Process Validation for Beginners - FDA - EMA Approach

66,729 views

Published on

In the last year or so the FDA and the EMA have issued new guidance/ draft guidance on "Process Validation".These align process validation activities with a product lifecycle concept and the International Conference on Harmonisation (ICH) guidances for industry, Q8(R2) Pharmaceutical Development, Q9 Quality Risk Management, and Q10 Pharmaceutical Quality System. The earlier guidelines were developed before the elaboration of the new ICH guidelines.With these new guidelines, additional opportunities are available to verify the control of the process by alternative means to the manufacture of traditional process validation batches. The main objective of process validation remains that a process design yields a product meeting its pre-defined quality criteria. ICH Q8, Q9 and Q10 provide a structured way to define product critical quality attributes, design space, the manufacturing process and the control strategy. ICH Q8 refers to an ‘enhanced’ approach to pharmaceutical development which includes an alternative to the traditional process validation.
Continuous process verification [see definition in ICH Q8(R2) glossary] can be utilised in process validation protocols for the initial commercial production and for manufacturing process changes for the continual improvement throughout the remainder of the product lifecycle.

There is now a new paradigm in process validation. This presentation has been prepared from material available from FDA , EMA and ICH for beginners to have an overview of the new paradigm.

58 Comments
124 Likes
Statistics
Notes
No Downloads
Views
Total views
66,729
On SlideShare
0
From Embeds
0
Number of Embeds
358
Actions
Shares
0
Downloads
2
Comments
58
Likes
124
Embeds 0
No embeds

No notes for slide

Process Validation for Beginners - FDA - EMA Approach

  1. 1. www.drugragulations.org 1 Presentation prepared by Drug Regulations – a not for profit organization. Visit www.drugregulations.org for the latest in Pharmaceuticals. August 15
  2. 2.  This presentation is compiled from freely available resources like the website of FDA & EMA specifically  “Guidance for Industry Process Validation: General Principles and Practices , Revision 1, 2011” “EU Guidelines for Good Manufacturing Practice Annex 15: Qualification and Validation” and” EMA Guideline on process validation for finished products - information and data to be provided in regulatory submissions”  “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. 8/18/2015 2 Drug Regulations : Online Resource for Latest Information
  3. 3.  Effective process validation contributes significantly to assuring drug quality.  Quality, safety, and efficacy are designed or built into the product.  Quality cannot be adequately assured merely by in-process and finished-product inspection or testing. www.drugragulations.org 3August 15
  4. 4.  Process Validation is now defined as the collection and evaluation of data, from the process design stage through commercial production, which establishes scientific evidence that a process is capable of consistently delivering quality product. Process validation involves a series of activities taking place over the lifecycle of the product and process www.drugragulations.org 4August 15
  5. 5.  Validation is the act of demonstrating and documenting that a procedure operates effectively.  Process validation is the means of ensuring and providing documentary evidence that processes ( within their specified design parameters) are capable of consistently producing a finished product of the required quality. www.drugragulations.org 5August 15
  6. 6.  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. www.drugragulations.org 6August 15
  7. 7.  Stage1:Process Design: ◦ The commercial manufacturing process is defined during this stage based on knowledge gained through development and scale-up activities.  Stage 2: Process Qualification: ◦ During this stage, the process design is evaluated to determine if the process is capable of reproducible commercial manufacturing.  Stage 3: Continued Process Verification ◦ Continued Process Verification: Ongoing assurance is gained during routine production that the process remains in a state of control. www.drugragulations.org 7August 15
  8. 8.  Manufacturing process should consistently produce APIs and drug products meeting quality attributes.  Assurance based on objective information and data from laboratory-, pilot-, and/or commercial-scale studies.  Information and data should demonstrate that the commercial manufacturing process is capable of consistently producing acceptable quality products within commercial manufacturing conditions. www.drugragulations.org 8August 15
  9. 9.  Information and knowledge from product and process development.  Understanding sources of variation  Detecting the presence and degree of variation  Understanding the impact of variation on the process and ultimately on product attributes  Controlling the variation in a manner commensurate with the risk it represents to the process and product. www.drugragulations.org 9August 15
