Background introduction
In recent years, Asia's external pharmaceutical supply market has grown rapidly, causing global production of active pharmaceutical ingredients (APIs), semi-finished products and raw materials to be concentrated 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 large share of the supply.
Law enforcement and regulatory authorities in the United States and the European Union have accordingly begun to pay attention to the quality of imported drugs and take relevant actions and plans to protect the safety of users.
Asia's test
The GMP standards set by the United States and the European Union have become codes that Asian suppliers and exporters need to abide by. At the same time, they also need to comply with their own country's GMP regulations. This intense pressure to meet the standards of one or more jurisdictions has been and will be a major test for Asian suppliers in the years to come.
The three most influential governing bodies and their standards
The three most influential drug regulatory agencies in the world, the European Medicines Agency (EMEA), the U.S. Food and Drug Administration (FDA) and the Japanese Ministry of Health, Labor and Welfare (MHLW), each adopt different methods to ensure the quality of domestic and foreign drug production.
Europe
EMEA adopts a risk assessment-based approach and stipulates the use of pre-processed materials produced in accordance with EU GMP standards, placing the main responsibility for ensuring acceptable quality on the pharmaceutical manufacturer (or marketing authorization holder [MAH]).
Currently, EMEA inspections outside the European Economic Area (EEA) are limited to suppliers that are questionable or may pose a risk to patient safety. "EU Directive 2004/27" stipulates that GMP certification issued by foreign health care institutions is sufficient to prove that products comply with EU GMP standards.
MAH is responsible for evaluating its suppliers and submitting the evaluation results to management. Therefore, EMEA promotes self-inspections conducted by the second party (manufacturer), third party (manufacturer’s contractor) or audits conducted by the second party and third party.
USA
Currently, the FDA conducts GMP inspections on selected pharmaceutical companies regardless of region. However, this method has recently been criticized by many, saying that the number of pharmaceutical companies inspected by the FDA is almost unrepresentative compared to the number of foreign suppliers exporting APIs to the United States.
FDA has begun to establish more branches in major exporting countries. Recently, it has opened branches in some cities in China, such as Beijing, Shanghai, Guangzhou, etc., to strengthen its global presence. FDA is about to increase export country inspections in China and India.
Japan
MHLW regulates the pharmaceutical industry through the Japan Pharmaceutical Manufacturers Association (JPMA) and the Japan Pharmaceuticals and Medical Devices Agency (PMDA). According to a survey report titled "Japanese Pharmaceutical Market 2008-2023", Japan, as the world's second largest pharmaceutical market, should set the world's most stringent standards for the quality and cleanliness of pharmaceutical production.
Despite the implementation of the International Conference on Harmonization of Technical Requirements for Registration of Drugs for Human Use (ICH) standards, Japan has yet to reach a consensus on GMP inspections with the FDA or EMEA. In the past, Japan once restricted outsourcing and imports, keeping pharmaceutical activities within its borders.
However, times have changed, and the globalization of the Japanese market is just around the corner. Recently, pharmaceutical activities have been outsourced to Taiwanese manufacturers that have passed inspections by Japanese regulatory agencies in the past two years.
Regulators around the world are currently taking more measures to increase the frequency of inspections in addition to those conducted by MAH to control the quality of pharmaceuticals from Asia. China and India, the region's largest exporters, will be subject to most of the above inspections.
Proper training and defect assessment are important for pharmaceutical manufacturers in China and India to prepare for these inspections. Training, education and outsourced inspection services are MAH's first choice when working with Asian suppliers.
Standards and developments in other countries
China/Hong Kong
In 2004, Chinese pharmaceutical manufacturers underwent GMP inspection in order to obtain GMP certification. China's market share continues to grow and it is now the largest producer and exporter of APIs, intermediates, excipients and raw materials.
According to China Chemical Industry Report, by the end of 2007, there were approximately 7,000 pharmaceutical manufacturers operating in China, including approximately 4,700 API manufacturers.
FDA realized that China might become the most important pharmaceutical market in the world. In order to control the quality of Chinese products, the FDA launched the first pharmaceutical GMP training in China in 2005. This was followed by a series of training sessions in 2006 and 2007.
China's State Food and Drug Administration (SFDA) revised GMP standards in 2006, strengthening requirements for employee quality and training, production processes, quality management and document certification. The number of inspection items per audit has been increased to 259.
India
The Indian pharmaceutical industry has been one of the fastest growing sectors in its economy over the past few decades, and this growth is expected to continue. India, like China, is currently one of the most important health care markets, with its own domestic market and huge export customer resources.
However, India is generally considered to be superior to China in terms of quality management of pharmaceutical production. India's ability to provide low-cost contract research and production services has attracted pharmaceutical companies around the world to sign long-term outsourcing contracts with it.
In order to attract more investment from international pharmaceutical companies, India introduced a "product patent system" in 2005. Many Indian manufacturers have renovated their manufacturing plants, and India has become one of the countries with the largest number of pharmaceutical plants inspected by the FDA, the European Agency for Quality and Health Care (EDQM), and other regulatory agencies.
Singapore
Singapore's commitments and investments in the pharmaceutical industry make it the second most developed Asian country after Japan. Singapore is known for its role as a strategic manufacturing base for global pharmaceutical companies and its ability to comply with global regulations. Over the past few years, Singapore's domestic market has maintained healthy development.
Malaysia
In March 2001, Malaysia accepted the assessment of the GMP inspection and licensing system managed by the National Pharmaceutical Control Board (NPCB) of Malaysia by the International Pharmaceutical Inspection Consortium (PIC/S).
This assessment shows that Malaysia’s system almost meets the requirements for PIC/S member countries as it attempts to align with international standards. However, due to the lack of specialized technology, the depth of this GMP audit is still lacking. NPCB has since been committed to training GMP auditors in professional fields and inspections.
Malaysia became a member of PIC/S in 2002 and issues licenses to pharmaceutical manufacturers who fully meet the GMP regulations established under the current PIC/S managed by the World Health Organization (WHO) International Center for Cooperative Monitoring of Medicines.
Drugs registered in Malaysia have a registration number printed on their labels or packages, starting with PBKO or MAL to prove that their quality, safety and effectiveness test results are satisfactory.
Taiwan
Taiwan's Bureau of Pharmaceutical Administration (BPA), established by the Department of Health, manages Taiwan's pharmaceutical industry. GMP requirements were first formulated in the 1980s after several modifications and additions. GMP pharmaceutical facilities are inspected by regulatory agencies every two years.
In 2007, in order to make domestic pharmaceutical activities more attractive to international pharmaceutical companies, Taiwan's Strategic Review Committee decided to revise drug registration regulations. The Department of Health is currently implementing revised regulations requiring pharmaceutical manufacturers in Taiwan to comply with the EU's PIC/S standards starting in 2009.
South Korea
After signing a free trade agreement with the United States and experiencing 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 also abide by ASEAN GMP rules. However, because there is no unified inspection standard, its qualification level can only be compared marginally with countries that comply with EU and US standards.
The development of Vietnam's pharmaceutical industry is still in its infancy. In order to compete in the international market, the Ministry of Health of Vietnam is investing in meeting GMP requirements for pharmaceuticals.
A May 2007 survey report said that the global pharmaceutical market and the Philippine biotechnology industry are expected to continue to grow over the next five years. In 2007, Sweden's Pharmadule signed a contract with the Philippines' Servac to build a rabies vaccine manufacturer. Winthrop Pharmaceuticals, a subsidiary of Sanofi-Aventis, also opened a branch in Cebu province.
Thailand remains one of the most challenging regions for the development of the pharmaceutical industry in Asia, and companies around the world must obtain compulsory licenses from the Thai government.
According to a report from Business Monitor International in February this year, overseas investment risks and restrictions 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 inspection methods adopted by EMEA and FDA in Asia
EMEA
According to the EMEA document (EMEA/INS/GMP/23022/2007) issued in January 2007, 400 API and finished product suppliers not within the scope of EMEA were inspected between 1995 and 2005. The inspection showed that there were 8785 defects, of which 138 (1.57%) were very serious, 977 (11.12%) were more serious, and 7670 (87.31%) were moderately serious. The average number of defects found per inspection was 22.
The 15 most common defects are:
- Quality system basics/procedure documents;
- Factory design and maintenance;
- Equipment design and maintenance;
- Manufacturing documents;
- 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;
- Device verification;
- Hygiene/Dress;
- Key personnel responsibilities;
- Potential for chemical/physical contamination.
FDA
The United States' Freedom of Information Act (FOIA) makes all FDA GMP inspection results available to the public. About 7,000 foreign companies importing drugs into the United States are listed in the FDA database.
However, the number of companies inspected by the FDA has been criticized as not being representative. In 2007, only 13 of the 714 Chinese drug importers in the United States accepted FDA inspections, and only 65 of the 410 Indian drug importers accepted inspections.
It is expected that 7% foreign API manufacturers will undergo FDA inspections every year. In contrast, 97% U.S. factories will undergo the above inspections every two years. Western pharmaceutical companies believe that this comparison is unfair when the standards for control, deterrence or sanctions on foreign manufacturers are different.
In 2007, the FDA issued warning letters to Kunshan Chemical and Pharmaceutical Raw Materials Co., Ltd. and Northeast Pharmaceutical General Factory, which did not comply with GMP standards, and refused to allow their products to enter the U.S. market. Two of the 13 Chinese import manufacturers inspected received warning letters, which is believed to reflect a high proportion of violations.
In 2006, the United States Pharmacopeia (USP) launched the "Pharmaceutical Ingredients Verification Program" (PIVP) to certify the quality of APIs and excipients, thereby alleviating the FDA's pressure on foreign importers to inspect.
This provides important assurance that products entering the United States have undergone strict inspection by certification agencies. The party receiving the inspection is responsible for the inspection costs. But USP certification is not an identification.
About SGS
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