Validation policy and methodology
1. The manufacturers’ overall policy and methodology for validation, including the validation of production processes, cleaning procedures, analytical methods, in- process control test procedures, computerised systems and the appointment of persons responsible for design, review, approval and documentation of each validation phase, shall be established and documented.
2. The critical process parameters or attributes of the active substances shall be identified during its development stage or from historical data, and the ranges necessary for the reproducible operation shall be defined, including:
(a)
critical product attributes of the active substance;
(b)
process parameters that may affect the critical quality attributes of the active substance;
(c)
the range for each critical process parameter expected to be used during routine manufacturing and process control.
3. Validation shall extend to those operations determined to be critical to the quality and purity of the active substance.
Validation documentation
1. A written validation protocol, specifying how validation of a particular process will be conducted, shall be established. The protocol shall be reviewed and approved by the quality unit and other designated units.
2. The validation protocol shall specify:
(a)
the critical process steps and acceptance criteria;
(b)
the type of validation to be conducted (e.g. prospective, concurrent);
(c)
the number of process runs.
3. A validation report that refers to the validation protocol shall be prepared. That validation report shall contain:
(a)
a summary of the results obtained;
(b)
any deviations from the validation protocol observed;
(c)
comments and conclusions on the deviations under point (b);
(d)
recommendations for change to correct deficiencies.
4. Any deviations from the validation protocol shall be documented with appropriate justification.
Qualification
1. Before starting the process validation, appropriate qualification of critical equipment and ancillary systems shall be completed.
2. Qualification may be carried out by conducting the following activities, individually or combined:
(a)
design qualification: documented verification that the proposed design of the facilities, equipment, or systems is suitable for the intended purpose;
(b)
installation qualification: documented verification that the equipment or systems, as installed or modified, comply with the approved design, the manufacturer’s recommendations and/or user requirements;
(c)
operational qualification: documented verification that the equipment or systems, as installed or modified, perform as intended throughout the anticipated operating ranges;
(d)
performance qualification: documented verification that the equipment and ancillary systems, as connected together, can perform effectively and reproducibly based on the approved process method and specifications.
Process validation
1. Prospective validation shall be used for all active substance processes.
2. Prospective validation performed on an active substance process shall be completed before the commercial distribution of the veterinary medicinal product manufactured from that active substance.
3. By way of derogation from paragraph 1, concurrent validation may be conducted in the following cases:
(a)
data from replicate production runs are unavailable because only a limited number of active substance batches have been produced;
(b)
active substance batches are produced infrequently; or
(c)
active substance batches are produced by means of a validated process that has been modified.
4. Prior to the completion of concurrent validation, batches may be released and used in the manufacturing of a veterinary medicinal product based on thorough monitoring and testing of the active substance batches.
5. By further way of derogation from paragraph 1, retrospective validation may be performed for well-established processes that have been used without significant changes to active substance quality due to changes in raw materials, equipment, systems, premises or the production process. That validation approach may be used if all the following conditions are met:
(a)
critical quality attributes and critical process parameters have been identified;
(b)
appropriate in-process acceptance criteria and controls have been established;
(c)
there have not been significant process or product failures attributable to cause other than operator error or equipment failures unrelated to equipment suitability;
(d)
impurity profiles have been established for the existing active substance.
6. Batches selected for retrospective validation shall be:
(a)
representative of all batches made during the review period, including any batches that failed to meet specifications;
(b)
sufficient in number to demonstrate process consistency.
7. Retained samples may be used for retrospective validation testing.
Process validation programme
1. The number of process runs for validation shall depend on the complexity of the process or on the criticality of the process change being considered.
2. A minimum of three consecutive successful production batches shall be used for prospective and concurrent validation. In situations where additional process runs are warranted to prove consistency of the process (e.g. complex active substance processes or active substance processes with prolonged completion times), this number shall be increased.
3. For retrospective validation, data from ten to thirty consecutive batches shall be examined to assess process consistency.
4. By way of derogation from paragraph 3, fewer batches can be examined for retrospective validation, if justified.
5. Critical process parameters shall be controlled and monitored during process validation studies. Process parameters unrelated to quality, such as variables controlled to minimise energy consumption or equipment use, may be excluded from the process validation.
6. Process validation shall confirm that the impurity profile for each active substance is within the specified limits. The impurity profile shall be comparable to or better than historical data and, where applicable, comparable to or better than the profile determined during process development or for batches used for pivotal clinical and toxicological studies.
Periodic review of validated systems
1. Validated systems and processes shall be periodically reviewed.
2. 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, no revalidation is required.
Cleaning validation
1. Cleaning procedures shall be validated. Cleaning validation shall be directed to situations or process steps where contamination or carryover of materials poses the greatest risk to active substance quality.
2. Validation of cleaning procedures shall reflect actual equipment usage patterns. Where various active substances or intermediates are manufactured in the same equipment and the equipment is cleaned by the same process, a representative intermediate or active substance may be selected for cleaning validation. This selection shall be based on:
(a)
the solubility of the intermediate or active substance;
(b)
the difficulty of cleaning;
(c)
the calculation of residue limits based on potency, toxicity, and stability.
3. The cleaning validation protocol shall describe:
(a)
the equipment to be cleaned;
(b)
the procedures;
(c)
the materials;
(d)
the acceptable cleaning levels;
(e)
the parameters to be monitored and controlled;
(f)
the analytical methods to be applied;
(g)
the type of samples to be obtained and how they are collected and labelled.
4. Sampling shall include swabbing, rinsing or alternative methods (e.g. direct extraction), as appropriate, to detect both insoluble and soluble residues. The sampling methods used shall allow the quantitative measurement of the levels of residues remaining on the equipment surfaces after cleaning.
5. Validated analytical methods sensitive to detect residues or contaminants shall be applied. The detection limit for each analytical method shall be sufficiently sensitive to detect the established acceptable level of the residue or contaminant. The method’s attainable recovery level shall be established. Residue limits shall be practical, achievable, verifiable and based on the most deleterious residue. Limits may be established based on the minimum known pharmacological, toxicological, or physiological activity of the active substance or its most deleterious component.
6. Equipment cleaning or sanitisation tests shall address microbiological and endotoxin contamination for those processes where there is a need to reduce total microbiological count or endotoxins in the active substance, or for other processes where such contamination could be of concern (e.g. non-sterile active substances used to manufacture sterile products).
7. Cleaning procedures shall be monitored at appropriate intervals after validation to ensure that those procedures are effective when applied during routine production. Equipment cleanliness may be monitored by analytical testing and visual examination, where feasible. Visual inspection may allow detection of gross contamination concentrated in small areas that could otherwise go undetected by sampling or analysis.
Validation of analytical methods
1. Analytical methods shall be validated unless the method employed is included in the relevant pharmacopoeia or other recognised standard reference. The suitability of all testing methods used shall be verified under actual conditions of use and this verification of suitability shall be documented.
2. The validation of the analytical methods shall be performed in accordance with the requirements set out in the guideline on validation of analytical procedures: methodology ( 6 ) . The degree of analytical validation performed shall reflect the purpose of the analysis and the stage of the active substance production process.
3. Complete records shall be maintained of any modification of a validated analytical method. Such records shall 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.
Source: EUR-Lex (Publications Office of the EU), © European Union, reuse permitted under Commission Decision 2011/833/EU.
