February 2007 - Japan's Pharmaceutical Affairs Law (PAL): Opportunities and Challenges
By Paul D’Eramo, Chairman, ISPE Regulatory Affairs Committee
Introduction
In recent years, the structure of Japan’s Ministry of Health, Labor and Welfare (MHLW) has undergone numerous changes that have altered the regulatory system for pharmaceuticals and medical devices. These changes reflect a “global harmonization” of regulations and safety measures to align them more closely with those in the EU, Australia, Canada, and the US.
In July 2002, Japan passed legislation to revise the Pharmaceutical Affairs Law (PAL) and, in April 2005, established the Pharmaceuticals and Medical Devices Agency (PMDA) to create a more efficient and transparent review process.
The key points of the PAL revision include:
- A new risk-based classification system for products
- Adoption of internationally consistent pre-market submission documents, known as Summary Technical Documentation (STED)
- Revised manufacturing controls and quality assurance (GMP), manufacturing/distribution quality control regulations (GQP), and post-marketing surveillance criteria (GPSP), among other regulations
- Requirements for the Market Authorization Holder (MAH), the entity which is issued a “license for manufacturing/marketing business”
Shifting Responsibility
In the past, a foreign company marketing a product in Japan was required to obtain a “manufacturing approval” (seizo shonin) assuring the quality, safety and efficacy of a product, as well as a “site license” (kyoka) ensuring that the entity met certain requirements with regard to its facilities and personnel qualifications. Furthermore, any importer, distributor or subsidiary of a foreign firm was required to actually conduct business in Japan. A foreign company operating outside of Japan could only obtain manufacturing approval if a Japanese company acted as the foreign firm’s.
The “In Country Caretaker” (ICC) practice was abolished under PAL, primarily as a way of shifting the regulatory system from the point of manufacturing to the point of sale, creating a seismic shift in Japan’s regulatory practices. Now there is greater emphasis on the entire process of quality and safety, where once the focus was solely on the product manufacturing process.
For the MAH, this now means greater responsibility on several fronts. First, the MAH must be physically located in Japan and is required to have three controllers: a general controller (one person per license), a safety management controller (one person per license) and a quality assurance controller (one person per license). In addition, the MAH must obtain marketing approval for each product by accomplishing the following:
- Guaranteeing safety, quality and efficacy of the product
- Complying with Good Quality Practices (GQPs) governing product quality, which include ensuring compliance with Good Manufacturing Practices (GMPs) for all manufacturing sites where the product is manufactured
- Complying with Good Vigilance Practices (GVPs) that monitor post-market sales in the markets where the product is sold
Preparing for the Inspection Process
Under PAL, PMDA is expected to conduct GMP inspections globally. High-profile high-risk products will probably be the first to experience a Japanese inspection. A new filing (submission) under PAL can trigger an inspection within six months. Because Japan is still in the process of hiring 150 inspectors – they currently have about 28 – it is difficult to know how the new law will be interpreted and enforced by the government. The Japanese are seeking assistance from the industry in training inspectors, and many companies and professional associations have been actively involved. ISPE is also pursuing opportunities to work with Japanese regulatory authorities in the development of training programs for pharmaceutical manufacturing cGMPs.
In addition, the Japanese are using international standards such as ISO and ICH, and guidance from the Global Harmonization Task Force – all of which are closely aligned with the current “Quality-by-Design” philosophy for pharmaceutical development as well as implementation of robust quality systems and management review processes. Such established systems and practices may require a certain level of adaptation in complying with PAL, but clearly represent a “head start” in the marketplace.
What to Expect Moving Forward
Many questions remain regarding PAL that must be addressed as the implementation process evolves. These include:
- Will Japan’s requirements and regulatory practices truly harmonize with international guidelines?
- How long will it take to implement these changes?
- Will transition measures for products already on the market be adequate, and how much will changes cost?
- How will PMDA recruit, train, and retain sufficient expertise in diverse medical technologies?
- To what extent may evidence of conformity obtained elsewhere be used to satisfy Japan’s requirements?
- In exchange for higher user fees, what performance targets and transparency can we expect from PMDA?
Below are links to references that will be helpful as we continue moving forward in the Japanese marketplace:
Other links:
