STATE OF THE ART
Plasma fractionation in Asia–Pacific: challenges and perspectives
Thierry Burnouf, PhD, Human Plasma Product Services (HPPS), 86 rue Deleval, 59249 Aubers, Lille, France
Patients in every country should have access to quality blood products. National health authorities play a critical role in ensuring that patients’ needs are met with safe and cost-effective products. Fractionated plasma products, as other blood products, are essential therapeutics used in the prevention, management, and treatment of life-threatening conditions resulting from trauma, metabolic congenital deficiencies, immunological disorders or infections. A few high development index (HDI) countries in the region have sufficient access to a broad portfolio of plasma products (coagulation factors, immunoglobulin, albumin) through domestic (e.g. Australia, Japan, Korea) or contract (e.g. Singapore, New Zealand) plasma fractionation programmes. China is gradually establishing a modern plasma fractionation industry. Other countries face plasma product shortages leading to inappropriate clinical use of plasma for transfusion and of non-virally inactivated cryoprecipitate, and ultimately to inappropriate treatment of patients.
The volume of plasma fractionated in the region is too low to meet the needs. The volume (about 6 million l) represents 20% of the total volume fractionated worldwide for 60% of the world population. There is a rationale to encourage plasma contract fractionation programmes or operation of domestic facilities (when justified) to use local resources. However, many challenges are being faced as national plasma fractionation programmes require a mature blood collection infrastructure. Unfortunately, several LDI countries lack a mature national blood programme and a legislative framework on national policies and legislation on blood donations. They lack a safe blood donor base and a well-organized, nationally coordinated blood transfusion services; their blood collection system is scattered among different entities, resulting in non-uniform screening and testing procedures. Financial and human resources are lacking. Still, a few countries (e.g. Hong Kong, Malaysia, Singapore, Taiwan) have strengthened the national blood programmes, national blood policies have been implemented and the management of the blood transfusion service improved, allowing to implement contract plasma fractionation programme with established fractionators. Others are considering initiating (Indonesia and Malaysia) or enhancing (Thailand) domestic fractionation.
Plasma fractionation programmes require good awareness and understanding by national regulatory authorities on quality criteria of plasma products. Local plasma product market and potential trends should be evaluated to determine plasma needs and the capacity to implement collection of plasma by apheresis from volunteer dedicated donors to supplement recovered plasma as a source material for fractionation. Appropriate choice of a contract fractionation partner should be made and contract terms discussed carefully. The fractionation technology and product portfolio should be evaluated to make sure that intended products can meet domestic needs (e.g. range, potency and formulation). A reimbursement policy (in particular for IVIG) for a range of proven indications should be established, as approved in the marketing authorization dossier. Confidence of clinicians and patients in the quality and safety of domestic vs. imported products should be built.
With the economical development of the region and the ageing population trends, the needs for plasma products are expected to increase, justifying efforts to fractionate domestic plasma (e.g. initially through contract fractionation) and increase guarantee of supply in quality plasma products.
In spite of the increasing availability of recombinant coagulation factors , the fractionation of human plasma remains needed to ensure access of patients to a range of medicinal products to treat severe bleeding and immunological disorders and metabolic diseases associated to congenital of acquired plasma protein deficiency. To highlight the role played by plasma products for national health care and raise awareness of governments, coagulation factor VIII concentrate (haemophilia A), factor IX complex (coagulation factors II, VII, IX, X) (bleeding disorders), human normal immunoglobulins (primary immunodeficiency and Kawasaki disease), and/or anti-D or antitetanus immunoglobulins are on the WHO Model List of Essential Medicine for adults (17th edition, March 2011, http://whqlibdoc.who.int/hq/2011/a95053_eng.pdf), or children (3rd edition, March 2011, http://whqlibdoc.who.int/hq/2011/a95054_eng.pdf). The supply in plasma-derived medicines relies on the availability of plasma collected from human donors. The total volume of plasma fractionated worldwide in 2010 by 78 fractionators is slightly over 33 million l . There are major discrepancies at global level in the capacity to collect and fractionate plasma. Most plasma collection/fractionation capacity is in North America and Western Europe. Supply of plasma for fractionation has historically been based on voluntary whole blood donations generating a significant number of plasma units, as by-product of cellular components. In these countries, plasma is also obtained by plasmapheresis from volunteer donors. In addition, in the United States and some European countries, plasmapheresis from remunerated donors is generating the additional volume of plasma required to meet the increasing product demand. Today, 75% of the plasma used for fractionation is obtained by plasmapheresis . Many countries in Africa, Middle-East, South and Central America, and Asia face a shortage in plasma and plasma products, and do not have access to plasma fractionation facilities. This article addresses the current situation and perspectives of the plasma fractionation industry in Asia–Pacific.
