AABB Chapter 03

C h a p t e r

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Regulatory Issues in Blood Banking 䊱 Glenn Ramsey, MD

five million Americans depend on the safety and efficacy of blood components and other blood products as an essential part of their medical care.1 To protect the public health, the federal government regulates the manufacture and use of blood products under the laws for pharmaceutical agents as well as biologics. From this perspective, blood products are especially complicated biological drugs that are collected from individual donors, then manufactured (often one dose at a time), stored under specific conditions, and administered to patients using specialized testing procedures and medical devices. Blood banks and transfusion services are also medical laboratories that are regulated under public health laws for health-care facilities. Government-approved accreditation programs, although voluntary, can demonstrate compliance with regulations for the purpose of mandatory laboratory certification.

E

VE R Y Y E A R , O V E R

FE DE R A L L AW S A N D RE G U L A T IO N S FO R D R U G S In the United States, when federal laws are enacted, they are published chronologically as

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statutes and placed into the appropriate one of 50 subject areas (titles) of the United States Code (USC).2 The government agency responsible for the law then writes regulations (rules) to enforce the law. Proposed rules for public comment and final rules, along with background and interpretive information, are published chronologically in the daily Federal Register.3 The current edition of all rules is collated annually in the appropriate subject area (title) of the Code of Federal Regulations (CFR).4 Some rules have associated guidance documents, which are published online by the responsible agency to provide current thinking about regulatory topics. Guidances are recommendations, not requirements, but they are usually followed by industry. Before 1998, guidances were issued as memoranda to blood establishments; some are still active references. Each type of these publications can be accessed from the Food and Drug Administration (FDA) Web site, which provides links to lists of documents in reverse chronological order.5 The publication titles can then be searched by Web browser for words of interest.

Glenn Ramsey, MD, Medical Director, Blood Banks, Northwestern Memorial Hospital and Children’s Memorial Hospital, Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois The author has disclosed no conflicts of interest.

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The FDA regulates drugs and medical devices under the Food, Drug, and Cosmetic Act of 1938. The currently amended version of the act is found in Chapter 9 of Title 21 (Food and Drugs) of the USC (21 USC 301399).6 Blood products are included in the definition of drugs because they are intended to cure, mitigate, treat, or prevent disease (21 USC 321).7,8 The law requires manufacturers to register with the FDA, obtain approvals, and follow current good manufacturing practice (cGMP). It also prohibits adulteration and misbranding, authorizes inspections, and defines civil and criminal penalties for violations. The act controls the use of unapproved drugs and devices during their investigational phases and during public health emergencies.

Medical devices were added to the Food and Drug Act in 1976. They include instruments, in-vitro reagents, and their parts and accessories for the diagnosis and treatment of disease. The FDA classifies devices as Class I, II, or III, in ascending order of associated risk.9 Class I devices have no potential unreasonable risk. Class II devices must meet performance standards beyond generic FDA regulations. Some Class I and most Class II devices must be cleared by the FDA based on substantial equivalence with another device already marketed. This process is called 510(k) clearance, referring to the section of the act describing the submission of these applications to the FDA (21 USC 360).10 Class III devices pose potential unreasonable risk and require specific premarket approval from the FDA, as do unprecedented new devices before their class is determined.

BIO LO G I CA L PRO D U C TS Biological products come from living sources and include blood, blood components, derivatives, therapeutic sera, and vaccines applicable to the prevention or treatment of disease.

The Public Health Service Act of 1944 included section 351, Regulation of Biological

Products, which introduced licensure, labeling, inspections, recalls, and penalties for violations in producing biological drugs. Blood components and derivatives were explicitly defined as biologicals in a 1970 amendment.

