Validation is an integral part of a quality system. For a readable overview of quality systems, see
- Hanson M. The "p's and q's" of quality systems. Archives Pathol Lab Med 1999;123(7):576-9.
To the novice reader, much of the literature on validation may be confusing. For example:
- Process control, process validation, and method (procedure) validation may seem pretty similar.
- Types of qualifications (installation, operational, and product performance) may seem like bafflegab.
- Often evaluation and validation are used as synonyms.
- Validation plans, master plans, protocols, reports- what do they all mean?
This section will provide key definitions used in validation studies and explain the relationship between various terms. The discussion is not meant to be definitive or all inclusive.
- More terms: Evaluation, validation, verification, et al.
- Validation documentsSelf study questions
- Further Reading
Simply put, validation is the process of proving and documenting that something works the way it is supposed to work. Strictly speaking, validations are performed on processes, not equipment and reagents. Other validation-related definitions:
- A process to ensure that a new method or instrument repeatedly does what you want it to under pre-defined conditions, using your process 1a
- The establishment of documented and objective evidence that the particular requirements for a specific intended use can be consistently fulfilled1b
- Establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its pre-determined specifications and quality attributes1c
Equipment validation: More correctly called equipment qualification. Documented evidence that provides a high degree of assurance that equipment will consistently operate within established limits and tolerances.
Method validation: The process to confirm that the analytical procedure employed for a specific test is suitable for its intended use.
Process validation: Establishing by objective, documented evidence that a process consistently produces a result or product meeting predetermined specifications.
Note: In this case study, validation is a term used to include both validation and revalidation.
Notice that process is a term that is often used when referring to validation. Aprocess uses resources to transform inputs into outputs and generally involves more than one person performing several discrete procedures and tasks over time, e.g., a transfusion reaction investigation may involve physicians, nurses, technologists, blood collectors, and more; and take place over an extended time, with no predetermined stop point.
In contrast, a procedure often involves only one person performing a defined task within a larger process, e.g., taking the patient's vital signs pre- and post-transfusion or collecting a blood sample post-transfusion or performing a post-transfusion antibody screen.
Process control is a planned system for keeping processes within boundaries and minimizing variation, thereby controlling their outputs. In practice, process control consists of a series of controls that ensure that each critical part of a process (i.e., each procedure and each critical step in a procedure) is performedcorrectly. Critical refers to any step or procedure in the process that directly affects the quality of the output (product) or patient safety.
In effect, what we think of as quality control and quality assurance (and related procedures, processes, and policies) are all part of process control.
- Validation, whether it be of an entire process or a single method in a process, is but one of many components of process control.
Change control is another aspect of process control and is sometimes called process change control. Change control ensures that output quality is maintained or optimised after changes have been made to a process or one of its procedures.Change control encompasses the process and procedures used to identify, validate, document, review, and approve changes to processes and procedures.
- Validation forms part of change control when it is used to validate new methods and equipment or re-validate them after changes have been made.
Validation literature often refers to installation, operational, and product performance qualifications. What are these terms and how do they relate to validation?
Qualifications are parts of the validation process that relate to medical devices and include equipment such as laboratory information systems (LIS), automated instruments, and semi-automated test systems used in blood centers and TS. The usual components are as follows, although they overlap to some extent in the literature. The definitions are composites derived from references. 2-3.
1. Installation qualification: Documented evidence/verification that all aspects of equipment and ancillary systems are calibrated correctly, adhere to approved specifications, are correctly installed, and that staff are properly trained to perform the qualification.
2. Operational qualification: Documented evidence/verification that all aspects of the process / equipment are effective and reproducible, i.e., operate as intended throughout all anticipated ranges, including typical parameters and challenge or worst-case conditions so that the full range of expected use is verified. Sometimes called process performance qualification.
What sample size to use for the operational qualification is an issue that needs to be determined. Ideally, sample size should be based on a statistical rationale (e.g., typically with a p value of 0.05 and a power of 80%) but is sometimes based on historical precedent in the literature or on an organization's available resources.
3. Performance qualification (Product Performance qualification): Documented evidence/verification that the output (product) produced by a process / equipment in the work environment with expected volume meets all predetermined acceptance criteria and all release requirements for functionality and safety.
As discussed, process control includes validation as one if its parts, and the validation process may include different types of qualifications.