  10. 10.  Manufacturer judging whether it has gained sufficient understanding of the process.  Not focusing exclusively on qualification efforts  Understanding the manufacturing process and associated variations.  Maintaining the process in a state of control over the life of the process, even as materials, equipment, production environment, personnel, and manufacturing procedures change.  Collecting and analyzing product and process data to evaluate the state of control of the process. www.drugragulations.org 10August 15
  11. 11.  Life cycle approach  Good project management  Good archiving  An integrated team approach  Studies based on sound scientific principles  Risk based decision making  Criticality as a continuum rather than a binary state www.drugragulations.org 11August 15
  12. 12.  Evaluate attribute(s) (quality, product, component) & parameter(s)( process, operating, & equipment) in terms of their roles in the process and impact on the product or in-process material.  Reevaluate above as new information becomes available.  Exercise degree of control on attributes & parameters commensurate with their risk to the process and process output www.drugragulations.org 12August 15
  13. 13.  cGMP conditions not required at this stage  Follow good documentation practices  Use sound scientific methods and principles  Conduct internal review & document decisions and justification of the controls  Use knowledge and data from product development ◦ Critical quality attributes ◦ Critical material attributes ◦ Critical process parameters  Consider functionality and limitations of commercial manufacturing equipment www.drugragulations.org 13August 15
  14. 14.  Consider contributions to variability posed by ◦ Different component lots, ◦ Production operators, ◦ Environmental conditions, and ◦ Measurement systems in the production setting.  Use laboratory or pilot-scale models designed to be representative of the commercial process www.drugragulations.org 14August 15
  15. 15.  Use DOE to develop process knowledge by ◦ Revealing relationships, ◦ Multivariate interactions, between the variable inputs (e.g., component characteristics or process parameters) and the resulting outputs (e.g., in-process material, intermediates, or the final product).  Use risk analysis tools to screen variables for DOE www.drugragulations.org 15August 15
  16. 16.  Based on the DOE results Establish ranges of ◦ Incoming component quality, ◦ Equipment parameters, and ◦ In-process material quality attributes  FDA does not generally expect manufacturers to develop and test the process until it fails.  Use lab or pilot scale to predict performance at commercial scale  Use the data to model or simulate a commercial scale process  Understand the degree to which the models represent a commercial process www.drugragulations.org 16August 15
  17. 17.  Process controls should address variability  Design process control to ◦ Reduce Input variation, or ◦ Adjust for input variation during manufacturing or ◦ Combine both approaches  Controls can consist of ◦ Material analysis and ◦ Equipment monitoring at significant processing points  Use risk assessment for type and extent of process controls www.drugragulations.org 17August 15
  18. 18.  Use operational limits & in-process monitoring ◦ When the product attribute is not readily measurable due to limitations of sampling or detectability (e.g., viral clearance or microbial contamination or ◦ When intermediates and products cannot be highly characterized and well-defined quality attributes cannot be identified  Establish these controls in Master production & controls record www.drugragulations.org 18August 15
  19. 19.  Advanced strategies like PAT can be used  Strategies can include timely analysis and control loops to adjust the processing conditions so that the output remains constant.  These systems can provide higher degree of process control than non-PAT systems.  In case of PAT system approach to process validation will be different www.drugragulations.org 19August 15
  20. 20.  Process Qualification ◦ Determines if the process designed is capable of reproducible commercial manufacture. ◦ Has two elements  Design of the facility and qualification of the equipment and utilities  Process performance qualification ◦ Requires cGMP compliant procedures ◦ Completion of this stage is required before commercial distribution. ◦ Products manufactured during this stage can be released for distribution , if they are acceptable. www.drugragulations.org 20August 15
  21. 21.  Design & commissioning of facilities & utilities precede process performance qualification ( PPQ).  Qualification refers to demonstration that utilities and equipment are suitable for their intended use and perform properly. www.drugragulations.org 21August 15