Blood transfusion services in the region range from regulated, well-organized services based on voluntary non-remunerated blood donors in developed countries to those in the least developed countries that are fragmented, lack resources, have inadequate safety and quality monitoring, and are dependent on paid donors. There are over 35 plasma fractionation plants in the region , more than 50% of the world total. Still, there is under-capacity in plasma fractionation with regards to the population (>4 billion; 60% of the world population). The total plasma volume fractionated in 2010 is close to 6·4 million l (Table 1), less than 20% of the global volume. Many plants are small or manufacture a limited range of products.
Table 1. Overview of plasma fractionation in Asia–Pacific region (based on country classification by ISBT)
|Australia||Yes||1||500–520||Perform contract fractionation for other countries in the region (Hong Kong, Malaysia, New Zealand, Singapore, Taiwan)|| |
|China||Yes||(>) 25||3700|| ||New facilities (including relocation/modernization of existing plants) are expected to be built in the next 5 years|
|Hong Kong||No||0||25–27||Contract fractionation in Australia|| |
|India||Yes||1||83|| ||One hundred and fifty tonnes fractionation plant project in Chennai, approved by the Indian government, but delayed|
|Indonesia||No||0||–||Under consideration||Domestic fractionation plant under consideration|
|Japan||Yes||4||1100|| ||Integration of Japanese Red Cross Society and Mitsubishi Tanabe Pharma Corporation (Benesis Corporation) plasma fractionation operations under discussions|
|Malaysia|| || ||25–32||Contract fractionation in Australia||Domestic fractionation plant under consideration|
|New Zealand||No|| ||50||Contract fractionation in Australia. Recently renewed for three years with two renewable terms|| |
|Singapore|| || ||10–16||Contract fractionation in Australia|| |
|Republic of Korea||Yes||3||870||One of the plant performs contract fractionation for other countries (e.g. Thailand)|| |
|Taiwan||No||–||20||Contract fractionation in Australia||The project of a domestic fractionation plant has not been initiated|
|Thailand||Yes||10||30||Contract fractionation in Korea||MOU signed in July 2011 for a 100–200 tonnes plasma fractionation plant operated by the Thai Red Cross in collaboration with the South Korea|
|Vietnam||No||–||–||–||A project for local fractionation plant was considered and postponed by lack of plasma meeting quality requirements|
|Brunei, Burma, East Timor, Cambodia, Laos, Macau, Mongolia, Myanmar, North Korea, Pakistan, Philippines, Papua New Guinea||No||–||–||–||–|
|Total|| ||(>) 35||6426–6462|| || |
Plasma fractionation has been established for many years in several countries in the region. There is one for-profit fractionator in Australia that process over 500 000 l of domestic plasma into a wide range of advanced products, and contract-fractionate for other countries in the region (Hong Kong, Malaysia, New Zealand, Singapore, and Taiwan). There are four plasma fractionators in Japan, one not-for-profit (Japanese Red Cross) and three private which fractionated 1·1 million l of plasma in 2010. The coverage of local needs by products prepared from domestic Japanese plasma is about 25% (factor VIII), 58% (albumin) and 95% (immunoglobulins) in 2010 . On 17 June 2011, the Japanese Red Cross Society and Mitsubishi Tanabe Pharma Corporation (Benesis Corporation) have agreed to discuss the integration of their plasma fractionation operations into a new not-for-profit entity, with the goal of helping Japan to reach national self-sufficiency through economy of scale. A new plasma fractionation plant (ethanol fractionation process) should be established to fractionate all raw materials needed at national level. Three plants are located in the Republic of Korea, one is not-for-profit (Korean Red Cross) and two are private. The volume of plasma fractionated is about 870 000 l. China has over 25 plasma fractionation plants for a theoretical total capacity of about 12·4 million l. About 3·4 million l of domestic plasma were fractionated in China in 2010. This volume is collected exclusively by plasmapheresis from remunerated donors. The range of products is relatively small with a traditional focus on albumin production. Few centres can produce intravenous immunoglobulin (IVIG) and coagulation factors. The regulatory requirements to create apheresis centres, license new preparations, and meet international GMP standards are increasing. Several new – 1 million l capacity – plasma fractionation facilities are planned, but difficulty to generate apheresis plasma for fractionation may last for several years. This may lead to continuous shortage in albumin (the only plasma product that can currently be imported), and increased difficulties to meet growing domestic demand for IVIG and other products. Use of recovered plasma for fractionation is under consideration. Thailand has a small plasma fractionation facility run by the Thai Red Cross Society, to produce intramuscular IgG and albumin; about 30 000 l of plasma are sent to the Korea (Green Cross) for contract fractionation. A memorandum of understanding has been signed in July 2011 between the Thai Red Cross Society and Korean Green Cross to collaborate in the construction of a domestic facility of a capacity of 100–200 000 l. Five countries in the region (Hong Kong, Malaysia, New Zealand, Singapore and Taiwan) have contract fractionation agreement with Australia (respective annual volume: 27 000, 32 000, 46 000, 16 000 and 20 000 l). Most often, (5% and/or 20%) albumin, IVIG, factor VIII and factor IX are manufactured and