Available online at www.sciencedirect.com

Biologicals 37 (2009) 94e102www.elsevier.com/locate/biologicals

Role of regulatory agencies

Jay Epstein a,*, Rainer Seitz b, Neelam Dhingra c, Peter R. Ganz d, Ahmad Gharehbaghian e,Renato Spindel f, Diana Teo g, Ravi Reddy h

a Food and Drug Administration, Rockville, MD, USAb Paul-Ehrlich-Institut, Langen, Germany

c WHO Headquarters, Geneva, Switzerlandd Centre for Biologics Evaluation, Health Canada, Ottawa, Ontario, Canada

e Iranian Blood Transfusion Organization (IBTO) Research Center, Tehran, Iranf Gerencia Geral de Sangue, Outros Tecidos, Celulas e Org~aos (GGSTO)/Agencia Nacional Vigilancia Sanitaria (ANVISA), Brazil

g Health Sciences Authority, Republic of Singaporeh South African National Blood Transfusion Service, Cape Town, South Africa

Received 9 January 2009; accepted 9 January 2009

Abstract

In this paper the authors discuss the role of regulation in assuring blood safety. After an overview of the subject by a leading expert, examplesare provided of regulatory systems for blood transfusion services in several countries and regions. Additionally, the perspective of WHO is givenon the essential role of national regulatory authorities in assuring the quality of national blood programmes.

Collectively, the sections of this paper afford an opportunity for readers to make comparisons among different regulatory frameworks and to"benchmark" among the existing systems. Despite many differences in approach, a clear pattern emerges of worldwide efforts to strengthenblood regulatory systems.Published by Elsevier Ltd on behalf of The International Association for Biologicals.

Keywords: Blood regulation; WHO; Reform; Public health

1. Introduction coordinated blood services which operate under the effective

Dr. Jay Epstein (jay.epstein@fda.hhs.gov)A safe and adequate blood supply is essential to modern

medicine, but has yet to be achieved in all countries. In anyregion, meeting the goal of universal access to safe bloodtransfusion requires a highly integrated system includingrecruitment of suitable donors; performance of infectiousdisease and blood group compatibility tests; preparation andstorage of blood products according to established qualitystandards; effective distribution systems; and appropriateclinical use. Experience in many countries has taught us thata successful blood program depends upon nationally

* Corresponding author.

E-mail address: jay.epstein@fda.hhs.gov (J. Epstein).

1045-1056/09/$36.00 Published by Elsevier Ltd on behalf of The International As

doi:10.1016/j.biologicals.2009.01.004

oversight of a legally empowered regulatory authority. In thispaper, the authors provide a broad discussion of the nationaland international role of regulation in assuring blood safety.Selected examples of blood systems in several developed anddeveloping countries and regions provide insight on the globalvariation in blood programs and their regulatory frameworks.Despite some differences in the approach, a clear patternemerges of worldwide efforts to strengthen blood regulatorysystems consistent with principles that have been articulatedby the World Health Organization.

2. Safe blood: a regulator’s reflection and perspective

Prof. Rainer Seitz (seira@pei.de)Blood products, i.e., both blood components for trans-

fusion and plasma derivatives, are an essential element in

sociation for Biologicals.

95J. Epstein et al. / Biologicals 37 (2009) 94e102

the state-of-the-art medicine. Blood transfusions are oftenlife-saving or permit crucial interventions; coagulation factorconcentrates provide a dramatic improvement in life expec-tancy and quality of life of haemophilia patients. However,the mass transmission of virus infections by blood productsin the early 1980s was one of the worst incidents of moderntherapy, demonstrating potential hazards and the need tointroduce precautionary measures and regulatory control.

In Europe e as well as in other industrialised areas e hugeefforts have been made by all involved parties, particularlyblood establishments and industry, as well as regulatoryauthorities. There is now a comprehensive system of regulatorycontrol [1], the basis of which is stringent legislation on both theEuropean Community (EC) and member state (national) levels.Particularly a dedicated ‘‘blood law’’, directive 2002/98/EC and‘‘daughter’’ directives, provides a regulatory framework.Important technical standards are provided by the EuropeanPharmacopoeia monographs, and guidance documents issuedby the Council of Europe and the European Medicines Agency(EMEA). Plasma derivatives have been subject to pharmaceu-tical legislation since 1989 and are subject to marketingauthorisation and official batch release.

Three protective walls against pathogen transmission havebeen built up: criteria ensuring healthy blood donors, testing ofdonations with sensitive methods including NAT, and elimi-nation of pathogens from the product. Blood safety regardingthe most relevant viruses is now very high in Europe, withonly a few recent transmissions by blood components. Forexample, in Germany with about 4.5 million whole blood and1.8 million apheresis donations, only one single transfusiontransmitted HCV case since 1999, and one single HIV casesince 2001 has been observed. In the past 10 plus years, therewas no documented transmission of HIV, HCV or HBV byplasma derivatives licensed in the EC. The efforts and finan-cial input behind this safety achievement are very substantial,but appear to have been a good investment, since the confi-dence of the public in the safety of blood has largely beenrestored.