Terminology becomes more confused if we consider that evaluation and validation are used differently in the literature. For example, CLSI (formerly the entertainer known as Prince, errrr...NCCLS ) recommends that evaluate be used as a generic term for any study that assesses the performance of an assay and outlines three evaluation subclasses relevant to clinical laboratories4 (Another subclass, establish performance, involves studies done by a manufacturer or research scientist in the R&D or manufacturing phase and is beyond the scope of CLSI protocols). In brief, the three subclasses are
- Validate. Studies to determine if a test system meets user (laboratory) needs. Called external validation if testing occurs in the user's facility (as opposed to the manufacturer's)
- Verify. Studies to determine if the specifications claimed by the manufacturer are met. Called external verification if testing occurs in the user's facility. Could be applied to equipment, kits, instruments, and reagents. Is usually done in the first phase of process validation.
- Demonstrate. Studies done by a laboratory to demonstrate that it is able to use the test system in its particular environment to obtain expected performance.
CLSI notes that the scope of a study may be influenced by what is already known about a test system and how extensively it has been assessed, as well as a laboratory's available resources.
On the other hand, in the UK one BCSH guideline (Recommendations for evaluation, validation and implementation of new techniques for blood grouping, antibody screening and crossmatching5) uses the terms as comparison studies with different degrees of extensiveness and rigour:
- Evaluation. An extensive in-house comparison study of new and existing test systems that assesses sensitivity, specificity, reproducibility, robustness, as well as other factors such as safety, speed, ease of use, required skill level, training implications, and cost-effectiveness. Types of samples and minimum sample sizes are specified.
- The guideline also specifies that not all laboratories will need to do "full evaluations" if suitable evaluations have been done by other laboratories.
- Validation. Parallel testing with full documentation of a minimum of one week's routine samples with the new and existing test systems.
Bottom line. Given the different ways that terms are used in the literature, TS should choose a model for validations (CLSI, etc.) and then define terms based on the selected model.
* If you are aware of other published validation guidelines and models suitable for use by TS, please e-mail Pat.
All aspects of the validation process must be documented. Typical documents include:
A generic SOP on how to perform validation (equivalent to an SOP on writing SOPs). Provides general guidance and responsibilities, including detailed instructions for preparing protocols, change control requirements for revalidation, approval processes, and document control procedures to ensure that only official protocols are used in the validation.
Validation master plan
An organization's quality management system should have a validation master plan that describes its general policies regarding the validation of equipment, methods, processes and automated systems. As well, individual validations require a master plan that helps management, validation team members, and auditors to better understand a specific validation. The plan presents an overview of the entire validation, its scope, organisational structure with designated responsibilities, content, planning, and schedules. The plan's core component is a list of the items to be validated and the planning schedule. Should be a concise summary and refer to other documents such as SOPs, protocols, etc. Planned activities can be summarized in a matrix to include the extent of each validation, SOPs to be used, general criteria for acceptance, and how deviations and abnormalities will be investigated. The plan should be approved by senior management.
A specific set of test procedures and acceptance criteria for each system being validated, including equipment, supplies, samples, critical process parameters, etc. Strategies for problem solving anomalies and handling validation deficiencies, as well as criteria for revalidation, must be specified. The protocol should include places for reviewers signatures or initials. A complex validation may include more than one protocol. Protocols may include specific SOPs for validation qualifications.
Reports details of what was done in each validation protocol and qualification (if there were more than one), and summarizes results of the entire validation. Contains data analysis and conclusions. Must be reviewed and approved by senior management.
1. What is the difference between process verification and process validation?
2. Describe the relationship between process control, validation, and qualification.
3. A validation document includes a detailed set of procedures and acceptance criteria for validating an automated instrument for pretransfusion antibody screening, including equipment, supplies, samples, etc. The document is likely a validation:
- master plan
- Part 1: Introduction to terminology <--You are here
- 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)
1a. Hamilton-Niagara Quality Essentials for Safe Transfusion (QUEST). Sharing our Strategies (SOS ) Manual
1b. UK Government. The Blood Safety and Quality Regulations 2005
1c. FDA. Guideline on general principles of process validation (May,1987; reprinted February, 1993)
2. FDA. Guideline on General Principles of Process Validation (May,1987; reprinted February, 1993)
3. Weese DL, Buffaloe VA. Conducting process validations with confidence. Medical Device & Diagnostic Industry Magazine, Jan. 1998.
4. CLSI. A Framework for NCCLS Evaluation Protocols; A Report (EP 19-R):
Hanson M. The "p's and q's" of quality systems. Arch Pathol Lab Med 1999;123(7):576?9.