[DOCKET NO. 91N-0450] GUIDELINE FOR QUALITY ASSURANCE IN BLOOD ESTABLISHMENTS July 11, 1995 For further information about this document, contact: Center for Biologics Evaluation and Research (HFM-635) Food and Drug Administration 1401 Rockville Pike Rockville, MD 20852-1448 301-594-3074 Submit written comments on this document to: Dockets Management Branch (HFA-305) Food and Drug Administration Rm. 1-23 12420 Parklawn Dr. Rockville, MD 20857 Submit requests for single copies of this document to: Congressional and Consumer Affairs Branch (HFM-12) Food and Drug Administration 1401 Rockville Pike Rockville, MD 20852-1448 301-594-1800 FAX 301-594-1938 Comments and requests should be identified with the docket number found in brackets at the heading of this document. TABLE OF CONTENTS PURPOSE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 SCOPE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 INTRODUCTION. . . . . . . . . . . . . . . . . . . . . . . . . . . 2 QUALITY CONTROL/ASSURANCE PROGRAM . . . . . . . . . . . . . . . . 3 QUALITY ASSURANCE FUNCTION. . . . . . . . . . . . . . . . . . . . 3 Reporting Responsibilities. . . . . . . . . . . . . . . . . . . 4 QUALITY CONTROL/ASSURANCE UNIT RESPONSIBILITIES . . . . . . . . . 5 Standard Operating Procedures (SOPs). . . . . . . . . . . . . . 5 Training and Education. . . . . . . . . . . . . . . . . . . . . 6 Competency Evaluation . . . . . . . . . . . . . . . . . . . . . 7 Proficiency Testing . . . . . . . . . . . . . . . . . . . . . . 7 Validation. . . . . . . . . . . . . . . . . . . . . . . . . . . 8 Equipment . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 Error/Accident Reports, Complaints, and Adverse Reactions . . . . . . . . . . . . . . . . . . . . . . . . 8 Records Management. . . . . . . . . . . . . . . . . . . . . . . 9 Lot Release Procedures. . . . . . . . . . . . . . . . . . . . . 9 Quality Assurance Audits. . . . . . . . . . . . . . . . . . . . 10 APPENDICES. . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 GLOSSARY. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 REFERENCES. . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 Health and Human Services References. . . . . . . . . . . . . . 34 General References. . . . . . . . . . . . . . . . . . . . . . . 34 QUALITY ASSURANCE IN BLOOD ESTABLISHMENTS PURPOSE The purpose of this guideline is to assist manufacturers of blood and blood components, including blood banks, transfusion services, and plasmapheresis centers, in developing a quality assurance (QA) program in their effort to be consistent with recognized principles of quality assurance and current good manufacturing practice (CGMP). SCOPE This guideline provides general information on procedures and practices and may be useful to blood establishments in developing and administering a QA program. Because the Food and Drug Administration (FDA) is in the process of revising 21 CFR 10.90(b), this document is not being issued under the authority of 21 CFR 10.90(b), and the document, although called a guideline, does not bind the agency and does not create or confer any rights, privileges, or benefits for or on any person. Blood establishments may follow the guideline or may choose to use alternative procedures not provided in the guideline. If a blood establishment chooses to use alternative procedures, the establishment may wish to discuss the matter further with the agency to prevent expenditure of resources on activities that may be unacceptable to the FDA. Blood and blood components applicable to the prevention, treatment, or cure of human diseases or injuries are biological products subject to regulation pursuant to Section 351 of the Public Health Service (PHS) Act [42 U.S.C. 262]. Similarly, blood and blood components intended for use in the diagnosis, cure, mitigation, treatment, or prevention of diseases in humans are drugs as defined in Section 201(g) of the Federal Food, Drug, and Cosmetic (FD&C) Act [21 U.S.C. 321(g)]. Section 501 (a)(2)(B) of the FD&C Act states, in part, that a drug shall be deemed to be adulterated if "the methods used in, or the facilities or controls used for, its manufacture, processing, packing, and holding do not conform to or are not operated or administered in conformity with current good manufacturing practice to assure that such drug meets the requirements" of the FD&C Act. Because blood and blood components are drugs under the FD&C Act, the Current Good Manufacturing Practice regulations in 21 CFR, Parts 210 and 211 are applicable. In addition, FDA has issued CGMP regulations for blood and blood components in 21 CFR, Part 606. This guideline is intended to be used in conjunction with the applicable federal standards in 21 CFR, Parts 600 through 680 and Parts 210 and 211. Section 210.2 provides that the regulations in Parts 210 through 226 and 600 through 680 are considered to supplement, not supersede, each other. Where it is impossible to comply with the applicable regulations in both Parts 210 through 226 and