Case Study O3: Method Validation in the Transfusion Service (TS)
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Case Study O3 deals with validation, a relatively new concept to hospitaltransfusion services. Although TS have always evaluated new methods and equipment, the need for formal, documented validation has arisen out of the adoption of quality systems and the requirements of new standards and regulations targetted at TS.
- The case was motivated by the many citations for validation deficiencies found in the audit literature related to blood centers, transfusion services, diagnostic test and biomedical device manufacturers.
This format is different from typical serologic cases (which focus on a patient's laboratory and clinical data and the resulting serologic investigation). Instead, various issues related to the case are discussed, along with links to external resources.
This case takes a topic- validation - and covers different aspects similar to a self-study module.The aim is to introduce validation concepts and to gather resources to use as tools and for further study when faced with validating a process. The case can act as a primer on validation or as just-in-time learning.
Upon completion of this exercise, participants should be able to
- Define the following related terms: process control, evaluation, validation, verification.
- List the 3 types of qualifications typically done on diagnostic equipment such as automated instruments.
- Differentiate between validation SOPs, master plans, and protocols.
- Differentiate between evaluation and validation.
- Describe various types of validation (SOP, method, equipment, LIS, process, etc.)
- List the common elements of a method validation.
- State when validation of methods and equipment is required.
- Explain why validation is a key component of a quality system.
- Describe regulations and standards involvingvalidation in the TS.
- Differentiate between standards and regulations.
This case was motivated by the many citations for validation deficiencies found in the audit literature.
- In the examples below [redacted] is used by the FDA to indicate that company or proprietary names or other identifying information has been removed.
- The deficiencies applied at the time (note the citation dates).
Validation of equipment
Validation of equipment is one of the most frequently cited deficiencies on the College of American Pathologists (CAP) transfusion medicine checklist:
- TRM.32000: Is there a program documenting that serologic centrifuges and other equipment function properly, including validation on receipt, after adjustments or repairs and when there has been a change in technique?
FDA 2003 Warning letter to Walter L. Shepeard Community Blood Center (03-ATL-10) included several on validation
1. Failure to have in place written validation protocols, maintenance of complete and accurate documentation of the performance of the validation protocols, and an analysis of the results by the blood bank computer system [21 CFR 211.68(a) & (b)] in that:
- a. You have no written protocol requiring or describing the validation of the [redacted] ABO/RH machine, including accept/reject criteria, number of samples per run, stress testing, and investigations of samples classified as ?Invalid? by the blood bank computer system.
- b. Record review of the initial and update validation for the [redacted] ABO/RH automated equipment disclosed that the donation dates for various donors were different from the donation dates listed in the validation data and that two of the sample numbers were ?invalid? when entered into the [redacted] computer system. The firm's records must be adequate to demonstrate that the validation [redacted] ABO/RH automated equipment is accurate.
- c. Parallel testing of the [redacted] analyzer was to be performed for 30 days according to the "Validation [redacted] protocol, dated 9/01, however, it was only performed for 12-15 days and did not include acceptable values for both Pre & Post Platelet Pheresis counts. In addition, that protocol, dated 9/01, did not require a sufficient degree of input/output verification, based on the complexity and reliability of the [redacted] analyzer. For example, the protocol did not contain or even reference the validation requirements set forth in the manufacturer?s instructions.
- d. Some of the validation test results for the [redacted] analyzer, including some of the raw data, were missing or unavailable for review during the inspection.
FDA 2003 Warning letter to Johns Hopkins Hospital Blood Bank (03-BLT-14)
Observation 1: The response is inadequate, in that the "validation" data lacks specific details regarding the steps taken to qualify the equipment. For example, your response indicated that the incubation of the [redacted] instruments was performed for [redacted] minutes. However, there was no data or information regarding the assessment of the incubation temperature for the intended use of the equipment. Additionally, how were the times for the incubator assessed? Also, your response noted ?target? and "actual" times for the incubator and [redacted] shaker. However, there was no indication as to how the measurements were taken.