returned to the country of origin. There is a project for a plasma fractionation facility in Malaysia, while the one for Taiwan has not been initiated. India has no plasma fractionation plant able to manufacture the major plasma products at this moment. The National Plasma Fractionation Center (NPFC) established in 1997 at KEM Hospital, Mumbai for an annual capacity of 10 000 l has been shut down several years ago. Contract fractionation activities with foreign fractionators have started for a volume of about 50 000 l. A 150 000 l plasma fractionation plant facility in Chennai (budget of Rs 250 Crore; US$ 50 million) was approved by the Government in 2007 to prepare albumin, IVIG, factor VIII and factor IX, but is delayed till now. One major difficulty lies in the high number of blood collection establishments (>2700), only 30% of them preparing blood components. Needs for plasma product being high and unmet, a fractionation industry is expected to eventually develop with appropriate planning. A project for a plasma fractionation facility in Vietnam has been abandoned due to difficulty in sourcing enough plasma meeting GMP requirements in a country with fragmented blood collection services. Indonesia is studying the possibility to enter a contract fractionation agreement and build a domestic facility. Other countries in the region such as Brunei, Burma, East Timor, Cambodia, Laos, Macau, Mongolia, Myanmar, North Korea, Pakistan, Philippines, Papua New Guinea, have no fractionation.
Table 2 provides examples of challenges faced in the implementation of domestic plasma fractionation programmes.
Table 2. Examples of challenges to be considered in the establishment of an industrial plasma fractionation programme
|Legislative framework||• National policies and legislation on blood donations should be in place|
|National blood transfusion service||• Should be coordinated at national level to:|
|○ ensure uniform practices for donors’ selection and collection and testing procedures|
|○ contribute to the establishment of a safe blood donor base nationwide|
|Plasma quality||• The blood establishments have to adjust plasma preparation procedures to meet GMP requirements for fractionation defined by the plasma fractionator and approved/enforced by the NRA|
|• Examples of new requirements may include: new criteria for epidemiological surveillance of donor population; additional donor selection/exclusion criteria; use of viral test kits and validated testing procedures required by the fractionator; reinforced post-donation follow-up; modified separation, freezing and storage procedures of plasma; collection and preparation of samples for NAT minipool testing,a etc.|
|• Audits by the fractionators and inspections by NRA (s)|
|Plasma quantity||• The volume should be sufficient to justify a contract fractionation programme or a domestic facility|
|Local national regulatory authorities||• NRA should be appropriately financed and have trained and expert human resources to:|
|○ make proper scientifically based judgments|
|○ enforce GMP in plasma collection and fractionation|
|○ ensure quality and safety of plasma products|
|○ grant marketing authorization to plasma products|
|○ overview pharmacovigilance system and reports|
|○ perform specialized quality control tests (national control laboratory)|
|Plasma fractionation technology||• Should be validated to yield products with established quality, safety and consistency|
|• Skilled and properly trained local manpower|
|Product portfolio||• The products made by the fractionators may not match the local market demand, creating surplus by-products that accumulate and generate financial difficulties for instance if/when:|
|○ recombinant coagulation factors are used widely|
|○ clinical use of IVIG is not developed or not properly reimbursed|
|• Surplus by-products may, upon agreement be marketed by the fractionator. This implies regulatory approval, solving of liability issues, endorsement by blood donors association, local authorities, etc|
|• The range of products from one single fractionator may be restricted, requiring some leveraging to access a wider range of products or to establish relationships with other fractionators active in the region|
|Contingency planning||• Dependency on one fractionator exposes to potential supply issues|
|Product quality||• Quality of products made from local plasma may in some countries be perceived as being inferior to that of imported products, creating a marketing disadvantage|
|Products reimbursement policy||• A fair reimbursement policy should be implemented for the clinical indications approved in products marketing authorizations|
|Financial aspects||• The cost to design, build, qualify, validate and operate a local GMP-compliant facility is high and is often under-estimated|
Importance of government support and role of national regulatory authorities
Government support is crucial to the success of a plasma fractionation programme by establishing policies on blood donations and plasma products, and legal and regulatory framework. National Regulatory Authorities (NRAs) play a critical role to: (i) regulate, overview, and verify, through formal inspections, the implementation of GMP during the collection process of plasma and its fractionation, and (ii) overview the pharmacovigilance system. Coordination with the foreign NRA is needed when a contract fractionation programme is in place, allowing cross-fertilization in regulations and coordination in inspections. NRA of many countries need to raise the level of understanding of quality and safety criteria of plasma products, allowing scientifically based regulations and decisions.