  22. 22.  Qualification of utilities and equipment generally include ◦ Selection of utilities and equipment construction materials, operating principles, and performance characteristics. ◦ Verification that utility systems and equipment are built and installed in compliance with the design specifications. ◦ Verification that utility systems and equipment operate in in all anticipated operating ranges. www.drugragulations.org 22August 15
  23. 23.  Qualification of utilities and equipment generally include ◦ Challenge to the equipment or system functions while under load comparable to that expected during routine production. ◦ Performance of interventions, stoppage, and start-up as is expected during routine production. ◦ Performance for as long as necessary during actual production at operating ranges www.drugragulations.org 23August 15
  24. 24.  Can be preformed under individual plans or part of overall plan  Use risk assessment for prioritization  Use risk assessment for level of effort in performance & documentation www.drugragulations.org 24August 15
  25. 25.  Plan should identify the ◦ Studies or tests to use, ◦ Criteria appropriate to assess outcomes, ◦ Timing of qualification activities, ◦ Responsibilities of relevant departments and the quality unit, and ◦ Procedures for documenting and approving the qualification. www.drugragulations.org 25August 15
  26. 26.  Process Performance Qualification Combines following to produce commercial batches. ◦ Actual facility ◦ Utilities ◦ Equipment (each now qualified) ◦ Trained personnel with ◦ Commercial manufacturing process, ◦ Control procedures ◦ Components www.drugragulations.org 26August 15
  27. 27.  Process Performance Qualification ◦ Confirms process design ◦ Demonstrates that the commercial manufacturing process performs as expected.  Commercial distribution succeeds PPQ completion www.drugragulations.org 27August 15
  28. 28.  Process performance qualification should be based on ◦ Overall level of product and process understanding ◦ Level of demonstrable control ◦ Data from lab, pilot & commercial batches ◦ Effect of scale ◦ Previous credible experience with sufficiently similar products and processes ◦ Objective measures to achieve adequate assurance www.drugragulations.org 28August 15
  29. 29.  Process performance qualification should be based on ◦ Higher level of sampling ◦ Additional testing, ◦ Greater scrutiny of process performance than would be typical of routine commercial production ◦ Level of monitoring and testing sufficient to confirm uniform product quality throughout the batch ◦ Not necessary to explore entire operating range at commercial scale www.drugragulations.org 29August 15
  30. 30.  Establish levels and frequency of routine sampling and monitoring based on increased sampling  Base duration of increased sampling on ◦ Volume of production ◦ Process complexity ◦ Level of process understanding ◦ Experience with similar products and processes. www.drugragulations.org 30August 15
  31. 31.  Different approach for processes using PAT  PAT process designed to ◦ Measure attributes of in process material ◦ Adjust the process in a control loop ◦ Maintain desired quality of output  The process design and qualification stage should focus on measurement system and control loop. www.drugragulations.org 31August 15
  32. 32.  The protocol should address following: ◦ The manufacturing conditions, including operating parameters, processing limits, and component (raw material) inputs ◦ The data to be collected and when and how it will be evaluated. ◦ The sampling plan, including sampling points, number of samples, and the frequency of sampling for each unit operation and attribute. www.drugragulations.org 32August 15
  33. 33.  The protocol should address following: ◦ The number of samples should be adequate to provide sufficient statistical confidence ◦ The confidence level selected can be based on risk analysis as it relates to the particular attribute under examination ◦ Criteria and process performance indicators that allow for a science- and risk-based decision about the ability of the process to consistently produce quality products www.drugragulations.org 33August 15
  34. 34.  The protocol should address following: ◦ A description of the statistical methods to be used in analyzing all collected data ◦ Provision for addressing deviations from expected conditions and handling of nonconforming data. ◦ Design of facilities and the qualification of utilities and equipment, personnel training and qualification, and verification of material sources. ◦ Status of the validation of analytical methods used ◦ Review and approval of the protocol www.drugragulations.org 34August 15
  35. 35.  Execution to begin after approval of protocol  Any departures form protocol should follow quality system  All departures should be justified & approved  Follow commercial manufacturing process & routine procedures www.drugragulations.org 35August 15
  36. 36.  Normal operating conditions should include the ◦ Utility systems, ◦ Material, ◦ Personnel, ◦ Environment, and ◦ Manufacturing procedures. www.drugragulations.org 36August 15