Blood safety is no longer a purely national issue. Bloodproducts, particularly plasma derivatives, are exchangedacross borders where conditions and health standards are quitedifferent. However, the status of blood systems and theadequacy of supply of the population with blood products ofgood quality and safety are apparently very differentthroughout the world. Pathogens continue to originate, evolveor re-emerge, and may rapidly be spread by ever-growinginternational travel. Recent examples of emerging (new andnewly relevant) pathogens include West Nile Virus and theChagas’ disease agent, while older recognized pathogens likemalaria continue to be a problem. The fear of a new influenzapandemic and the observed transmissibility of vCJD arefurther issues. Under these circumstances, it is a great chal-lenge to adopt and keep updated safety measures, which takeaccount of domestic factors (e.g., epidemiology of the donorpopulation, transfusion practices, as well as priorities in faceof limits to available resources), while being harmonized asmuch as possible with other regions.

International collaboration is of crucial importance inpromoting safety and availability of blood and blood productsglobally. The World Health Organization (WHO) is a keyplayer, with many important activities which include theInternational Conference of Drug Regulatory Authorities(ICDRA), the Global Collaboration for Blood Safety (GCBS),the Expert Committee on Biological Standardization (ECBS),and the recently established WHO Blood Regulators Network(BRN). In particular, the ECBS provides guidelines, e.g., onplasma for fractionation, and International Standard (IS)preparations facilitating standardization and control of bloodproducts and related diagnostics worldwide.

The challenges we face will include further infectioushazards, such as new or emerging pathogens, and their globalspread by international travel. In parallel, we must enhanceblood safety by working to optimize the use of blood, i.e.,refining indications (e.g., transfusion trigger) and limiting sideeffects (e.g., immunological reactions). There is a dynamicdevelopment of health technologies, such as test systems orpathogen inactivation methods, the benefits, risks and costs ofwhich will have to be scrutinized. An upcoming, quite vexingproblem is the appearance of counterfeits of plasma deriva-tives or test kits on the markets, particularly of less richcountries with less stringent regulatory surveillance.

In order to cope with these challenges, we will need Inter-national Health Policy programmes and activities on the globalscale. The WHO and scientific and professional societies suchas the IABs will be important actors. Enhanced cooperation ofregulatory authorities should aim at harmonizing and dissemi-nating standards and combating malpractice and counterfeits.These activities need to be accompanied by a permanent dia-logue with blood services, industry, physicians, patients andother stakeholders. And, last, but not least, we will needcontinuing research, e.g., into the biology and epidemiology ofpathogens, technologies of testing and manufacture of bloodproducts, and their best use in the interest of our patients.

3. Insights and advice from WHO

Dr. Neelam Dhingra (dhingran@who.int)

3.1. WHO guidance to National Blood TransfusionServices: ‘The Essential Role of NRA’s’

The need for safe blood transfusion as an essential andintegral part of a health care system has been reiteratedthrough several World Health Assembly (WHA) and Execu-tive Board (EB) resolutions [2]. Resolution WHA28.72 ofMay 1975 addressed the issue of utilization and supply ofblood and blood products and urged WHO Member States topromote development of National Blood Transfusion Services(NBTS) based on voluntary non-remunerated blood donors, aswell as to enact effective legislation governing operation ofblood services, promote and protect health of blood donorsand of recipients of blood and blood products. Blood Safetyand Availability, ensuring access to safe blood for all patientsrequiring transfusion, was also endorsed through resolution

96 J. Epstein et al. / Biologicals 37 (2009) 94e102

WHA58.13. Blood safety: proposal to establish World BloodDonor Day, which urged WHO Member States to support thefull implementation of well-organized, nationally coordinatedand sustainable blood programmes with appropriate regulatorysystems. However, despite these resolutions, the WHO GlobalDatabase on Blood Safety 2004e2005 demonstrated thata mechanism for regulation of the blood transfusion service isonly present in 67 of 126 countries, with another 24 in theprocess of developing a regulatory framework. Of these 67, 64have a national regulatory authority, 50 indicate that there isa system of regular inspections of the NBTS/blood transfusionservices, and 40 have inspectors with specialized training inblood transfusion.

The WHO advocates an integrated strategy for blood safetyto the national blood programmes. This strategy addresses fivekey areas:

� The establishment of well-organized, nationally coordi-nated blood transfusion services, with legislation andeffective mechanism for oversight, to ensure the timelyavailability of safe blood and blood products for allpatients requiring transfusion.� The collection of blood from voluntary non-remunerated

blood donors from low-risk populations.� Testing for transfusion-transmissible infections, blood

grouping and compatibility testing.� The safe and appropriate use of blood and a reduction in

unnecessary transfusions.� Quality systems covering the entire transfusion process,

from donor recruitment to the follow-up of the recipientsof transfusion.

Major stakeholders in a national blood programme includethe government or National Health Authority for developmentof policy, plan, standards and legislation; regulatory agencyfor regulatory oversight; donor services for recruitment andretention of blood donors and blood donation; blood trans-fusion services for blood collection, processing, testing,inventory management, and distribution; hospital blood banksfor blood inventory management and compatibility testing;clinicians and nurses for transfusing blood; patients as recip-ients of blood products; educational and training institutionsand universities for education and training of staff; suppliers ofmaterials, reagents, and equipment; and accreditation andcertification bodies for voluntary accreditation/certification.

3.2. WHO guidance to National Blood TransfusionServices: "The Essential Role of NRAs"

The establishment of a legal basis and regulatory strategyprovides for, and protects the health of the population.Legislation gives expression to public policy and providessupport and governance to those who are charged withauthority and responsibility to implement the policy. Whateverits merit, without law, no public policy could be clearlyformulated, effectively implemented, and sustained. Appro-priate blood transfusion legislation and adequate regulation is

a public health priority to ensure safety and availability ofblood and blood products. Regulation of blood transfusionservices is required to ensure compliance with all nationallegislation related to blood transfusion, to establish efficientsystems for the control of the NBTS, to ensure that safe bloodproducts are available to all patients and to establish a nationalquality system and management that will ensure appropriatequality and standards for the NBTS. A regulatory frameworkis necessary to establish and maintain an appropriate andeffective system for the inspection, licensing, audit and/oraccreditation.

Safety of transfusion is not assured globally, particularly incountries with less developed health care systems. Threatsassociated with transfusion include inadequate supplies of safeblood/blood products to meet the needs of all patientsrequiring transfusion; risk of transmission of infection throughunsafe blood, technical and clerical errors in the processingand testing; inappropriate use; and unnecessary transfusionsand errors in the administration. There is a need to have basicand minimum level of uniformity, standardization and qualityin blood transfusion services across any country. WHO ‘BasicRequirements for Blood Transfusion Services’ provide guid-ance to countries in setting standards for quality, safety,adequacy and accessibility of blood supply and safety ofclinical transfusion process and provide a foundation for theestablishment of quality systems in blood centers, hospitalblood banks and clinical transfusion settings.

An essential requirement on Policy and Organization isa national blood policy, plan, legislation and regulation withinwhich the blood transfusion service is organized, managed andregulated. Regulation of the blood transfusion service indi-cates how the system is functioning for implementing therelevant policies, strategies, goals and objectives. The keyingredients for a successful blood programme include goodorganization; efficient management; and effective regulation.

For more information on WHO guidance in this area,interested persons may visit: www.who.int/bloodsafety andwww.who.int/worldblooddonorday.

4. Perspectives on regulatory systems at the nationallevel e evolving regulatory processes to enhancenational blood safety: the Canadian experience

Dr. Peter R. Ganz (peter_ganz@hc-sc.gc.ca)

4.1. Blood systems reform and biologics regulation

The blood system in Canada has undergone tremendouschange following Justice Horace Krever’s Commission ofInquiry on the Blood System in Canada in the period1994e1997. Health Canada, as the regulator of the bloodsystem, has been transformed from a reactive to a proactiveregulatory authority. Canada’s two blood system operators,Canadian Blood Services and Hema Quebec, have evolved tomature blood operators who have championed the course ofvoluntary blood donation in Canada and the principle thatblood safety is paramount. Amongst these key stakeholders,

97J. Epstein et al. / Biologicals 37 (2009) 94e102

lines of responsibility and accountability are clear and there isgreater transparency in decision making with all stakeholdershaving a say in setting policy and the overall direction of theblood programme.

The path followed for the blood system in Canada has beento use the precautionary principle to assess and manage risk ina manner in which real and perceived threats to the bloodsystem are dealt with, in an anticipatory fashion. The mannerin which infectious disease threats to blood systems such asHIV and hepatitis C were managed has evolved so that newinfectious agents such as variant Creutzfeldt Jacob Disease(vCJD), West Nile Virus (WNV) and Simian Foamy Virus(SFV) are identified in advance as requiring action so that allstakeholders can contribute to policy to address these threats.A key characteristic of this proactive regulatory shift has beenthat issues are addressed much earlier. More effort is placed toforecast emerging threats in order to allow for adequate andtimely risk management. A defining characteristic of Canada’spast blood system was that threats such as HIV and hepatitiswere managed over many years, resulting in delays in reme-dial action whereas in today’s blood system, the time intervalbetween risk identification and actively managing the risk isvery much diminished in time. Indeed, much emphasis todayis placed on forecasting issues and developing strategiesbefore threats are realized. The examples in recent years havebeen vCJD, WNV and SFV. Management of all of these riskshas involved research, international consultation and stake-holder involvement resulting in regulatory decisions thatreflect a high degree of confidence bolstered through collab-orative efforts. Another recent example would be planning forpandemic influenza and consequent effects on blood safetyand availability. In a broader context, many of the riskmanagement lessons that are learned from blood systemsreform also have applicability to broader areas, such asmanaging the safety of other types of biologicals such asvaccines. In these instances, the precautionary principle wouldapply as well as other risk mitigation strategies such as theneed for active surveillance.

Since the release of the Krever Report, the regulatorytoolbox for Health Canada has also evolved to include issu-ances of new Directives and Guidances as well as promulga-tion of National Blood Safety Standards. Operationally thesechanges have signalled timely response, clarity, and trans-parency to decision making.

In 1997, Health Canada began an exercise to create nationalstandards for blood. This included updated standards for donorselection and screening, component manufacturing, qualitysystems, testing and distribution including standards for bloodbanks. A clear focus was also given to harmonizingapproaches as best as possible with similar standards globally.This process was consensus driven through a matrix approachas managed by the Canadian Standards Association whichallowed for accreditation of the standard as a ‘‘NationalStandard of Canada’’. Industry groups, regulatory authorities,advocacy groups, professional organizations as well asmembers of the public were included in the standards settinggroup. This standards based approach to regulation has been

a model for Health Canada in regulating cells and tissues aswell as blood. Given the ability to make rapid changes tostandards (as opposed to legislative change), standards basedregulation will likely be considered as a future option forregulatory oversight of other types of emerging new therapiesor medical technologies.

4.2. International collaboration

The collective realization from these efforts is that riskmanagement of blood system safety is not just a nationalchallenge, but a global one. Developed and developingcountries can gain much from sharing their experiences andmanaging issues from an international perspective. Enhance-ment of international cooperation in the area of blood safety isthus a key driver for Canada.

Lessons learned from managing threats to blood systemssuch as vCJD and WNV have re-affirmed the value of inter-national cooperation. Sharing of risk assessment data andoptions considered for risk management of local threats orissues can be extremely useful for other jurisdictions wheresimilar risks may occur and where pre-emptive measureswould be warranted. In the case of vCJD, risk assessmentsand risk mitigation strategies were shared between Canadaand the U.S. before travel deferrals were put in place forblood donors simultaneously by both FDA and HealthCanada. Communication from both regulatory agenciesserved to educate the public about the scientific basis for thedeferrals and re-emphasized that the threat was not just con-tained within the U.S. or Canada but was present interna-tionally. As another example of beneficial regulatorycooperation, Health Canada built upon FDA’s proactive effortsto spur industry to facilitate development of a WNV screeningtest that was reviewed with priority and implemented in bloodsystems to allow for coordinated North American testing ofblood donors and subsequent sharing of WNV surveillancedata.

Collaboration and communication with our domestic andinternational stakeholders and partners is essential in copingwith emerging threats to blood safety. As we considerappropriate regulatory oversight for new biologics and thera-pies, we aim to innovate our approach keeping in mind ourmandate and link to public health.

5. Blood regulation in the Islamic Republic of Iran

Dr. Ahmad Gharehbaghian (gharehbaghian@ibto.ir)

5.1. Introduction to Iran

Located centrally within the Middle East, Iran bordersArmenia, Azerbaijan, and Turkmenistan to the north;Afghanistan and Pakistan to the east; and Turkey and Iraq tothe west. In addition, it borders the Persian Gulf, an importantoil-producing area, as well as the Gulf of Oman, and theCaspian Sea. Due to its geography, the country faces manynatural hazards including earthquakes and periodic droughts,

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floods, dust storms, and sandstorms. Iran has an area of1,648,195 square miles and a population of 70,472,846 people(2005) with average life expectancy of 69.1 years for malesand 72.1 years for females. The capital city is Tehran, theofficial religion is Islam, the official language is Farsi(Persian), and the monetary unit is the Rial. Iran has an esti-mated GDP (PPP) of $610 billion (2006) representing $8700per capita.

5.1.1. The Iranian Blood Transfusion Organization (IBTO)and its regulatory system

IBTO is the sole nationally accredited organization in Iranthat is responsible for the entire process of the blood supplyfrom donor recruitment to blood distribution [3]. IBTO isa centralized national and non-profit organization with bloodcenters across Iran in all provinces and cities that was estab-lished in 1974. According to the most recent estimates, thereare 24/25 blood donors per 1000 population in Iran. At thepresent time (2008), 100% of blood donations in Iran arecollected from voluntary non-remunerated blood donors withno replacement donations whatsoever. There are roughly 200fixed collection centers located across the country out ofwhich 65 embark on blood components preparation, testing,and release; the other 17 out of the total number embark juston collection and preparation with no testing.

The IBTO also is the only organization in Iran whichstandardizes the procedures that should be followed in allblood centers across Iran. The IBTO formulates all executivestrategies leading to the establishment of necessary standardprocesses. It formulates all standard operating procedures,upgrades standards and training, and is responsible to ensurecompliance with all these requirements and standards. Addi-tionally, IBTO is very active in the fields of research andeducation. It has published the first and the only scientificjournal in Iran, covering all articles related to transfusionmedicine and transfusion sciences that is called ‘‘Khoon’’(Blood) that is quarterly published and is indexed by IMEMRand Index Copernicus.

IBTO is a higher education center as well, recruiting MSand PhD students in hematology and blood banking. So far, 40MS students of hematology and blood banking have graduatedduring the last 8 years; 34 faculty members are full-time activecontributing to research and educational programmes of IBTO.

IBTO Research Center is another affiliated entity whoseestablishment has further streamlined research activitieswithin the scope of transfusion medicine.

The most important step taken by IBTO was its success toestablish very recently an independent high research andeducation institute for transfusion medicine. This instituteoperates in independence with no involvement in IBTOservices so that it only focuses on research and education. It isa suitable model for similar countries seeking to strengthenresearch and education without being entangled with routineand daily blood transfusion services.

