China's pharmaceutical industry is making massive strides towards meeting modern global standards. Hilary Ayshford describes what some of the most advanced facilities and progressive companies have to offer
On 2 August, 1996 a co-operation agreement was signed by the Ministry of Science & Technology, Ministry of Health, Chinese Academy of Science, State Food & Drug Administration and Shanghai Municipality to set up the State Biotech and Pharmaceutical Base (Shanghai) in Zhangjiang hi-tech park. To integrate biotech and pharmaceutical resources and consolidate the development of biopharmaceutical industry in Zhangjiang, Shanghai Zhangjiang Biotech & Pharmaceutical Base Company was established in September 2001.
Today, more than 200 projects have moved into the Base, where a modern biopharmaceutical innovation system has been built up, consisting of training, scientific research, technological development, pilot incubation, commercial scale production and marketing and logistics.
Phase I of the development, covering 1.28km2, has been completed and work on the 1.5km2 Phase II is now underway. The second phase will see the Base upgraded to become a full service provider, incorporating professional clinical research organisations, standard biopharma incubator units, public laboratories, a GMP preclinical base and GCP clinical centre.
The overall planned area is some 25km2, comprising the Technical Innovation Zone, Hi-Tech Industry Zone, Scientific Research and Education Zone, and Residential Zone. International companies with r&d centres in Zhangjiang include Novartis, Pfizer, Roche, Lilly China, GE China, Dow, USP, PerkinElmer, DuPont China, Hutchison and Rohm & Haas.
By the end of 2005, the Park was home to 4,297 new enterprises, and had attracted foreign investment amounting to US$13.748bn and a fixed asset investment RMB69.514bn ($8.905bn). It is situated in the heart of Pudong New Area, which covers 556km2 and has a population of 3 million, conveniently located between the inner and outer Shanghai ringroads and on both the metro and Maglev lines.
The key lifescience manufacturing industries of Zhangjiang include pharmaceutical manufacturing, biopharma manufacturing, modern traditional Chinese medicine and medical equipment and machinery.
The pharmaceutical focus is on reinforcing pre-clinical and clinical research and developing the r&d outsourcing service sector while encouraging in-house development of innovative drugs. The biopharma sector concentrates on attracting biomedicine manufacturers with strengths in international technology and outsourcing the production to contract manufacturing companies.
On the traditional Chinese medicine side, research is being carried out into standardisation and modernisation; introduction of GLP, GMP and GCP standards; adoption of new technologies in Chinese medicines; and increasing the production scale of the industry.
To this end, one of the most recent arrivals in the Zhangjiang High-tech Park is Shanghai Lei Yun Shang Pharmaceutical Co., Ltd, part of Shanghai Pharmaceutical Group Co., Ltd, which hopes to bring about development of Chinese traditional medicine industry in Zhangjiang.
Shanghai Lei Yun Shang Pharmaceutical Co., Ltd. is one of the biggest Chinese traditional medicine enterprises in China. Shanghai Chinese Traditional Medicine Research Institute is a research unit of Shanghai Lei Yun Shang Pharmaceutical Co., Ltd and boasts enormous strength in scientific research, having developed more than 30 Chinese medicine products for which it owns IP rights.
The Shanghai Chinese Traditional Medicine Research Institute will act as a research base for traditional and natural medicines, build a powerful position in high-tech industrialisation of traditional medicine, and enter into specialised co-operation and collaboration with other research centres and r&d platforms.
Modern biopharmaceuticals is another of the principal industries of Zhangjiang Hi-Tech Park, which is home also to The Shanghai National Biomedical Industry Base.
Multinational pharma company Novartis has announced its intention to set up a comprehensive biomedical r&d centre in Zhangjiang Hi-tech Park, which will become an indispensable part of the company's global r&d network. Initial investment will be US$100m and the centre will become operational from May 2007.
Other big pharma companies to establish r&d centres in China include Novo Nordisk, AstraZeneca, Eli Lilly, Roche, GlaxoSmithKline and Pfizer.
Novartis expects to carry out pioneering medical and pharmaceutical r&d in China and at the same time further expand its current r&d co-operative network in China. Initially, the company says, the priority of the centre will be to meet urgent medical needs in China and Asia, especially for cancer.