  37. 37.  Report should  Discuss and cross-reference all aspects of the protocol.  Summarize data collected and analyze the data, as specified by the protocol.  Evaluate any unexpected observations and additional data not specified in the protocol.  Summarize and discuss all manufacturing nonconformance  Describe in sufficient detail any corrective actions or changes www.drugragulations.org 37August 15
  38. 38.  Report should  State a clear conclusion as to whether the data indicates the process met the conditions established in the protocol and whether the process is considered to be in a state of control  If not, the report should state what should be accomplished before such a conclusion can be reached  Review and sign off www.drugragulations.org 38August 15
  39. 39.  Goal to ensure that process remains in a state of control during commercial manufacture  System to detect unplanned departures from designed process is essential to achieve the goal  Collect & evaluate data to determine process variability  Identify problems and implement corrective actions if required www.drugragulations.org 39August 15
  40. 40.  Establish a program to collect & analyze product & process data ◦ Process trends ◦ Quality of incoming materials or components, ◦ In-process material, ◦ Finished products  Statistically review and trend the data  Use statistical and qualitative tools to detect variation  Scrutinize inter batch and intra batch variation www.drugragulations.org 40August 15
  41. 41.  Continue monitoring and sampling of process parameters and quality attributes at the level established during the process qualification stage until sufficient data are available to generate significant variability estimates.  These estimates can provide the basis for establishing levels and frequency of routine sampling and monitoring for the particular product and process. www.drugragulations.org 41August 15
  42. 42.  Monitoring can then be adjusted to a statistically appropriate and representative level.  Process variability should be periodically assessed and monitoring adjusted accordingly. www.drugragulations.org 42August 15
  43. 43.  Detect variation by assessment of ◦ Defect complaints, ◦ Out-of-specification findings, ◦ Process deviation reports, ◦ Process yield variations, ◦ Batch records, ◦ Incoming raw material records, and ◦ Adverse event reports. www.drugragulations.org 43August 15
  44. 44.  Periodic meeting between quality unit and production staff to ◦ Evaluate data ◦ Discuss possible trends ◦ Undesirable process variation ◦ Co-ordinate any correction or follow-up actions by production. www.drugragulations.org 44August 15
  45. 45.  Improve/optimize the process based on the data by altering ◦ Operating conditions (ranges and set-points), ◦ Process controls, ◦ Component, or ◦ In-process material characteristics  Document, justify & approve the change as per PQS  Additional process design and process qualification activities could be warranted www.drugragulations.org 45August 15
  46. 46.  Important to maintain facility, utilities, and equipment  Maintain qualification status through routine monitoring, maintenance, and calibration procedures and schedules.  Re-assess data periodically to determine the need of re-qualification  Adjust maintenance and calibration frequency based on above inputs. www.drugragulations.org 46August 15
  47. 47.  Commercial distribution of product only after ◦ Successful completion of PPQ ◦ After obtaining high degree of assurance in process  Under special circumstances PPQ batches can be released concurrently  FDA expects that concurrent release will be used rarely  Circumstances and rationale for concurrent release should be fully described in the PPQ protocol www.drugragulations.org 47August 15
  48. 48.  Lot released concurrently must comply with all CGMPs, regulatory approval requirements, and PPQ protocol lot release criteria  Lot release under a PPQ protocol is based upon meeting confidence levels appropriate for each quality attribute of the drug www.drugragulations.org 48August 15
  49. 49.  Appropriate for processes used infrequently for various reasons  Manufacture drugs for which there is limited demand ◦ Orphan drugs, ◦ Minor use and ◦ Minor species veterinary drugs  Drugs with short half live ◦ Radio pharmaceuticals ◦ Positron emission tomography drugs  Drugs manufactured in co-ordination with agency to alleviate short supply www.drugragulations.org 49August 15
  50. 50.  Document each step for life cycle management  Documentation ensures knowledge gained is accessible to others  Documentation is dependent on the stage of validation  Documentation requirements are greatest during Stage 2, process qualification, and Stage 3, continued process verification www.drugragulations.org 50August 15
  51. 51.  Diagram the process flow for the full-scale process. ◦ Describe each unit operation, ◦ its placement in the overall process, ◦ monitoring and control points, and ◦ the component, as well as other processing material inputs (e.g., processing aids) and ◦ expected outputs (i.e., in-process materials and finished product). www.drugragulations.org 51August 15