Parts 600 through 680, the regulations specifically applicable to the product shall apply and supersede the more general regulations. Some examples of 21 CFR, Parts 210 and 211 and Parts 600 through 680 supplementing each other are set forth in Appendix A. This guideline may be amended periodically as needed. Blood establishments should be aware that under the Clinical Laboratory Improvement Amendments of 1988 (CLIA), establishments performing laboratory testing, including blood banks, transfusion services, and plasmapheresis centers, must also comply with applicable regulations in 42 CFR, Part 493. These regulations, generally effective September 1, 1992, establish standards for laboratory personnel, quality control, proficiency testing, patient test management, and QA based on test complexity and patient risk factors. INTRODUCTION It is generally believed that the United States has one of the safest blood supplies in the world. This is due in large part to the development and implementation of standards for donor suitability and product quality. Since 1983, many significant developments have occurred including the implementation of new tests and donor suitability criteria. In addition, the FDA has intensified its oversight of blood establishments and has documented the release of unsuitable blood and blood components in a number of situations due to deficiencies from established standards. These findings may be related to several factors: (1) the increase in the number of tests performed (increased testing increases the opportunity for errors and contributes to the complexity of the operation), (2) the increasing use of complex advanced technology in testing procedures and equipment including computerized systems, (3) a shortage of appropriately trained health care and laboratory personnel, and (4) the need for more sophisticated process and system control procedures in blood establishments, including procedures for training and supervising existing personnel. In a memorandum dated April 6, 1988, FDA's Center for Biologics Evaluation and Research (CBER) requested that blood establishments review procedures and employee training programs to determine the adequacy of safeguards to prevent the release of unsuitable blood products. CBER issued a memorandum on March 20, 1991, notifying blood establishments of the increasing number of product recalls due to errors and accidents in manufacturing. CBER described examples of the types of errors and accidents that have resulted in the release of unsuitable products. In addition, CBER reminded establishments of the reporting requirement for errors and accidents and the need for follow-up investigation. To ensure the continued safety of the nation's blood supply, it is essential that blood establishments implement effective control over manufacturing processes and systems. FDA believes that this can be accomplished by each blood establishment developing a well planned, written, and managed QA program designed to recognize and prevent the causes of recurrent deficiencies in blood establishment performance. The goals of QA are to significantly decrease errors, ensure the credibility of test results, implement effective manufacturing process and system controls, and ensure continued product safety and quality. QA includes measures to prevent, detect, investigate, assess, and correct errors. The emphasis is on preventing errors rather than detecting them retrospectively. Implementing a QA program requires a commitment of time and resources. The design and scope of a QA program depend on the size and complexity of manufacturing operations performed by the establishment. The potential public health consequences require that all establishments, regardless of size, invest in QA. QUALITY CONTROL/ASSURANCE PROGRAM A QA program is a system designed and implemented to ensure that manufacturing is consistently performed in such a way as to yield a product of consistent quality. QA is the sum of activities planned and performed to provide confidence that all systems and their elements that influence the quality of the product are functioning as expected and relied upon. There are several dimensions to QA including quality control (QC) procedures and current good manufacturing practice. Adequate quality control procedures are an element of conformity with CGMP and include the routine on-line or in- process monitoring of manufacturing procedures [See 21 CFR 211.22(a), 211.100(a), 606.140(b)]. Other dimensions of QA relevant to the control of production include standards for personnel, facilities, procedures, equipment, testing, and recordkeeping activities. QUALITY ASSURANCE FUNCTION A quality control unit having the responsibility and authority to ensure product quality is required by 21 CFR 211.22(a). In the pharmaceutical industry, the group performing this function often has been titled the Quality Control Unit. With the evolution of the concept of QA during the past 20 years, the group responsible for oversight