FDA. American National Red Cross Consent Decree (1993 - ongoing to 2003), particularly as related to computer software
FDA. American Red Cross Transplantation Service (11 March 2004)
Failure to perform adequate process validation with a high degree of assurance. [21 CFR 820.75(a)] For example: The antibiotic disinfection process validation approved 9/25/93, Antibiotic Challenge, was not adequate. A worst case multiple microbe challenge was not performed, organisms were individually tested in the disinfection solution. A two log reduction was not achieved for Candida albicans. Additionally, the rationale for the organisms selected for the study could not be explained. [21 CFR 820.75 (a)]
FDA. Dear colleague letter - Abbott consent decree (1999)
We took this action because of the firm?s long-standing failure to comply with FDA?s Good Manufacturing Practices (GMP) regulation, now called the Quality System regulation, and its failure to fulfill commitments to correct deficiencies in its manufacturing operations.
These failures go back to 1993, when our inspection of the facilities where Abbott Diagnostics Division manufactures diagnostic products showed non-compliance with the GMP requirements. Areas of non-compliance included process validation, corrective and preventive action and production and process controls. The company?s failure to comply with these requirements increases the likelihood that the diagnostic products produced at these facilities may not perform as intended.
Because some provincial Colleges of Physicians and Surgeons are now going to accredit Canadian TS using CSTM Standards for Hospital Transfusion Services, v 1 and CSA Standard Z902-04, and because the UK is implementing legislation based on the EU blood directive, a case study on how and when to validate methods, equipment, etc., seems timely.
To test your knowledge and as an advance organizer for the discussion section, read and consider these questions:
Why do methods, equipment, etc., need to be validated?
What is a validation master plan and what is typical content?
- What types of qualifications are done in the TS and how do they relate to validation?
- What are the common elements in a method validation, regardless of what process is being validated?
Proceed to Discussion (includes interactive questions with feedback):
- Part 1: Introduction to terminology
- Part 2: Types of validation
- Part 3. Determining when and how extensively to validate a method
- Part 4: Regulations and standards
- Part 5: Validation examples (tools and resources)
This case study has examined formal, documented validation as a quality system requirement of new standards and regulations for TS, with an emphasis on method validation. Many resources are available to help with validating processes. However, the task remains difficult due to its newness and the relative lack of exemplary validation protocol modelsthat can be adapted to the needs of individual TS.
- A final quiz will be available soon.
AuBuchon JP. Optimizing the cost-effectiveness of quality assurance in transfusion medicine. Arch Pathol Lab Med 1999;123(7):603-6.
Adams MR, Dumont LJ, McCall M, Heaton WA. Clinical trial and local process evaluation of an apheresis system for preparation of white cell-reduced platelet components. Transfusion 1998 Oct; 38(10):966-74.
Aulesa C, Pastor I, Naranjo D, Piqueras J, Galimany R. Validation of the Coulter LH 750 in a hospital reference laboratory.,Lab Hematol 2003; 9(1):15-28.
Burgstaler EA, Pineda AA. Plateletapheresis: instrumentation validation. Transfus Sci 1999 Oct;21(2):153-61.
Cowan DF, Gray RZ, Campbell B. Validation of the laboratory information system. Arch Pathol Lab Med 1998 Mar;122(3):239-44.
Dumont LJ, Dzik WH, Rebulla P, Brandwein H. Practical guidelines for process validation and process control of white cell-reduced blood components: report of the Biomedical Excellence for Safer Transfusion (BEST) Working Party of the International Society of Blood Transfusion (ISBT). Transfusion 1996 Jan;36(1):11-20.
Dunne W M, Case L K, Isgriggs L, Lublin D M. In-house validation of the BACTEC 9240 blood culture system for detection of bacterial contamination in platelet concentrates. Transfusion 2005 Jul;45 (7): 1138-42.
Fritsma GA, Marques MB. The top ten problems in coagulation. Advance for Med Lab Professionals, 2004 June 28. - see Problem 10: How to validate point-of-care (POC) coagulation tests
Green JM. A practical guide to analytical method validation. Analytical Chem 1996; 68: 305A-309A.
Hanson M. The"?p's and q's" of quality systems. Arch Pathol Lab Med 1999;123(7):576-9.
