QUALIFICATION AND VALIDATION
ANNEX VSupplementary provisions
ANNEX V QUALIFICATION AND VALIDATION I. SCOPE The requirements set out in this Annex shall apply to the qualification of equipment, facilities, utilities and systems used for the manufacture of veterinary medicinal products and the validation of the manufacturing process. Computerised systems used for the manufacture of veterinary medicinal products shall be validated according to the requirements set out in Annex IV. II. GENERAL REQUIREMENTS II.1. Decisions on the scope and extent of the qualification/validation shall be based on a documented risk assessment. Retrospective qualification/validation is not acceptable. Data supporting qualification/validation studies that were obtained from sources outside of the manufacturers own programmes may be used provided that this approach is justified and that there is adequate assurance of the reliability thereof to support the intended qualification/validation. II.2. Qualification and validation activities shall take into consideration the life cycle of the relevant equipment, facilities, utilities, systems and of the veterinary medicinal product. II.3. Any planned changes to the equipment, facilities, utilities, systems or manufacturing process that may affect the quality of the veterinary medicinal product shall be formally documented and its impact on the validated status or control strategy shall be assessed. II.4. Qualification and validation activities shall only be performed by suitably trained personnel who follow approved procedures, including on reporting. There shall be appropriate oversight over the whole validation life cycle. II.5. The key elements of the site qualification and validation programme shall be clearly defined and documented in a validation master plan or in an equivalent document, which – as a minimum – shall include or refer to the following: (a) the general qualification and validation approach applied by the manufacturer; (b) the organisational structure, including roles and responsibilities for qualification and validation activities; (c) a summary of the equipment, facilities, utilities, systems, manufacturing processes on site and their qualification/validation status; (d) the strategy for the implementation of changes (‘change control’) and management of deviations for qualification and validation; (e) guidance on developing acceptance criteria; (f) references to documents supporting/recording qualification and validation; (g) the qualification and validation strategy/plan for the equipment, facilities, utilities, systems or processes, including requalification, where applicable. II.6. A quality risk management approach shall be used for qualification and validation activities. Where required, in light of increased knowledge acquired during the life-cycle, the risk assessments shall be repeated. The way in which risk assessments are used to support qualification and validation activities shall be documented. II.7. Appropriate checks shall be incorporated into qualification and validation work to ensure the integrity of all data obtained. III. DOCUMENTATION III.1. All documents generated during qualification and validation shall be approved and authorised by appropriate personnel as defined in the pharmaceutical quality system. III.2. The inter-relationship between documents in complex qualification/validation projects shall be clearly defined. III.3. Qualification/validation protocols defining the critical systems, attributes and parameters and the associated acceptance criteria shall be prepared. III.4. Qualification documents may be combined together, where appropriate, e.g. installation qualification and operational qualification. III.5. Where qualification/validation protocols and other documentation are supplied by a third party providing validation services, appropriate personnel at the manufacturing site shall confirm their suitability and compliance with internal procedures before approval. Vendor protocols may be supplemented by additional documentation/test protocols before use. III.6. Any significant changes to the approved protocol during execution (e.g. acceptance criteria, operating parameters, etc.) shall be documented as a deviation and be scientifically justified. III.7. Results that fail to meet the pre-defined acceptance criteria shall be recorded as a deviation and be fully investigated. Implications for the qualification/validation status shall be discussed in the report. III.8. The review and conclusions of the qualification/validation shall be reported and the results obtained summarised against the acceptance criteria. Any subsequent changes to acceptance criteria shall be scientifically justified and a final recommendation made as to the outcome of the qualification/validation. III.9. A formal release for the next stage in the qualification/validation process shall be authorised by the relevant responsible personnel either as part of the qualification/validation report approval or as a separate summary document. Conditional approval to proceed to the next qualification/validation stage may be given where certain acceptance criteria or deviations have not been fully addressed and there is a documented assessment supporting that there is no significant impact on the next activity. IV. QUALIFICATION STAGES FOR EQUIPMENT, FACILITIES, UTILITIES AND SYSTEMS IV.1. Qualification activities shall consider all stages, from the initial development of the user requirements specification up to the end use of the equipment, facility, utility or system. While the specific stages/criteria are to be adapted to the specific project characteristics, the main stages and some criteria that may be included in each stage are indicated in Sections IV.2 to IV.7 for orientation purposes. IV.2. User requirements specification Specifications for equipment, facilities, utilities or systems shall be defined in a user requirements specification or a functional specification document. The essential elements of quality shall be built in at this stage and any risks mitigated to an acceptable level. The user requirement specification is a point of reference throughout the validation life cycle. IV.3. Design qualification Design qualification is the documented verification that the proposed design of the equipment, facilities, utilities or systems is suitable for the intended purpose. Through design qualification the compliance of the design with good manufacturing practice