Located in the south-eastern part of the Park is the Incubation Base, which occupies an area of 1,600m2 and a total construction area of 10,319m2. All laboratories are equipped with Internet communication facilities, independent water and electricity meters, laboratory benches, fume cupboards and offices.
The Public Technical Platform Base Zhangjiang Biomedicine is administered by Shanghai Act Nyima Peregrine Ltd, a CRO founded in 2004 to provide technical consultancy relating to the research and development of new drugs, such as clinic trials management, medicines registration and investment consultation.
The Biomedicine R&D Outsourcing Service Centre forms an essential part of Zhangjiang Biomedicine Base Public Technical Platform and Outsourcing Service Base. It integrates various development resources and provides biopharma r&d outsourcing services. The Centre is capable of providing services for original r&d at each main preclinical stage in drug development.
The Apparatus Sharing Platform is an initiative of the Science and Technology Bureau of Pudong New Area and the Biomedicine Association of Pudong New Area, which jointly rolled out the biomedicine scientific research equipment network in July 2003. This network aims to integrate existing resources and equipment to promote information sharing among various biomedicine scientific research institutions, improve utility of scientific equipment, enhance service and incubation functionality of the Base and reduce the r&d costs of small and medium pharmaceutical manufacturers.
Eight institutes became the first group of registered members of the network providing scientific equipment for sharing. Up to 60 sets of scientific equipment have been put into public service in areas including cytology, molecular biology, biochemistry, large-scale albumen purification, biological chip design and detection, and drug innovation, compounding, analysis, pharmacodynamics, pathology, preparation and pilot-scale manufacturing.
Shanghai Zhangjiang Drug Valley Vocational Technical Training Centre is a non-profit institute established by Shanghai Zhangjiang Biomedicine Base Development Co., Ltd with assistance from relevant functional governmental sectors of Pudong New Area. It provides services including international standard project training, market-orientated career project training, various certificate training and lectures on science and technology.
Sundia MediTech is one of the new breed of Chinese pharma companies to base itself in the hi-tech park. Since its launch in June 2004, it has established collaborations with more than 25 client companies in the US, Canada, Europe and Japan. It has provided a variety of services from custom synthesis to lead optimisation; small-scale milligram to multi-kg production; synthetic processes of a few simple steps to 18-step sequences; and new chemistry development.
All the six founders of the company received advanced training and more than 10 years of work experience in the US before relocating to Shanghai with their families. By June 2006, the number of employees had grown to more than 100.
Revenue increased rapidly from Euro 40,000 in 2004 to €500,000 in 2005. It exceeded €1m in the first half of 2006 and was expected to reach €2.5m for the whole year. The research centre has been expanded from 800m2 in June 2004 to 4,600m2 in June 2006.
Sundia sees ADME as one of the largest causes of attrition in drug development and believes the way forward is to screen out those molecules with inappropriate ADME properties during discovery, before they reach development.
The company has a proprietary lead optimisation platform dubbed SELO (Speed up Engine for Lead Optimisation) that can carry out comprehensive multi-property/activity modelling, optimisation and virtual screening to select novel small molecule drug candidates with well-balanced potency and ADME properties. This SELO lead optimisation platform is claimed to be unique because it integrates synthetic, combinatorial and medicinal chemistry, high throughput screening, and computer-aided drug design. Sundia has completed four successful lead optimisation projects.
The company also offers analytical chemistry, parallel library synthesis, lead optimisation, preparation of intermediates and novel templates (g-kg scale), synthesis of novel building blocks (g-kg scale), medicinal ingredients sets (mg-g scale), and specially designed diverse/focused libraries (10-50 mg for each library member with >90% average purity).
Sundia's long-term strategy is to use its expertise in custom synthesis, library production, and medicinal chemistry, CADD strength, pharmacology experience and the SELO platform to serve pharmaceutical and biopharmaceutical companies.
Biotech company Hutchison MediPharma (HMPL), founded in September 2002, is also located in the Zhangjiang High Tech Park. HMPL is the r&d subsidiary of Hutchison China MediTech, which is listed on the UK's AIM stock market. Dedicated to the discovery and development of innovative medicines for the global markets, HMPL has a fully integrated drug discovery and development infrastructure, cutting-edge drug discovery platforms, and an experienced senior management team drawn largely from leading US pharmaceutical and biotechnology companies.
