REGULATORY OUTLOOK
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McRoberts
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Japan's consumption of medical devices makes it an attractive market for global medical device manufacturers. But manufacturers hoping to sell their devices in Japan must pay careful attention to the revised Pharmaceutical Affairs Law (PAL). It aligns Japan's regulatory requirements more closely with those of other advanced nations. In this article, we examine the changes, challenges, and benefits of the revised PAL.
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Ohyama
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After the financial slowdown in the mid-1990s, Japan's economic fortunes have begun to increase—and so has the country's appetite for medical devices. In 2004, medical devices constituted an estimated $19 billion–market in Japan, larger than all other Asian markets. During the next few years, as Japan's economy continues to grow, imports of foreign medical devices are expected to grow by 5–8% annually and continue to represent 10% of the world market for medical devices.1
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Kambeitz
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Despite the favorable prospects for exporting medical devices to Japan, all foreign medical manufacturers must still contend with a legal requirement stipulating that all medical products be registered with the Japanese Ministry of Health, Labour, and Welfare (MHLW), Japan's equivalent of FDA. This law has become increasingly instrumental to Japan's device market because products grandfathered in prior to 2005 must comply with the revised PAL when their existing Shonin (regulatory approval) expires. Manufacturers will also have to deal with the PAL when they need to make a significant change to a product that would require premarket clearance. In Japan, medical device manufacturers and importers are also expected to demonstrate certain behaviors associated with corporate social responsibility. Hence, the Japanese government requires foreign device manufacturers to maintain a physical presence in Japan so that remedies for identified safety problems with a device can be applied immediately.
Amended Legislation for Medical Devices
The PAL is the most important legislation for foreign device firms hoping to sell products in the Japanese market. In July 2002, the Japanese House of Representatives passed the amended PAL, which is applicable to all medical devices, drugs, quasidrugs, and cosmetics entering the Japanese market. It became effective April 1, 2005, and has the following objectives:
- To enhance safety measures for medical devices sold in Japan.
- To strengthen postmarketing safety measures for medical devices.
- To align Japan's medical device regulatory system with prevailing international systems.
In order to apply for the necessary regulatory clearance to market a device, manufacturers outside of Japan must appoint a marketing authorization holder (MAH) as their representative in Japan. The MAH may be a subsidiary of the manufacturer through common ownership or may be an independent entity, but the manufacturer must establish a detailed contract with the MAH in accordance with the requirements of the amended PAL and related ministerial ordinance (MO).
If a manufacturer wishes to have its subsidiary or sales office as the MAH, then the subsidiary must be licensed as an MAH by the appropriate prefecture (comparable to county) government in Japan in accordance with MOs 135 and 136. This enables the MAH to be accredited by MHLW to apply for PAL certification. Only these legal license holders can apply for and hold PAL certification of medical devices. For a foreign manufacturer to become an MAH on its own, it must be accredited as a special MAH by the Pharmaceuticals and Medical Devices Agency (PMDA), an executive arm of MHLW also known as Kiko. The manufacturer must also nominate a representative in Japan.
Under the amended PAL, foreign manufacturers of all classes of medical devices are also required to obtain foreign manufacturing accreditation for their manufacturing facilities. This accreditation can only be obtained by applying through the MAH to PMDA. MO 2 outlines the requirements for accreditation. Manufacturers that sold products in Japan before the PAL was amended may have been granted temporary foreign manufacturing accreditation, which means they can delay their application for accreditation until 2008. After 2008, foreign manufacturing facilities must be reaccredited under the new regulation (MO 2).
The Quality Management Systems Ministerial Ordinance on Medical Devices and In Vitro Diagnostics (MO 169, also known as the QMS ordinance), implemented in 2005, lacked certain requirements integral to ISO 13485:2003. These requirements, which outlined management responsibility, risk management in production, design controls (if applicable), criteria for suppliers, process validation, and analysis of data, were not mandatory in Japanese regulations until April 2007. Therefore, it is possible that early accreditation assessments to MO 169 did not include these elements. Manufacturers with a current Japanese QMS and those submitting new applications should ensure that these requirements are properly satisfied in time for surveillance visits.
Another key change brought by the revised PAL is that Class II medical devices, which are designated as controlled medical devices, have now shifted from ministerial-level approval to designated third-party approval (see Table I). In other words, MAHs for Class II medical devices can obtain a certification of product conformance from a registered third-party certification body rather than directly from PMDA. This change allows manufacturers to get their products certified faster and also tap into the technical expertise of third-party certification bodies. However, only certain designated Class II medical devices can benefit from the third-party approval process. A Japanese Industrial Standard (JIS)—a mandatory performance standard—must be established for a medical device to be eligible. In many instances, the mandatory JIS standard is equivalent to an IEC standard, such as the second edition of IEC 60601-1. Class II devices for which no JIS standard has been established may not use a third-party certification body and must apply to PMDA directly.
Out of the 4044 total device types identified by MHLW, only 1785 are designated as Class II, and less than half of those are currently designated as controlled medical devices eligible for third-party approval. The JIS conformity assessment standard and essential requirements are designated by MHLW by device type, which enables third-party assessment of such Class II devices. Article 41 of the revised PAL requires the minister to establish necessary standards after seeking the opinion of the Pharmaceutical Affairs Food and Sanitation Council (also called Bukai). The list of devices eligible for third-party approval is continually growing as MHLW approves additional essential-principles checklists.