of all activities relating to product quality (including quality control) often has been titled the Quality Assurance Unit. Subsequently, in practice, the term quality control often has been considered by many as limited to describing the component of a QA program that includes the activities and controls used to determine the accuracy of the establishment's equipment and operations in manufacturing (i.e., on-line or in-process testing) and product release. Irrespective of the title of the person or persons performing QA duties, a quality assurance function should be established. Although the term "quality assurance" is not used in 21 CFR, Parts 210 and 211 and Parts 600 through 680, these regulations clearly require a program of activities to control the manufacturing process to prevent the release of unsuitable products. For purposes of clarity, this document uses the term "quality assurance" to describe the actions, planned and performed, to provide confidence that all systems and elements that influence the quality of the product are working as expected. The person or group of persons who perform this function will be referred to as the QC/QA Unit. The terms "quality control" and "quality assurance" will be defined as stated above and in the glossary. The QC/QA Unit should coordinate, monitor, and facilitate all QA activities. The QC/QA Unit may include one or more individuals dedicated solely to QA functions or individuals who also perform other tasks in the establishment. In the latter situation, however, individuals should not have final oversight of their own work [See 21 CFR 606.100(c), 211.194]. In a small firm, it may be feasible for one individual to function as the QC/QA Unit. That person has the responsibility for implementing controls and reviewing results of manufacturing to ensure that product quality standards are met. Reporting Responsibilities A QC/QA Unit should report to management or its designee. In licensed firms, this unit should report to the Responsible Head who is the individual designated in the establishment license application to represent the firm in its regulatory activities with CBER [See 21 CFR 600.10(a)] or his/her designee. In unlicensed firms, the QC/QA Unit should report to a "designated qualified person" [See 21 CFR 606.20(a)] or his/her designee. The Responsible Head or the designated qualified person is required to exercise control over the establishment in regard to all matters related to compliance with FDA requirements including the FD&C Act and the PHS Act, and should have the authority to implement corrective action when necessary. These individuals are responsible for ensuring corrective action has been taken. The Responsible Head or designated qualified person is also responsible for ensuring that personnel are appropriately assigned and trained to accomplish their duties [See 21 CFR 211.25, 600.10, 606.20]. The QC/QA Unit reports independently from production to management. The QC/QA Unit should ensure that production personnel follow CGMP. When necessary, the QC/QA Unit should have the authority to stop production and/or release of product. QUALITY CONTROL/ASSURANCE UNIT RESPONSIBILITIES The responsibilities of a QC/QA Unit in blood establishments should include, but are not limited to, the following areas: Standard Operating Procedures (SOPs) [See 21 CFR 211.100, 606.65(e), 606.100] QA activities relevant to SOPs include: (1)Determining that SOPs exist for all manufacturing procedures including, but not limited to, testing, and that SOPs accurately describe and define the procedure, including a statement of what the procedure is intended to accomplish. The actual content of the SOPs may be the responsibility of the production units [See Federal Register, Volume 43, No. 190, Sept. 29, 1978, pp. 45014, 45032]. (2)Reviewing and ensuring written approval of all SOPs prior to implementation and confirming that SOPs comply with all applicable statutory and regulatory requirements. Additionally, prior to the implementation of each SOP, the QC/QA unit ensures that the following items are written and in place: (a) procedures to establish validation protocols to ensure that methods and processes accomplish their intended purpose; (b) identification of personnel responsible for performing each procedure; (c) procedures for training and certifying individuals identified in (b); (d) responsibilities of supervisors for oversight of the performance of all procedures; (e) methods for periodic proficiency testing; (f) methods for periodic competency evaluation of the individuals performing each procedure; (g) methods for evaluating the performance of each procedure during QA audits; (h) designation of each procedure as a critical or non-critical control point (as defined in the glossary); and (i) instructions for records maintenance consistent with requirements for recordkeeping. (3)Maintaining an index of all SOPs, a master copy, and an archive of obsolete SOPs. (4)Ensuring that the SOP content