REGULATIONS & STANDARDS
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Ames Gross is president and founder of
Pacific Bridge Medical (Bethesda, MD). He can be reached at adgross@pacific bridgemedical.com. |
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Momoko Hirose is an associate at
Pacific Bridge Medical (Bethesda, MD). She can be reached at momokohirose@ pacificbridgemedical.com. |
New Law Overview
In April 2005, Japan’s Ministry of Health, Labor, and Welfare (MHLW) implemented the Pharmaceutical Affairs Law. Many aspects of this law focused on increasing global harmonization. Three of the law’s main reforms that apply to IVD products were the following: adopting international standards such as good manufacturing practices (GMPs), allowing third-party certification instead of requiring direct MHLW approval, and developing a market authorization holder (MAH) system. Today, application forms and certification processes for IVD products differ slightly from other medical devices. Such processes for IVDs tend to be a combination of requirements for devices and drugs.
International Standards
MHLW has adopted many international standards such as global medical device nomenclature, risk classification of medical devices, GMP regulations based on ISO 13485, and summary technical documentation.
The risk classifications have been revised since the changes introduced by the Pharmaceutical Affairs Law, and apply to IVD devices. Former Class III and class IV devices have been merged under Class III and are called highly controlled medical devices. Class II devices are called controlled medical devices, and Class I devices are general medical devices.
Prior to production and sales approval or certification, IVD manufacturers should demonstrate conformity to GMP regulations by submitting appropriate documents. Such documents include a copy of a GMP inspection report from the past two years, an ISO 13485 compatibility certificate, a copy of the registration file, and other documents required by a GMP inspection body. The application form consists of the manufacturer’s contact information, an authorization number and date, the manufacturing category of the production site, and the name of the product manufactured at the site. MHLW or a third party may choose to inspect an IVD manufacturer, even in a foreign country.
Deregulating Product Approval
For certain products, IVD companies can opt for third-party certification instead of direct approval from MHLW. Such third parties, or notified bodies, are approved by MHLW and follow international notification standards (e.g., ISO/IEC Guide 62 on quality systems, and ISO/IEC Guide 65 on product notification). The substantial requirements in Japan for IVD products comply with such established standards, and about 320 IVD reagents fall into this new process of third-party certification. Other deregulation measures include self-certification for Class I IVD devices, provided that the required standards for IVDs are met.
Market Authorization Holder
Under the Pharmaceutical Affairs Law, MHLW developed the MAH system to increase quality and safety controls for medical devices. In the past, foreign IVD manufacturers made the products and released them into the market. However, the MAH system separates the manufacturing responsibilities, which are now under the manufacturer, from market release and postmarketing surveillance tasks, which are under the MAH.
All IVD companies selling their products in Japan are required to appoint an MAH. The MAH may be either a distributor or an independent third party. The company may also designate itself as the MAH if it has its own office in Japan.
By designating a distributor as the MAH, a foreign IVD company can cut down on expenses. A distributor will usually cover the product registration costs and monthly ongoing MAH expenses, expecting the profit margins on the company’s product sales to more than cover such expenses. However, using a distributor as the MAH presents several disadvantages. A foreign company’s confidential information is at risk, since a distributor must have access to pertinent regulatory information (e.g., details on product manufacturing and raw materials). It can also be difficult for a foreign company to change distributors if the current distributor is not performing well.
A foreign IVD company that uses an independent third party as its MAH will be subject to product registration and monthly MAH service fees. However, a third party acting as the MAH should in theory ensure the confidentiality of an IVD company’s product information, more so than a distributor. By definition, it is easier to switch distributors with an independent third party as the MAH since the registration is under the manufacturer’s name.
An IVD company could also utilize its subsidiary or branch office as its MAH, as long as the office is located in Japan and meets MHLW’s MAH standards. The benefits include being able to send confidential information only to trusted employees and having more direct control over marketing strategies. However, in this scenario, the costs of hiring people, renting an office, and other related fees will not be cheap in Japan.
MAHs are primarily focused on product registration and postmarketing issues, such as recalls or adverse events. Quality assurance in the MAH must comply with good quality practices. The MAH is responsible for assuring proper manufacturing and quality control, and must maintain self-inspections and employee training. Any quality defects and quality information also fall under the MAH’s responsibility. In addition, the MAH can control storage of the product, and take care of documents and records.
MHLW has set specific requirements for the MAH’s structure and the number of staff, depending on the classification of the IVDs being sold in Japan. For general devices (Class I), an MAH can be established with one regulatory person. Controlled devices (Class II) require an MAH with two persons: a quality assurance controller and a postmarketing safety controller. One of the controllers may also serve as general manager. Highly controlled devices (Class III) require an MAH with three people, each serving as a controller.
The MAH should maintain good relationships with all IVD manufacturing sites to ensure that all parties involved can coordinate together. Each party should agree on the scope of their responsibilities, including not only standard operating procedures for manufacturing process control, quality control, and shipment of product, but also on the technical requirements of the manufacturing processes and testing methods. The MAH should verify periodically that operations at any manufacturing site are in accordance with GMPs and quality management systems. Quality control systems should be in place for transportation and delivery of the products. Any changes or other issues should be coordinated and agreed upon by the involved parties. To uphold all these responsibilities and maintain coordination, a cohesive communication system between the manufacturing sites and the MAH is essential.