An application for a Class II device license requires an assessment of the quality management system of the device manufacturer (including foreign manufacturers) to the requirements of MO 169. This ordinance is based entirely on ISO 13485:2003, with some additional requirements for the Japanese market. Manufacturers of Class II active medical devices may include or exclude requirements for design and development depending on the designation by MHLW. This assessment may be carried out by local assessors trained on Japanese requirements and qualified by the third party. Some third parties, because of the location of their audit staff, must dispatch their assessors from Japan and coordinate logistics, including travel and lodging for the audit team and its translators.
Obtaining a device license also involves an evaluation of the technical documentation for the medical device. This is similar to the requirements outlined in the Global Harmonization Task Force's Summary Technical Documentation for Demonstrating Conformity to the Essential Principles of Safety and Performance of Medical Devices document. Japanese regulations may also require additional information, such as proof of compliance with the JIS performance standard. The MAH is required to present this information in Japanese to the third-party assessor.
Selecting a Third-Party Approval Body
There are a variety of services provided by third parties. By carefully choosing a third-party approval body, an MAH can take advantage of additional accreditations and services that the third-party organizations offer. Some third parties allow the supporting documents, which demonstrate a device's conformity to the applicable JIS or IEC standards, to be assessed in English (to deliver a degree of confidence) before undergoing a costly translation process. Foreign manufacturers may want to consider this service when their original technical file has already been approved by another public health authority. Allowing supporting documents to be assessed in English would ensure that all requirements of the Japanese regulations are included in a device's technical file, since some requirements may be specific to the Japanese regulatory system.
A medical device company should also consider testing requirements when choosing its third party. Not all JIS standards are based on IEC requirements. If a device has already been tested for markets outside of Japan, it is possible that some of the mechanical and engineering decisions can be made based on previous tests, especially if the device is not electrical (nonactive) or if a switching power supply is used. (It is important to note that the electrical system in Japan is 100 V ac at both 50 and 60 Hz.)
Manufacturers that want to market devices in Japan should consider that marketing goal in their design phase and incorporate flexibility into their design to meet the country's requirements. This gives them a better opportunity to have EN (European Union), NRTL (United States and Canada), and JIS testing done simultaneously. Although additional samples and time may be needed to complete the JIS testing, a third party that is accredited in all of the company's current and anticipated sales markets can minimize redundant tests whenever possible.
As mentioned, the revised PAL brought with it a requirement to manufacture under an audited quality management system, which ensures conformity with JGMP requirements. When a device manufacturer chooses a third party, it should also consider the location of the JGMP-qualified auditors and whether the JGMP audit can be combined with the quality management system audits required by the United States, Canada, and the European Union.
FDA's accredited persons inspection program audits to 21 CFR 820 requirements, but the program is only open to those companies that are not under FDA scrutiny (i.e., increased FDA attention owing to nonconformities, product recalls, etc.). Because low-risk device manufacturers are only periodically audited by FDA and these audits cost very little, the only incentive for FDA establishments to use a third party for inspections is the predictability of the audit.
The European Union allows an ISO 13485–based audit to meet Annex V requirements under the Medical Devices Directive and Annex IV under the In Vitro Diagnostic Directive. The Canadian Medical Devices Conformity Assessment System is strictly based on ISO 13485. Therefore, many manufacturers maintain an ISO 13485 registration with many clauses and elements similar to JGMP requirements. As a result, third parties that offer accreditations for all of these regulatory programs can offer integrated audits, which are less time-consuming, less intrusive, and potentially less costly to the manufacturer.
Other considerations the MAH should make in choosing a third party are experience, trust, and the MAH's relationship with the organization. Bear in mind that all applications for device licensing to a third party can only be made through the MAH located in Japan to the third-party certification body in Japan. However, the value of local support for foreign manufacturers is worth considering in understanding the requirements these manufacturers must meet.
The Goal of Alignment
As indicated, one of the goals of the revised PAL was to align Japan's medical device regulatory system with those of other advanced nations, namely those of the United States and the European Union. Because these nations produce and consume the majority of the world's medical devices, the regulatory practices in these regions are generally the ones accepted and adopted by device manufacturers worldwide. Just as with the regulatory systems from these regions, Japan's revised PAL allows third parties to conduct assessments of Class II medical devices for certification to market and sell in a particular region. Both EU and U.S. health authorities also require an audit of each manufacturing location to ensure that the quality system conforms to GMPs. The last similarity is the identification of an in-country representative—the MAH in Japan, the agent in the United States, and the authorized representative (AR) in the European Union. The biggest difference is that the MAH, as the name implies, takes over ownership and responsibility for certification, whereas the AR and the agent work on behalf of the manufacturer.
Conclusion
Although the revised PAL aligns more closely with general international requirements for medical devices, demonstrating conformance with the PAL still requires manufacturers to invest time and effort to understand its requirements. Once the regulatory process is defined, manufacturers must still contend with the challenges and cost of device-specific processes for reimbursement, distribution, and packaging. However, if the Japanese medical device market continues to grow and maintains its need for foreign medical devices, meeting PAL and MHLW requirements may be a worthwhile investment for device manufacturers.
Steve McRoberts is Underwriters Laboratories' (UL) global principal engineer for medical regulatory programs. Seiko Ohyama is a lead engineering associate working for UL-Japan Inc. Tara Kambeitz is the global marketing manager for UL's medical business unit. She can be reached at [email protected].
1. U.S. International Trade Commission, Medical Devices and Equipment: Competitive Conditions Affecting U.S. Trade in Japan and Other Principal Foreign Markets, March 2007; available from Internet: http://hotdocs.usitc.gov/docs/pubs/332/pub3909.pdf.
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