This week the term/phrase specific to Japan, the doctor would like to introduce to the readers is “Kore wa nan desu ka
” and if the individual from PMDA asks this question with a stern frown or begins laughing hysterically, you know you just might be in some trouble. The literal translation is the question; “What is this?” If the terms mess, nonsense, or crap, are the object of this question then your organization is definitely in trouble.
All kidding aside, this week’s guidance is all about the manufacturing control of sterile medical devices, validation, and more validation. Regardless of what country’s regulatory bible an organization is reading from and hopefully, complying with, validation of processes is always a salient requirement. Another little known expectation is that sterile medical devices should actually be sterile! Ministerial Ordinance 169 is no different. No one has called the doctor yet, in regards to correcting spelling errors found in the translated version of MO 169, the application of English, and the use of “s” versus “z.” Dr. D has been employing the spell-check feature of MS Word ™ to correct these errors. I do apologize to my friends abroad that frown down upon American English, but hey that is just how the doctor rolls. In this era of continuous regulatory changes, sometimes regulations appear to become “Anthropomorphic” (look-it-up) taking on almost life-like characteristics as they come to life only to rein terror upon those tasked with understanding and complying with these regulations. That being said, Dr. D hopes you enjoy this week’s guidance.
Ministerial Ordinance Number 169 (2004)
Chapter Two “Manufacturing Control and Quality Control in Manufacturing Sites of Medical Device Manufacturers, etc.”
Section Five – Product Realization
(Manufacturing Control of Sterile Medical Devices)
Article 44 The manufacturer in the category specified in Item (2) of Paragraph 5 of Article 26 of Enforcement Regulations or the foreign manufacturer in the category specified in Item (2) of Paragraph 4 of Article 36 of Enforcement Regulations (hereinafter collectively referred to as “sterile-medical-device-category manufacturer, etc.”) shall maintain the records of the process parameters for the sterilization process which was used for each sterilization lot.
2. The sterile-medical-device-category manufacturer, etc. shall ensure that the sterilization records specified in preceding Paragraph 1 are traceable to each production lot of the products.
3. The sterile-medical-device-category manufacturer, etc. shall provide and maintain the following infrastructure in addition to those specified in Paragraphs 1 and 2 of Article 24.
- The buildings and facilities necessary for preventing contamination with dust or microorganisms, according to the manufacturing process of the products, with the proviso that this provision shall not apply in case where the manufacturing facilities, etc. provide equivalent functions,
- The buildings and facilities for maintaining the degree of cleanliness according to the manufacturing process of the products in the work rooms or controlled work areas (the areas consisting of the work rooms, corridors, etc. that are controlled so as to maintain a uniform quality of cleanliness, and hereinafter referred to as such) where the assembling or packaging operations for the products are conducted,
- The facilities for supplying water of the quality and quantity necessary for the manufacturing, according to the type of the products and manufacturing process in the work rooms or controlled work areas where the assembling or packaging operations for the products are conducted,
- The sterilization apparatuses necessary for the manufacturing according to the type of the products, and
- The facilities and equipment necessary for controlling the sterilization process according to the type of the products.
(Validation of Processes for Production and Service Provision)
Article 45 The manufacturer, etc. shall validate any process for the production and service provision where the resulting output cannot be verified by the subsequent monitoring or measurement. This includes any processes where deficiencies become apparent only after the products are in use or the service has been delivered.
2. The manufacturer, etc. shall ensure that the validation demonstrates the ability of the processes specified in preceding Paragraph 1 to achieve the planned results specified in Paragraph 1 of Article 14.
3. The manufacturer, etc. shall establish the arrangements for the processes which should be validated in accordance with the provision of preceding Paragraph 1 including the following items, as applicable
- The defined criteria for the review and approval of the processes,
- The approval of the equipment and the qualification of the personnel,
- The use of the specific methods and procedures,
- The requirements for the records specified in Article 9, and
- The revalidation (conducting the validation again in case where the manufacturing procedure has been changed, etc.).