From its 54,000ft2 r&d centre, HMPL takes a tripartite discovery approach, including botanical drugs, natural-product semi-synthesis, and synthetic small molecules. It offers chemistry platforms in medicinal and phytochemistry, high performance biological screening platforms, animal facilities with a full panel of models against cancer and Inflammation, and In vitro and in vivo pharmacokinetic screening and evaluation.
The company has established an emerging portfolio of preclinical and clinical candidates in oncology and anti-autoimmune/inflammatory diseases. HMPL-002, a radiosensitiser, is currently in phase I/II trials in the US in combination with radiotherapy and chemotherapy for the treatment of head and neck cancer. HMPL-004, a proinflammatory cytokine inhibitor, is in phase II trials in the US for the treatment of inflammatory bowel disease. Several preclinical and clinical studies are also ongoing in China.
HMPL's leading candidate targeting autoimmune diseases such as rheumatoid arthritis, inflammatory bowel disease, lupus, and psoriasis. It is now in Phase II clinical trials in the US to treat Crohn's disease. The company has multiple preclinical/discovery candidates against the targets along the inflammation pathway.
Drug discovery technologies include molecular and cell biology, high throughput screening, genomics and informatics. To date, multiple proprietary drug discovery platforms have been created. These include gene-targeted and cell-based screening assays, ligand-dependent screening assays and signal transduction pathway screening assays in addition to conventional cytotoxicity, protein assays and enzymatic assays, receptor tyrosine kinase assays, primary cell culture assays, recombinant DNA technologies, gene-chip technologies, recombinant protein expression technologies, and retroviral-mediated gene transfer technologies.
The company is also building a natural product library in both single compounds and extracts for use in new drug discovery screening and aims to collect samples from thousands of plants commonly used in traditional Chinese medicines.
Biochip technology has been widely cited as the key point for biology industry development. Shanghai Biochip Company (SBC) has set up a series of biochip platforms, which include gene chip, protein chip, tissue array and micro-fluidic chip. It has also promoted gene chip products for scientific and civil uses, established spin-off companies and joint ventures, and undertaken extensive national and international collaborations.
Established in August 2001, SBC owns a vast campus in excess of 400,000ft2, with research building space of more than 200,000ft2, located at Shanghai Zhangjiang Hi-Tech Park.
SBC is also the national Engineering Centre for biochip design and engineering. With advanced biotech platforms, GLP, GCP and GMP labs, and strong research, services, marketing and sales teams, it provides not only a series of biochips and related technical services, but also proprietary drug targets and relevant diagnostic products.
SBC was founded in 2001 with total funding of US$50m from the Chinese government and 11 shareholders consisting of the top academic universities, research institutes, hospitals and leading biotech companies in Shanghai.
- Gene Chips: The company has built and improved the high density gene expression chip platform in terms of design, production and services. It provides mouse gene expression and other chip-based oligo microarray technology. It has established chemical modification process of chip substrates, constructed whole genome chips for several micro-organisms, and introduced Affymetrix and Agilent gene chips and applied them in research and services. The company has become the first technical service provider in China with Affymetrix's certification.
- Protein Expression and Purification, and Antibody Production: The company has finished the initial stage of a large-scale protein expression and purification platform and formed multiple protein purification systems. Polyclonal and monoclonal antibody technology has been established with r&d capability of tens of poly- and monoclonal antibodies per year.
- Tissue Chips: The tissue chip platform from design to application has also been established including various pathological, analytical methods such as IHC, FISH, etc. More than 50 tissue microarray products are in the market.
- Large-scale Genotyping: Since Illumina large-scale SNP detection and genotyping system was introduced, the company has been able to participate in the international HapMap Program and took on 10% of the project for Great China area. This platform will focus on disease genomics and develop related knowledge and products.
- Microfluidic Chip: A microfluidic chip and signal detection system has been established under a young, multidisciplinary team from different training background such as electronics, physics, material sciences, chemistry, computer sciences and biological sciences. This team has developed a microfluidic laser-induced fluorescence detection instrument, a urea protein analytical microsystem, Isoenzyme detection system, an integrated micro-PCR chip, an injection microarray system and protein enrichment chip, while the data handling software was also optimised.