is reviewed to assess impact on other systems and their functions. (5)Ensuring that each employee is provided with, and has ongoing access to, the necessary SOPs to perform assigned duties. (6)Ensuring that validation protocols are designed prospectively, performed and evaluated, and that written validation reports are prepared. Validation of a process already in use may be based upon accumulated production, testing, and control data. (7)Ensuring that modifications or changes in SOPs are appropriately documented including the rationale for the change. Ensuring that revised or new methods and processes are validated and do not create an adverse impact elsewhere in the system or operation. Changes in SOPs should be made in accordance with a written procedure and be formally approved before implementation. (8)Ensuring that SOPs for all QC/QA unit activities exist and define the QC/QA unit's responsibility for performing SOP review, approval, or authorization or, if appropriate, ensuring review, approval, or authorization has been performed. (9)Ensuring pertinent SOPs are promptly updated to reflect changes in manufacturer's directions for use and all SOPs and manufacturing records are reviewed at least annually. Training and Education The QC/QA Unit should assist in developing, reviewing, and ensuring the approval of training and educational programs for all personnel [See 21 CFR 211.25]. Training should include the following programs: New employee orientation, CGMP training, SOP training, Technical training, Supervisory training, Managerial training, QA training, Computerized system training, and Continuing education and training. The QC/QA Unit should be aware of factors that indicate a need for training or retraining. Information regarding the need for such training may be derived from management observations, proficiency test results, competency evaluations, technical changes, error/accident reports, complaints, QA audits, and problems discovered at critical control points identified in each system within the establishment's total operation. Thresholds for implementing retraining programs should be established. Competency Evaluation To ensure that all staff are trained and maintain their competency to perform all assigned tasks, the QC/QA Unit should implement a formal regular competency evaluation program. A competency evaluation program should evaluate theoretical and practical knowledge of procedures including, but not limited to, the following: (1)Direct observations of performance of routine and quality control procedures including, as applicable, donor suitability, sample handling, processing, testing, labeling, and instrument preventive maintenance; (2)Monitoring the recording and reporting of test results by reviewing work sheets, quality control records, preventive maintenance records, and other records and entries (both manual and automated); (3)Written tests to assess problem solving skills, knowledge of SOPs, and theory; and (4)Assessment of performance using internal blind specimens and external proficiency test specimens. Minimum acceptable scores, performance, and remedial measures to correct inadequate performance on competency evaluations should be documented and retained in personnel records. Evaluation summaries provide useful information to correct individual or group performance problems. Proficiency Testing Proficiency tests are commonly one part of the QA program for testing laboratories. In addition to the facility's standard review of proficiency test results, the QC/QA Unit should also review, evaluate, and monitor the proficiency testing program to ensure the adequate evaluation of test methods and equipment and competency of personnel performing testing. Blood establishment proficiency testing procedures should ensure that proficiency samples are tested by all personnel normally performing routine testing, using routine test equipment, during routine test runs. Blood establishments should provide for proficiency testing of back-up or alternate test methods, e.g., manual procedures or "stat" tests. Procedures should ensure accurate, reliable, and prompt test results. Supervisors, management, and the QC/QA unit should review and evaluate proficiency test results. Additionally, the QC/QA Unit should analyze results for trends or patterns to identify specific problems. There should be a written plan for remedial action in the case of unsuccessful proficiency test performance. Other quality control procedures may be useful in monitoring laboratory performance. These include statistical reviews of unknown and control sample results, comparisons of initial and repeat test values, and results of the same test performed by different methods or at different sites. Validation The FDA has provided general guidance in its Guideline on General Principles of Process Validation (May, 1987) which should be referenced to determine the validation principles applicable to an individual establishment's systems and processes. The