Well-organized, national blood transfusion services, coordinated under a common quality system, and collecting enough whole blood donations from voluntary and regular non-remunerated blood donors are usual pre-requisites for a plasma fractionation programme. National blood policies and legislation on blood donations should not only be enacted but also fully implemented. Such requirements are lacking in many poor countries in the region, where blood services lack financial support and human resources .
Plasma quality and quantity
The collection of plasma for fractionation is the first step in the manufacture of fractionated plasma products , and impacts the quality and safety of products [6,7]. Recovered plasma should achieve the standards set by fractionators and regulators. Blood establishments should comply with GMP , are audited by fractionator and inspected by local NRA. Inspection by foreign NRA may occur, in particular when end-products/intermediates are used/sold by the fractionator. This may affect substantially the operations of the blood establishments, and/or may lead to the exclusion of some collection centres for collecting plasma for fractionation for reasons that may include improper post-donation information system, unsatisfactory plasma freezing conditions or storage capacity. Recommendations on the collection, quality control and regulation of plasma for fractionation  and on GMP in blood establishments  can be found on the WHO website.
There is no general rule regarding the minimal volume of plasma needed for contract-fractionation. This is negotiated with the fractionator depending upon plasma pool and product batch size, regulatory efforts, and financial aspects. Examples in the region (e.g. Singapore) and elsewhere  show programmes involving annual volumes close of 10 000–15 000 l. Volumes over 150 000–200 000 l may exceed the capacity of a single fractionator. For technical or regulatory reasons, fractionators are often unwilling to process low-volume (e.g. 100 ml) plasma units (which are common in the regions).
In most countries, the priority is to use recovered plasma for fractionation. Collection of apheresis plasma by apheresis can also be considered from non-remunerated donors to generate enough plasma for fractionation. Examples include collection of hyperimmune plasma for preparing specific immunoglobulins (hepatitis B, tetanus, etc.). Plasmapheresis can also be used to produce plasma for coagulation factors, albumin and IVIG. In a non-regulated environment, characterized by absence of GMP framework for donors’ epidemiological surveillance and screening procedures, donations’ testing, look-back and traceability, the collection of plasma from remunerated donors may expose to higher rates of infectious donations.
Assessment of clinical needs/reimbursement policy/national health care system
Accurate assessment of clinical needs and trends should be made, considering number of patients, treatment approaches (on-demand, prophylaxis, home treatment), and possible under-recognized or under-diagnosed conditions . This estimate should consider reimbursement policies in place and in particular the indications covered for IVIG in auto-immune disorders . Many countries face an imbalance in the plasma products use, thereby generating excess products (e.g. factor VIII or IVIG) which challenge the economics of the plasma fractionation programme. During contract fractionation, it may be possible, as done by the New Zealand Blood Service, to negotiate the purchase of unused intermediates or end-products by the fractionator. This generally leads to inspections of the collection centres by foreign NRAs and their inclusion in the Plasma Master File. Liability issues should be carefully considered to address products defects. Government approval and adhesion to the concept by blood donors should be obtained.
Economical constraints in plasma products supply may make importers threatened by a domestic plasma fractionation project. This may lead to various political and media actions against the programme, usually by raising questions on quality and safety of resulting products. In the absence of a strong NRA able to analyse objective quality and safety criteria, and of a strong political support, misleading allegations may seriously affect a domestic programme.
Choice of the fractionation technologies
Countries in Asia/Pacific considering to build a plasma fractionation facility need to select a fractionation technology, a choice with heavy economical and regulatory/validation impacts. A frequent issue is to select a technology based on ethanol precipitation (Cohn or Kistler–Nitschmann processes) [12,13], which is perceived as old-fashioned, or on chromatography . Modern fractionation methods still relies on cryoprecipitation combined with an integrated ethanol fractionation/chromatography process [5,15]. Chromatography is the main purification method of coagulation factors, protease inhibitors and anticoagulants from cryo-poor plasma, while ethanol fractionation remains largely used for albumin production. Higher-yield IgG are increasingly purified by chromatography of fractions I + II + III or II + III . Processes based exclusively on chromatographic cascades to sequentially capture protein fractions have been described . They can be serious alternatives to the cryoprecipitation/chromatography/ethanol fractionation core process when licensed by established regulatory authorities. It is often considered reasonable to initiate a domestic plasma fractionation programme by contract fractionation with the expected technology provider .
Benefits and perspectives
Need for plasma products are expected to increase markedly in the Asia–Pacific region, in particular in large emerging countries like China and India. Implementing a plasma fractionation programme is a means to address such needs.
Use of local resources
A contract fractionation programme, even for relatively low volumes, utilizes existing and valuable voluntarily donated plasma resources that would otherwise be discarded. There is an ethical responsibility and financial value in using these donations effectively to produce valuable plasma products.
Guarantee of supply
A plasma fractionation programme provides some guarantee of supply in plasma products, reducing exposure to market fluctuations at global level. Recent examples affecting supply include:
- 1 Interruption of production by US fractionators following FDA’s Team Biologics inspections.
- 2 Interruption of supply of one recombinant factor VIII.
- 3 Policies on Creutzfeldt–Jacob disease (CJD) and vCJD.
- 4 Manufacturing issues: e.g. thrombogenic side-effects of an IgG product.
Benefits of contract fractionation programmes on product supply and/or cost have been reported in Norway , Iran [19,20], and Brazil .
Safety of treatment
Increased availability of fractionated products decreases the use of crude fractions like non-virally inactivated plasma or cryoprecipitate, improving the standard of care.
Ensuring early treatment of patients with chronic diseases through access to plasma products reduce morbidity, improve quality of life, and is cost-effective . In addition, using excess local plasma may reduce plasma product cost since plasma is the most important cost factor (about 40%) of fractionated products.
Improvement of collection practices and impact on public health
A plasma fractionation programme typically helps improving the level of quality of the operations at blood establishments, with positive impact on the quality and safety of blood components . Collection practices, exposed to the GMP requirements of highly regulated countries, have been found to improve in aspects including (i) donors selection criteria, (ii) plasma donation testing, (iii) epidemiological surveillance, (iv) post-donation information systems, (v) handling of blood and (vi) plasma freezing, storage, and cold chain transportation [8,9]. Positive impact on public health by upgrading transfusion safety and epidemiologic surveillance can be significant.
Industrial plasma fractionation is a sophisticated industry which shares a great deal of technical and regulatory similarities with the biotech industry, in aspects related to traceability, protein downstream, viral reduction treatments, hygiene requirements, etc. Building up such expertise can help local biotech industry, optimizing local human resources.
Sincere appreciation is expressed to the following experts who have provided information used in this work: Dr Ranjeet Ajmani (National Expert: Plasma Fractionation Project at National Aids Control Organization NACO, India); Mr Vincent Cazenave (Director, LFB-China); Dr Jeff Davies (Executive Vice President, CSL Biotherapies, Australia); Dr Peter Flanagan (National Medical Director, New Zealand Blood Services, New Zealand); Mrs Nanik Gunawan (Synergi, Indonesia); Dr Roshida Hassan (Director, National Blood Center, Malaysia); Dr Ho Hhan (CEO, Nanogen, Vietnam); Mr Anuar Danial Khairul (Managing Director, Tree Med SDN BDH, Malaysia); Dr Che-Kit Lin (Director, Hong-Kong Red Cross, Hong-Kong); Pf. Kuo-Sin Lin (Chairman, Taiwan Blood Service Foundation, Taiwan); Dr Sujen Lin (CEO, Taiwan Blood Service Foundation, Taiwan); Mr Yoshiaki Numata (Executive officer, Blood service board of management, Japanese Red Cross, Japan); Dr Soisaang Phikulsod (Director, National Blood Centre, the Thai Red Cross Society, Thailand); and, last but not least, Dr Diana Teo (Group Director, Blood Services Group, Health Sciences Authority, Singapore). My thanks are also conveyed to Dr Ana Padilla (WHO, Geneva) for helpful comments.
No potential conflict of interests to declare.