(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, andm. 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, andg. 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.
- 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.
- 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.
Table 1.0 – Sample Requirements Matrix
21 CFR, Part 820
EN ISO 13485:2012
MHLW MO 169
1254-1 Rev B
Production & Process Control
7.5 & 7.5.1
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.
- 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).
- 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