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EudraLex Volume 4
EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use
Annex 15: Qualification and Validation

October 1st, 2015

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Of special interest are:
It is a GMP requirement that manufacturers control the critical aspects of their particular operations through qualification and validation over the life cycle of the product and process. Any planned changes to the facilities, equipment, utilities and processes, which may affect the quality of the product, should be formally documented and the impact on the validated status or control strategy assessed.
Retrospective validation is no longer considered an acceptable approach.
1.4. The key elements of the site qualification and validation programme should be clearly defined and documented in a validation master plan (VMP) or equivalent document.
1.5. The VMP or equivalent document should define the qualification/validation system and include or reference information on at least the following:
i. Qualification and Validation policy;
ii. The organisational structure including roles and responsibilities for qualification and validation activities;
iii. Summary of the facilities, equipment, systems, processes on site and the qualification and validation status;
iv. Change control and deviation management for qualification and validation;
v. Guidance on developing acceptance criteria;
vi. References to existing documents;
vii. The qualification and validation strategy, including requalification, where applicable.
2.6. Where validation protocols and other documentation are supplied by a third party providing validation services, appropriate personnel at the manufacturing site should confirm suitability and compliance with internal procedures before approval. Vendor protocols may be supplemented by additional documentation/test protocols before use.
2.7. Any significant changes to the approved protocol during execution, e.g. acceptance criteria, operating parameters etc., should be documented as a deviation and be scientifically justified.
2.8. Results which fail to meet the pre-defined acceptance criteria should be recorded as a deviation and be fully investigated according to local procedures. Any implications for the validation should be discussed in the report
2.9. The review and conclusions of the validation should be reported and the results obtained summarised against the acceptance criteria. Any subsequent changes to acceptance criteria should be scientifically justified and a final recommendation made as to the outcome of the validation.
3.1. Qualification activities should consider all stages from initial development of the user requirements specification through to the end of use of the equipment, facility, utility or system.
User requirements specification (URS)
3.2. The specification for equipment, facilities, utilities or systems should be defined in a URS and/or a functional specification. The essential elements of quality need to be built in at this stage and any GMP risks mitigated to an acceptable level. The URS should be a point of reference throughout the validation life cycle.
Design qualification (DQ)
3.3. <...> The requirements of the user requirements specification should be verified during the design qualification. Factory acceptance testing (FAT) /Site acceptance testing (SAT)
3.6. Where appropriate and justified, documentation review and some tests could be performed at the FAT or other stages without the need to repeat on site at IQ/OQ if it can be shown that the functionality is not affected by the transport and installation.
Installation qualification (IQ)
3.8. IQ should be performed on equipment, facilities, utilities, or systems.
Operational qualification (OQ)
3.11. OQ should include but is not limited to the following:
i. Tests that have been developed from the knowledge of processes, systems and equipment to ensure the system is operating as designed;
ii. Tests to confirm upper and lower operating limits, and /or “worst case” conditions.
3.12. The completion of a successful OQ should allow the finalisation of standard operating and cleaning procedures, operator training and preventative maintenance requirements.
Performance qualification (PQ)
3.14. PQ should include, but is not limited to the following:
i. Tests, using production materials, qualified substitutes or simulated product proven to have equivalent behaviour under normal operating conditions with worst case batch sizes. The frequency of sampling used to confirm process control should be justified;
ii. Tests should cover the operating range of the intended process, unless documented evidence from the development phases confirming the operational ranges is available.
4.1. Equipment, facilities, utilities and systems should be evaluated at an appropriate frequency to confirm that they remain in a state of control.
4.2. Where re-qualification is necessary and performed at a specific time period, the period should be justified and the criteria for evaluation defined. Furthermore, the possibility of small changes over time should be assessed.
5.1. <...> It is implicit in this annex that a robust product development process is in place to enable successful process validation.
5.2. Section 5 should be used in conjunction with the current EMA guideline on Process Validation.
5.3. Manufacturing processes may be developed using a traditional approach or a continuous verification approach. However, irrespective of the approach used, processes must be shown to be robust and ensure consistent product quality before any product is released to the market. <...> Retrospective validation is no longer an acceptable approach.