QC/QA unit should ensure that adequate validation procedures have been performed. Complaints, errors, accidents, and problems at critical control points should be reviewed to determine the need for revalidation or revision of validation procedures. Equipment Equipment installation qualification is performed to establish "confidence that process equipment and ancillary systems are capable of consistently operating within established limits and tolerances" [Guideline on General Principles of Process Validation (May, 1987)]. The QC/QA Unit should ensure that procedures are in place for equipment qualification, process validation, and revalidation after repairs to ensure the proper function of all equipment. Appropriate records of the results of validation testing should be reviewed and maintained. There should be written procedures for equipment qualification, validation, maintenance, and monitoring. Additionally, there should be schedules for equipment monitoring, calibration, and maintenance sufficient to ensure that performance is according to specifications. Equipment monitoring procedures should include evaluation of consequences of malfunctioning or out-of-calibration equipment. Computer systems used in manufacturing are equipment subject to 21 CFR 211.68 and 606.60. Error/Accident Reports, Complaints, and Adverse Reactions The QA program should provide assurance that procedures are in place and exactly followed for the review, evaluation, investigation, and correction of manufacturing errors and accidents. There should also be a system to ensure timely reporting to CBER of errors and accidents that may affect the safety, purity, identity or quality of blood products [See 21 CFR 600.14]. QA procedures should ensure that all complaints regarding product quality are investigated to determine whether the complaint is related to an error or accident in manufacturing. Investigative procedures should include provisions for review to determine whether the complaint represents an adverse reaction. Donor or recipient adverse reactions may be life-threatening, permanently disabling, or fatal. Procedures should be in place to ensure that donor and recipient adverse reactions are thoroughly investigated and completely documented. Fatalities must be reported to CBER in accordance with 21 CFR 606.170(b). The QC/QA Unit should ensure that product recalls and market withdrawals are handled according to established procedures and guidelines [See 21 CFR, Part 7]. Procedures should be in place to ensure transfusion reactions are investigated. A program should be in place to train patient care staff to recognize symptoms of adverse reactions so that appropriate intervention can be taken. Procedures should include review of manufacturing procedures when bacterial contamination of the product is suspected. Possible bacterial contamination should be reported to the blood collection facility. An essential element of QA is feedback into the QA system of knowledge acquired through investigations of complaints, error/accident incidents, and adverse reactions. If there is no investigation of complaints, error/accidents, or adverse reactions, factors contributing to the problems cannot be identified and corrected. Errors or accidents in manufacturing may be identified either by employees in the course of routine activities or by supervisors during record review. The QC/QA Unit should assess all errors that occur during manufacturing, including those identified before products are released. The QC/QA Unit should receive copies of error/accident reports and ensure appropriate follow-up actions have been taken. There should be procedures for initiating and completing all corrective actions. Corrective actions may include system or process redesign, retraining, and procedural changes. Records Management The QC/QA Unit should approve or ensure approval of all recordkeeping systems (manual and automated). Electronic or computerized recordkeeping systems should be properly validated [See 21 CFR 211.68]. QA procedures should be implemented to ensure that required records [See 21 CFR 606.160] are reviewed as necessary to ensure the accurate and complete history of all work performed. Portions of the review may be performed at appropriate periods during or after blood collecting, processing, compatibility testing, and storing [See 21 CFR 606.100(c)]. Lot Release Procedures Each component, as defined in 21 CFR 606.3(c), (e.g., Red Blood Cells, Platelets, Plasma, or Cryoprecipitated AHF) prepared from a unit of whole blood represents one lot of product and bears a lot number, which is often the unit number assigned at the time of collection. QA procedures should be implemented to ensure that records are reviewed for accuracy, completeness, and compliance with established standards. A second person should review each significant step in each process associated with every component prior to release [See 21 CFR 606.100(c), 211.194(a)(7)&(8)]. QA procedures should be in place to