Case Study O3: Method Validation in the Transfusion Service (TS)

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NOTES  Case Study O3 deals with validation, a relatively new concept to hospital  transfusion 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. - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -

• Learning outcomes

• Case background

• Questions to be considered

• Discussion

• Summary

• Quiz

• Further Reading

LEARNING OUTCOMES

Upon completion of this exercise, participants should be able to

1. Define the following related terms: process control, evaluation, validation, verification.
2. List the 3 types of qualifications typically done on diagnostic equipment such as automated instruments.
3. Differentiate between validation SOPs, master plans, and protocols.
4. Differentiate between evaluation and validation.
5. Describe various types of validation (SOP, method, equipment, LIS, process, etc.)
6. List the common elements of a method validation.
7. State when validation of methods and equipment is required.
8. Explain why validation is a key component of a quality system.
9. Describe regulations and standards involving validation in the TS.
10. Differentiate between standards and regulations.

CASE BACKGROUND

This case was motivated by the many citations for validation deficiencies found in the audit literature. Notes: 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 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.

TOP

QUESTIONS TO BE CONSIDERED 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?

DISCUSSION

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)