shall also be demonstrated and documented. The requirements of the user requirements specification shall be verified during the design qualification. IV.4. Factory acceptance testing / Site acceptance testing Where applicable, equipment may be evaluated at the vendor site, prior to delivery. This may be particularly relevant in case of novel or complex technologies. Prior to installation, the equipment shall be confirmed to comply with the user requirements specification / functional specification at the vendor site, if applicable. Where appropriate and justified, documentation review and some tests may be performed as part of the factory acceptance testing or other stages without the need for repetition thereof on site as part of installation qualification or operational qualification, provided that it is shown that the functionality is not affected by the transport and installation. Factory acceptance testing may be supplemented by the execution of a site acceptance testing following the receipt of equipment at the manufacturing site. IV.5. Installation qualification (IQ) Installation qualification is the documented verification that the equipment, facilities, utilities or systems, as installed or modified, comply with the approved design and the manufacturer’s recommendations. Installation qualification shall include, but is not limited to the following: (a) verification of the correct installation of components, instrumentation, equipment, pipe work and services against the engineering drawings and specifications; (b) verification of the correct installation against the pre-defined criteria; (c) collection and collation of supplier operating and working instructions and maintenance requirements; (d) calibration of instruments; (e) verification of the materials of construction. IV.6. Operational qualification (OQ) Operational qualification is the documented verification that the equipment, facilities, utilities or systems, as installed or modified, perform as intended throughout the anticipated operating ranges. While operational qualification usually follows installation qualification, depending on the complexity of the equipment, a combined installation/operation qualification may be performed. Operational qualification shall include, but is not limited to, the following: — tests that have been developed from the knowledge of processes, systems and equipment to ensure the system is operating as designed; — tests to confirm upper and lower operating limits, including worst case conditions. IV.7. Performance qualification Performance qualification is the documented verification that equipment, facilities, utilities or systems can perform effectively and reproducibly based on the approved specifications and manufacturing process. While this step shall generally take place after the successful completion of installation and operational qualification, in some cases, it may be appropriate to perform it in conjunction with operational qualification or process validation. Performance qualification shall include tests, using production materials, qualified substitutes or a simulated product that has been demonstrated to have an equivalent behaviour under normal operating conditions with worst case batch sizes. The frequency of sampling used to confirm process control shall be justified. Tests shall cover the operating range of the intended process, unless documented evidence from the development phases confirming the operational ranges is available. Other requirements IV.8. The quality of steam, water, air and other gases shall be confirmed after the installation in accordance with the approach above-referred. The period and extent of the qualification shall take due consideration of seasonal variations (where relevant) and the intended use of the utility. IV.9. A risk assessment shall be carried out in cases where there may be a direct contact with the product (e.g. heating, ventilation and air-conditioning (HVAC) systems) or an indirect contact (e.g. through heat exchangers) to mitigate any risks of failure. IV.10. The qualification of the equipment used for primary packaging shall be carried out at the minimum and maximum operating ranges defined for the critical process parameters such as temperature, machine speed and sealing pressure. V. RE-QUALIFICATION V.1. Equipment, facilities, utilities and systems shall be re-evaluated at an appropriate frequency to confirm that they remain suitable for the intended operations. V.2. The need for re-qualification (e.g. following changes to equipment/systems) shall be evaluated on the basis of quality risk management principles. VI. PROCESS VALIDATION VI.1. General requirements VI.1.1. Process validation is the documented evidence that the process, operated within the established parameters, can perform effectively and reproducibly to produce a veterinary medicinal product within the required specifications and quality attributes and in compliance with the terms of the marketing authorisation. VI.1.2. Through the process validation it shall be shown that all quality attributes and process parameters that are important for ensuring the required product quality can be consistently met by the process. The classification of process parameters and quality attributes as critical or non-critical shall be conducted having regard to available product and process knowledge ( 1 ) and based on a risk assessment; it shall be duly documented. VI.1.3. Manufacturing processes shall be shown to be capable of ensuring consistent production of a product of the required quality and in compliance with the requirements set in the marketing authorisation before the veterinary medicinal products are placed on the market. Retrospective validation is not acceptable. VI.1.4. Process validation of new products shall cover all intended marketed strengths and sites of manufacture. Bracketing may be justified for new products based on extensive process knowledge from the development stage in conjunction with an appropriate ongoing verification programme. VI.1.5. For process validation of products that are transferred from one site to another or within the same site, the number of validation batches may be reduced by the use of a bracketing approach. This approach shall be scientifically justified on the basis of existing product knowledge. Different strengths, batch sizes and pack sizes/container types may also use a bracketing approach, if justified. VI.1.6. Batches used for process validation