Section 351, which is now 42 USC 262, provides the core of federal law most specific to blood products.11 Section 361, Control of Communicable Diseases (42 USC 264), granted the Surgeon General inspection and quarantine powers to prevent the spread of infectious diseases and is also invoked in the regulation of tissues (see below).12 After jurisdiction over biologicals was transferred from the National Institutes of Health to the FDA in 1972, the modern framework of regulations was developed over the following several years. The FDA’s key regulations enforcing the Food and Drug Act and the Public Health Service Act are in Title 21 of the CFR and, in particular, in parts 200-299 for drugs, 600-680 for biologicals, 800-898 for devices, and 1270-1271 for human cells, tissues, and cellular and tissue-based products (HCT/Ps).13 Table 3-1 shows selected parts of relevance for manufacturing biologicals. The FDA Web site (www.fda.gov) has links to laws in the USC and regulations in the CFR. Within the FDA, the Center for Biologics Evaluation and Research (CBER) (www.fda. gov/cber) regulates blood products, HCT/Ps, and most other biological therapies. The Center for Devices and Radiological Health (CDRH) (www.fda.gov/cdrh) regulates most medical devices, but CBER retains primary jurisdiction over medical devices used in conjunction with the manufacture of biologics. In 2003, some therapeutic biotechnology products were transferred from CBER to the Center for Drug Evaluation and Research (CDER, www.fda.gov/cder), including monoclonal antibodies, hematopoietic growth factors and cytokines, and other natural and recombinant proteins. However, all blood and plasmaderived products and proteins remained under CBER. The Office of Regulatory Affairs

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(ORA, www.fda.gov/ora) has FDA’s responsibility for all field operations, which includes inspections and investigations.

TABLE 3-1. Regulations of Interest in Title 21 of

the CFR Topic

Section

FDA general Enforcement Research and development Labeling cGMP for drugs

1-19 50-58 201 210-211

Biological products General Licensing cGMP for blood components Personnel, resources Standard operating procedures Labeling Compatibility testing Records Adverse reactions Product deviations Establishments General standards Donor testing Donor deferral Look-back Dating periods Labels Donor notification Blood product standards Donor eligibility Blood collection Blood testing Red Blood Cells Platelets Plasma Cryoprecipitated AHF Source Plasma Exceptions, alternatives

600-680 600 601 606 606.20-.65 606.100 606.120-.122 606.151 606.160-.165 606.170 606.171 607 610 610.40 610.42 610.46-.47 610.53 610.60-.62 630.6 640 640.3 640.4 640.5 640.10-.17 640.20-.27 640.30-.34 640.50-.56 640.60-.76 640.120

Medical devices Adverse events Hematology and pathology

800-898 803 864

Tissues

1270-1271

cGMP = current good manufacturing practice.

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The development of FDA regulations and guidances includes several forums for input from the public and from regulated groups.14 Proposed rules and draft guidances are published to invite written comments, and these comment files, or dockets, are also accessible online. When final rules are published in the Federal Register, the accompanying commentaries respond to key questions raised. The FDA also receives petitions—written requests to write or change regulations. Expert opinions on current issues are sought from several advisory committees, including the FDA Blood Products Advisory Committee and the Health and Human Services Advisory Committee on Blood Safety and Availability. The FDA also hosts public meetings and hearings on selected topics.

Facilities may apply to CBER for approval of exceptions or alternative procedures to the regulations for blood products under 21 CFR 640.120(a). Those that are granted are periodically published, although individual circumstances may not apply to another facility.15 L I CE N S U R E AN D RE G I S T R AT I O N Blood establishments are classified in three general categories of regulation by the FDA: 1) licensure and registration for interstate commerce, 2) registration for manufacturers not in interstate commerce, and 3) exemption from registration for transfusion services certified by the Centers for Medicare and Medicare Services (CMS).16 Licensed and/or registered facilities are inspected by the FDA. For transfusion services that perform minimal manufacturing and are certified for reimbursement by CMS, the FDA accepts CMSsanctioned laboratory inspections and CMS approval, according to terms of a memorandum of understanding (MOU) with CMS.17 However, the FDA still has jurisdiction and may inspect if warranted. All military blood facilities, including transfusion services, regis-

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ter with and are inspected by the FDA under another MOU with the Department of Defense.18 Facilities seeking licensure use the Biologics License Application (BLA, Form 356h)19 to apply for both their establishment license and for the products they wish to have licensed for interstate commerce. Subsequent license amendments are handled according to the potential for adverse effects of the changes.20 Unlicensed blood products, whether from a licensed or an unlicensed facility, may be shipped across state lines for a medical emergency if necessary, but this should be infrequent and not used as a means to avoid sale, barter, or exchange.21 The shipping facility must retain documentation of the emergency for FDA review.