IBTO enjoys a quality system that consists of (1) personnel;(2) organization; (3) equipment; (4) supplier issues; (5)handling; (6) records; (7) deviations and non-compliances; (8)

external and internal evaluation; (9) corrective measures forimprovement of procedures; (10) facilities and safety; (11)adverse reactions; and (12) documents. IBTO holds bi-weeklysessions with managers of different blood centers in thepresence of IBTO managing director, his deputies, and rele-vant managers. In such sessions, the pertinent blood centeractivities ranging from blood donor recruitment, bloodcollection to blood distribution and withdrawal are reportedand discussed. The merits and pitfalls are highlighted so thatthe former is promoted and communicated across all bloodcenters and the latter is advised to be avoided. Considering thenumber of blood centers all over Iran, each center would berepresented in such sessions at least once a year.

Based on a detailed and comprehensive 24-page checklistthat addresses all relevant points, the Quality ControlDepartment of every regional blood transfusion centerconducts a biannual inspection, the results of which are sentback to IBTO Headquarters for analysis. There is also a unitthat inspects the process of plasma production to make sure allsteps are according to the standards for collection, storage, andpreparation for export. Training records of the personnel arealso inspected by the Education Department to see whether theemployees have received the necessary training and haveundergone the proficiency testing. The raw materials,including equipment, consumer goods, kits, anti-sera and thelike are also inspected. The Recruitment and Retention Officeof IBTO also takes care of blood donors and their status tomake sure they are aware of all points; the relevant data arealso collected for future necessary measures.

5.2. Regulatory mechanism in the IBTO

A regulatory body uses mechanisms such as transparencyof information and decision making, consultation and partic-ipation, responsiveness and explanation for actions, promotionof non-arbitrary and responsive decisions, and arrangementsfor review of administrative decisions by courts or otherbodies. In the area of blood transfusion, regulatory agenciesare supposed to make sure that blood donated is free frominfections, the process of blood collection and transfusion issafe, the blood transfusion services comply with all require-ments, regulations and guidance, the blood transfusion serviceestablishments are inspected, evaluated, and accredited, andperiodic and objective quality assessments are made.

Within Iran, the IBTO Headquarter Quality ControlInspection System provides the regulatory function. Althoughpart of the IBTO, it can be stated that ‘‘We are running theheadquarter quality control department acting independentlyand totally separate from blood centers with no conflict ofinterests so it may success in this regard; at the same time,there is not a single unit, except IBTO, competent enough toknow about blood transfusion to implement inspection withthorough knowledge.’’ The IBTO Headquarter Quality ControlInspection System monitors the manufacturing procedure ofblood components, the number of blood components,consumption of kits and blood bags, the status of blooddonors, the statistics of blood donation and demography,

99J. Epstein et al. / Biologicals 37 (2009) 94e102

screening test results, results of confidential self-deferralattempts, the situation of blood drives, the status of deferralsand deferral causes, the equipment status, the status of humanresources, blood component use, and blood component with-drawal. With respect to screening tests, the details of every runare received and analyzed regarding test validity, C.V., SD,invalid runs, and the executive algorithm. Quality control ofblood components is evaluated according to standards toensure that corrective measures are taken. The outcomes ofcorrective actions are reported back to IBTO to be analyzedagain. Additionally, samples for external quality control areforwarded to all blood centers across the country; the testresults are reported back to IBTO Headquarters and the resultsare provided back to the centers.

6. The role of regulatory agencies in Brazil: developmentsand perspectives of the national agency for public healthand surveillance

Renato Spindel, MD (rspindel@uol.com.br)

6.1. Health sector regulation in general

Economic reasons for health sector regulation includeaddressing distortions of the market, mitigating the risks ofmonopoly, enabling collective action for public well-being,providing adequate public information, and promoting educa-tion. In the traditional model, public health regulation isa responsibility of the State and involves universal taxation,gathering of statistical data, record keeping and a voluminousbureaucracy. However, priorities are defined by the market, andthere is little or no transparency, making the system vulnerableto undue influences. The Brazilian government is aiming toprevent or reduce such vulnerability in the system by imple-menting evidence based action, i.e., action based on the analysisof sentinel indicators, ranking of risks, epidemiological data,evaluation of the market situation and logistical capabilities, aswell as increased education and communication, in order toproduce transparency and integration of the public healthsystem within the public sector. Through an integrated publichealth surveillance system, the Brazilian government aims atthe promotion, protection and restoration of public health bytaking action based on relevant information.

Decision making for public health activities is based onscientific information taking into account frequency andseverity of cases, risk factors such as exposure and suscepti-bility of populations, and availability of technology. Publichealth regulation is developed and applied depending on bothneed and technical availability and planned according toepidemiological data and priorities. The regulation of tech-nological tools by the government includes the evaluation ofsafety, potency and efficacy, as well as needs and priorities.The increased longevity of the population and the publicdemand for availability of advanced technology generatediscrepancies between demands and priorities creatingurgency for regulatory decisions.

6.2. Public health surveillance in Brazil

The public health surveillance system in Brazil includesregulation, dissemination of information, surveillance per se(including hemovigilance), technical evaluation, publiccommunication, training and education and inspections toassure quality. The decision making process is determined bysocial factors dictated by public demand and involves 4 sectors:

� The Ministry of Health defines the financial appropriationof resources and plans for social assistance.� The regulatory agency, ANVISA, is responsible for quality

assurance including standard setting, training, funding fordevelopment, fostering collaboration and cooperation, andenforcement through inspections to assure quality.ANVISA regulates (a) industry and commerce includingfood, cosmetic, drugs and agriculture; and (b) providers ofmedically related services including blood, cells, tissuesand organs. ANVISA regulates industry and serviceproviders through clearance of products, performance offinancial and technical evaluations, and dissemination ofknowledge and information by issuance of public infor-mation and alerts. GGSTO is aligned with ANVISA andcurrently focuses on volunteer donations of blood, tissue,cells and organs and regulation of product distribution andappropriate usage aiming to reduce and prevent risk.� The regulated sector includes industry and providers of

any service that may impact the public health.� The public sector is defined by users and consumers who

demand availability of quality products and services.

The law 8.080/90 addresses the relationship between theindustry and the public health surveillance system. It takes intoaccount both epidemiological risk and population risk(susceptible populations) in order to promote and assurequality of life, by eliminating, reducing and/or preventing riskto the public heath. Public health surveillance employs stan-dard epidemiological tools (i.e., incidence prevalence, odd,odds ratio, sensitivity, specificity, predictive value, etc.). Thepublic health surveillance system adopts the precautionaryprinciple, i.e., it is cautious to avoid undesirable outcomes andprevent anticipated risks that cannot be yet measured in thecurrent state of scientific knowledge. Public health risk isdefined as the probability of occurrence of an adverse eventusing evidence or scientific knowledge in conjunction witha statistic evaluation that will determine the appropriate actionthat should be taken to reduce or eliminate the risk. The publichealth system promotes quality and risk reduction byincreasing access to safe and effective technology in areas andpopulations with limited resources. There is a cost associatedwith quality that comes from the evaluation and preventionprocedures. Those costs are controllable and should beconsidered as an investment, while the cost associated with thelack of quality comes from internal or external deviations and/or failures are non-controllable and represent losses.

The public health surveillance role is to prevent risksassociated with the use of blood, cells, tissues and organs,

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including prevention of transmission of infectious diseases andmorbidityemortality through these products. The control andmanagement of risks is based on existing national and inter-national regulatory standard criteria and includes takingmeasures to prevent, identify and correct potential risksassociated with production, release and usage of products;assure use according to label specifications and technical/medical indication; investigate, identify and notify deviationsand/or adverse reactions. The supply chain perspective isadopted. Several organizations provide complementary activ-ities that are needed to generate a given product(s) orservice(s) and to deliver the final product to the user. As anexample, the risk factors associated with the need for blood,tissues and organs as safe therapeutics include (a) logisticaland structural issues (equipment maintenance and calibration,physical space, human resources); (b) product manufacturing/process issues (collection, screening, result reporting, recordkeeping, processing, storage, distribution), (c) usage issues(indications, component selection, recipient evaluation,compatibility tests and actual treatment) and (d) vigilance/monitoring of results (adverse events, identification andreporting of deviations, contingency plans, traceability, noti-fication, corrective measures).

The GGSTO strategy includes a national health planincluding guidelines and goals for blood, organs, tissues, cellsand assisted human fertilization; institutional alignment withhealth policies including planning, review of processes,quality programmes, and development of partnerships; anddevelopment of human resources to develop a critical mass oftechnical knowledge within the sanitary vigilance programme.The actions of sanitary vigilance also include a feedbacksystem that incorporates an evaluation of the effectiveness ofthe actions taken by sanitary monitoring and their impact onhealth of the population (profile of morbidity and mortality).

7. Regional perspectives

7.1. Regulation of blood and blood products in SoutheastAsia

Dr. Diana Teo (diana_teo@hsa.gov.sg)

7.1.1. Southeast Asia e the regionThe region of Southeast Asia (SEA) is made up of 11

countries e Brunei, Cambodia, Indonesia, Laos, Malaysia,Myanmar, the Philippines, Singapore, Thailand, Timor Lesteand Vietnam. Ten countries (except Timor Leste, currentlya candidate for membership) are members of the Associationof Southeast Asian Nations (ASEAN), a geo-political andeconomic organization that aims for regional cooperation andintegration [4].

SEA is a region of diversity, whether in land area (from690 sq km to 1,919,440 sq km), population (from 0.37 millionto 234.69 million), population density (from 25 per sq km to6236 per sq km) or urban population (from 16% to 100%).Differences are seen in GDP per capita (US$1800e31,400),infant mortality rates (2.3e81.44 per 1000 live births), and life

expectancy (61.3e75.3 years). This diversity has significantinfluence on regional integration efforts.

In recent years, much of SEA has experienced higheconomic growth, with GDP growth rates of 5e8%. This hasstrong impact on health care needs and development in thesecountries, with resulting pressure on their blood supplysystems to improve capacity, quality and safety.

7.1.2. Blood supply systems in SEAThe blood supply systems in SEA include hospital-based

blood banks and centrally coordinated blood services. In mostcountries, it is a mix of both e with large centralized bloodservices located in the cities and smaller hospital-based bloodbanks in the countryside. Blood services are usually run bythe government (Malaysia, Myanmar and the Philippines) or theRed Cross (Thailand, Laos and Indonesia). In Singapore, thegovernment-run blood service outsources the blood donorrecruitment programme to the Red Cross in a unique part-nership model.