  52. 52.  Accurate & precise analytical techniques are essential.  Validated methods not required for product/process- development. However ◦ Sound & reliable methods are required. ◦ Assurance of proper equipment function. ◦ Documented maintenance & calibration procedures. ◦ New analytical technology and modifications to existing technology can be used to characterize the process or the product.  Methods for commercial batch release must follow cGMP’s www.drugragulations.org 52August 15
  53. 53.  Replaces the emphasis on the first few commercial-scale validation batches with enhanced assurance of product quality in many, or even all, batches;  Provides the foundation for a robust process performance and product quality monitoring system, increasing product and process knowledge and facilitation of continual improvement opportunities for process and product quality;  Enables earlier detection of manufacturing-related problems and trends; www.drugragulations.org 53August 15
  54. 54.  Provides immediate feedback of the effect of a change, thereby facilitating the management of changes;  Provides a higher assurance of an ongoing state of control, as more data from CPV provide higher statistical confidence for ongoing monitoring and trending;  Is particularly suited to the evaluation of continuous manufacturing processes; and  Contributes to the verification of the design space, if used, throughout the product lifecycle. www.drugragulations.org 54August 15
  55. 55.  Irrespective of whether a medicinal product is developed by a traditional approach or an enhanced approach, the manufacturing process should be validated before the product is placed on the market.  In exceptional circumstances concurrent validation may be accepted.  Please refer to GMP Annex 15 for further guidance or our presentation on the same. ( Click here ) www.drugragulations.org 55August 15
  56. 56.  Process validation ◦ Should confirm that the control strategy is adequate to the process design and the quality of the product. ◦ Should cover all manufactured strengths ◦ Should cover all manufacturing sites used for production of the marketed product. ◦ Data should be generated for all products to demonstrate the adequacy of the manufacturing process at each site of manufacture. ◦ Should be carried out in accordance with GMP ◦ Data should be held at the manufacturing location and made available for inspection if not required in the dossier ◦ A bracketing approach may be acceptable for different strengths, batch sizes and pack sizes. www.drugragulations.org 56August 15
  57. 57.  Process validation can be performed in a traditional way, regardless of the approach to development taken.  Continuous process verification can be implemented if ◦ An enhanced approach to development has been performed or ◦ Where a substantial amount of product and process knowledge and understanding has been gained through historical data and manufacturing experience. www.drugragulations.org 57August 15
  58. 58.  Traditional process validation is normally performed when ◦ The pharmaceutical development and/or process development is concluded, after scale-up to production scale and prior to marketing of the finished product. www.drugragulations.org 58August 15
  59. 59.  As part of the process validation lifecycle, some process validation studies may be conducted on pilot scale batches if the process has not yet been scaled up to production scale.  It should be noted that pilot batch size should correspond to at least 10% of the production scale batch (i.e. such that the multiplication factor for the scale-up does not exceed 10).  For solid oral dosage forms this size should generally be 10% of the maximum production scale or 100,000 units whichever is the greater. www.drugragulations.org 59August 15
  60. 60.  Where the intended batch size is less than 100,000 units, the predictive value of the pilot batches may be limited  A justified approach should be followed.  For other dosage forms the pilot batch size should be justified taking into account risk to the patient of failure of the dosage form.  Since it is not generally considered useful to conduct full validation studies on pilot scale batches, the process validation scheme outlined in subsequent slides should be completed for each product for subsequent execution at production scale;  Bracketing may be acceptable. www.drugragulations.org 60August 15
  61. 61.  Where validation data on production scale batches are not provided with the application and traditional process validation is proposed, the process validation scheme described below should be submitted by the applicant.  This should outline the formal process validation studies to be conducted on production scale batches.  The number of batches used would depend on the variability of the process, the complexity of the process / product and the experience of the manufacturer,  However would usually be a minimum of 3 consecutive batches. www.drugragulations.org 61August 15