Facilities must register annually with the FDA if they collect, manufacture, prepare, or process blood products (Form FDA 2830).16,19 Transfusion services are exempt from this requirement if they are approved for reimbursement by CMS and their preparation activities are basic, such as preparing Red Blood Cells from whole blood, converting unused plasma to Recovered Plasma, pooling components, implementing leukocyte reduction with bedside filters, or collecting blood only in emergencies. However, facilities that routinely collect blood (including autologous units) or perform such procedures as irradiation, washing, laboratory leukocyte reduction, freezing, deglycerolization, and rejuvenation must register as community or hospital blood banks. Transfusion services that act as depots for forwarding a blood bank’s products to other hospitals must register as distribution centers. Clinical laboratories performing infectious disease testing required for blood donors must register and be certified under CLIA. If blood irradiation is performed outside the blood bank or transfusion service, such as in a nuclear medicine department, that facility must register as well.

FDA IN S P E C T I O N S New facilities are inspected within 1 year by a team from CBER and ORA. Subsequent routine inspections are performed by ORA at least every 2 years depending on the compliance history of the facility.

ORA publishes online manuals and instructions for FDA investigators for inspections in general and for licensed and unlicensed blood banks in particular.22,23 The blueprints for blood bank inspections are the general regulations for cGMP and drugs (21 CFR 210-211) and the specific requirements for blood components (21 CFR 606).24 Routine inspections address the FDA’s five required layers of blood safety—donor screening, donor testing, product testing, quarantining, and monitoring and investigating problems.

Investigators review the following operational systems that create these safety layers: quality assurance, donor eligibility, product testing, quarantining/inventory management, and production and processing. Full inspections of all systems are designated Level I. After a favorable inspection profile, facilities with four or five systems sometimes may have streamlined Level II inspections of three systems. (Focused inspections for problems or fatalities need not follow these formats.)

Within each system, the investigators review standard operating procedures, personnel and training, facilities, equipment calibration and maintenance, and records. Specific requirements for individual systems and processes are discussed in detail in other chapters of this book.

If the investigator judges that significant objectionable practices, violations, or conditions are present under which a drug or device is or could be adulterated or injurious to health, these observations are written and presented to the facility (Form 483). Investigators are instructed to seek and record the management’s intentions for corrections.22 However, most facilities also respond in writ-

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ing immediately with questions or corrective actions. Final determination of violation is made after ORA review.

The agency can take a number of steps in response, including no action at all. For significant violations, the FDA may choose to issue a warning letter, an advisory action to provide the facility with the opportunity for voluntary compliance. Enforcement actions are categorized as administrative, judicial, or recall. Administrative actions include formal citations of violation and, for licensed facilities, suspension or revocation of license. Judicial actions range from seizure of products to court injunctions, civil monetary penalties, and criminal prosecution. The FDA may also conduct recalls if necessary. ORA’s Regulatory Procedures Manual provides details of available sanctions.25 BL O O D - RE L A TE D D E V I CE S CBER has lead responsibility in collaboration with CDRH for equipment marketed for the transfusion service and the collection and processing of blood products, hematopoietic stem cells, and autotransfusions.26,27 This includes diagnostic tests for infectious disease in blood donors and pretransfusion testing in patients. Blood bank computer software programs are CBER devices. Most blood-related devices are in Class II and cleared by 510(k) equivalence. Examples of Class I devices are copper sulfate solutions for hemoglobin screening, blood grouping viewboxes, and heat sealers. Human immunodeficiency virus (HIV) and hepatitis B and C virus (HBV, HCV) test kits for diagnosis and prognosis are regulated as Class III devices. Screening tests for blood donations are regulated under BLAs. BLAs and Class III devices require specific premarket approval. Each category of device is assigned a code, and all cleared or approved vendors and products for that code are searchable in the Product Classification database on the FDA CDRH Web site.28

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Serious adverse events related to medical devices must be reported (21 CFR 803).29 User facilities must report deaths or serious injuries in which a device was or may have been a factor. Serious injury is defined as life-threatening, or permanent impairment or damage, or needing medical or surgical intervention.

These reports are sent to the device maker on FDA Medwatch Form 3500A19 within 10 working days, and deaths must also be reported to the FDA. In years when a Form 3500A report is submitted, an annual summary must be sent to the FDA by January 1 (Form 3419).19 Users may voluntarily report other device-related adverse events to the FDA (Form 3500).19 All possible adverse events, whether reported or not, must be investigated and details kept on file for 2 years.