shall usually be of the same size as the intended commercial scale batches; the use of any other batch sizes shall be duly justified. VI.1.7. Equipment, facilities, utilities and systems used for process validation shall be qualified. In addition, test methods used for process validation shall be validated for their intended use. VI.1.8. Validation batches may be released to the market only if this is pre-defined and provided that they comply with good manufacturing practice (including the validation acceptance criteria or continuous process verification criteria) and with the terms of the marketing authorisation. VI.2. Traditional process validation VI.2.1. Under the so-called traditional approach, a number of batches of the finished product are manufactured under routine conditions to confirm reproducibility. VI.2.2. While it is generally considered acceptable that a minimum of three consecutive batches manufactured under routine conditions can constitute a validation of the process, the number of batches used for process validation shall be justified on the basis of a risk assessment that takes into consideration the complexity of the process and the variability of the results from the process as well as other relevant factors. An alternative number of batches may be justified taking into account whether standard methods of manufacture are used and whether similar products or processes are already manufactured/used at the site. An initial validation exercise with three batches may need to be supplemented with further data obtained from subsequent batches as part of an on-going process verification exercise. VI.2.3. A process validation protocol shall be developed which shall define the critical process parameters (i.e. process parameters the variability of which have an impact on critical quality attributes and which therefore shall be monitored or controlled to ensure the desired product quality), critical quality attributes (i.e. physical, chemical, biological or microbiological characteristics that shall be controlled to ensure the desired product quality) and the associated acceptance criteria based on development data or process knowledge. VI.2.4. Process validation protocols shall include, but are not limited to, the following: (a) a short description of the process and a reference to the respective batch record; (b) functions and responsibilities; (c) a summary of the critical quality attributes to be investigated; (d) a summary of critical process parameters and their associated limits; (e) a summary of other (non-critical) attributes and parameters to be investigated or monitored during the validation activity, and the reasons for their inclusion; (f) a list of the equipment/facilities to be used (including measuring/monitoring/recording equipment) together with the calibration status; (g) a list of analytical methods and method validation, as appropriate; (h) proposed in-process controls with acceptance criteria and the reason(s) why each in-process control is selected; (i) additional testing to be carried out with acceptance criteria; (j) the sampling plan and the rationale behind it; (k) methods for recording and evaluating results; (l) the process for release and certification of batches (if applicable). VI.3. Continuous process verification VI.3.1. Continuous process verification may be used as an alternative to traditional process validation for products developed under a quality by design approach, where it has been scientifically established during the development phase that the established control strategy provides a high degree of assurance of product quality. VI.3.2. The method by which the process will be verified shall be defined. There shall be a science-based control strategy for the required attributes for incoming materials, critical quality attributes and critical process parameters. The control strategy shall be regularly evaluated. Process analytical technology and multivariate statistical process control may be used as tools. VI.3.3. The number of batches necessary to demonstrate that the process is capable of consistently delivering a product of the desired quality and in compliance with the terms of the marketing authorisation shall be set case by case having regard to the specificities of the product and applying quality risk management principles. VI.4. Hybrid approach VI.4.1. A hybrid of the traditional approach and continuous process verification may be used where there is a substantial amount of product and process knowledge gained from manufacturing experience and historical batch data. VI.4.2. This approach may also be used for any validation activities after changes or during ongoing process verification even though the product was initially validated using a traditional approach. VI.5. Ongoing process verification during lifecycle VI.5.1. Ongoing process verification (also known as continued process verification) is the documented evidence that the manufacturing process is capable of ensuring consistent production of a product of the required quality and in compliance with the requirements set in the marketing authorisation. Ongoing process verification is applicable regardless of the approach to process validation implemented (traditional, continuous or hybrid). VI.5.2. The extent and frequency of the ongoing process verification shall be reviewed periodically having regard to the level of process understanding and process performance. VI.5.3. Ongoing process verification shall be conducted under an approved protocol or equivalent documents and a report shall be prepared to document the results obtained. Statistical tools shall be used, where appropriate, to support any conclusions. VI.5.4. Ongoing process verification shall be used throughout the product lifecycle to support the validated status of the product, taking into consideration the outcome of the product quality review. Incremental changes over time shall also be considered and the need for any additional actions, e.g. enhanced sampling, shall be assessed. VI.6. Concurrent validation VI.6.1. In exceptional circumstances, where there is a strong benefit-risk ratio for the treated animal, it may be acceptable not to complete a validation programme before routine production starts and concurrent validation may be used. However, the decision to carry out concurrent validation must be justified, documented and approved by authorised personnel. VI.6.2. Where a concurrent validation approach has