall not apply to the manufacturing process subsequent to the process of inactivating or removing viruses.

What device manufacturers need to know
When dealing with devices that contain a component consisting of material(s) of biological-origin, manufacturers are required to implement additional controls to prevent contamination. To the doctor, this sound pretty much like plain old-fashion common sense. For example:

• Suppliers of distilled water, used in device manufacturing, must ensure the water is not contaminated;
• Buildings, facilities, and manufacturing areas (controlled environments) must be adequately maintained and cleaned; and
• Dedicated clean carriers and clean containers (the key word here is CLEAN) employed for product drying or sterilization must be dedicated to the functional area.

Facilities and/or rooms employed for: (a) storing microorganisms; (b) keeping animals utilized in manufacturing or testing of inoculation of microorganisms; (c) treating animals employed in product manufacturing; (d) inoculating microorganisms into culture media; (e) cultivating microorganisms; (f) collecting, inactivating, sterilizing, and performing other relevant activities ending in the “ing” of cultivated microorganisms; and (g) disinfecting equipment and instruments employed during manufacturing and testing must be segregated. You see, contamination is a bad thing; and since Dr. D is not a microbiologists, my view of contamination and germs is eloquently simple. Contamination and germs are bad!

Other relevant points manufacturers need to be aware of are:

• Walls, ceiling tiles, flooring, and work surfaces must be conducive to being easily cleaned with a disinfectant (as applicable);
• Aseptic rooms (rooms free of pathogenic microorganisms) shall be employed (as appropriate); and
• Anterooms (adjacent rooms typically employed for gowning) shall be employed (as appropriate).

For cell-tissue based devices there are additional requirements device manufacturers need to implement: (a) areas employed for receiving, processing, and storage must be segregated; and (b) the areas for receiving, processing, and storage must be adequate for the activities being performed. Finally, areas employed for manufacturing products that contain human blood or plasma must be “distinctly segregated” from other areas. That means not keeping blood products in the same fridge used to store employee lunches (unless on your employees is a vampire). Facilities and equipment used must be dedicated for products employing human blood or plasma. This means device manufacturers cannot move this equipment routinely around their facility for other applications.

What device manufacturers need to do
First off, written procedures are required that delineate the appropriate controls are in place to handle material and devices containing materials of biological origin. Because of the diversity of need for handling biologics, several procedures are typically required. For example, device manufacturers that employ a biological-origin component are going to need to consider some of the following procedures (note: some of these requirements can be combined within one succinct procedure):

• Cleanroom/Controlled Environment Monitoring Procedure (containing RH, temperature, positive pressure, and particle count requirements, including control and action limits);
• Maintenance Procedure (focus on HEPA Filtration);
• Gowning Procedure (don’t forget about the washing of hands);
• Bioburden, Air, and Surface Contamination Testing Procedure;
• Personal Employee Hygiene Procedure;
• Handling and Storage Procedure;
• Receiving Procedure;
• Cleanroom/Controlled Environment Cleaning Procedure;
• Product Decontamination Procedure; and
• Equipment Handling Procedure.

Additionally, training is extremely important when handing material and devices containing biological-origin material. The training focus should be placed on proper material handling, storage, and correct gowning techniques for the cleanroom/controlled environment. Furthermore, do not forget to validate the cleanroom/controlled environment (static and dynamic states). Finally, when in doubt remember one of Dr. D’s mantras; “Germs are bad.”

In Table 1.0, the doctor would like to point out that Article 73, by design, will align with multiple requirements depicted in regulations and standards. Infrastructure and Work Environment are just two of the possibilities. Material handling and storage are also important.

Table 1.0 – Sample Requirements Matrix
Procedure(s)	Procedure Name(s)	Requirement	21 CFR, Part 820	EN ISO 13485:2012	MHLW MO 169
1248-1, Rev D	Infrastructure Work Environment	Infrastructure	820.70	6.3 6.4	Article 73

Takeaways
For this edition of DG, the doctor will leave the readers with four takeaways. One – the Japanese regulatory authorities take seriously the need to adequately identify and control medical devices that contain a biological-origin component. This means device manufacturers must establish and validate a cleanroom/controlled environment for manufacturing activities. Two – procedures, procedures, and more procedures are required. Make sure all elements required by Article 73 are covered by a procedure or some form of written work instruction. Three – training, training, and more training is the key to success when manufacturing devices with a component of biological-origin. Never take anything to chance when it comes to conveying the importance of handling, processing, or storing devices containing a component of biological-origin. Why? Because. Because why Dr. D? Because, Mr. Murphy is alive and well and loves to hang around the manufacturing facilities of medical device manufacturers, regardless of their location. Four – probably not wise to let vampires work around devices that contain a human blood derivative. If this cannot be avoided, ensure these employees work the night shift.

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 74 – Documents Concerned with Manufacturing Control and Quality Control), sayonara from Dr. D and best wishes for continued professional success.

References: 

1. Code of Federal Regulation. (2011, April). Title 21 Part 820: Quality system regulation. Washington, D.C.: U. S. Government Printing Office.
2. EN ISO 13485:2012. (2012, February). Medical devices – quality management systems – requirements for regulatory purposes (EN ISO 13485:2012).
3. Linguanaut the Japanese phrases and expressions. (2012). Retrieved September 8, 2012, from http://www.linguanaut.com/english_japanese.htm.
4. 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.
5. 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.