1) PROCESS VALIDATION
Ø prospective validation
Ø concurrent validation
Ø retrorospective validation
2) cleaning validation
3) change control
4) Re- validation
Documented evidence to establish that cleaning procedures are removing residues to predetermined levels of acceptability, taking into consideration factors such as batch size, dosing, and toxicology and equipment size.
Action of proving and documenting that any process, procedure or method actually and consistently leads to the expected results.
Documented evidence which provides a high degree of assurance that a specific process will consistently result in a product that meets its predetermined specifications and quality characteristics
Validation carried out during routine production of products intended for sale.
Validation carried out during the development stage on the basis 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 may lead to critical situations.
Involves the evaluation of past experience of production on the condition that composition, procedures, and equipment remain unchanged.
- The sources of data for this validation may include batch documents, process control chart, maintaince logbook, records of personnel change process capability studies, fp data and stability results.
Validation report (VR)A document in which the records, results and evaluation of a completed validation programme are assembled and summarized. It may also contain proposals for the improvement of processes and/or equipment.
Process Validation Program
The number of process runs for validation should depend on the complexity of the process or the magnitude of the process change being considered. For prospective and concurrent validation, three consecutive successful production batches should be used as a guide, but there may be situations where additional process runs are warranted to prove consistency of the process
For retrospective validation, generally data from 10 to 30 consecutive batches should be examined to assess process consistency, but fewer batches can be examined if justified.
Critical process parameters should be controlled and monitored during process validation studies. Process parameters unrelated to quality, such as variables controlled to minimize energy consumption or equipment use, need not be included in the process validation.Process validation should confirm that the impurity profile for each API is within the limits specified. The impurity profile should be comparable to, or better than, historical data and, where applicable, the profile determined during process development or for batches used for pivotal clinical and toxicological studies.
Approaches to validation
5.1.1 There are two basic approaches to validation—one based on evidence obtained through testing (prospective and concurrent validation), and one based on the analysis of accumulated (historical) data (retrospective validation). Whenever possible, prospective validation is preferred. Retrospective validation is no longer encouraged and is, in any case, not applicable to the manufacturing of sterile products.
5.1.2 Both prospective and concurrent validation, may include:
• extensive product testing, which may involve extensive sample testing (with the estimation of confidence limits for individual results) and the demonstration of intra- and inter-batch homogeneity;
• simulation process trials;
• challenge/worst case tests, which determine the robustness of the process; and
• control of process parameters being monitored during normal production runs to obtain additional information on the reliability of the process.
5.2 Scope of validation
5.2.1 There should be an appropriate and sufficient system including organizational structure and documentation infrastructure, sufficient personnel and financial resources to perform validation tasks in a timely manner. Management and persons responsible for quality assurance should be involved.
5.2.2 Personnel with appropriate qualifications and experience should be responsible for performing validation. They should represent different departments depending on the validation work to be performed.
5.2.3 There should be proper preparation and planning before validation is performed. There should be a specific programmed for validation activities.
5.2.4 Validation should be performed in a structured way according to the documented procedures and protocols.
5.2.5 Validation should be performed:
— for new premises, equipment, utilities and systems, and processes and procedures;
— at periodic intervals; and
— when major changes have been made. (Periodic revalidation or periodic requalification may be substituted, where appropriate, with periodic evaluation of data and information to establish whether requalification or revalidation is required.)
5.2.6 Validation should be performed in accordance with written protocols. A written report on the outcome of the validation should be produced.
5.2.7 Validation should be done over a period of time, e.g. at least three consecutive batches (full production scale) should be validated, to demonstrate consistency. Worst case situations should be considered.
5.2.8 There should be a clear distinction between in-process controls and validation. In-process tests are performed during the manufacture of each batch according to specifications and methods devised during the development phase. Their objective is to monitor the process continuously.
5.2.9 When a new manufacturing formula or method is adopted, steps should be taken to demonstrate its suitability for routine processing. The defined process, using the materials and equipment specified, should be shown to result in the consistent yield of a product of the required quality.
5.2.10 Manufacturers should identify what validation work is needed to prove that critical aspects of their operations are appropriately controlled. Significant changes to the facilities or the equipment, and processes that may affect the quality of the product should be validated. A risk assessment approach should be used to determine the scope and extent of validation required.