4. The manufacturer, etc. shall establish the documented procedure for the validation of the application of computer software (and changes to such software and/or its application) for the production and service provision that affect the ability of the products to conform to the specified requirements.
5. The manufacturer, etc. shall ensure that such software applications are validated prior to the initial use.
6. The manufacturer, etc. shall ensure that the records of the validation specified in preceding Paragraphs 1 to 5 are maintained.
(Validation of Sterilization Process)
Article 46 The sterile-medical-device-category manufacturer, etc. shall establish the documented procedure for the validation of the sterilization process.
2. The sterile-medical-device-category manufacturer, etc. shall ensure that the sterilization processes are validated prior to the initial use.
3. The sterile-medical-device-category manufacturer, etc. shall ensure that the records of the validation of each sterilization process are maintained.
What device manufacturers need to know
If your organization’s sterilization process consists of wiping down the product with alcohol, then Houston, Dr. D thinks you have a problem. If the alcohol is of the drinking variety (Jack Daniels) then Houston, we have a big problem. Folks, unlike EN ISO 13485:2003; MO 169 is prescriptive in regards to manufacturing controls influencing product sterilization. Can you say micro-organisms (get your minds out of the gutter) are bad? You see, there is a little tiny monitoring process associated with the manufacturer of sterile medical devices and that is called bioburden. For those of you that read last week’s edition of DG, the doctor lamented on the fact that medical devices must not be built in one’s garage or basement. Besides, stating the obvious, can you imagine the colony forming units hanging around the litter box looking for a free meal? Seriously, MO169 does delineated salient requirements for the manufacturing environment for sterile medical devices. These include:
- Adequate buildings and facilities to prevent contamination (a.k.a. not the garage or basement);
- The work areas actually need to be maintained and cleaned (definitely not Dr. D’s garage);
- The water needs to be controlled (clean); and if necessary sterile (and that doesn’t mean boiling the H2O or nuking it in the microwave);
- The sterilization process must be suitable for the medical device (e.g., gamma radiation versus Ethylene Oxide – EO); and
- Using a sterilization facility that has the appropriate equipment and maintenance to ensure the product is actually sterile (e.g., if antifreeze is leaking from the pipes of a sterilization facility tasked with performing EO sterilization; that would be a bad thing).
If the reader is familiar with 7.5.2 of EN ISO 13485:2003, then MO 169 requirements should look familiar, kind of like a flashback man. In fact, similar validation requirements are expected from the FDA and 21 CFR, Part 820.75. In short, if an output from a process cannot be verified by inspection, monitoring, or measuring, then validation becomes a salient requirement (a.k.a. translated this means not optional dudes). As a minimum, the following elements associated with an effective validation program must be considered:
- Validation must demonstrate the feasibility, accuracy, and repeatability of processes;
- Process validations (IQ, OQ, PQ, and PPQ) actually require a written procedure that delineates the requirements for a validation protocol, including the review and approval process; and
- Validation protocols need to contain/address: (a) equipment approval; (b) qualification of personnel; (c) use of test methods (validated of course); (d) use of procedures; (e) data and record requirements; and (f) the conditions for when re-validation is required.
Similar to ISO and the QSR software must also be validated prior to its use. For example, one cannot just write the code or load the software and state; “It looks like it is working as advertised.” Device manufactures must actually script a procedure for software validation and execute validation protocols for software. Who knew?
Remember Dr. D’s innocuous little poke at sterilizing medical devices with alcohol? If that is your process, and the doctor is guessing it probably is not, it would need to be validated, prior to use. Chances are, your organization is using gamma, e-beam, or EO sterilization in accordance with ISO 11135-1:2007 or ISO 11137-1:2006. Make sure you work with your sterilization facilities when validating the sterilization loads. For example; sterile load configuration, location of dosimeters, residual EO readings, Limulus Ameboycte Lysate (LAL) testing, pyrogen testing etc. all must be considered (depending upon the sterilization method). FYI – Dr. D is not a micro-biologist so all I can state with any confidence is that germs are bad things for sterile medical devices; and so are those little microbial skeletal remains. One final thought, ensure meticulous records are retained in regards to sterilization. You see, regulatory bodies, like records and on occasion they have been known to spend hours-on-end reviewing them.