HE M A TOP O IE T IC PRO G EN ITO R C E L L S A N D O T H ER TIS SU E S Most hematopoietic progenitor cell products are regulated as tissues by the FDA.30 The Public Health Service Act, Section 361, Control of Communicable Diseases (42 USC 264) granted the Surgeon General inspection and quarantine powers to prevent the spread of infectious diseases.12 Under this authority, the FDA established a new regulatory framework for manufacturing tissues collected after May 25, 2005 that are not classified as drugs, biologics, or devices (21 CFR 1271).13 These items are termed HCT/Ps. By definition (21 CFR 1271.10), their structural or cellular characteristics and functions are not changed in production, they are not combined with other products of concern beyond sterilization or preservation purposes, and they either 1) do not have a systemic effect and are not dependent on metabolically active living cells for their primary function (eg, tendon, heart valve), or 2) are autologous or allogeneic from a first- or second-degree relative.

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Tissues collected on or before May 25, 2005 are regulated under 21 CFR 1270, which requires registration, donor screening, testing, and record-keeping.13 Tissues collected after May 25, 2005 that do not meet the HCT/ P definition in 21 CFR 1271.10 are regulated as drugs, biologics, and/or devices under Public Health Service Act Section 351 (42 USC 262) and must be licensed if for interstate commerce.11,31 Marrow products that are not manipulated to become biologics are not considered tissues in these regulations. Table 3-2 shows how various hematopoietic progenitor cell products are regulated.

Under 21 CFR 1271, all facilities that manufacture tissues must register with the FDA (Form 3356),19 perform or arrange donor screening and testing, and follow current good tissue practice. Unlike other biologics, the FDA’s narrower regulatory emphasis for HCT/Ps under Section 361 is to prevent the transmission of communicable diseases. For example, biological product deviation reports are required only for potentially infectious problems, not for general safety, purity, and potency. FDA inspection manuals are avail-

able for tissue establishments for collections made before and after May 25, 2005 (Compliance Programs 7341.002A and 7341.002).32 The FDA tissue regulations do not apply to facilities that receive, store, and administer tissues but do not perform any manufacturing steps. However, The Joint Commission (TJC, formerly the Joint Commission for Accreditation of Healthcare Organizations) enacted hospital standards in 2005 for handling and tracing tissues and investigating adverse events (PC.17.10-.30) (see Chapter 32).33 TE ST I N G FO R IN FE C T IO U S DI S EA S ES Confirmed, newly diagnosed cases of selected infectious diseases must be reported to state or local public health departments for epidemiologic purposes.34 HIV/AIDS, acute and chronic HBV and HCV, syphilis, and West Nile virus are notifiable infections. HIV reporting has been either name-based or code-based, but nearly all states have or are shifting to name-based systems because of

TABLE 3-2. Regulations for Manufacturing Hematopoietic Progenitor Cells Product

Regulation

Marrow, minimally manipulated

Excluded from tissue regulations

Peripheral blood progenitor cells, umbilical cord progenitor cells, donor lymphocyte infusions: Collected on or before May 25, 2005

21 CFR 1270*

Collected after May 25, 2005 Autologous donor or first- or seconddegree-related donor HCT/Ps

Section 361, 21 CFR 1271*

Biologics, Section 351, 21 CFR 600-680 and others* Unrelated donor, or altered characteristics or function, or combined with other products or devices (beyond sterilization and preservation) *See also FDA CBER Tissue Compliance Programs 7342.002A and 7342.002.32 HCT/Ps = Human cells, tissues, and cellular and tissue-based products.

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Centers for Disease Control and Prevention (CDC) recommendations and a federal HIV/ AIDS funding mandate. Donor testing laboratories should be familiar with their local requirements.

When a new test is being evaluated before clearance or approval, the test manufacturer must obtain an investigational device exemption from the FDA and conduct the evaluation within a research protocol approved by an institutional review board (21 CFR 50-58 and 812).35 Subjects (donors) must give informed consent if the test results are linked to identity.