ensure that any lot discrepancies or failure of a lot or unit to meet its specifications are thoroughly investigated. Labeling control procedures should be appropriate to the system and equipment. If automated labeling equipment retains information that could be erroneously printed during subsequent use, strict control procedures to prevent this should be implemented [See 21 CFR 211.125]. There should be written procedures designed and followed to ensure that correct labels, labeling, and packaging material are used for drug products [See 21 CFR 211.130]. Blood and blood components are labeled at various stages in the manufacturing process. At collection, products may be labeled as to the type of product the facility anticipates manufacturing. Products may be labeled as to blood group and expiration date at a later point in the manufacturing process. Products may be converted from one product type to another (e.g., Fresh Frozen Plasma to Recovered Plasma, Whole Blood to Red Blood Cells) and subsequently relabeled. Relabeling of blood products due to conversion to another product must undergo the same control procedures and have the same records maintained as the initial labeling operation. At each stage in the manufacturing process where labeling occurs, there should be process controls that ensure correct labels have been applied. Prior to release, the completely labeled product should be reviewed. Control procedures for final label review should include review of applicable production records and a record of verification by a second individual to ensure products have been properly labeled, e.g., donor classification, blood group, expiration date, and product name. When proper control procedures for labeling are followed, labeling errors are minimized. Quality Assurance Audits A QA audit is one mechanism for evaluating the effectiveness of the total QA system. Comprehensive audits should be conducted periodically in accordance with written procedures [See 21 CFR 211.180(e)]. A comprehensive audit should consist of review of a statistically significant number of records. A focused audit may be necessary when quality problems have been identified, or to monitor, more effectively, a particularly critical area. However, isolated audits restricted to one area may not detect system-wide problems. The QC/QA Unit's written procedures for a focused audit should be flexible enough to allow for additional audits without requiring changes in SOPs. Audit procedures will vary in complexity depending on the size of the establishment and the specific processes under review. Individuals conducting audits should possess sufficient knowledge, training, and experience to identify problems in the specific processes under review. The auditor or audit team should not be responsible for performing the procedures being audited. In situations in which an external audit program is used, the QC/QA unit is responsible for assuring that the audit meets the needs of the establishment and is consistent with 21 CFR 211.180(e). The annual review required by 21 CFR 211.180(e) is not viewed as a QA audit, and records of these reviews must be available during FDA inspections. There should be a written report documenting audit procedures and results. Procedures should include a plan for the Responsible Head or designated qualified person and other appropriate responsible officials to review and evaluate the results of the audit. The purpose of the review and evaluation is to ensure that responsible individuals are aware of problems, and corrective action is implemented. Audit reports should be retained for a period consistent with product record retention requirements. QA audits should be structured using a systems approach. Major systems of a blood manufacturing operation are identified in Tables 1-8, Appendix B. The systems which may comprise blood establishment operations and that should be audited should include, at a minimum, the following: Quality Control/Assurance; Donor Suitability; Blood Collection; Component Manufacturing; Product Testing; Storage and Distribution; Lot Release; and Computer. Each system may function independently or collectively with other systems. The critical control points in each system refer to areas that may affect the safety and quality of the product if key elements are not performed or functioning correctly. The key elements are individual steps in each critical control point. QA audits should evaluate critical control points and key elements in each system. Examples of critical control points and associated key elements are included in Tables 1-8, Appendix B. Each establishment should customize its audit for its own systems. ============================================================================ NOTE THAT TABLES 1-8 ARE NOT AVAILABLE IN THIS ASCII VERSION. THEY ARE AVAILABLE IN WORDPERFECT 5.1 FORMAT AT THE FTP SITE, CDV2.CDER.FDA.GOV, OR IN HARD COPY FROM THE FAX INFORMATION SYSTEM, 301-594-1939, DOCUMENT NUMBER 