EMA Qualification & Validation Requirements

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This presentation describes the principles of qualification and validation which are applicable to the facilities, equipment, utilities and processes used for the manufacture of medicinal products. It is a GMP requirement that manufacturer’s 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.

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EMA Qualification & Validation Requirements

  1. 1. This presentation is compiled by “ Drug Regulations” a non profit organization which provides free online resource to the Pharmaceutical Professional. Visit http://www.drugregulations.org for latest information from the world of Pharmaceuticals. 4/19/2014 1
  2. 2. This presentation is compiled from freely available resources like the website of EMA & specifically “Volume 4 : EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use Annex 15: Qualification and Validation” “Drug Regulations” is a non profit organization which provides free online resource to the Pharmaceutical Professional. Visit http://www.drugregulations.org for latest information from the world of Pharmaceuticals. 4/19/2014 2 Drug Regulations : Online Resource for Latest Information
  3. 3.  Qualification and validation of facilities, equipment, utilities and processes used for the manufacture of medicinal products is a GMP requirement.  Manufacturer’s should control the critical aspects of their 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. 4/19/2014 3Drug Regulations : Online Resource for Latest Information
  4. 4.  The impact of above changes on the validated status or control strategy should be assessed.  Computerised systems used for the manufacture of medicinal products should be validated according to the requirements of Annex 11.  The relevant concepts and guidance presented in ICH Q8, Q10 and Q11 should also be taken into account. 4/19/2014 4Drug Regulations : Online Resource for Latest Information
  5. 5.  Apply a quality risk management approach throughout the lifecycle  Base the scope and extent of validation and qualification on documented risk assessment of the facilities, equipment, utilities and processes.  Apply principles of ICH Q8, Q9, Q10 and Q11 to support validation and qualification activities.  Outsourced data supporting qualification and/or validation studies may be used with documented justification. 4/19/2014 5Drug Regulations : Online Resource for Latest Information
  6. 6.  Plan all qualification and validation activities  Consider the life cycle of equipment, process and product  Suitably trained persons should perform validation activities  Use & follow approved validation procedures  Preferable for validation personnel to report into Quality Management or Quality Assurance  However Validation personnel should report as defined in the pharmaceutical quality system  Essential to have appropriate oversight over the whole validation life cycle 4/19/2014 6Drug Regulations : Online Resource for Latest Information
  7. 7.  Define key elements of the site validation programme  Documented it in a validation master plan (VMP) or equivalent document.  The VMP should be a summary document which is brief, concise, clear and contain data on at least the following: 1. Validation policy. 2. The organisational structure for validation activities. 3. Summary of the facilities, systems, equipment, processes on site and the current validation status. 4. Template formats to be used for protocols and reports. 4/19/2014 7Drug Regulations : Online Resource for Latest Information
  8. 8.  The VMP should be a summary document which is brief, concise, clear and contain data on at least the following: 5. Planning and scheduling. 6. Change control and deviation management for validation. 7. Handling of acceptance criteria 8. References to existing documents. 9. An assessment of the resources required. 10. The ongoing validation strategy, including revalidation and / requalification, where applicable. 11. Confirmation that the materials used for validation are of the required quality and suppliers are qualified to the appropriate level. 4/19/2014 8Drug Regulations : Online Resource for Latest Information
  9. 9.  For large and complex projects, planning takes on added importance and it may be necessary to create a separate VMP.  Use a quality risk management approach for validation activities  Repeat risk assessments as required in light of ◦ Increased knowledge ◦ Changes during the project phase ◦ Changes during commercial production.  Clearly document the risk assessments 4/19/2014 9Drug Regulations : Online Resource for Latest Information
  10. 10.  Support knowledge management throughout the validation lifecycle with Good Documentation Practices  Approve & authorize all documents by appropriate personnel as defined in the pharmaceutical quality system  Define & document relationship between documents in complex validation projects  Prepare a written validation protocol ◦ Define the critical systems, attributes and parameters which are important and the acceptance criteria for each. 4/19/2014 10Drug Regulations : Online Resource for Latest Information
  11. 11.  Confirm suitability and compliance of validation protocols with company procedures before approval when supplied by a third party  Document & scientifically justify any changes/deviations to the approved protocol during execution  Record as deviation any results which fail to meet the pre- defined acceptance criteria  Investigate all deviations and determine any implications for the validation 4/19/2014 11Drug Regulations : Online Resource for Latest Information
  12. 12.  Report the conclusions of the validation  Summarize results obtained against the acceptance criteria  Scientifically justify any subsequent changes to acceptance criteria  Make a final recommendation as to the outcome of the validation  Document & authorise formal release for the next step in the validation process  Make it part of either the validation report or as a separate summary document  Give conditional approval to proceed to the next stage where acceptance criteria or deviations have not been fully addressed  Document assessment that there is no significant impact on the next activity. 4/19/2014 12Drug Regulations : Online Resource for Latest Information
  13. 13.  Consider ◦ User requirements specification ◦ Process development ◦ End of use of the equipment, facility or process  The main stages are indicated in following slides : 4/19/2014 13Drug Regulations : Online Resource for Latest Information
  14. 14.  User requirements specification (URS) ◦ Define the specification for new facilities, systems or equipment in a URS and/or a functional specification ◦ Build essential elements of quality ◦ Minimize any GMP risks ◦ The URS should be a point of reference throughout the validation life cycle. 4/19/2014 14Drug Regulations : Online Resource for Latest Information
  15. 15.  Design qualification (DQ) ◦ Next element in the validation of new facilities, systems or equipment ◦ Demonstrate & document the compliance of the design with GMP ◦ Verify the user requirement specification during this stage 4/19/2014 15Drug Regulations : Online Resource for Latest Information
  16. 16.  Factory acceptance testing (FAT) /Site acceptance testing (SAT) ◦ Evaluate the equipment at the vendor site prior to delivery ◦ Confirm compliance to URS & functional specifications prior to installation, at the vendor site unless otherwise justified ◦ Perform documentation review and some tests at the FAT stage without the need to repeat on site if it can be shown that the functionality is not affected by the transport and installation. ◦ Supplement FAT by the execution of a SAT following the receipt of equipment at the manufacturing site 4/19/2014 16Drug Regulations : Online Resource for Latest Information
  17. 17.  Installation qualification (IQ) ◦ Perform IQ on new or modified facilities, systems and equipment. ◦ Include following in IQ  Installation of equipment, pipe work, services and instrumentation as detailed in the design  confirmation of current engineering regarding drawings and specifications.  Verification of the correct installation against pre-defined criteria. 4/19/2014 17Drug Regulations : Online Resource for Latest Information
  18. 18. ◦ Include following in IQ  Collection and collation of supplier operating and working instructions and maintenance requirements.  Calibration of instrumentation.  Verification of the materials of construction. 4/19/2014 18Drug Regulations : Online Resource for Latest Information
  19. 19.  Operational qualification (OQ) ◦ OQ normally follows IQ ◦ Depending on the complexity of the equipment it may be performed as a combined Installation/Operation Qualification (IOQ). ◦ OQ could include but is not be limited to the following:  Tests that have been developed from the knowledge of processes, systems and equipment.  Tests to confirm upper and lower operating limits, and /or “worst case” conditions. ◦ Finalise maintenance plans, standard operating and cleaning procedures, operator training and preventative maintenance requirements upon completion of OQ 4/19/2014 19Drug Regulations : Online Resource for Latest Information
  20. 20.  Performance qualification (PQ) ◦ Perform PQ after completion of IQ and OQ. ◦ PQ is a separate activity ◦ In some cases it may be appropriate to perform it in conjunction with OQ or Process Validation. ◦ Use production materials, qualified substitutes or simulated product proven to have equivalent behaviour under normal operating conditions with worst case batch sizes ◦ Justify the sampling frequency used to confirm process control ◦ Cover the operating range of the intended process  unless documented evidence from the development phases which confirm the operational ranges are available 4/19/2014 20Drug Regulations : Online Resource for Latest Information
  21. 21.  Principles outlined applicable to ◦ All dosage forms ◦ The initial validation of new processes ◦ Subsequent validation of modified processes ◦ Site transfers and ongoing process verification 4/19/2014 21Drug Regulations : Online Resource for Latest Information
  22. 22.  Use this section in conjunction with the current EMA guideline on Process Validation.  Guideline on Process Validation is intended to provide guidance on the information and data to be provided in the regulatory submission  GMP requirements extend beyond this  Lifecycle approach is applied linking product and process development, validation of the commercial manufacturing process and maintenance of the process in a state of control during routine commercial production. 4/19/2014 22Drug Regulations : Online Resource for Latest Information
  23. 23.  Traditional approach  Continuous verification approach  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  Prospective validation programme wherever possible prior to marketing of the product 4/19/2014 23Drug Regulations : Online Resource for Latest Information
  24. 24.  Cover all intended marketed strengths and sites of manufacture for new products  Products transferred from one site to another or within the same site the number of batches could be reduced. ◦ Use Bracketing approach  Different strengths,  batch sizes  pack sizes  container types ◦ For above approach there should be product knowledge including the content of the previous validation. 4/19/2014 24Drug Regulations : Online Resource for Latest Information
  25. 25.  Site transfer of legacy products the manufacturing process and controls should ◦ Comply with the Marketing Authorisation ◦ Meet current expected licensing standards for that product type ◦ If necessary, variations to the Marketing Authorisation should be submitted 4/19/2014 25Drug Regulations : Online Resource for Latest Information
  26. 26.  Establish whether all quality attributes and process parameters can be consistently met by the process  Document the process by which process parameters and quality attributes were identified as being critical or non-critical  Consider the results of any risk assessment activities 4/19/2014 26Drug Regulations : Online Resource for Latest Information
  27. 27.  Batch size should be the same as commercial scale  Use of any other batch sizes should be justified ◦ e.g. for a continuous manufacturing process.  Facilities, systems, utilities and equipment should be qualified first  Test methods should be validated 4/19/2014 27Drug Regulations : Online Resource for Latest Information
  28. 28.  Process knowledge from development studies should be the basis for validation activities  For process validation batches, production, development, or other site transfer personnel may be involved  Only trained personnel should manufacture batches  Manufacture in accordance with GMP using approved documentation  Involve production personnel  Facilitates product understanding when commercial manufacture starts. 4/19/2014 28Drug Regulations : Online Resource for Latest Information
  29. 29.  Qualify suppliers of critical starting and packaging materials prior to validation  Alternatively document justification based on quality risk management  Document underlying process knowledge for the design space justification (if used)  Development of any mathematical models used to confirm a state of control should be available 4/19/2014 29Drug Regulations : Online Resource for Latest Information
  30. 30.  Pre define the release of validation batches to the market  Manufacturing conditions should fully comply with ◦ GMP ◦ Validation acceptance criteria ◦ Continuous process verification criteria ◦ Marketing Authorisation 4/19/2014 30Drug Regulations : Online Resource for Latest Information
  31. 31.  Concurrent validation ◦ Use when strong risk – benefit to the patient ◦ Justify & document decision ◦ Should be approved by authorised personnel ◦ Product uniformity & compliance with acceptance criteria should be based on sufficient data. ◦ Document results and conclusions ◦ Data should be available to the Qualified Person prior to certification of the batch 4/19/2014 31Drug Regulations : Online Resource for Latest Information
  32. 32.  Manufacture number of batches under routine conditions to confirm reproducibility.  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  Decide number of batches on QRM principles  Decide number of samples on QRM principles  Allow the normal range of variation and trends to be established  Provide sufficient data for evaluation 4/19/2014 32Drug Regulations : Online Resource for Latest Information
  33. 33.  A minimum of three consecutive batches for sucessful validation still may be acceptable  Alternative number of batches may be justified ◦ Standard methods of manufacture are used ◦ Whether similar products are used at the site ◦ Whether similar processes are used at the site  Supplement initial validation exercise with three batches with further data obtained from subsequent batches as part of an on-going process verification exercise 4/19/2014 33Drug Regulations : Online Resource for Latest Information
  34. 34.  Prepare a process validation protocol  Define ◦ Critical process parameters (CPP) ◦ Critical quality attributes (CQA) and ◦ Associated acceptance criteria  Base above on ◦ Development data or ◦ Documented process knowledge 4/19/2014 34Drug Regulations : Online Resource for Latest Information
  35. 35.  Validation protocols should include, but are not be limited to the following: a) A short description of the process b) Summary of the CQA’s to be investigated c) Summary of CPP’s and their associated limits d) Summary of other (non-critical) attributes and parameters which will be investigated or monitored during the validation activity, and the reasons for their inclusion. 4/19/2014 35Drug Regulations : Online Resource for Latest Information
  36. 36.  Validation protocols should include, but are not be limited to the following: e) List of the equipment/facilities to be used (including measuring/ f) monitoring/recording equipment) together with the calibration status. g) List of analytical methods and method validation, as appropriate. h) Proposed in-process controls with acceptance criteria and the reason(s) which each in-process control is selected. i) Additional testing to be carried out, with acceptance criteria. 4/19/2014 36Drug Regulations : Online Resource for Latest Information
  37. 37.  Validation protocols should include, but are not be limited to the following: j) Sampling plan and the rationale behind it. k) Methods for recording and evaluating results. l) Process for release and certification of batches (if applicable). m) Functions and responsibilities. n) Proposed timetable. 4/19/2014 37Drug Regulations : Online Resource for Latest Information
  38. 38.  Use Continuous Process Verification for ◦ Products developed by a quality by design ◦ Processes with scientifically established routine process controls ◦ Processes which provide a high degree of assurance of product quality 4/19/2014 38Drug Regulations : Online Resource for Latest Information
  39. 39.  Define process verification system  Have in place a science based control strategy for ◦ Required attributes for incoming materials ◦ Critical quality attributes and ◦ Critical process parameters  Evaluate control strategy regularly  Use Process Analytical Technology and multivariate statistical process controls  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 4/19/2014 39Drug Regulations : Online Resource for Latest Information
  40. 40.  A hybrid approach ◦ Traditional approach and continuous process verification for different production steps ◦ Initial Validation can be based on traditional approach  Once substantial product and process knowledge is gained continuous verification may also be used 4/19/2014 40Drug Regulations : Online Resource for Latest Information
  41. 41.  Monitor product quality  Maintain state of control throughout product lifecycle  Evaluate relevant process trends  Review the extent and frequency of ongoing process verification  Modify process controls based on process understanding and process performance 4/19/2014 41Drug Regulations : Online Resource for Latest Information
  42. 42.  Conduct on going process verification under an approved protocol  Document the results in a report  Use statistical tools where appropriate to support conclusions about ◦ Variability ◦ Capability ◦ And ensure a state of control.  Support the validated status of the product in the Product Quality Review  Consider incremental changes over time and the need for any additional actions (e.g. enhanced sampling)  Evaluate any individual change or successive incremental changes during the product lifecycle  Evaluate impact on the validated status of the process 4/19/2014 42Drug Regulations : Online Resource for Latest Information
  43. 43.  Transportation as per conditions defined in the Marketing Authorisation, product specification file for ◦ Finished medicinal products ◦ Investigational medicinal products ◦ Bulk product  Validation of transportation may be challenging due to the variable factors  Define transportation routes clearly  Consider seasonal variation for transport across continents 4/19/2014 43Drug Regulations : Online Resource for Latest Information
  44. 44.  Perform a risk assessment to consider the impact of ◦ Temperature ◦ Humidity ◦ Vibration ◦ Handling ◦ Delays ◦ Failure of data-loggers ◦ Topping up liquid Nitrogen ◦ Product susceptibility ◦ Any other relevant factors.  Perform continuous monitoring of any critical environmental conditions 4/19/2014 44Drug Regulations : Online Resource for Latest Information
  45. 45.  Primary packaging processes should undergo validation ◦ Variation in equipment processing parameters during primary packaging ◦ Significant impact on the integrity and correct functioning of the pack (e.g. blister strips, sachets and sterile components)  Perform qualification of the machine settings at the minimum & maximum operating ranges for the critical components & parameters such as ◦ Temperature, ◦ Machine speed ◦ Sealing pressure ◦ For any other factors 4/19/2014 45Drug Regulations : Online Resource for Latest Information
  46. 46.  Qualify utilities as descried under qualification  Confirm the quality of steam, water, air, other inert gases, coolants  The period and extent of qualification should also reflect any seasonal variations if applicable  Perform a risk assessment ◦ where there may be direct contact with the product e.g.  HVAC systems ◦ Indirect contact  Such as through heat exchangers 4/19/2014 46Drug Regulations : Online Resource for Latest Information
  47. 47.  Validate all analytical test methods used in qualification, validation or cleaning exercises  Set an appropriate detection and quantification limit, where necessary, as described in Chapter 6 of the EU-GMP guide Part I.  Where microbial testing of product is carried out, the method should be validated to confirm that the test product does not influence the result.  Where microbial testing of surfaces in clean rooms is carried out, validation should be performed on the test method to confirm that sanitising agents do not influence the result. 4/19/2014 47Drug Regulations : Online Resource for Latest Information
  48. 48.  Perform cleaning validation to confirm the effectiveness of any cleaning procedure for all product contact equipment  Provide justification of the specific equipment selected for cleaning validation when equipment are grouped.  A visual check for cleanliness is important  Visual check can not be the only criteria for cleaning validation  Repeated cleaning “until clean” is also not considered an acceptable approach 4/19/2014 48Drug Regulations : Online Resource for Latest Information
  49. 49.  Cleaning validation programme may take some time to complete  Validation with ongoing verification after each batch may be required  Evaluate data from the verification to support a conclusion that the equipment is clean  Consider the level of automation in the cleaning process  Validate the specified normal operating range of the utilities for automated process  Preform assessment to determine the variable factors which influence cleaning effectiveness in a manual process ◦ Operators ◦ Level of detail in procedures such as rinsing times  For manual cleaning, if variable factors have been identified, the worst case situations should be used as the basis for cleaning validation studies 4/19/2014 49Drug Regulations : Online Resource for Latest Information
  50. 50.  Base limits for the carry over of product residues on a toxicological evaluation  Determine the product specific permitted daily exposure (PDE) value  Document the justification for the selected PDE value in a risk assessment  Confirm the removal of any cleaning agents  Consider multiple equipment in the process equipment train while determining Acceptance criteria 4/19/2014 50Drug Regulations : Online Resource for Latest Information
  51. 51.  Assess the potential for microbial and, or if relevant, endotoxin contamination  Define hold time : Dirty & Clean  Consider the influence of the storage time on hold time  Consider the impact on ease of cleaning for campaign manufacturing ◦ The maximum length of a campaign (in both time and number of batches) should be the basis for cleaning validation exercises. 4/19/2014 51Drug Regulations : Online Resource for Latest Information
  52. 52.  Where a worst case product approach  Justify the rationale for selection of the worst case product  Assess the impact of new products to the site assessed  Consider toxicity , PDE value & solubility when there is no single worst case product for multi purpose equipment  Preform worst case cleaning validation for each cleaning method used  Detail in cleaning validation protocols ◦ Locations to be sampled ◦ Rationale for the selection of these locations ◦ Define the acceptance criteria 4/19/2014 52Drug Regulations : Online Resource for Latest Information
  53. 53.  Sampling ◦ Swabbing and/or ◦ Rinsing at the last stage of cleaning or ◦ By other means depending on the sampling location. ◦ Swab material should not influence the result.  Rinse Method ◦ Perform sampling during the final rinse in the cleaning procedure.  Demonstrate recovery from all materials used in the equipment with all the sampling methods  Perform the cleaning procedure an appropriate number of times based on a risk assessment  Meet the acceptance criteria in order to prove that the cleaning method is validated 4/19/2014 53Drug Regulations : Online Resource for Latest Information
  54. 54.  Investigational medicinal products or products which are only manufactured infrequently, ◦ Use cleaning verification instead of cleaning validation. ◦ Perform cleaning verification after each batch ◦ Use principles enumerated earlier ◦ Use dedicated equipment where  Cleaning validation has shown to be ineffective  Cleaning validation is not appropriate for some equipment 4/19/2014 54Drug Regulations : Online Resource for Latest Information
  55. 55.  Evaluate facilities, utilities, systems, equipment at an appropriate frequency to confirm that they remain in a state of control.  Perform re- qualification at a specific time period  Define & justify the criteria for evaluation  Asses the possibility of incremental changes  Confirm the effectiveness periodically where manual processes are used ( e.g. cleaning ) 4/19/2014 55Drug Regulations : Online Resource for Latest Information
  56. 56.  Important part of knowledge management  Handle within the pharmaceutical quality system  Have written procedures in place for changes in ◦ Starting material ◦ Product component ◦ Process ◦ Equipment ◦ Premises ◦ Product range ◦ Method of production or testing ◦ Batch size ◦ Design space ◦ Any other change during the lifecycle that may affect product quality or reproducibility 4/19/2014 56Drug Regulations : Online Resource for Latest Information
  57. 57.  Consider the impact on changes to the design space against the registered design space  Assess the need for any regulatory actions  Use Quality risk management 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 ◦ To plan for any necessary process verification or requalification efforts 4/19/2014 57Drug Regulations : Online Resource for Latest Information
  58. 58.  Authorize & approve changes in accordance with the pharmaceutical quality system  Generate supporting data to confirm that the impact of the change has been demonstrated prior to approval  Evaluate the effectiveness of change carried out to confirm that the change has been successful 4/19/2014 58Drug Regulations : Online Resource for Latest Information
  59. 59. This presentation was compiled from freely available resources like the website of EMA & specifically “Volume 4 : EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use Annex 15: Qualification and Validation” “Drug Regulations” is a non profit organization which provides free online resource to the Pharmaceutical Professional. Visit http://www.drugregulations.org for latest information from the world of Pharmaceuticals. 4/19/2014 59 Drug Regulations : Online Resource for Latest Information

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