Introduction
Japan’s long recession is over. After a frustrating period of starts, stops, and even reverses in economic growth (1990-2002), Japan’s GDP growth has stayed near or above 2% since 2003.
With its affluent and aging population, Japan is the second-largest medical market in the world. Over the past ten years, Japan has seen its elderly population rise sharply, with those over 65 years of age increasing from 10% of its total population to over 20%. With a declining overall population, a low birthrate, and a shrinking ratio of productive population to aging population, maintaining adequate healthcare has been a priority of the Japanese government. From 1997 to 2003, government spending on healthcare increased from 6.8% of GDP to approximately 8.0%. Japan remains a key market for medical devices, especially higher-end products, with its medical device market still towering over the rest of Asia’s at $25 billion.
Despite increased spending and the general acceptance of more foreign products, Japan’s healthcare market is quite different from the US healthcare market. In the US, we often have the best technology and strive to provide an “A” level of healthcare to those who can afford it. Of course, about 45 million people in the US do not have health insurance and thus have no access to such an “A” plan. By contrast, in Japan, the healthcare system is universal. So, in general terms, Japan policymakers are often seeking to provide a “B” level of healthcare universally and may not want to accept a recent new product which may only help a small fraction of the population, or spend a lot of money keeping almost-terminal patients alive.
Japan is a huge, sophisticated market, but also one with a powerful regulatory system and many unique requirements. To enter or expand in the Japanese device market, it is crucial to stay on top of regulatory developments.
The 2005 PAL amendments to Japan’s medical product laws contained a number of significant regulatory changes. There were changes to requirements for importing, clinical trials, and post-marketing surveillance. Also included was a new implementation of GMP for medical devices, which affected all device manufacturers selling their products to Japan. Passing audits under these new standards is essential to get one’s device registered in Japan. This article will outline the varying kinds of audits Japan’s Pharmaceuticals and Medical Devices Agency (PMDA) now conducts for foreign manufacturers, their objectives and contents, and best practices for handling them.
Types of audits
There are two main types of inspection that the PMDA conducts. The first is simply to accredit the buildings and facilities of a manufacturer, and at the end issue a foreign manufacturer accreditation. The second is to evaluate the manufacturer’s quality management system (QMS) and see that it meets Japanese QMS standards, as part of obtaining registration for a specific device. Only the second inspection is a GMP-based inspection. For short, the first is called an accreditation inspection, and the second is called a QMS compliance inspection. Although these are called audits or inspections, they do not necessarily involve on-site inspections.
To date, all reported accreditation inspections have been conducted through document review, with no on-site inspections. At this point the PMDA is not planning to use on-site inspections in accreditation. The only possible future exception is if a particularly risky device comes up they wish to examine more closely, but this is unlikely.
QMS compliance inspections, unlike accreditation inspections, may often be on-site. Their structure will be discussed further below.
Accreditation certification
It is necessary to receive accreditation as a foreign device manufacturer before submitting a device registration application, and the main requirement for this is an inspection focusing on building and facilities. It should be noted that for Class I devices, no inspection is required to be accredited. For Class II devices, a Notified Body can do the inspection, but only if the Japanese government has issued technical standards for the device. (These standards, issued by the PMDA to standardize various devices such as stents, tend to correspond to ISO/ASTM standards.) For everything in higher risk levels, the PMDA itself must do the inspection. This means devices in class II without technical standards, class III, or class IV need inspection by the PMDA.
If we trace the whole accreditation process, the initial application should be made to the PMDA’s Evaluation and Licensing Division (ELD). The Quality Control Division then performs the actual assessment. It passes its results back to the ELD, which gets the official manufacturer certification from the Ministry of Health, Labor and Welfare (MHLW), and then passes the foreign manufacturer certification (nintei) to the applicant.
The PMDA requires the submission of a number of documents to receive accreditation. Although these may vary, they can be divided into a few categories. First is information on the staff: an organization chart, the plant manager’s curriculum vitae, and the same manager’s self-declaration of health. Second is information on the product, including details of its manufacturing process, as well as its Certificate to Foreign Government or Free Sale Certificate. Last is information on the manufacturing site itself: outline, floor plan, area map, etc. Any site involved in production of the device is a subject for inspection. This includes subcontractors, but does not include suppliers of raw materials.
After document submission, the PMDA will review the submission and may also conduct a Q&A phase before approval or rejection. Accreditation generally takes a total of about 6 months.
So far, as of March 2006, the PMDA had accredited the facilities of 126 overseas device manufacturers. Another 142 inspections were underway. As mentioned above, none of these accreditations have required an on-site inspection yet. However, procedures have been set up in case an inspection is called for. Besides paying for accommodations and travel, the manufacturer must pay a daily allowance for the inspectors’ time. Allowance and accommodation fees are scaled based on the inspector’s rank and the expense of the city visited.
QMS Compliance Inspections
The type of inspection which is more likely to have an on-site phase is the QMS Compliance Inspection. This is an implementation of the “Japanese Quality Management System,” which was established in its current form in April 2005, the same time that the amended PAL came into effect. Japanese QMS is broadly equivalent to ISO13485:2003, or, in other words, medical device GMP. Therefore, this article will not go into its contents in detail but will describe the main ways in which it is different from its ISO counterpart.
QMS Compliance Inspections are divided up by risk level in the same way that accreditation inspections are. For class I, no inspection applies; for class II with technical standards, inspection by a Notified Body; for all other class II as well as all of classes III and IV, inspection by the PMDA. Again, the PMDA can choose whether to conduct the required inspection on-site or through documentation only. An inspection is a mandatory part of a new medical device application, or of a partial change application which involves the manufacturing or quality control process.
However, if the plant has already received QMS approval for another device of an equal or greater risk class, it will not need another inspection. This means that even though technically QMS inspection is part of the process of product registration, in practice, the approval is tied to the manufacturing site, not the product.
It is also important to keep in mind that the Japanese government requires applications to be submitted by way of the manufacturer’s Marketing Authorization Holder (MAH) in Japan. (The MAH is the legal entity importing devices into Japan on a manufacturer’s behalf.) This is because the MAH holds responsibility for the quality of the devices it sells, and for application purposes it is considered as a single unit with the manufacturer. Accreditation of the original manufacturer is also a requirement for the separate accreditation of the MAH itself.
In choosing for which devices to do an on-site inspection rather than document review, the PMDA generally looks for devices in a high risk class (i.e., classes III and IV), with past compliance issues, or with manufacturing process complexity. Most attention rests on new devices, cellular or tissue-based devices, etc.
In addition, QMS approvals do not last indefinitely. QMS approval expires after five years, and the manufacturer must apply for renewal six months before expiration. This renewal inspection can apply to all devices manufactured at the plant and registered in Japan. The PMDA can also conduct inspections at times of its own discretion, in case of reports of quality problems.
QMS inspections are performed on all facilities involved in the quality management process. This can include outside design and development facilities or testing labs, whether they are done by the manufacturer itself or subcontracted. However, these outside facilities are not included in inspections for license renewal.
Documentary requirements
A key difference between Japanese QMS requirements and conventional ISO13485:2003 requirements is the production and maintenance of a document called the Seihin HyÅjunsho, roughly equivalent to a “Device Master Record” (DMR). The purpose of this document is to detail the relationship between the individual product’s specifications and the site’s overall quality system. As such, it has a large number of required items.
Items 1 through 8 in the DMR are items that also appear in a standard form in a product registration document: device name, specifications, operation procedures, manufacturing method, design and drawings, countries of origin and sale, labeling and packaging, etc. But there are twelve more items besides these. They range widely from testing methods and storage conditions to the document of agreement between the manufacturer and its MAH. Also, if more stringent testing methods than those required are used, they too must be detailed. Every item in the DMR must connect to a provision in the plant’s general quality management system which is applicable to that specification. In that way, the inspectors can examine the QMS system in the context of any individual device.
In a pre-approval inspection (i.e., one done in order to get product registration), the PMDA needs to review the following documents before it determines whether to also perform an on-site inspection: a detailed floor plan, the quality management manual, device information (including the Seihin HyÅjunsho), manufacturing process flow, etc. If the inspection is meant to cover multiple devices, device information for each one should be provided.
In a post-approval inspection (i.e., for renewal), more documents must be submitted as well as the ones listed above. Further required documents include, for the plant as a whole, a record of all product recalls for the past 5 years and a declaration of compliance with Japanese QMS standards. For the selected product(s), they include the Japanese product registration application, any partial or minor change applications, ISO13485:2003 compliance certification, and the past 2 years’ QMS surveillance reports. The documentation should also include the number of products manufactured per year for the past 3 years, as well as explanations for any changes to the quality control system.
The PMDA will, of course, issue a complete list of the documents it requires to the manufacturer being audited. It has the authority to request other documents at its discretion.
Inspection Process
In the auditing process, there will be a document review phase no matter whether there is also an on-site phase. This means that, first of all, the various documents described above should be submitted to the PMDA. The PMDA will review them, and only afterwards decide whether it also intends to do an on-site inspection. The documents submitted will be approved or rejected separately, before the audit. The PMDA will also use those documents to help draw up its own inspection plan.
As a rule, the PMDA informs a manufacturer of an on-site inspection with 3 to 6 weeks’ notice, usually closer to 6 weeks. Daily fees and travel and lodging reimbursement apply, as described above for accreditation inspections. The team usually consists of two or three inspectors, who will work as a group. If they request any additional information, they will want to receive it within 1 to 2 weeks of their trip.
The process of inspection is fairly straightforward and comparable to FDA inspections. An inspection is typically scheduled to take about 3 days. The main processes reviewed are those of product quality management, management review, resource control, product realization, and measurement, analysis, and improvement.
The standard sequence of events is as follows: opening remarks; document review; plant tour (inclusive of questions and comments by auditors); internal meeting among inspectors; and closing meeting between inspectors and participants. The closing meeting will verbally bring up any observations or compliance issues, which are put into written form later. A full and complete list of participants should be prepared in advance for each of these events.
If there are compliance issues, the inspectors will issue a corrective action report, followed by a verification phase. This puts the auditing process on hold, but does not increase fees. Once there are no compliance issues remaining, a conformity report will be sent directly to the manufacturer, and the full audit results will be sent to the applicant (i.e., the MAH).
Preparing for an inspection
The number-one factor which will smooth along an inspection process is a close understanding of the Japanese QMS regulations. They are available from the PMDA as MHLW Ministerial Ordinance 169, issued December 17th, 2004 (in Japanese only). Besides the requirements for the Device Master File, you should also familiarize yourself with the more minor ways Japanese QMS is different from ISO13485:2003. Obviously, an interpreter will be needed to communicate effectively with the inspectors. However, it is even better to get an interpreter who also has some competence in Japanese QMS. It is also helpful to translate some major quality-related documents, such as SOPs, in advance, for the inspectors’ reference.
Inspectors also appreciate being able to go through their items in an orderly fashion, so try to make up their tour schedule with a focus on efficiency. They will come with their list of inspection items already prepared, which cannot be changed during the inspection.
QMS inspection activity
Over the first year after the amended PAL came into effect (April 2005 to March 2006), the PMDA approved a total of 32 applications for Japanese QMS certification. Of those 32, only 4 underwent on-site inspections, and 2 of those 4 were for foreign manufacturers. The rest of the inspections were done through document review only. There were no failures or withdrawals, although another 69 applications were still in process in March 2006. At present, the PMDA may be focusing more on pharmaceutical manufacturing sites, where 35 out of 53 applicants underwent on-site inspections over the same twelve-month period.
Conclusion
The inspection of principal importance for product registration in Japan is the QMS compliance inspection, whereas the accreditation inspection is more basic and does not involve on-site inspections. The best strategy for compliance is to make certain that the small differences between Japanese QMS and ISO13485:2003 are provided for in your company’s quality system. You should also facilitate communication with inspectors through close understanding of Japanese QMS rules, preparatory translation of key documents, and a skilled interpreter. Audits are a critical gateway process to selling products in Japan, and applications should be prepared with a great deal of care.