been adopted, there shall be sufficient data to support a conclusion that any given batch of product is uniform and meets the defined acceptance criteria. The results and conclusions shall be formally documented and available to the qualified person prior to the certification of the batch. VII. VALIDATION OF TEST METHODS VII.1. Analytical methods that are used for the manufacture or control of veterinary medicinal products (including those supporting validation and qualification) shall be validated. The validation shall demonstrate the suitability of the analytical methods for the intended purpose. VII.2. Analytical procedures, which are either described in the European Pharmacopoeia, the pharmacopoeia of a Member State, or are linked to a product specific monograph, and are performed according to the monograph, are generally considered as validated. In such cases, the suitability of the validated test for the intended purpose shall be verified. VII.3. Where microbial testing of product is carried out, the method shall be validated to confirm that the product does not influence the recovery of microorganisms. VII.4. Where microbial testing of surfaces in clean rooms is carried out, the test method shall be validated to confirm that the use of sanitising agents does not influence the recovery of microorganisms. VIII. CLEANING VALIDATION VIII.1. Cleaning validation is the documented evidence that a given cleaning procedure reproducibly removes contaminants, residues from previous product and cleaning agents below a pre-defined threshold. Cleaning validation is required to confirm the effectiveness of cleaning procedures for all product contact equipment. VIII.2. Simulating agents (i.e. materials that closely resemble the specific characteristics of the relevant product) may be used provided that it is scientifically justified. VIII.3. The cleaning validation for similar types of equipment may be grouped together provided that it is duly justified. VIII.4. While a visual check for cleanliness is part of the acceptance criteria for cleaning validation, this criterion alone is generally not sufficient. Moreover, repeated cleaning and retesting until acceptable residue results are obtained is not considered an acceptable approach. VIII.5. It is recognised that cleaning validation may take some time to complete and that, in such cases, verification ( 2 ) after each batch is required until the validation is complete. When this approach is implemented, there shall be sufficient data from the verification to support a conclusion that the equipment is clean and available for further use. VIII.6. Validation shall consider the level of automation in the cleaning process. Where an automatic process is used, the specified normal operating range of the utilities and equipment shall be validated. VIII.7. An assessment shall be performed to determine the variable factors that influence the effectiveness and performance of the cleaning procedure (e.g. operators, the level of detail in procedures such as rinsing times, etc.) If variable factors have been identified, the worst case situations shall be used as the basis for the cleaning validation studies. VIII.8. Limits for the carryover of product residues shall be based on a toxicological evaluation ( 3 ) , The justification for the selected limits shall be documented in a risk assessment including all the supporting references. Limits shall also be established for the removal of the cleaning agents used. Acceptance criteria shall consider the potential cumulative effect of multiple items of equipment used. The following adaptations are however possible: (a) therapeutic macromolecules and peptides are known to degrade and denature when exposed to pH extremes and/or heat, and may become pharmacologically inactive. A toxicological evaluation may therefore not be applicable in these circumstances; (b) if it is not feasible to test for specific product residues, other representative parameters may be selected, e.g. total organic carbon (TOC) and conductivity. VIII.9. The risk presented by microbial and endotoxin contamination shall be considered during the development of cleaning validation protocols. VIII.10. The influence of the time between the manufacture and the cleaning, and the time between the cleaning and the use shall be taken into account to define dirty and clean hold times for the cleaning process. VIII.11. Where campaign manufacture is carried out, the impact on the ease of cleaning at the end of the campaign shall be considered and the maximum length of a campaign (in time and/or number of batches) shall be the basis for cleaning validation exercises. VIII.12. Where a worst-case product approach is used as a cleaning validation model, a scientific rationale shall be provided for the selection of the worst-case product and the impact of new products assessed. Criteria for determining the worst case may include solubility, cleanability, toxicity and potency. VIII.13. Cleaning validation protocols shall specify or make reference to the locations to be sampled and the rationale for the selection of these locations and shall define the acceptance criteria. VIII.14. Sampling may be carried out by swabbing, rinsing or by other means depending on the production equipment. The sampling materials and method applied shall not influence the result. Recovery shall be shown to be possible from all product contact materials sampled in the equipment with the sampling methods used. VIII.15. The cleaning procedure shall be performed an appropriate number of times based on a risk assessment and meet the acceptance criteria in order to prove that the cleaning method is validated. VIII.16. Where a cleaning process is ineffective or is not appropriate for some equipment, dedicated equipment or other appropriate measures shall be implemented. VIII.17. Where manual cleaning of equipment is performed, the effectiveness of the manual process shall be confirmed at a justified frequency. ( 1 ) Adequate process knowledge is particularly relevant where the concept of design space is used as well as for the development of any mathematical models. ( 2 ) For the purposes of this Annex, ‘cleaning verification’ means the gathering of evidence through chemical analysis after each batch/campaign to show that the residues of the previous product or cleaning agents have been reduced below the scientifically set maximum limit. ( 3 ) See EMA Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities.