GMP Trends in Asia

In recent years, more manufacturing facilities for active pharmaceutical ingredients (APIs) have relocated to Asia. According to an article published in in-pharmatechnologist.com in December 2007, about 80% of the APIs used in the US and the European Union (EU) to manufacture finished pharmaceutical products come from Asia, with China and India accounting for much of the supply.

Given this shift in the supplier base, regulatory bodies in the US and the EU have become concerned over quality and safety issues, resulting in a slew of different good manufacturing practice (GMP) standards from various agencies and bodies that are charged with safeguarding patient health in North America and the EU. Besides, there is also the local adoption and interpretation of these standards by governments and suppliers in Asia.

Suppliers and exporters in Asia therefore Asian pharmaceutical suppliers need solutions that would enable them to ensure regulatory compliance and to address the global concerns on quality and authenticity. Over the past few years, there arose factors that have created a need for a harmonized approach to GMP audits of API suppliers in Asia. (Source: SGS Hong Kong) need to develop effective strategies to comply with the various GMP standards required in API production. This has been, and will remain for some time, a significant issue for the pharmaceutical industry in the region.

Pressures Asia Faces

Asian pharmaceutical suppliers need solutions that would enable them to ensure regulatory compliance and to address the global concerns on quality and authenticity. Over the past few years, there arose factors that have created a need for a harmonized approach to GMP audits of API suppliers in Asia. Some of them include:

• The rapid market growth of outsourced manufacturing of pharmaceutical ingredients in Asia;

• Markets in Europe and the US predominantly use APIs sourced from Asia in final stages of drug manufacturing;

• The different approaches between EU, US These countries generally do not recognize local GMP guidelines as sufficient to produce safe, quality APIs.

API suppliers in Asia are under the tremendous pressure to meet the standards of between one and three jurisdictions. However, it would require more discussion among the industry players to determine of a set of harmonized and internationally recognized GMP standards.

International Standards and Influential Regulatory Authorities

The European Medicines Agency (EMEA), the US Food and Drug Administration (FDA) and the Japan Ministry of Health, Labour and Welfare (MHLW), arguably the three most globally infl uential pharmaceutical regulatory authorities, have different approaches to ensure the quality of both domestic and outsourced pharmaceutical manufacturing.

• Europe

The EMEA has adopted a risk assessmentbased approach laying primary responsibility on drug manufacturers (or market authorization holders [MAHs]) to ensure quality compliance among their suppliers by specifying the requirements for using starting materials manufactured according to EU GMP standards.

Currently, inspections facilitated by the EMEA outside of the European Economic Area (EEA) are restricted to suppliers who are considered suspicious or who may pose possible threats to patient safety. The EU Directive 2004/27 stipulates that a GMP certifi cate issued by a foreign health authority is insuffi cient evidence for compliance with EU GMP standards.

The MAHs are responsible for assessing their suppliers and providing the results to regulators. In this way, the EMEA promotes self-inspection by second parties (manufacturers), third parties (contractors for the manufacturers) or joint audits combining the services of second and third parties.

• US

The FDA now performs GMP inspections on selected pharmaceutical enterprises, regardless of location. However, there has been recent criticism of this approach, citing that the number of pharmaceutical enterprises the FDA has been able to inspect is not nearly representative of the total number of foreign suppliers exporting pharmaceutical ingredients to the US.

The FDA has started to establish more affiliates in the main exporting countries. It recently opened affi liates in Chinese cities such as Beijing, Shanghai and Guangzhou to strengthen its global presence. FDA inspections in exporting countries are expected to increase primarily in China and India.

• Japan

The MHLW regulates the pharmaceutical industry with the Japan Pharmaceutical Manufacturers Association (JPMA) and the Pharmaceutical and Medical Devices Agency (PMDA) in Japan. According to a Lead Discovery report entitled The Japanese Pharmaceutical Market 2008 – 2023, as the world’s second largest drug market, Japan is thought to have some of the most stringent standards in the world on quality and cleanliness of pharmaceutical manufacturing.

Although it has adopted the standards of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), Japan has yet to mutually agree on GMP inspections with the FDA or the EMEA. It had in the past restricted outsourcing and importation, keeping pharmaceutical activities within its borders.

However, this is changing rapidly and the globalization of the Japanese market is expected, as seen in a recent outsourcing of pharmaceutical activities to Taiwanese manufacturers who have undergone inspections by Japanese regulators over the past two years.

Regulators worldwide are now taking more measures to control the quality of pharmaceutical products imported from Asia, with an increased frequency of inspections in addition to those carried out by the MAHs. The largest exporters in the region, China and India, will be subjected to most of these inspections.

Appropriate training and evaluation for deficiencies will be essential to prepare Chinese and Indian pharmaceutical manufacturers for such inspections. Training, education and outsourced inspections services will be top priorities for MAHs as they work with their suppliers throughout Asia.

• India

The pharmaceutical sector in India has been one of the fastest growing sectors of its economy over the past several years and it is forecast to continue growing. Similar to China, India is now one of the most important healthcare markets in the world having its own domestic market as well as a huge pool of clients for exports.

However, India is considered to be ahead of China in terms of its control of quality over pharmaceutical manufacturing. It provides economical contract research and manufacturing services, which attracts longterm agreements for outsourcing from global pharmaceutical companies.

In order to attract more investment from international pharmaceutical companies, India introduced the “Product Patent Regime” in 2005. Many Indian manufacturers have also upgraded their manufacturing plants making it one of the countries with the highest numbers of plants inspected by the FDA, the European Directorate for the Quality of Medicines & HealthCare (EDQM) and other regulatory agencies.

• Singapore

Singapore’s commitment and investment in the pharmaceutical sector has made the country perhaps the second most advanced country, behind Japan, in Asia. Singapore is well known for being a strategic manufacturing base for global pharmaceutical companies and its ability to comply with global regulations. Its domestic market has also grown healthily in the past few years.

• Malaysia

In March 2001, Malaysia was subjected to an assessment by the Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme (jointly referred to as PIC/S) on the system of GMP inspection and licensing managed by the Malaysian National Pharmaceutical Control Bureau (NPCB).

The assessment showed that Malaysia’s system was almost comparable to the requirements of a PIC/S member as it attempted to align itself with international standards. However, the depth of GMP audits was found to be insufficient due to lack of expertise. The NPCB has since become committed to training GMP auditors in specialized areas and inspection.

It became a member of the PIC/S in 2002 and issues licenses to pharmaceutical manufacturers who are deemed to be in full compliance with the code of GMP based on the current PIC/S regulated by the World Health Organization (WHO) Collaborating Centre for Regulatory Control of Pharmaceuticals.

A drug registered in Malaysia carries a registration number on its label or package starting with either PBKD or MAL to indicate satisfactory results on quality, safety and efficacy.

• Taiwan

The Bureau of Pharmaceutical Affairs (BPA), established by the Department of Health, handles pharmaceutical regulation in Taiwan. GMP requirements were fi rst established in the 1980s followed by several revisions and additions to tighten the standards. GMP pharmaceutical facilities are subject to inspection every two years by the regulatory body.

In 2007, the Taiwanese strategic review board decided to revise regulations on drug registration in order to make the country’s pharmaceutical activities more appealing to international pharmaceutical companies. The Department of Health is now implementing revised regulations requiring Taiwanese pharmaceutical manufacturers to comply with EU’s PIC/S standards by 2009.

• South Korea

Having signed a free trade agreement with the US and given its rapid economic growth, South Korea’s pharmaceutical market is considered as one of the most attractive in the Asia Pacifi c region after Japan, China and India.

• Vietnam, the Philippines and Thailand

These three countries, all members of the Association of South East Asian Nations (ASEAN), adhere to the ASEAN GMP codes. However, with a lack of consistent inspection standards, the degrees of success are marginal compared to the EU and US standards compliant nations.

The development of the Vietnam’s pharmaceutical sector is still in the early stages. The Vietnamese Ministry of Health is investing in pharmaceutical GMP compliance in order to compete in the international market.