MA N A G I N G RE C A L L S AN D WI TH D R AW A L S The FDA’s requirements for monitoring and investigating problems with drugs extend to after a product’s release. When blood banks discover after issue that a blood product was in violation of rules, standards, specifications, or cGMP, they must report the problem to the FDA and to their consignee(s). These problems also constitute a subset of biological product deviations (BPDs), events in which the safety, purity, or potency of a distributed blood product may be affected, and which must be reported to the FDA.36 Recalls are defined as removal or correction of a marketed product that is in violation of the law (21 CFR 7.3).37 The FDA classifies recalls by severity. Most blood component recalls are in Class III, not likely to cause adverse health consequences. Class II recalls are for products that may cause temporary adverse effects or remotely possible serious problems. Class I recalls involve a reasonable probability of serious or fatal adverse effects.

All recalls are published by the FDA and involve about 1 in 2000 blood components issued in the United States.38-40 Market withdrawals are required for products found to be in minor violation.

Problems beyond the control of the manufac-

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turer, such as postdonation information, are often in this category. Withdrawals are much more common than recalls but are not published.

Transfusion services must have procedures and training for rapid responses as advised when recalls and withdrawals are received, along with records of actions, reviews, and follow-up as indicated. Accreditation requirements of the AABB (Standards 7.1.3 and 7.1.4) and the College of American Pathologists (CAP) (TRM.42120 and .42170) address aspects of this topic.41,42 Most of these blood components are transfused before notice is received of their nonconformance. In some recent blood guidances on infectious diseases, the FDA has included recommendations on whether or not to notify the recipient’s physician about transfused units. In cases of possible recent infectious-disease exposure in donors or transfusion recipients, the seroconversion window periods for tests should be borne in mind. This can be helpful either for scheduling prospective testing or for reviewing retrospective results, such as a donor who has been retested since an exposure. A general set of recommendations about managing common product deviations has been published for consideration.43 The most common reasons for BPDs and blood component recalls are listed in Table 33. Look-back investigations on previous units from donors found to have HIV or HCV are discussed elsewhere (Chapter 8).

ME D I CA L L A B O R ATO R Y L AW S A N D RE G U L AT I O N S CMS regulates all US medical laboratories under the authority of the Public Health Service Act of 1944, Section 353, as amended by the Clinical Laboratory Improvement Amendments (CLIA) of 1988 (42 USC 263a).45 Regulations for CLIA are found at 42 CFR 493.46 The law and regulations establish

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TABLE 3-3. Most Common Reasons for Biological Product Deviations and Blood Component

Recalls Biological Product Deviations (Ranked by number of events)

Blood Component Recalls (Ranked by number of units)

Malaria travel/residence

Collection sterility and arm preparation

Creutzfeldt-Jakob disease travel/residence

Storage temperature

Illness, not cancer

Production current good manufacturing practice

Cancer

Donor eligibility

Tattoo

Product quality control

Biological product deviations shown are from licensed establishments.44 Blood component recalls are compiled from FDA Enforcement Reports.39 Market withdrawals are not included in public recalls data.

the requirements and procedures for laboratories to be certified under CLIA. Besides being required, this is also a prerequisite for receiving Medicare and Medicaid payments.

In broad terms, all laboratories must have adequate facilities and equipment, supervisory and technical personnel with training and experience appropriate to the complexity of testing, a quality system (Chapter 1), and successful ongoing performance in CMSapproved proficiency testing. All laboratories must register with CMS, are subject to inspection by CMS or its designees, and must be recertified every 2 years.

Laboratory requirements start with the complexity of tests performed. All laboratory tests are rated for complexity by the FDA for CMS as waived, moderate complexity, and high complexity. Waived tests are simple and easily performed with limited technical training. Examples include over-the-counter tests, urinalysis dipsticks, copper sulfate specificgravity hemoglobin screens, spun microhematocrits, and some simple devices for measuring hemoglobin. Laboratories that perform only waived tests register with CMS for a certificate of waiver. The CDC provides technical and advisory support to CMS for laboratory regulation and has published

practice recommendations for waived testing sites.47 Nonwaived tests are classed as moderate or high complexity based on a scoring system of needs for training, preparation, interpretive judgment, and other factors (42 CFR 493.17). The FDA CDRH Web site provides a searchable database (“CLIA”) for the complexity of specific tests.28 For example, manual reagents for compatibility testing are of moderate complexity, automated systems for immunohematology and hematology testing are moderate or high complexity, and viral tests for blood donors are high-complexity tests.