But Shanghai is not the only city in China with a flourishing high tech pharmaceutical sector. GeneScience Pharmaceuticals Co., Ltd. (GenSci) is the leading biopharmaceutical company in China focused on developing, manufacturing and marketing protein therapeutic products and biological supergenerics with special emphasis on endocrinology and related areas, aiming at providing affordable and innovative biopharmaceutical products to patients.
Located in one of the top six national biomedical centers, Changchun High-Tech Development Zone, GenSci's manufacturing facility covers more than 20,000m2 of land with 11,000m2 of production area. It is one of the largest and best-equipped biopharmaceutical production facilities in China.
GenSci's profitability has been ranked top among Chinese biopharmaceutical companies. The company's annual growth rate exceeded 70% in last five years and it is determined to be a global player in biogenerics. Founded in 1996, it has six products on the market, and 10 innovative biological products in its pipeline. The company is determined to become a strong global player in biopharmaceuticals through international partnerships with strategic manufacturers, distributors and suppliers.
Most of the GenSci management team were trained and have professional experience in the US. The founder and ceo, Dr Lei Jin, graduated from the Department of Biochemistry at Peking University in 1985 and gained his M.Sc at the Institute of Biophysics, Academia Sinica, Beijing. In 1989, he went to study in the University of California at San Francisco (UCSF) majoring in molecular and structural biology.
In 1996, he co-founded GenSci with Changchun High-tech Group Co. Ltd to pioneer the growth hormone development in China. In 1997 its manufacturing facilities were completed and GenSci became the biopharmaceutical company with the largest manufacturing capacity in China. Early the following year GenLei Jintropin (rhGH, somatropin for injection) was officially approved by the Chinese Ministry of Health and become the first somatropin made by a domestic company. It became the leading brand of rhGH in China with a 70% share of the market.
In May 1998 GenLei Scimax filgrastim (rhG-CSF injection) was officially approved by the Chinese Ministry of Health and became the only G-CSF made by E. coli secretion technology in the world. In 2004 GenLei Jintrotide (octreotide acetate for injection) and GenLei Jintrirelin (triptorelin acetate injection) were formally approved for marketing by the SFDA, followed by GenLei Jintropin AQ liquid formulation in 2005. It is regarded as the best quality of hGH in China.
A new manufacturing facility with 12000m2 production floor space was completed in September 2004, which is capable of producing 3 million vials of lyophilised preparations and 5 million vials of liquid preparations annually.
Jintropin somatropin is produced at GenSci by recombinant DNA technology in a proprietary E.coli secretion expression system. This technology is said to have a number of advantages:
- Purer Products - Secretion of the proteins out of E.coli cells can minimise the contamination by E.coli toxic proteins
- Higher biological activity - Secretion can lead to products with the correct primary amino acid structure as well as 3-dimensional structures, contrary to the traditional inclusion body technology
- Higher yield - no refolding is required
- before reconstitution if refrigerated between 2-8°C it is good for over a year (until expiration date);
- at room temperature (up to 37°C) it is good for more than 30 days;
- at up to 45°C it is good for about a week. After reconstitution it has to be refrigerated at all times and will last for 20 days
Normal lyophilised hGH, because it contains trace amount of hGH aggregates, would always generate slight amount of hGH antibodies in small percentage of people (1-2%). Antibodies to hGH will compromise the long term benefit of hGH. However, Jintropin AQ doesn't cause any formation of antibodies because it contains absolutely no hGH aggregates, GenSci says.
Jintropin AQ hGH is the first ready-to-use liquid hGH formulation in Asia, supplied with a cartridge of 15IU (5mg) or 30IU (10mg) rhGH, and is stable at 2-8°C for about two years without lyophilisation. Therefore jintropin AQ is higher in quality and more potent than the normal powder form of Jintropin and any other powder form of generic hGH, the company claims.
Pediatrics research at GenSci has been closely related to Jintropin in treating growth hormone deficiency (GDH) in children. GenSci's long-acting somatropin, PEG-GH, which is in Phase II, will bring great convenience and efficacy to pediatric patients.
GenSci has focused on its product pipeline of protein therapeutics by recombinant DNA technology. With its patented E. coli secretion expression system, investigation programmes at GenSci cover more protein molecules in the areas of wound healing, infertility and hepatitis.