12. VALIDATION

12. VALIDATION
12.1 Validation Policy
12.10 The company's overall policy, intentions, and approach to validation, including the validation of production processes, cleaning procedures, analytical methods, in-process control test procedures, computerized systems, and persons responsible for design, review, approval and documentation of each validation phase, should be documented.
12.11 The critical parameters/attributes should normally be identified during the development stage or from historical data, and the ranges necessary for the reproducible operation should be defined. This should include:
− Defining the API in terms of its critical product attributes;
− Identifying process parameters that could affect the critical quality attributes of the API;
− Determining the range for each critical process parameter expected to be used during routine manufacturing and process control.
12.12 Validation should extend to those operations determined to be critical to the quality and purity of the API.
12.2 Validation Documentation
12.20 A written validation protocol should be established that specifies how validation of a particular process will be conducted. The protocol should be reviewed and approved by the quality unit(s) and other designated units.
12.21 The validation protocol should specify critical process steps and acceptance criteria as well as the type of validation to be conducted (e.g. retrospective, prospective, concurrent) and the number of process runs.
12.22 A validation report that cross-references the validation protocol should be prepared, summarising the results obtained, commenting on any deviations observed, and drawing the appropriate conclusions, including recommending changes to correct deficiencies.
12.23 Any variations from the validation protocol should be documented with appropriate justification.
12.3 Qualification
12.30 Before starting process validation activities, appropriate qualification of critical equipment and ancillary systems should be completed. Qualification is usually carried out by conducting the following activities, individually or combined:
− Design Qualification (DQ): documented verification that the proposed design of the facilities, equipment, or systems is suitable for the intended purpose.
− Installation Qualification (IQ): documented verification that the equipment or systems, as installed or modified, comply with the approved design, the manufacturer’s recommendations and/or user requirements.
− Operational Qualification (OQ): documented verification that the equipment or systems, as installed or modified, perform as intended throughout the anticipated operating ranges.
− Performance Qualification (PQ): documented verification that the equipment and ancillary systems, as connected together, can perform effectively and reproducibly based on the approved process method and specifications.
12.4 Approaches to Process Validation
12.40 Process Validation (PV) is the documented evidence that the process, operated within established parameters, can perform effectively and reproducibly to produce an intermediate or API meeting its predetermined specifications and quality attributes.
12.41 There are three approaches to validation. Prospective validation is the preferred approach, but there are exceptions where the other approaches can be used. These approaches and their applicability are listed below.
12.42 Prospective validation should normally be performed for all API processes as defined in 12.12. Prospective validation performed on an API process should be completed before the commercial distribution of the final drug product manufactured from that API.
12.43 Concurrent validation can be conducted when data from replicate production runs are unavailable because only a limited number of API batches have been produced, API batches are produced infrequently, or API batches are produced by a validated process that has been modified. Prior to the completion of concurrent validation, batches can be released and used in final drug product for commercial distribution based on thorough monitoring and testing of the API batches.
12.44 An exception can be made for retrospective validation for well established processes that have been used without significant changes to API quality due to changes in raw materials, equipment, systems, facilities, or the production process. This validation approach may be used where:
(1) Critical quality attributes and critical process parameters have been identified;
(2) Appropriate in-process acceptance criteria and controls have been established;
(3) There have not been significant process/product failures attributable to causes other than operator error or equipment failures unrelated to equipment suitability; and
(4) Impurity profiles have been established for the existing API.
12.45 Batches selected for retrospective validation should be representative of all batches made during the review period, including any batches that failed to meet specifications, and should be sufficient in number to demonstrate process consistency. Retained samples can be tested to obtain data to retrospectively validate the process.
12.5 Process Validation Program
12.50 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 (e.g., complex API processes or API processes with prolonged completion times). For retrospective validation, generally data from ten to thirty consecutive batches should be examined to assess process consistency, but fewer batches can be examined if justified.
12.51 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.
12.52 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.
12.6 Periodic Review of Validated Systems
12.60 Systems and processes should be periodically evaluated to verify that they are still operating in a valid manner. Where no significant changes have been made to the system or process, and a quality review confirms that the system or process is consistently producing material meeting its specifications, there is normally no need for revalidation.
12.7 Cleaning Validation
12.70 Cleaning procedures should normally be validated. In general, cleaning validation should be directed to situations or process steps where contamination or carryover of materials poses the greatest risk to API quality. For example, in early production it may be unnecessary to validate equipment cleaning procedures where residues are removed by subsequent purification steps.
12.71 Validation of cleaning procedures should reflect actual equipment usage patterns. If various APIs or intermediates are manufactured in the same equipment and the equipment is cleaned by the same process, a representative intermediate or API can be selected for cleaning validation. This selection should be based on the solubility and difficulty of cleaning and the calculation of residue limits based on potency, toxicity, and stability.
12.72 The cleaning validation protocol should describe the equipment to be cleaned, procedures, materials, acceptable cleaning levels, parameters to be monitored and controlled, and analytical methods. The protocol should also indicate the type of samples to be obtained and how they are collected and labelled.
12.73 Sampling should include swabbing, rinsing, or alternative methods (e.g., direct extraction), as appropriate, to detect both insoluble and soluble residues. The sampling methods used should be capable of quantitatively measuring levels of residues remaining on the equipment surfaces after cleaning. Swab sampling may be impractical when product contact surfaces are not easily accessible due to equipment design and/or process limitations (e.g., inner surfaces of hoses, transfer pipes, reactor tanks with small ports or handling toxic materials, and small intricate equipment such as micronizers and microfluidizers).
12.74 Validated analytical methods having sensitivity to detect residues or contaminants should be used. The detection limit for each analytical method should be sufficiently sensitive to detect the established acceptable level of the residue or contaminant. The method’s attainable recovery level should be established. Residue limits should be practical, achievable, verifiable and based on the most deleterious residue. Limits can be established based on the minimum known pharmacological, toxicological, or physiological activity of the API or its most deleterious component.
12.75 Equipment cleaning/sanitization studies should address microbiological and endotoxin contamination for those processes where there is a need to reduce total microbiological count or endotoxins in the API, or other processes where such contamination could be of concern (e.g., non-sterile APIs used to manufacture sterile products).
12.76 Cleaning procedures should be monitored at appropriate intervals after validation to ensure that these procedures are effective when used during routine production. Equipment cleanliness can be monitored by analytical testing and visual examination, where feasible. Visual inspection can allow detection of gross contamination concentrated in small areas that could otherwise go undetected by sampling and/or analysis.
12.8 Validation of Analytical Methods
12.80 Analytical methods should be validated unless the method employed is included in the relevant pharmacopoeia or other recognised standard reference. The suitability of all testing methods used should nonetheless be verified under actual conditions of use and documented.
12.81 Methods should be validated to include consideration of characteristics included within the ICH guidelines on validation of analytical methods. The degree of analytical validation performed should reflect the purpose of the analysis and the stage of the API production process.
12.82 Appropriate qualification of analytical equipment should be considered before starting validation of analytical methods.
12.83 Complete records should be maintained of any modification of a validated analytical method. Such records should include the reason for the modification and appropriate data to verify that the modification produces results that are as accurate and reliable as the established method.