This section will discuss when methods need to be validated and present ideas for deciding how extensively they should be validated.
Guidelines for when method validation is required are found in applicable standards and regulations (see Part 4).
Such guidelines specify that laboratory methods must be validated (or re-validated) under specific conditions:
- Before introduction into routine use
- Whenever the conditions change for which the method has been validated, e.g., using an instrument or reagent with different characteristics
- Whenever the method is changed, and the change is outside the original scope and may affect the results of the original validation
Laboratories may also use ongoing result abnormalities or deficiencies in proficiency testing as a trigger for revalidation of a method.
In effect, all operating procedures must be validated before being implemented and after any change. The harder question is to decide how to validate, in particular how much work is needed:
- How many samples? Depending on the circumstances, a suitable number could be a minimum of 30 specimens or one week's routine test volume or a number derived from statistical sample size calculations.
- Routine ("normal") samples or a range of rarer unusual samples?
- Routine work volumes or maximum volumes?
- Installation, operational, and performance qualification or only IQ and PQ?
How extensively to validate a method is an issue that confronts many TS. Most laboratories operate under resource constraints and want to do what is safe for the patient, satisfy standards and regulations, but at the same time fulfill requirements by efficient use of staff and other resources. To help decide how much is enough, some factors to consider are discussed below.
Full validations (evaluations)
Extensive validations are important when a method is
- relatively new and untested (few published studies)
- implemented for the first time
- modified in-house from the manufacturer's instructions
- completely developed in-house
Unfortunately, it is impossible to define what constitutes a partial (less extensive) validation, since the amount of assessment that is required varies greatly from situation to situation. Reading the literature and contacting colleagues to identify what others have done can help. When applied to instrument qualification, partial validation may mean omitting the operational qualification.
Less extensive (partial) validations may be suitable under particular circumstances.1-5 For example:
- Change of anticoagulant, e.g., using EDTA tubes instead of "red tops" for pretransfusion testing
- Method transfer between laboratories using the same SOPs, e.g., satellite labs within the same TS region
- Change of sample containers, e.g., using plastic tubes (approved by relevant regulatory bodies) instead of glass tubes
- Change of reagent manufacturer, e.g., using a different manufacturer's screen cells for automated antibody screening
- When multiple workstations have the same instruments that are configured identically and substantially equivalent
- When replacing a method or instrument with the same or similar method or instrument
- When a method has been extensively evaluated by other similar laboratories using sound validation principles that conform to current blood safety standards and guidelines for validation
For discussion on how extensively to validate when a smaller change such as switching to plastic tubes occurs, see
- CBBS e-Network Forum. Switching from glass tubes to plastic tubes for blood bank laboratory testing 6
For guidelines tailored to small facilities where resources are limited, see
- College of Physicians & Surgeons of Alberta (CPSA).Procedure / method statistical validation: Work-up guidelines - transfusion medicine 7
** When in doubt about how extensively to validate, directly consult appropriate regulators and standards providers.**
Although methods are validated differently, method validations have several common characteristics.
First, as discussed, if the method uses a particular piece of equipment or instrument, the common validation elements are the qualifications (implementation, operational, and performance).
In addition, method validations share these components:
1. Validation master plan.An overview of the entire validation, its purpose and scope, organisational structure with designated responsibilities, items to be validated, planning, and schedules. See Developing a Master Plan for Complex Validation Projects 7
2. Validation protocol. A specific set of validation test procedures (experiments) and acceptance criteria, including equipment, supplies, samples, critical parameters, reviewing personnel, statistics, references, etc. Strategies for handling validation deficiencies and criteria for revalidation must be specified.
3. Method SOPs. SOPs for performing the method in the routine. These SOPs must also be validated.
4. Training. A training plan and training documents for staff performing the validation and for implementing the method.
5. Documentation. Complete documentation of all aspects of the validation, including a final report. The final report describes what was done in each validation protocol; provides data analysis, conclusions, and evidence of approval by senior management; and summarizes results of the entire validation
1. Is it acceptable to do a partial validation or do methods always have to be extensively validated?
2. List 3 resources that can be used to decide how much work to do when validating a method?
3. Which validation document provides detailed evidence of experiments done to validate a method?
- Part 1: Introduction to terminology
- Part 2: Types of validation
- Part 3. Determining when and how extensively to validate a method <--You are here
- Part 4: Regulations and standards
- Part 5: Validation examples (tools and resources)
1. FDA Guidance for industry. Bioanalytical method validation. May, 2001.
3. A Framework for NCCLS Evaluation Protocols; A Report (EP 19-R)
4. Quinley E. Process validation: Will it ever be "no big deal"? Transfusion Diagnostics Update (Ortho-Clinical Diagnostics & Chiron), Sept. 1999:4?5.
5. Westgard JO. Final CLIA Rule. Part V: Method Validation Process and Procedures (see Adaptations for individual laboratories)
6. CBBS e-Network Forum. Switching from glass tubes to plastic tubes for blood bank laboratory testing
7.College of Physicians & Surgeons of Alberta (CPSA). Procedure / method statistical validation: Work-up guidelines - transfusion medicine