5.4. Process validation of new products should cover all intended marketed strengths and sites of manufacture. Bracketing could be justified for new products based on extensive process knowledge from the development stage in conjunction with an appropriate ongoing verification programme.
5.5. For process validation of products which are transferred from one site to another or within the same site, the number of validation batches could be reduced by the use of a bracketing approach. However, existing product knowledge, including the content of the previous validation, should be available. <...> 5.6. For the site transfer of legacy products, the manufacturing process and controls must comply with the marketing authorisation and meet current standards for marketing authorisation for that product type. If necessary, variations to the marketing authorisation should be submitted.
5.7. Process validation should establish whether all quality attributes and process parameters, which are considered important for ensuring the validated state and acceptable product quality, can be consistently met by the process. The basis by which process parameters and quality attributes were identified as being critical or non-critical should be clearly documented, taking into account the results of any risk assessment activities.
5.8. Normally batches manufactured for process validation should be the same size as the intended commercial scale batches and the use of any other batch sizes should be justified or specified in other sections of EudraLex, Volume 4.
5.9. Equipment, facilities, utilities and systems used for process validation should be qualified. Test methods should be validated for their intended use.
5.10. For all products irrespective of the approach used, process knowledge from development studies or other sources should be accessible to the manufacturing site, unless otherwise justified, and be the basis for validation activities.
5.11. For process validation batches, production, development, or other site transfer personnel may be involved. Batches should only be manufactured by trained personnel in accordance with GMP using approved documentation. It is expected that production personnel are involved in the manufacture of validation batches to facilitate product understanding.
5.12. The suppliers of critical starting and packaging materials should be qualified prior to the manufacture of validation batches; otherwise a justification based on the application of quality risk management principles should be documented.
5.13. It is especially important that the underlying process knowledge for the design space justification (if used) and for development of any mathematical models (if used) to confirm a process control strategy should be available. <...>
Concurrent validation
5.16. In exceptional circumstances, where there is a strong benefit-risk ratio for the patient, it may be acceptable not to complete a validation programme before routine production starts and concurrent validation could be used. However, the decision to carry out concurrent validation must be justified, documented in the VMP for visibility and approved by authorised personnel.
5.17. Where a concurrent validation approach has been adopted, there should be sufficient data to support a conclusion that any given batch of product is uniform and meets the defined acceptance criteria. The results and conclusion should be formally documented and available to the Qualified Person prior to certification of the batch.
Traditional process validation
5.18. In the traditional approach, a number of batches of the finished product are manufactured under routine conditions to confirm reproducibility.
5.19. The number of batches manufactured and the number of samples taken should be based on quality risk management principles, allow the normal range of variation and trends to be established and provide sufficient data for evaluation. Each manufacturer must determine and justify the number of batches necessary to demonstrate a high level of assurance that the process is capable of consistently delivering quality product.
5.20. Without prejudice to 5.19, it is generally considered acceptable that a minimum of three consecutive batches manufactured under routine conditions could constitute a validation of the process.
5.21. A process validation protocol should be prepared which defines the critical process parameters (CPP), critical quality attributes (CQA) and the associated acceptance criteria which should be based on development data or documented process knowledge.
5.22. Process validation protocols should include, but are not limited to the following: i. A short description of the process and a reference to the respective Master Batch Record;
ii. Functions and responsibilities;
iii. Summary of the CQAs to be investigated;
iv. Summary of CPPs and their associated limits;
v. Summary of other (non-critical) attributes and parameters which will be investigated or monitored during the validation activity, and the reasons for their inclusion;
vi. List of the equipment/facilities to be used (including measuring/monitoring/recording equipment) together with the calibration status;
vii. List of analytical methods and method validation, as appropriate.
viii. Proposed in-process controls with acceptance criteria and the reason(s) why each in-process control is selected;
ix. Additional testing to be carried out with acceptance criteria;
x. Sampling plan and the rationale behind it;
xi. Methods for recording and evaluating results;
xii. Process for release and certification of batches (if applicable).
Continuous process verification
5.23. <...> continuous process verification can be used as an alternative to traditional process validation.
5.24. <...> There should be a science based control strategy for the required attributes for incoming materials, critical quality attributes and critical process parameters to confirm product realisation. This should also include regular evaluation of the control strategy. Process Analytical Technology and multivariate statistical process control may be used as tools. <...>
Ongoing Process Verification during Lifecycle
5.29. Manufacturers should monitor product quality to ensure that a state of control is maintained throughout the product lifecycle with the relevant process trends evaluated.
5.30. The extent and frequency of ongoing process verification should be reviewed periodically. At any point throughout the product lifecycle, it may be appropriate to modify the requirements taking into account the current level of process understanding and process performance.
5.31. <...> Statistical tools should be used, where appropriate, to support any conclusions with regard to the variability and capability of a given process and ensure a state of control.
5.32. Ongoing process verification should be used throughout the product lifecycle to support the validated status of the product as documented in the Product Quality Review. <...>
7.1. <...> primary and secondary packaging equipment for finished and bulk products should be qualified.
7.2. Qualification of the equipment used for primary packing should be carried out at the minimum and maximum operating ranges defined for the critical process parameters such as temperature, machine speed and sealing pressure or for any other factors.
8.2. The period and extent of qualification should reflect any seasonal variations, if applicable, and the intended use of the utility.
8.3. A risk assessment should be carried out where there may be direct contact with the product, e.g. heating, ventilation and air-conditioning (HVAC) systems, or indirect contact such as through heat exchangers to mitigate any risks of failure.
9.1. All analytical test methods used in qualification, validation or cleaning exercises should be validated with an appropriate detection and quantification limit, where necessary, as defined in Chapter 6 of the EudraLex, Volume 4, Part I.
10.1. Cleaning validation should be performed in order to confirm the effectiveness of any cleaning procedure for all product contact equipment. <...>
10.2. A visual check for cleanliness is an important part of the acceptance criteria for cleaning validation. It is not generally acceptable for this criterion alone to be used. Repeated cleaning and retesting until acceptable residue results are obtained is not considered an acceptable approach.
10.15. Where manual cleaning of equipment is performed, it is especially important that the effectiveness of the manual process should be confirmed at a justified frequency.
11.2. Written procedures should be in place to describe the actions to be taken if a planned change is proposed to a starting material, product component, process, equipment, premises, product range, method of production or testing, batch size, design space or any other change during the lifecycle that may affect product quality or reproducibility.
11.3. Where design space is used, the impact on changes to the design space should be considered against the registered design space within the marketing authorisation and the need for any regulatory actions assessed.
11.4. Quality risk management should be used to evaluate planned changes to determine the potential impact on product quality, pharmaceutical quality systems, documentation, validation, regulatory status, calibration, maintenance and on any other system to avoid unintended consequences and to plan for any necessary process validation, verification or requalification efforts.
12. Glossary
Bracketing approach. A science and risk based validation approach such that only batches on the extremes of certain predetermined and justified design factors, e.g. strength, batch size and/or pack size, are tested during process validation. The design assumes that validation of any intermediate levels is represented by validation of the extremes. <...>
Continuous process verification. An alternative approach to process validation in which manufacturing process performance is continuously monitored and evaluated. (ICH Q8)
Critical process parameter (CPP). A process parameter whose variability has an impact on a critical quality attribute and therefore should be monitored or controlled to ensure the process produces the desired quality. (ICH Q8)
Critical quality attribute (CQA). A physical, chemical, biological or microbiological property or characteristic that should be within an approved limit, range or distribution to ensure the desired product quality. (ICH Q8)
Design Space.
The multidimensional combination and interaction of input variables, e.g. material attributes, and process parameters that have been demonstrated to provide assurance of quality. Working within the design space is not considered as a change. Movement out of the design space is considered to be a change and would normally initiate a regulatory post approval change process. Design space is proposed by the applicant and is subject to regulatory assessment and approval. (ICH Q8)
Process Validation. The documented evidence that the process, operated within established parameters, can perform effectively and reproducibly to produce a medicinal product meeting its predetermined specifications and quality attributes.
Worst Case. A condition or set of conditions encompassing upper and lower processing limits and circumstances, within standard operating procedures, which pose the greatest chance of product or process failure when compared to ideal conditions. Such conditions do not necessarily induce product or process failure.
User requirements Specification (URS). The set of owner, user and engineering requirements necessary and sufficient to create a feasible design meeting the intended purpose of the system.