Extremes in blood donation rates are seen, with 2e5 per1000 in two-thirds of countries, and 17e26 per 1000 in theother one-third [5]. The type of blood services also vary, fromblood centers, which collect and supply whole blood, toadvanced facilities, providing the full range of blood compo-nents and laboratory services. Only about a third of countriesproduce plasma derivatives through toll fractionation ofsurplus plasma.

7.1.3. Regulation of bloodAlthough the regulation of blood has not been well devel-

oped, steps are being taken in most countries to implement thenecessary legislation and regulatory measures. National stan-dards have been or are in the process of implementation in allcountries, and legislation covering blood transfusion in eightcountries.

Within most of SEA, the regulation of blood does not fallunder the sole purview of a single regulatory authority. Freshblood and blood components are usually regulated througha combination of controls on practice, personnel, premises,and processes (e.g., medical clinic and clinical laboratorylicensing, professional registration of medical and nursingpractitioners) enforced by the Ministry of Health. Plasmaderivatives are separately regulated as medicinal productsthrough medicine controls (e.g., product evaluation, registra-tion and licensing, and post-license monitoring) enforced bydrug regulatory authorities.

In some countries, communicable disease control agenciesmay have oversight of blood safety, while hospital authoritiesmaintain oversight of transfusion safety. Other stakeholders epublic, media, NGOs e also play a part as ‘‘passive regula-tors’’ keeping an eye on blood supply integrity and quality.

7.1.4. Regional partnerships and initiativesThere has been a strong drive in recent years to improve

the quality and safety of the blood supply in the region, withthe implementation of initiatives aimed towards strengthening

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the blood services in these countries. Regional partnershipshave been formed to facilitate many of these initiatives.

The Asia Pacific Blood Network (APBN), a network ofnine blood services in the Asia Pacific region, aims forregional cooperation in promoting blood safety and opera-tional efficiency, commitment to voluntary non-remuneratedblood donation, information sharing, disaster preparedness,and technology assessment and access. A recent initiative inAPBN is the comparison of practices amongst its members.

The World Health Organization (WHO) and InternationalFederation of Red Cross and Red Crescent Societies (IFRC)assist countries in developing safe and sustainable bloodprogrammes, national standards, legislation and regulatorysystems. The IFRC is actively involved in regional capabilitystrengthening activities particularly in blood donor recruitmentand retention. The WHO provides policy and technical supportto the Ministries of Health, and has made notable stridestowards strengthening blood supply quality and safety throughits Quality Management Project, and many training workshopsand consultations.

Drug regulatory agencies in the region have also embarkedon harmonization schemes for pharmaceutical regulations.Within ASEAN member states, the ASEAN ConsultativeCommittee for Standards and Quality Pharmaceutical ProductWorking Group (ACCSQ PPWG) has made much progressand developed the ASEAN Common Technical Dossier;ASEAN Quality Guidelines for product stability, processvalidation, analytical validation and bioequivalence; MRA onGMP inspection; post-marketing alert system; and the VaccineChapter Forum [6].

7.1.5. The changing face of regulationThe role of the regulator is undergoing a paradigm shift.

Regulatory philosophy and approach is moving from a zero-failure one-size-fits-all regime (which is neither possible nordesirable) to smart regulation with its risk-based approach.Smart regulation requires collaboration and partnerships andconsultative processes with stakeholders to determine whatconstitutes mutually acceptable regulatory risk managementpositions. This underpins the importance of moving towardsgreater cooperation and the formation of strategic partnerships.

The new Health Products Act introduced in Singapore in2007, is an example of a modular and flexible system based onsmart regulation [7]. It allows incremental inclusion ofdifferent categories of health products in phases and modularapplication of different parts of the Act to different categoriesbased on assessed risk profile of that category [8].

7.1.6. ConclusionMany challenges lie ahead for blood services in SEA.

Adequacy, safety and availability of the blood supply are yetto be universally achieved. Increasingly stringent donorselection, threat of pandemics, changing public perceptionsand expectations, and political change add to the uncertaintiesof the future. Staff retention and brain drain and the tech-nology boom will increase costs and impact on the afford-ability of blood products and sustainability of blood

programmes. Nonetheless, with the many initiatives and stra-tegic partnerships based on regional cooperation efforts, theoutlook for SEA is best described as sunny skies ahead withthe occasional light showers.

8. The role of regulatory agencies in South Africa andelsewhere in Africa

Ravi Reddy (Ravi.Reddy@sanbs.org.za)Regulatory bodies have a critical role to play in designing and

implementing policies and regulations, as well as ensuring thatblood services comply with regulations and standards viaregular inspection of blood services. These bodies need to beindependent and have staff members who are knowledgeable ofthe subject matter. A well-functioning National Blood Pro-gramme and Regulatory authority is critical to ensure publicconfidence in the sustainability, quality and safety of the bloodsupply.