  62. 62.  The information from these studies should be available for verification post authorization by the supervisory authority.  The process validation scheme should be submitted in the marketing authorization dossier and should include the following information as a minimum: ◦ Short description of the process with a summary of the critical processing steps or critical process parameters to be monitored during validation; ◦ Finished product release specification (references to the dossier);  details of analytical methods (references to the dossier); www.drugragulations.org 62August 15
  63. 63.  The process validation scheme should be submitted in the marketing authorization dossier and should include the following information as a minimum: ◦ In-process controls proposed with acceptance criteria; ◦ Additional testing intended to be carried out (e.g. with proposed acceptance criteria and analytical validation as appropriate); ◦ Sampling plan - where, when and how the samples are taken;  details of methods for recording and evaluation of results;  proposed timeframe www.drugragulations.org 63August 15
  64. 64.  Following completion of the scheme, a report containing the following information and signed by the appropriate authorized person should be generated and made available for inspection: ◦ Batch analytical data ◦ Certificates of analysis ◦ Batch production records ◦ Report on unusual findings, modifications or changes found necessary with appropriate rational ◦ Conclusions. www.drugragulations.org 64August 15
  65. 65.  It is a science and risk-based real-time approach to verify and demonstrate that a process that operates within the predefined specified parameters produces material which meets all its Critical Quality Attributes (CQAs) and control strategy requirements. www.drugragulations.org 65August 15
  66. 66.  Again, the focus is put explicitly on extensive ◦ In-line or ◦ At-line controls and ◦ On monitoring process performance and product quality in a timely manner.  Relevant process quality attributes of incoming materials or components should be collected. www.drugragulations.org 66August 15
  67. 67.  This should include the verification of ◦ Attributes ◦ Parameters ◦ End points ◦ Assessment of CQA and Critical Process Parameter (CPP) trends. www.drugragulations.org 67August 15
  68. 68.  Process analytical technology applications can be viewed as enablers for continuous process verification. ◦ NIR spectroscopy with or without feedback loop  End point determination of blend homogeneity  Determination of granules surface area  Determination of content uniformity with large sample size)  Multivariate statistical process control (MSPC) www.drugragulations.org 68August 15
  69. 69.  Scope and extent of CPV are influenced by a number of factors including: ◦ Development and manufacturing knowledge from similar products and/or processes; ◦ The extent of process understanding gained from development studies and commercial manufacturing experience; ◦ The complexity of the product and/or manufacturing process; www.drugragulations.org 69August 15
  70. 70. ◦ The level of process automation and analytical technologies used; ◦ With reference to the product lifecycle, process robustness and manufacturing history since point of commercialization as appropriate.  The process should be verified on commercial scale batches prior to marketing. www.drugragulations.org 70August 15
  71. 71.  Continuous process verification can be introduced at any time of the lifecycle of the product:  It can be used to design ◦ Process validation protocols for the initial commercial production, ◦ To re-validate as part of process changes or ◦ To support continual improvement throughout the lifecycle. www.drugragulations.org 71August 15
  72. 72.  If a design space has been implemented continuous process verification may contribute to ensuring its validity throughout the product lifecycle. www.drugragulations.org 72August 15
  73. 73.  Continuous process verification performance depends strongly on compliance with GMP, if necessary complemented by Pharmaceutical quality systems (PQS) as described in ICH Q10.  GMP matters and PQS should not be included in the submission.  They are assessed and handled by GMP inspectors. www.drugragulations.org 73August 15
  74. 74.  It may be necessary to use either the traditional process validation or the continuous process verification approach for different steps within the manufacturing process.  A justification for using this hybrid approach should be presented in the dossier www.drugragulations.org 74August 15
  75. 75.  It should be clear which approach to validation has been taken for which part of the manufacturing process.  The validation requirements in terms of batch size and number of batches would depend on the extent to which continuous process verification has been used. www.drugragulations.org 75August 15