1000. ============================================================================= GLOSSARY Action Level: A limit that indicates the need to immediately identify the source of a discrepancy and make the necessary corrections to avoid a compromise in product quality. The QA/QC unit approves and evaluates adherence to this limit. Alert Level: A limit that a potential problem needs to be identified and corrected but does not indicate that an effect on product quality has resulted. The QC/QA unit approves and evaluates adherence to this limit. Audit: See Quality Assurance Audit. Competency Evaluation: An internal process for assessing an individual's ability to perform all assigned tasks. A variety of performance appraisal methods may be used. Component: (1) That part of a single-donor unit of blood separated by physical or mechanical means [See 21 CFR 606.3(c)]. (2) Any ingredient intended for use in the manufacture of a drug product, including those that may not appear in such drug product [See 21 CFR 210.3(b)(3)]. (3) A piece of equipment or software associated with a computerized system. Computer Change Control: The process of identifying, evaluating, coordinating, implementing, documenting, and obtaining formal approval of changes in a computerized system or database. Critical Control Point: A function or an area in a manufacturing process or procedure that failure or loss of control may have an adverse effect on the quality of the finished product and may result in a health risk. Current Good Manufacturing Practice (CGMP): Methods used in, and the facilities or controls used for, the manufacture, processing, packing, or holding of a drug including, but not limited, to blood products to assure that such product meets the requirements of the FD&C Act as to safety and has the identity and strength, and meets the quality and purity characteristics, which it purports or is represented to possess [See FD&C Act, Sec. 501(a)(2)(B)]. CGMP ensures products are consistently manufactured and controlled by quality standards appropriate to their intended use. It encompasses both manufacturing and quality control/quality assurance procedures. Key Element: An individual step in a critical control point of the manufacturing process. Maintenance: Activities such as adjusting, cleaning, modifying, overhauling equipment to assure performance in accordance with requirements. Maintenance to a software system includes, among other things, correcting software errors, adapting software to a new environment, or making enhancements to software. Manufacture: Blood is produced by the body and requires further processing before it can be safely transfused. The term manufacture is defined, in part, in 21 CFR 600.3(u), as all steps in the propagation or manufacture and preparation of products. The biologics regulations prescribe requirements concerning all aspects of the manufacture of blood even before it is collected from the donor (e.g., donor suitability criteria). Manufacture is also used in the FD&C Act and the PHS Act in direct reference to blood and blood products [40 FR 53532, November 18, 1975]. Parallel Test or Parallel Run. Functional testing performed using two or more different systems simultaneously. This may include comparison of an established system to a new system. (International Standards Organization definition: A test run of a new or an altered data processing system with the same source data that is used in another system; the other system is considered as the standard of comparison.) Production: The name given to personnel and/or operations involved in manufacturing. Proficiency Testing: An evaluation of "the ability to perform laboratory procedures within acceptable limits of accuracy, through the analysis of unknown specimens distributed at periodic intervals by an external source" (Deboy and Jarboe, 1991). Program Description: A narrative that describes a computer program's functions and interaction with other programs. Qualification: Establishing confidence that process equipment, reagents, and ancillary systems are capable of consistently operating within established limits and tolerances. Process performance qualification is intended to establish confidence that the process is effective and reproducible. Quality: Conformance of a product or process with pre-established specifications or standards. Quality Assurance (QA): The actions, planned and performed, to provide confidence that all systems and elements that influence the quality of the product are working as expected individually and collectively. Quality Assurance Audit: A documented, independent inspection and review of manufacturing and associated systems, performed periodically according to written procedures to verify, by examination and evaluation of objective evidence, the degree of compliance with those elements of the QA program under review. Quality Assurance Program: An organization's comprehensive system for manufacturing safe, effective, and quality products according to regulatory