A report by the Inquirer in May 2007 says the global pharmaceutical market and biotechnology sector for the Philippines are expected to continue to expand over next five years. In 2007, Pharmadule, a Swedish company, contracted Servac Philippines to build a production facility for a rabies prevention vaccine. Winthrop Pharmaceuticals, Sanofi -Aventis’ subsidiary, has also opened a branch in Cebu Province.

Thailand continues to be one of the most challenging environments for pharmaceutical development in Asia with global firms subjected to mandatory licensing by the Thai government.

A report by Business Monitor International in February this year said the growth of the Thai market is expected to be modest due to risks and limits on foreign investments that has stopped the launch of new products and deterred foreign direct investment.

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EMEA and FDA’s Approach to GMP Inspections Performed in Asia

EMEA

According to the EMEA document (EMEA/INS/GMP/23022/2007) issued in Jan 2007, 400 API and finished products suppliers outside the EEA were inspected between 1995 and 2005. These inspections show a total of 8,785 defi ciencies of which 138 (1.57%) were critical, 977 (11.12%) were major, and 7,670 (87.31%) were other significant deficiencies. The average number of deficiencies identified in each inspection was 22.

The top 15 most frequently identified deficiencies by category were:

• Quality system elements/procedures documentation,

• Design and maintenance of premises,

• Design and maintenance of equipment,

• Manufacturing documentation,

• Potential for microbiological contamination,

• Specification and testing documentation,

• Facilities and equipment status labeling,

• Environmental monitoring,

• Process validation,

• Procedures and facilities sampling,

• Supplier and contractor audit and technical agreements,

• Equipment validation,

• Hygiene/clothing,

• Duties of key personnel, and

• Potential for chemical/physical contamination.

FDA

The US Freedom of Information Act (FOIA) has enabled the public to access the findings of all FDA GMP inspections. There are almost 7,000 foreign fi rms who import pharmaceutical products into the US listed on the FDA database.

However, the number of inspections performed on these firms by the FDA had been criticized to be unrepresentative. In 2007, 13 out of 714 Chinese importers of pharmaceutical products into the US were inspected by the FDA, whereas 65 out of 410 were inspected in India.

An estimated 7% of all foreign API facilities are inspected by the FDA each year, compared to 97% of US facilities inspected every two years. Pharmaceutical facilities in the West have expressed that this comparison is unfair given that the level of controls, deterrents or sanctions on foreign facilities are not of the same standards.

In 2007, warning letters were issued by the FDA for GMP non-compliance to Kunshan Chemical & Pharmaceutical and Northeast General Pharmaceutical resulting in denial of entry of products into the US. This was considered to reflect a high proportion where two out of 13 Chinese importers inspected were issued with warning letters.

In 2006, the US Pharmacopeia (USP) began the Pharmaceutical Ingredient Verification Program (PIVP) to certify the quality of APIs and excipients in order to ease the pressure on FDA to inspect foreign importers.

This has provided a significant level of assurance that the products entering the US have been subjected to rigorous review by a certification body. The party inspected is responsible for the cost of the investigation. However, the certification by the USP is not an accreditation.

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Suppliers and their Approach to GMP (China/Hong Kong)

In 2004, Chinese pharmaceutical manufacturers were subjected to GMP inspections for the purpose of obtaining a GMP certificate. China’s market share has continued to expand and it is now one of the major producers and exporters of APIs, intermediates, excipients and raw materials.

According to China Chemical Reporter, by the end of 2007, there were almost 7,000 pharmaceutical manufacturers operating in China, of which almost 4,700 were API producers.

Recognizing the potential of China becoming one of the world’s most important pharmaceutical markets, the FDA in 2005 began its first training in pharmaceutical GMP in China in an effort to control the quality of products purchased from China. This was followed by subsequent training sessions in 2006 and 2007.

China’s State Food and Drug Administration (SFDA) revised its GMP guidelines in 2006 to tighten the requirements on staff qualifi ation and training, product process, quality control and documentation verifi cation. The number of inspectional items per audit has risen to 268.

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