Obtaining MAH Approval
The following documents are required to obtain approval for an MAH:
Application form for an MAH license.
Letter of employment. Explain details of employer, employees, job titles, typical working hours, and holidays.
Background information of the MAH general manager. Explain the general manager’s related experience, such as the last three years of experience in a quality assurance or postmarketing safety role with a pharmaceutical or medical device company. Applicants should also attach a diploma verifying a bachelor’s degree in a science or engineering field.
Information map of the office location. Include a map explaining how to find the company, including address, phone number, etc.
Copy of corporate registration. Corporate registration is a public document specifying an IVD company’s name, address, corporate status, etc. The company must submit a certified copy obtained less than six months before the application.
Chart of the division of duties of the directors. Specify roles of members of board of directors, and who reports to whom.
Doctor’s certificate. Certify lack of mental disability or drug addiction. This document must have been issued less than three months before application, and requires a doctor’s signature.
Organizational chart (company tree). Explain relationships within the MAH: R&D department, distribution department, marketing department, etc.
Good quality practices structure. Explain the company’s structure as it relates to good quality practices, including clarification of relationships between the quality controller, R&D department in Japan, distribution department in Japan, marketing department in Japan, foreign manufacturer, third-party manufacturers, etc.
Good vigilance practices structure. Explain the company’s structure as it relates to good vigilance practices, including clarification of the relationships between the safety controller, R&D department in Japan, distribution department in Japan, marketing department in Japan, other customers, etc.
Storage information. If IVD products are stored, include storage information such as floor plan with location of shelves, etc.
Floor layout of the office. Provide a floor plan of the office. If labeling, packaging, or storage is done at the office, specify the locations of such processes.
Company code registration form. When an IVD manufacturer receives an MAH or manufacturing license, it will also be assigned a company code. In this registration form, include the applicant’s name, address, phone number, and the type of operation (manufacturing, marketing, or repairing). After the license is granted, the manufac- turer will receive the company code based on this form.
Foreign Manufacturer Authorization
As mentioned previously, foreign IVD manufacturers without an office in Japan must be accredited by MHLW authorization, while confirming compliance to GMPs. Though foreign manufacturers can choose to apply for authorization and IVD product approval concurrently, it is highly recommended that they receive authorization and confirm GMPs beforehand. Authorization usually consists of an MHLW audit, although ISO 13485:2003 holders may be deemed exempt from such an audit. The MAH will usually apply for authorization.
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Table I. (click to enlarge) Licenses and authorizations required for IVD manufacturing sites in Japan. Source: Pacific Bridge Medical (Bethesda, MD). |
The application consists of each manufacturing site’s contact information, the site’s manufacturing category, outline of the facility and equipment, the plant manager’s and managing director’s contact information, the managing director’s stamp or signature, and other documents. The supplemental forms include a self-declaration of the managing director, the plant manager’s resume, a list of products manufactured at the Japan sites, a copy of the manufacturing license, and other documents relating to the facility and equipment.
Applying for IVD Product Approval
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Table II. (click to enlarge) Application processes for IVD product approval for each risk class. Source: Pacific Bridge Medical (Bethesda, MD).
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For IVD devices, the product approval form is similar to other medical devices. Marketing and manufacturing licenses should be confirmed before applying for IVD product approval. Table II explains which application process (notification, certification, or approval) is appropriate for each risk class of IVD devices. Each device has a different application process depending on whether it meets the standard for its class, does not meet the standard for its class, or if standards are not applicable to the device. Highly controlled medical devices (Class III) require ap- proval from MHLW since they are often high-risk products.
The application form is detailed and lengthy, ranging from basic questions on product name, shape, and operating procedure to questions on quality control and requests for extensive data on the materials and products used. Other details on the application include specifications on shape and structural aspects that affect the performance of the product, versus those that do not affect performance.
Many of the IVD product’s specifications (e.g., storage, expiration date, ingredients, and manufacturing processes) must also be supported with data showing the reasons for picking certain expiration ranges or operating procedures. However, the specific requirements for data in the application form depend on the device’s risk classification and its parameters. For example, a Class III device that meets approval standards and confirmation would not need to describe data of important reaction conditions; but a Class II device not complying with the approval or certification standards would.
One reason for listing manufacturing sites is that even IVD companies involved in only labeling and packaging must have a manufacturing license, since they are considered manufacturing sites. Most companies manufacturing overseas tend to hire a Japanese company to package, label, and store the products. Flow-charts explaining each manufacturing process at each site are often required.
Conclusion
IVD product registration in Japan must start with the appropriate certifications, such as manufacturing licenses and marketing licenses. Before applying for IVD product approval, manufacturing sites will have to demonstrate GMPs and receive the correct approval, notification, or certification as required on the product. For foreign manufacturers without a branch office in Japan, MAHs will be integral in this process.
Once preliminary requirements have been fulfilled, an IVD manufacturer must go through a detailed and lengthy application process on the product itself. Accurate data on all aspects of the product are essential when filling out the forms, though specific requirements depend on the device classification and parameters.
Japan’s growing demand for IVDs is expected to spread throughout Asia, affecting China and India. From improved STD testing to more-sensitive cardiovascular assays, IVD devices are increasingly becoming important in preventive and diagnostic care in Japan.
