Background Introduction
In recent years, Asia's pharmaceutical supply market has grown rapidly, leading to a concentration of global production of active pharmaceutical ingredients (APIs), semi-finished products, and raw materials in Asia. According to an article published by in-pharmatechnologist.com in December 2007, 80% of the APIs used in the production of finished drugs in the United States and the European Union come from Asia, with China and India accounting for a significant share.
Law enforcement and regulatory authorities in the United States and the European Union have also begun to pay attention to the quality of imported medicines and have taken relevant actions and plans to protect the safety of users.
The challenges facing Asia
The GMP standards set by the United States and the European Union have become the code of conduct that Asian suppliers and exporters must follow, while at the same time, they also need to comply with their own national GMP regulations. This enormous pressure to meet the standards of one or more jurisdictions will be a major test for Asian suppliers in the past and for years to come.
The three most influential management bodies and their standards
The European Medicines Agency (EMEA), the U.S. Food and Drug Administration (FDA), and the Japanese Ministry of Health, Labour and Welfare (MHLW)—three of the world's most influential drug regulatory agencies—each employ different methods to ensure the quality of domestically produced and imported drugs.
Europe
The EMEA employs a risk-based approach that mandates the use of pre-processed materials manufactured according to EU GMP standards, placing primary responsibility for ensuring qualified quality on the pharmaceutical manufacturer (or marketing authorization holder [MAH]).
Currently, EMEA's inspections outside the European Economic Area (EEA) are limited to suppliers that are questionable or may pose a threat to patient safety. EU Directive 2004/27 stipulates that GMP certification issued by a foreign healthcare institution is sufficient to prove that a product complies with EU GMP standards .
MAH is responsible for evaluating its suppliers and submitting the evaluation results to management. Therefore, EMEA promotes self-inspection by second parties (manufacturers), third parties (contractors of manufacturers), or audits conducted jointly by second and third parties.
USA
Currently, the FDA conducts GMP inspections on pharmaceutical companies selected from various regions. However, this approach has recently faced considerable criticism, with many arguing that the number of pharmaceutical companies inspected by the FDA is almost entirely unrepresentative compared to the number of foreign suppliers exporting active pharmaceutical ingredients (APIs) to the United States.
The FDA has begun establishing more branches in major exporting countries. Recently, branches have opened in several Chinese cities, such as Beijing, Shanghai, and Guangzhou, to strengthen its global market share. The FDA will soon increase its inspections in exporting countries such as China and India.
Japan
MHLW oversees the pharmaceutical industry through the Japan Pharmaceutical Manufacturers Association (JPMA) and the Pharmaceuticals and Medical Devices Agency (PMDA). According to a survey report titled "Japan's Pharmaceutical Market 2008-2023," Japan, as the world's second-largest pharmaceutical market, sets some of the world's strictest standards for the quality and cleanliness of pharmaceutical production.
Despite having implemented the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) standards, Japan has yet to reach a consensus with the FDA or EMEA on GMP inspections. In the past, Japan had restricted outsourcing and imports, keeping pharmaceutical activities within its own borders.
However, times have changed, and the globalization of the Japanese market is just around the corner. Recently, there have been instances of outsourcing pharmaceutical activities to Taiwanese manufacturers that have passed the inspections of Japanese regulatory agencies in the past two years.
Global regulators are currently taking further steps to increase the frequency of inspections beyond those conducted by the MAH (Marketing Authorization Holder) to control the quality of pharmaceuticals originating from Asia. China and India, the region's largest exporters, will be subject to most of these inspections.
Proper training and defect assessment are crucial for pharmaceutical manufacturers in China and India to prepare for the aforementioned tests. Training, education, and outsourced testing services are the preferred options for MAHs when collaborating with Asian suppliers.
Standards and development in other countries
China/Hong Kong
In 2004, Chinese pharmaceutical manufacturers underwent GMP inspections in order to obtain GMP certification. China's market share has continued to grow, and it is now the largest producer and exporter of APIs, intermediates, excipients, and raw materials.
According to China Chemical Report, by the end of 2007, there were approximately 7,000 pharmaceutical manufacturers operating in China, of which about 4,700 were API manufacturers.
Recognizing that China could become the world's most important pharmaceutical market, the FDA conducted its first pharmaceutical GMP training in China in 2005 to control the quality of Chinese products. This was followed by a series of training sessions in 2006 and 2007.
In 2006, China's State Food and Drug Administration (SFDA) revised its GMP standards, strengthening requirements for employee qualifications and training, production processes, quality management, and document certification. The number of inspection items per audit increased to 259.
India
India's pharmaceutical industry has consistently been one of its fastest-growing sectors for decades, and this growth is expected to continue. Like China, India is also one of the most important healthcare markets, boasting its own domestic market and a large pool of export customers.
However, India is generally considered superior to China in pharmaceutical manufacturing quality management. India's ability to offer cost-effective contract investigation and manufacturing services has attracted pharmaceutical companies worldwide to sign long-term outsourcing contracts.
To attract more international pharmaceutical companies, India introduced a "product patent system" in 2005. Many Indian manufacturers have upgraded their production facilities, making India one of the countries with the most pharmaceutical plants inspected by the FDA, the European Medicines & Healthcare products Regulatory Agency (EDQM), and other regulatory bodies.
Singapore
Singapore's commitments and investments in the pharmaceutical industry have made it the second-largest developed Asian nation, after Japan. Singapore is renowned as a strategic manufacturing base for global pharmaceutical companies and for its ability to comply with global regulations. The domestic market in Singapore has maintained healthy growth over the past few years.