standards. This program includes preventing, detecting, and correcting deficiencies that may compromise product quality. Quality Control/Assurance (QC/QA) Unit: One or more individuals designated by, and reporting directly to, management with defined authority and responsibility to assure that all quality assurance policies are carried out in the organization. Quality Control (QC): A component of a QA program that includes the activities and controls used to determine the accuracy and reliability of the establishments' personnel, equipment, reagents, and operations in the manufacturing of blood products including testing and product release. Specification(s): Physical characteristics and composition, performance characteristics, parameters, requirements, standards, intended functions, behavior, or other characteristics of a product, system, or part of a system (as appropriate). Test Cases: (as applied to computerized systems) þ Normal: valid data sets are used to produce normal outputs; þ Exceptional: valid data which provide an unusual twist to force the program to react to the unexpected; þ Boundary: data which force the program to evaluate conditions that are of borderline validity or at the boundaries of pre-established alert or action levels for control; þ Stress: data which forces the system to reach its maximum level of performance (during development and in the environment of the user); þ Invalid: data that are not valid; test data should be designed to force a program to prove that it can detect and respond appropriately to invalid input. Examples of invalid test cases may include an invalid donation date, e.g., 02/30/91; an invalid ABO group, e.g., "P"; a negative hemoglobin value; or no data entry. Test Database: A database containing normal and abnormal values created by copying the production database and adding anomalous data. The test database is used to challenge a computerized system during validation and/or acceptance testing. Thresholds: Guideline values which are needed in reviewing records to determine the adequacy of performance. These are the acceptable limits for quality to determine when intervention is necessary. Thresholds may be expressed as a number or percentage. Validation: Establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality attributes. A process is validated to evaluate the performance of a system with regard to its effectiveness based on intended use. REFERENCES Health and Human Services References l. Title 21, Code of Federal Regulations, Parts 210, 211, 600, 606, 610, 640, 660. 2. FDA, Center for Drugs and Biologics and Center for Devices and Radiological Health (CDRH), Guideline on General Principles of Process Validation (May 1987). 3. FDA 91-4179: CDRH, Medical Device Good Manufacturing Practices Manual, 5th Edition (August 1991). 4. FDA Compliance Program Guidance Manual, Blood and Blood Products, 7342.001, 7342.002. 5. FDA Compliance Policy Guide, FDA Access to Results of Quality Assurance Program Audits and Inspections, 7151.02, 1989. 6. FDA Memorandum: April 6, 1988, Control of Unsuitable Blood and Blood Components. 7. FDA Memorandum: March 20, 1991, Deficiencies Relating to the Manufacture of Blood and Blood Components. 8. Federal Register, Volume 43, No. 190, September 29, 1978, Human and Veterinary Drugs, Current Good Manufacturing Practice in Manufacture, Processing, Packing, or Holding, 45013-45087. 9. Federal Register, Volume 40, No. 223, November 18, 1975, Human Blood and Blood Products, Collection, Storage and Processing, 53532- 53544. 10. Federal Register, Volume 57, No. 40, February 28, 1992, Clinical Laboratory Improvement Amendments of 1988; Final Rule, 7002-7288. 11. FDA, Center for Biologics Evaluation and Research (CBER), Draft Guideline for the Validation of Blood Establishment Computer Systems; Docket No. 93N-0394, October 28, 1993. General References Accreditation Manual for Hospitals. 1991. Joint Commission on Accreditation of Healthcare Organizations. Bartlett, R. Leadership for Quality. 1991. ASM News; 57:15-21. DeBoy, J. and Jarboe, B. Government-Mandated Cytology Proficiency Testing: Practical, Equitable and Defensible Standards. 1991. ORB; 152-161. Juran, J. Quality Control Handbook. 1974. McGraw-Hill. Kritchevsky, S. and Simmons, B. Continuous Quality Improvement: Concepts and Applications for Physician Care. 1991. JAMA; 266:1817- 1823. Melum, M.M. Total Quality Management: Steps to Success. 1990. Hospitals 64(23):42,44. Milakovich, M.E. Creating a Total Quality Health Care Environment. 1991. Health Care Manage Rev; 16(2):9-20 McLaughlin, C.P. and Kaluzny, A.D. Total Quality Management in Health: Making It Work. 1990. Health Care Manage Rev; 15(3): 7-14. Olso, A. Remmington's Pharmaceutical Sciences. 1980. Control; 16(82):1434-8. Rosvoll, R., Editor, Accreditation Requirements Manual of the American Association of Blood Banks. 1990. American Association of Blood Banks. Walker, R., Editor, Technical Manual, 11th Edition. 1993. American Association of Blood Banks.