What device manufacturers need to do
Yes, broken-record time. Written procedures are a requirement and yes, the doctor will continue to recommend a requirements matrix (reference Table 1.0) that maps regulatory requirements to procedures. However, when a device manufacturer is tasked with the manufacturing of sterile medical devices, new levels of controls are required. The good folks of MHLW and PMDA have a thorough understanding of the requirements and oversight necessary in support of manufacturing sterile product. It starts with creating a manufacturing environment that is suitable for the product. For example, if a medical device is an electrophysiological catheter, placed into the right atrium of the heart, the expectation is that manufacturing occur in a controlled environment, employing validated processes, including the sterilization process. All of the work, inspection, and test instructions better be well-documented, reviewed and approved prior to their release for use. Additionally, the operators and inspectors better be trained and their training documented. Furthermore, the controlled environment must actually be controlled. For example, the controlled environment should:
- Be validated;
- Have restricted access;
- Have an employee gowning and hygiene requirement;
- Have requirements for maintaining temperature, humidity, and positive pressure;
- Be monitored for particulate counts;
- Be monitored for potential work surface and air contamination, including the establishment of action levels; and
- Have specific work instructions for cleaning, including janitorial requirements.
Now the doctor is going to go out on a limb here an emphatically state, most of the readers probably work for device companies that do not have their own sterilization capabilities in-house, unless you subscribe to the alcohol wipe-down process. That being said, you will need to work with your sterilization vendor and a test lab to develop a validated sterilization process supported by objective evidence, a.k.a., test data. There are many qualified facilities such as Sterigenics and Nutek for sterilization and Nelson Labs for testing; and no, Dr. D is not a paid spokesperson for these suppliers. Regardless, of the sterilization method selected EO, Gamma Irradiation, E-Beam, Hydrogen Peroxide, Jack Daniels, etc. the processes must be validated. Remember, selection of the sterilization process is not only dependent on the device materials, but is also heavily dependent on the device packaging modality. For example, if permeable packing materials (Tyvek
) are used, EO will probably be the targeted validation method. For packaging schemes that employ foil bags, then sterilization by irradiation is probably going to be the method of choice. Regardless, developing the sterilization validation is going to take some intelligent thought. Who knew?
|1258-1 Rev C
|Control of Sterile Devices
|Manufacturing Control of Sterile Medical Devices
|1259-1 Rev B
|Validation of Processes for Production and
|1260-1 Rev A
|Validation of Sterilization Process
For this week’s guidance, Dr. D will leave the readers with just three takeaways. One – The manufacturing of sterile devices must take place in a controlled environment, with adequate procedures, training, and monitoring in place. Two – Manufacturing medical devices requires the use of validated processes. If an organization does not want to validate their processes, then manufacturing toys for cereal boxes is always a viable option. Three – The sterilization method employed must be validated. Make sure the packaging modality supports the sterilization method.
Until the next edition of DG, when the doctor begins providing guidance on MO 169 – Chapter 2, Section 5 “Product Realization” (Articles 47 through 50 – Identification, Traceability, Traceability of Specially Designated Devices, and Status Identification), sayonara from Dr. D and best wishes for continued professional success.
- Code of Federal Regulation. (2011, April). Title 21 Part 820: Quality system regulation. Washington, D.C.: U. S. Government Printing Office.
- EN ISO 13485:2003. (2004, February). Medical devices – quality management systems – requirements for regulatory purposes (ISO 13485:2003).
- ISO 11135-1:2007. (2007, May). Sterilization of healthcare products – Ethylene oxide – Part 1: Requirements for development and routine control of a sterilization process for medical devices.
- ISO 11137-1:2006. (2006, April). Sterilization of healthcare products – Radiation – Part 1: Requirements for development, validation and routine control of a sterilization process for medical devices.
- 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