Essential terminology associated with validation

4.9.1. Calibration

Calibration is the set of operations that establish, under specified conditions, the relationship between values indicated by an instrument or system for measuring (especially weighing), recording and controlling, or the

values represented by a material measure, and the corresponding known values of a reference standard. Limits for acceptance of the results of measuring should be established.

4.9.2. Change revalidation

Change revalidation involves the repeat of the initial validation process to provide assurance that changes in the process and/or in the process environment, whether intentional or unintentional, do not adversely affect process characteristics and product quality.

4.9.3. Computer validation

Computer validation is documented evidence that provides a high degree of assurance that a computerized system records data correctly and that data processing complies with predetermined specifications.

4.9.4. Cleaning validation

Cleaning validation is documented evidence to ensure that cleaning procedures are removing residues to predetermined levels of acceptability, taking into consideration factors such as batch size, dose, toxicology and equipment size.

TABLE 8. RESIDUAL SOLVENTS USED IN PET RADIO- PHARMACEUTICALS AND OTHER MEDICINES

Residual solvent Maximum mg/V (V is maximum recommended dose in millilitres)

Acetone 50

Acetonitrile 4.1

Chloroform 0.6

1, 2-dichloroethane 18.7

Methanol 30

Methylbutylketone 0.5

4.9.5. Design qualification

Design qualification is documented evidence stating that the premises, supporting utilities, equipment and processes have been designed in accordance with the requirements of good radiopharmacy practice.

4.9.6. Installation qualification

Installation qualification consists of the performance of tests to ensure that the installations (such as machines, measuring devices, utilities and manufacturing areas) used in a manufacturing process are appropriately selected and correctly installed and operate in accordance with established specifications.

4.9.7. Operational qualification

Operational qualification is documented verification that the system, or subsystem, performs as intended over all anticipated operating ranges.

4.9.8. Performance qualification

Performance qualification is the documentary evidence which verifies that the equipment or system operates consistently and gives reproducibility within defined specifications and parameters for prolonged periods (sometimes termed process validation).

Process validation is documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality characteristics.

4.9.9. Qualification

Qualification consists of proof and documentation that premises, systems and equipment are properly installed and/or work correctly, and lead to the expected results. Qualification is often a part (initial stage) of validation, but the individual qualification steps alone do not constitute the validation process.

4.9.10. Retrospective validation

Retrospective validation consists of an examination of past production experience on the assumption that composition, procedures and equipment remain unchanged.

4.9.11. Revalidation

Revalidation is repeated validation of an approved process (or a part thereof) to ensure continued compliance with established requirements.

4.9.12. Prospective validation of risk analysis

Prospective validation of risk analysis is validation carried out during the development stage by means of a risk analysis of the production process, which is broken down into individual steps; these are then evaluated on the basis of past experience to determine whether they might lead to critical situations.

4.9.13. Standard operating procedures

A SOP is an authorized written procedure that provides instructions for performing operations not necessarily specific to a given product or material, but rather of a more general nature (e.g., equipment operation, maintenance and cleaning; validation; cleaning of premises and environmental control;

sampling and inspection). Certain SOPs may be used to supplement product specific master and batch production documentation.

4.9.14. Validation

Validation is an action of proving and documenting that any process, procedure or method actually leads to the expected results (see also Qualifi-cation (Section 4.9.9)).

The test approach, which is applicable to both prospective and concurrent validation, may include:

(a) Extensive product testing, which may involve extensive sample testing, with the estimation of confidence limits for individual results and batch homogeneity;

(b) Simulation process trials;

(c) Challenge/worst case tests, which determine the robustness of the process;

(d) Control of process parameters being monitored during normal production runs to obtain additional information on the reliability of the process.

A validation protocol is a document describing the activities to be performed in a validation, including the acceptance criteria for the approval of a manufacturing process, or a part thereof, for routine use.

A validation report is a document in which the records, results and evaluation of a completed validation programme are assembled. It may also contain proposals for the improvement of processes and/or equipment.

4.9.15. Validation master plan

A validation master plan (VMP) is a high level document that establishes an umbrella validation plan for the entire project and summarizes the manufacturer’s overall philosophy and approach, to be used for establishing the adequacy of performance. It provides information on the manufacturer’s validation work programme and defines details of and timescales for the validation work to be performed, including stating the responsibilities relating to the plan.

The VMP should reflect the key elements of the validation programme. It should be concise and clear and contain at least:

(a) A validation policy;

(b) An organizational structure of validation activities;

(c) A summary of facilities, systems, equipment and processes validated and to be validated;

(d) A documentation format (e.g. a protocol and report format);

(e) Planning and scheduling;

(f) Change control;

(g) References to existing documents.

4.9.16. Verification

The application of methods, procedures, tests, and other evaluation and monitoring, in order to determine compliance with good practices.

4.9.17. Worst case

A condition or set of conditions encompassing upper and lower processing limits and circumstances, within SOPs, which pose the greatest chance of product or process failure when compared with ideal conditions.

Such conditions do not necessarily include product or process failure.