Jaeschke R ; Guyatt G ; Sackett DL. Users' guides to the medical literature. III. How to use an article about a diagnostic test. A. Are the results of the study valid? Evidence-Based Medicine Working Group. JAMA 1994 Feb 2;271(5):389-91.
Judd WJ, Barnes BA, Steiner EA, Oberman HA, Averill DB, Butch SH. The evaluation of a positive direct antiglobulin test (autocontrol) in pretransfusion testing revisited.Transfusion. 1986 May-Jun;26(3):220-4.
Judd WJ, Steiner EA, Oberman HA, Nance SJ. Can the reading for serologic reactivity following 37 degrees C incubation be omitted? Transfusion 1992 May;32(4):304-8.
Malone T. Bacterial Detection. Experience In the blood center. (44 slide presentation at USA Advisory Committee on Blood Safety and Availability)
Meyer EA, Shulman IA. The sensitivity and specificity of the immediate-spin crossmatch. Transfusion 1989 Feb; 29(2):99-102.
Owens MA, Vall HG, Hurley AA, Wormsley SB. Validation and quality control of immunophenotyping in clinical flow cytometry. J Immunol Methods 2000 Sep 21; 243(1-2):33-50.
Schaffner G, Kayser T, Tonjes A, Volkers P. Validation of flow cytometry to quantify the potency of anti-D immunoglobulin preparations. Vox Sang 2003 Feb; 84(2):129-36.
Seghatchian J, Beard M, Krailadsiri P. The role of in process qualification in quality improvement of the haemonetics MCS plus leucodepleted platelet concentrate. Transfus Sci 2000 Jun;, 22(3):165-9.
Weese DL, Buffaloe VA. Conducting process validations with confidence. Medical Device & Diagnostic Industry Magazine, Jan. 1998.
Yazer MH, Triulzi DJ. Use of a pH meter for bacterial screening of whole blood platelets. Transfusion 2005 Jul;45(7):1133-7.
Online Tools and Resources
American Association of Blood Banks.
BC Provincial Blood Coordinating Program
British Committee for Standards in Haematology (BCSH).
- Recommendations for evaluation, validation and implementation of new techniques for blood grouping, antibody screening and crossmatching. Transfus Med1995; 5:145?50.
California Blood Bank Society (CBBS) e-Network Forum
- Switching from glass tubes to plastic tubes for blood bank laboratory testing
- Who should validate computer software used in blood banks/transfusion services?
Canadian Blood Services:
Canadian Society for Transfusion Medicine (CSTM).
Centre for Evidence Based Medicine.
College of American Pathologists (CAP)
College of Physicians & Surgeons of Alberta (CPSA).
Clinical Laboratory Standards Institute (CLSI - formerly NCCLS)
Food and Drug Administration (USA)
- Abbott consent decree information (1999)
- American National Red Cross Consent Decree (1993)
- Guidance for industry. Bioanalytical method validation. May, 2001.
- General principles of software validation (Jan. 2002)
- Guideline on general principles of process validation (May,1987; reprinted February, 1993)
- Medical device quality systems manual
- Process validation
- Warning letters and responses
Hamilton-Niagara Quality Essentials for Safe Transfusion (QUEST).
- Annex to the GMP Guidelines for Schedule D Drugs, Part 2: Human Blood and Blood Components
International Society for Blood Transfusion (ISBT)
- Guidelines for validation and maintaining the validation state of automated systems in blood banking (Dec. 2002)
- Practical guidelines for process validation and process control of white cell-reduced blood components: report of the Biomedical Excellence for Safer Transfusion (BEST) Working Party of the International Society of Blood Transfusion (ISBT). Transfusion 1996 Jan;36(1):11-20.
Ontario Medical Association.
UK National Health Service.
University of Arkansas for Medical Sciences.
Westgard, James O.
- FDA - Abbott consent decree: A wakeup call for healthcare laboratories
- Basic method validation, ed 2.
- Final CLIA Rule. Part V: Method Validation Process and Procedures
- Method validation: Real world applications
- Method validation: the regulations
- Method validation. Selecting a method to validate
World Health Organization
- Blood establishment licence amendment requirements for information technology submissions (Oct. 2002)