Blood banks and transfusion services have three pathways for CMS approval48: 1) certificate of compliance: approval via state health department inspections using CMS requirements; 2) certificate of accreditation: approval via a CMS-approved accrediting organization; 3) CMS-exempt: in New York and Washington states, their licensure programs for nonwaived laboratories are accepted by CMS. The CLIA regulations delineate general requirements for facilities, quality systems (including quality assurance and quality control), and management and technical personnel qualifications. High-complexity tests require more stringent personnel qualifications.

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Immunohematology laboratories have standards for blood supply agreements, compatibility testing, blood storage and alarms, sample retention, positive identification of blood product recipients, investigation of transfusion reactions, and documentation (42 CFR 493.1103 and .1271). Viral and syphilis serologic tests are in the immunology requirements. CMS has published guidelines to surveyors for conducting surveys (inspections). 49 CMS currently approves six laboratory accreditation organizations with requirements meeting CMS regulations50: AABB, American Osteopathic Association, American Society for Histocompatibility and Immunogenetics (ASHI), CAP, COLA (formerly Commission on Office Laboratory Accreditation), and The Joint Commission. The Joint Commission has agreements with CAP and COLA (and, in part, ASHI) to accept their laboratory accreditations in The Joint Commission facility surveys.51 The Joint Commission laboratory accreditation manual cites AABB standards in the elements of performance (criteria) for several The Joint Commission blood bank standards, including written policies and procedures for transfusion services and donor screening and testing.52 AABB and CAP can coordinate joint surveys if desired by facilities seeking both accreditations. CMS requires hospital accreditation surveys to be unannounced in advance, and the AABB and CAP have adopted this for laboratory surveys as well. CMS may perform its own follow-up surveys to validate the accreditation organizations.

CMS requires successful proficiency testing (PT) for ongoing laboratory certification of nonwaived testing. Within each laboratory section, CMS regulations specify tests and procedures (regulated analytes) that must pass approved PT if the laboratory performs them. In immunohematology, these are ABO and Rh(D) typing, compatibility testing, unexpected antibody detection, and antibody

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identification. In immunology, the regulated blood donor tests are HIV antibody (nonwaived), hepatitis B surface antigen, hepatitis B core antibody, and syphilis serology. For regulated analytes, CMS requires at least five tests per PT challenge, and three PT challenges annually. An 80% pass rate is required within most challenges (four of five results correct), but, in immunohematology, 100% of ABO and Rh(D) typing and crossmatches must be correct. If a laboratory fails two consecutive, or two out of three consecutive challenges, CMS may require retraining or technical assistance, or may limit, suspend, or cancel the laboratory’s certification. The CMS Web site has a list of approved PT providers.53 All other tests not itemized in the regulations also must have approved PT performed [42 CFR 493.803(a)], or for tests with no approved PT, their accuracy must be verified at least twice a year [42 CFR 493.1236(c)].

ST A TE A N D LO CA L RE G U L A T IO N S All state and local laws and regulations for laboratories and blood banks also apply; they may be more comprehensive than the federal regulations. Each state has its own professional licensure requirements for medical and laboratory personnel. CLIA supplanted general laboratory regulations in many states.

Facilities should be familiar with their local requirements, which may extend beyond federal rules in areas such as donor age limits, directed donations, personnel qualifications, adverse event reports, inspection practices, laboratory certification, and transfusion consent. In some situations, facilities providing interstate products or services must comply with local regulations in the customer’s location. Some states accept approved accreditation programs for their laboratory requirements.

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CON CLU SI ON Blood components and other blood products are regulated as biologics and pharmaceutical agents, and blood banks and transfusion services are also regulated as medical laboratories. These many requirements make compliance complex. However, close regulation

underscores the recognized importance to public health of safe, effective blood products provided via good laboratory practices, using the quality systems described in Chapter 1 and the procedures discussed throughout this manual.

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17. Memorandum of understanding between the Health Care Financing Administration and the Food and Drug Administration. MOU number: 225-80-4000 (June 6, 1983). Rockville, MD: Food and Drug Administration, 1983. [Available at http://www.fda.gov/oc/mous/domestic/ 225-80-4000.html (accessed July 11, 2007).]

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Copyright © 2008 by the AABB. All rights reserved.