  76. 76.  A design space will normally be developed at laboratory or pilot scale.  During scale-up the commercial process is generally conducted and validated in a specific area of the design space, defined as the target interval or Normal Operating Range (NOR).  During the product lifecycle, moving from one area to another within the design space (i.e. change in the NOR) may represent higher or unknown risks not previously identified during initial establishment of the design space. www.drugragulations.org 76August 15
  77. 77.  For this reason there will be situations where it will be necessary to confirm the suitability of the design space and verify that all product quality attributes are still being met in the new area of operation within the design space.  This is termed ‘design space verification’. www.drugragulations.org 77August 15
  78. 78.  Verify Design Space when ◦ The parameters investigated during development of the design space have not been shown to be scale independent and ◦ The process has been validated using traditional process validation  If continuous process verification has been utilized, this may contribute towards ensuring the validity of the design space throughout the product lifecycle.  In this case, a design space verification strategy should be included as part of the continuous process verification strategy. www.drugragulations.org 78August 15
  79. 79.  Depending on the change and the extent of movement within the design space protocols for verification may include  Controls of quality attributes (QA’s)  Process parameters (PP’s) not included in the routine control system ◦ (e.g. monitoring or testing of QA’s and PP’s that are expected to be scale dependent and when applicable, equipment dependent). www.drugragulations.org 79August 15
  80. 80.  It is not necessary to verify entire areas of the Design Space or the edge of failure.  In principle more than one area of the design space should be verified  A stepwise approach taking into consideration the need to adjust the NOR within the approved design space during product lifecycle is acceptable. www.drugragulations.org 80August 15
  81. 81.  A discussion on the appropriateness and feasibility of the CPV strategy should be included in the development section of the dossier and should be supported with data from at least lab or pilot scale batches. www.drugragulations.org 81August 15
  82. 82.  A description of the CPV strategy including the process parameters and material attributes that will be monitored as well as the analytical methods that will be employed should be included (reference to Annex 1), with cross reference in the validation section of the dossier. www.drugragulations.org 82August 15
  83. 83.  Actual CPV data generated at commercial scale should be held at the site for inspection  The applicant should define the stage at which the product is considered to be validated and the basis on which that decision was made. www.drugragulations.org 83August 15
  84. 84. This rationale should include a justification for the number of batches used based on the complexity and expected variability of the process and existing manufacturing experience of the company. www.drugragulations.org 84August 15
  85. 85.  The objectives of process validation are unchanged when using ICH Q8, Q9, and Q10.  The main objective of process validation remains that a process design yields a product meeting its predefined quality criteria. www.drugragulations.org 85August 15
  86. 86.  ICH Q8, Q9, and Q10 provide a structured way to define product critical quality attributes, design space, the manufacturing process, and the control strategy.  This information can be used to identify the type and focus of studies to be performed prior to and on initial commercial production batches. www.drugragulations.org 86August 15
  87. 87.  As an alternative to the traditional process validation, continuous process verification can be utilized in process validation protocols for ◦ The initial commercial production and ◦ For manufacturing process changes for the continual improvement throughout the remainder of the product lifecycle. www.drugragulations.org 87August 15
  88. 88.  For detail of Stage 2 of Process Validation click on link below for a presentation on :  “ No. of batches required in Stage 2 Process Performance Qualification”  For Details on stage 3 of Process Validation click on link below for a presentation on  “ Continued Process Verification” www.drugragulations.org 88August 15
  89. 89.  This presentation is compiled from freely available resources like the website of FDA & EMA specifically  “Guidance for Industry Process Validation: General Principles and Practices , Revision 1, 2011” “EU Guidelines for Good Manufacturing Practice Annex 15: Qualification and Validation” and” EMA Guideline on process validation for finished products - information and data to be provided in regulatory submissions”  “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. 8/18/2015 89 Drug Regulations : Online Resource for Latest Information

×