Malaysia
In March 2001, Malaysia accepted the assessment of the GMP inspection and licensing system managed by the National Pharmaceutical Regulatory Authority of Malaysia (NPCB) by the Pharmaceutical Inspection Convention International (PIC/S).
This assessment showed that Malaysia's system almost met the requirements for PIC/S member countries due to its efforts to align with international standards. However, the depth of the GMP audit was somewhat lacking due to a lack of specialized technical expertise. NPCB will henceforth dedicate itself to training GMP auditors in professional fields and inspection.
Malaysia became a member of PIC/S in 2002, granting licenses to pharmaceutical manufacturers that fully comply with GMP regulations developed by PIC/S, which is currently managed by the World Health Organization (WHO) International Collaborating Centre for Monitoring Medicines .
Medicines registered in Malaysia bear a registration number on their labels or packaging, beginning with PBKO or MAL, indicating that their quality, safety, and efficacy have been verified.
Taiwan
The Pharmaceutical Administration Bureau (BPA) of Taiwan, established by the Department of Health, regulates the pharmaceutical industry in Taiwan. Good Manufacturing Practice (GMP) requirements were first established in the 1980s after several revisions and additions. GMP-compliant pharmaceutical facilities are subject to inspection by the regulatory agency every two years.
In 2007, to make domestic pharmaceutical activities more attractive to international pharmaceutical companies, Taiwan's Strategic Review Committee decided to amend drug registration regulations. The Department of Health is currently implementing the revised regulations, requiring Taiwanese pharmaceutical manufacturers to comply with the EU's PIC/S standards from 2009 onwards.
South Korea
Following a free trade agreement with the United States and rapid economic growth, South Korea's pharmaceutical market has become one of the most attractive markets in the Asia-Pacific region, after Japan, China, and India.
Vietnam, Philippines and Thailand
Vietnam, the Philippines, and Thailand are all members of the Association of Southeast Asian Nations (ASEAN) and adhere to ASEAN GMP regulations. However, due to the lack of unified inspection standards, their compliance levels can only be compared marginally with those of countries that comply with EU and US standards.
Vietnam's pharmaceutical industry is still in its early stages of development. In order to gain a foothold in the international market, the Vietnamese Ministry of Health is investing in meeting GMP requirements for pharmaceuticals.
A May 2007 survey report indicated that the global pharmaceutical market and the Philippine biotechnology industry were expected to continue growing over the next five years. In 2007, Sweden's Pharmadule signed a contract with the Philippines' Servac to establish a rabies vaccine manufacturing plant. Sanofi-Aventis' subsidiary, Winthrop Pharmaceuticals, also opened a branch in Cebu province.
Thailand remains one of the most challenging regions for the pharmaceutical industry in Asia, with companies worldwide subject to mandatory licensing by the Thai government.
According to a report by Business Monitor International in February of this year, risks and restrictions on overseas investment have affected the launch of new products and hindered foreign direct investment, so the development of the Thai market is expected to be very slow.
GMP testing methods used by EMEA and FDA in Asia
EMEA
According to the EMEA document issued in January 2007 (EMEA/INS/GMP/23022/2007), 400 API and finished product suppliers not covered by EMEA underwent inspection between 1995 and 2005. The inspection revealed 8785 defects, of which 138 (1.57%) were very serious, 977 (11.12%) were relatively serious, and 7670 (87.31%) were generally serious. The average number of defects found per inspection was 22.
The 15 most common defects are:
- Quality system basic/procedure documents;
- Factory design and maintenance;
- Equipment design and maintenance;
- Manufacturing documents;
- The potential for microbial contamination;
- Specifications and test documents;
- Facility and equipment status labels;
- Environmental testing;
- Process verification;
- Procedures and facility sampling;
- Supplier and contractor audits and technical agreements;
- Equipment verification;
- Hygiene/Dress;
- Key personnel responsibilities;
- Potential for chemical/physical contamination.
FDA
The U.S. Freedom of Information Act (FOIA) allows the public to access all FDA GMP test results. Approximately 7,000 foreign companies importing pharmaceuticals into the U.S. are registered in the FDA database.
However, the number of companies inspected by the FDA has been criticized as not representative. In 2007, only 13 out of 714 Chinese drug importers in the United States underwent FDA inspection, and only 65 out of 410 Indian drug importers were inspected.
It is estimated that 7% of foreign API manufacturers undergo FDA inspections annually, compared to 97% of US factories undergoing such inspections every two years. Western pharmaceutical companies argue that this comparison is unfair, given the different standards used to control, deter, or sanction foreign manufacturers.
In 2007, the FDA issued warning letters to Kunshan Chemical Pharmaceutical Raw Materials Co., Ltd. and Northeast Pharmaceutical General Factory for failing to comply with GMP standards, refusing their products entry into the U.S. market. Of the 13 Chinese importers inspected, two received warning letters, which was considered to reflect a high rate of violations.
In 2006, the United States Pharmacopeia (USP) launched the Pharmaceutical Ingredient Qualification Program (PIVP) to certify the quality of APIs and excipients, thereby relieving the pressure on the FDA to inspect foreign importers.
This provides an important guarantee that products entering the United States have undergone rigorous inspection by certification bodies. The party undergoing inspection is responsible for the inspection costs. However, USP certification is not a form of certification.