8.1. Blood regulation in South Africa

The blood services in South Africa are private, section 21,not for gain companies that operate under license from theMinistry of Health. Current regulations governing BloodTransfusion in South Africa are found in Human Tissue Act,1983 (No. 65 of 1983); Regulations Relating to Blood Prod-ucts No. R. 1935 of 17 August 1990. This legislation clearlyoutlines regulations pertaining to, inter alia, donor eligibility,blood collection, mandatory testing and issuing. They alsomake provision for a Department of Health (DoH) appointedinspector to visit and audit blood services on a regular basis.The inspector has powers to order the management of bloodservices to take necessary corrective action within specifictime frames and can order the closure of certain sections of theblood service in the event of major or continued non-compliance. However, while the DoH is responsible for theinspection of blood services to ensure compliance with regu-lations, they do not have the resources or expertise to inspectblood services. No visits or audits have been done for manyyears even though regulations are in place.

Blood services in SA recognized the need to have anexternal, independent body to regularly audit operations.Standards of Practice for Blood Transfusion in SA weredeveloped by the blood services. The management of theServices then engaged with an independent accreditation body,South African National Accreditation Systems (SANAS), forsector specific accreditation. Since 2003, all laboratories andblood collection centers are audited annually and all sites havebeen accredited. The Testing, Tissue Immunology andSpecialized labs have also received ISO 17025 certification.This strategy ensures that in the absence of inspection from theregulatory authority, there are at least external audits ona voluntary basis. SANAS does not, however, have authority toclose down sites for major non-conformances and the regu-latory authority (DoH) is not directly involved with oversightof Blood Transfusion Services even though it issues thelicense.

102 J. Epstein et al. / Biologicals 37 (2009) 94e102

Potential conflict situations could arise, especially if bloodservices implement certain strategies that are not in line withDoH policy. There is also potential for regulations becomingoutdated and new regulations not being implemented timo-rously. Whilst regulatory oversight of the blood services isnon-existent, oversight of the Plasma Fractionation Center isstringently controlled by the Medicines Control Council ofSouth Africa. This, thus, provides an additional avenue forindependent audits of blood services by the MCC.

8.2. Blood regulation elsewhere in Africa

A regulatory framework for oversight of blood services isnon-existent in most African countries. A few countries havelegislation and many countries have a national blood policy;however, there is no regulatory authority in place for over-sight. Most blood services operate under the Ministry ofHealth and in some countries there is a National BloodService, whilst in others, there are a number of small frag-mented blood services. Zimbabwe operates in a very similarmanner to South Africa. The National Blood TransfusionService is a private, section 22, non-profit company witha national committee as the highest authority. Even thoughpolicies are in place, there is little oversight by Ministry ofHealth and the service has also gone the route of voluntaryauditing and accreditation by an external body. Countries suchas Nigeria and Uganda also have policies in place, but noregulatory oversight/inspections due to lack of resources.

Many factors have proved to be an impediment to devel-opment of National Blood Safety programmes and regulatoryoversight in Africa. These include

� Civil war and strife in many countries leading to diffi-culties in establishing functional medical services.� Financial issues where many countries have very limited

health budgets.� Lack of medical expertise due to inadequate tertiary/

undergraduate programmes.� Difficulty in recruiting volunteer donors and reliance

mostly on family replacement donors.� Fragmented blood services.� Lack of understanding of the importance of safe blood for

the health industry.

Significant external funding and resources have made somedifference in improving the blood system infrastructure.However, the National Ministries of Health need to ultimatelytake responsibility to ensure a sustainable service provision.

It is imperative that the Ministries of Health of all countriesclearly understand the critical role they have in developinga National Blood Policy and Plan which is sustainable andsound. They need to play an active role in building a strongNational Blood Service with the appropriate:

� Governance and management infrastructure� Systems� Resources (financial, logistics, people)

Systems must be appropriate for the country takingresource constraints into consideration. A critical successfactor is to have passionate, trained blood bank staff who canimplement the systems and standards and regulatory oversightthat is largely corrective and not punitive. Assistance ofagencies and individual experts from developed countries isalso vital.

There is still much work to be done in Africa firstly todevelop and then to implement appropriate policies andsystems for delivery of safe blood to patients. The challengethen remains to have independent regulatory authorities inplace to inspect these institutions to ensure compliance.

References

[1] Seitz R, Heiden M, Nubling CM, Unger G, Lower J. The harmonization of

the regulation of blood products: a European perspective. Vox Sang 2008;

94:267e76.

[2] World Health Organization. Resolutions relating to blood safety adopted

by WHO governing bodies, <http://www.who.int/bloodsafety/en/>.

[3] Gharehbaghian A, Abolghasemi H, Tabrizi Namini M. Status of blood

transfusion services in Iran. Asian J Transfusion Sci 2008;2:13e7.

[4] Association of Southeast Asian Nations (ASEAN), <http://www.aseansec.

org>.

[5] World Health Organisation. WHO Global Database on Blood Safety 2002

& 2004.

[6] ASEAN Consultative Committee for Standards and Quality Pharmaceu-

tical Product Working Group, <http://www.aseansec.org/18215.htm>.

[7] Health Products Act, <http://statutes.agc.gov.sg>; 2007.

[8] Parliamentary speech for 2nd reading of the Health Products Bill, <http://

www.moh.gov.sg/mohcorp/speeches.aspx%3Fid¼12386>.