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US FDA Process Validation Stage 3: Continued Process Verification

FDA Process Validation Guidance (Guidance for Industry: Process Validation- General Principles and Practices, Jan. 2011) outlines process validation activities in three stages - Stage 1: Process Design, Stage 2: Process Qualification and Stage 3: Continued Process Verification. Completion of Stage 2 subsequent to Stage 1 is a major milestone in the Process Validation Lifecycle as it confirms the process design and demonstrates the expected consistent performance of the manufacturing process. Knowledge and information gained from the design stage through the process qualification stage is used to complete this assessment. Stage 2 demonstrates suitability for successful commercial distribution where the data indicates that the process meets the conditions established in the protocol. Continued Process Verification is initiated for the subsequent commercial batches. Stage 3 assures that the process remains in a state of control during commercial manufacture.

This presentation gives a practical approach to implement the stage 3 of the FDA Process Validation Guide.

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US FDA Process Validation Stage 3: Continued Process Verification

  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. 8/6/2015 1
  2. 2.  This presentation is compiled from freely available resource like the website of FDA, EMA and publically available literature from websites of PDA, ISPE and DIA.  “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. 8/6/2015 2 Drug Regulations : Online Resource for Latest Information
  3. 3.  This presentation addresses following: ◦ How is Stage 3 monitoring and testing determined as a part of Life cycle approach to Process Validation ( PV) ◦ What is the impact of the Life Cycle approach to monitoring and testing of legacy products.  More experience is required in implementing life cycle approach to PV to arrive at a Industry consensus. 8/6/2015 3 Drug Regulations : Online Resource for Latest Information
  4. 4.  FDA guidance on PV in January 2011. ◦ Process Validation: General Principles & Practices.  EMA issued revision to the Guideline on Process Validation.  EMA guidance clarifies ◦ How to implement the principles of ICH Q8, Q9 and Q10. ◦ The possibility to use “continuous process verification” ◦ Different from “Continued Process Verification” in FDA guidance. 8/6/2015 4 Drug Regulations : Online Resource for Latest Information
  5. 5.  PV Guidance of FDA is main focus of this presentation.  Life cycle approach to Process validation which links ◦ Product & process development ◦ Qualification of the commercial manufacturing process ◦ Maintenance of the process in a state of control during routine commercial production. 8/6/2015 5 Drug Regulations : Online Resource for Latest Information
  6. 6.  Process validation Definition ◦ “Collection and evaluation of Data from the process design stage through commercial production which establishes scientific evidence that a process is capable of continuously delivering quality product” there by also assuring reliability of supply. 8/6/2015 6 Drug Regulations : Online Resource for Latest Information
  7. 7.  Process validation  Emphasis that process validation should not be seen as one off event.  Goals of different stages of process validation are given in subsequent slides. 8/6/2015 7 Drug Regulations : Online Resource for Latest Information
  8. 8.  Process validation Goals  Stage 1 : ◦ Process Design ◦ Define & Design Process ◦ Build Knowledge & understanding generated through development and scale up activities and establish a strategy for process control 8/6/2015 8 Drug Regulations : Online Resource for Latest Information
  9. 9.  Process validation Goals  Stage 2 : ◦ Process Qualification ◦ Process design is evaluated to determine if the process is capable of reproducible commercial manufacturing. ◦ Design of a facility and qualification of utilities and equipment should be completed before commencing this step. 8/6/2015 9 Drug Regulations : Online Resource for Latest Information
  10. 10.  Process validation Goals  Stage 2 : ◦ Process Qualification ◦ Involves manufacture of number of Process Performance Qualification batches to  Confirm the process design  Demonstrate that the commercial manufacturing process performs as expected in the commercial manufacturing facility.  Level of sampling may be higher than routine manufacturing  No. of samples should provide a statistical confidence of quality within and between batches. 8/6/2015 10 Drug Regulations : Online Resource for Latest Information
  11. 11.  Process validation Goals  Stage 3 :  Continued Process Verification ◦ Ongoing assurance that the process remains in a state of control ◦ Ongoing program ◦ Collect and analyze product and process data ◦ Assure state of control ◦ Verify impact of variability. ◦ Identify potential issues ◦ Determine whether action must be taken to correct , anticipate and prevent problems 8/6/2015 11 Drug Regulations : Online Resource for Latest Information
  12. 12.  Process Performance has been adopted by some organizations to support continuous improvement  To bring this under PV is a significant change  Different interpretations and approaches possible 8/6/2015 12 Drug Regulations : Online Resource for Latest Information
  13. 13.  This presentation will  Provide practical approaches to CPV  Considerations for selection of appropriate attributes and parameters for sampling in CPV  Specific example developed by ISPE on how to establish and apply stage 3 monitoring. 8/6/2015 13 Drug Regulations : Online Resource for Latest Information
  14. 14.  Definition of CPV  “ Assuring that during routine production the process remains in a state of control”  Refers to cGMP section 211.180(e)  Requires ◦ Collection and evaluation of information and data about the performance of the process ◦ Verification that the Quality attributes are being appropriately controlled throughout the process ◦ Provide statistical confidence of Quality ◦ Evaluation of process stability and capability ◦ Identification of variability and/or potential process improvements. 8/6/2015 14 Drug Regulations : Online Resource for Latest Information
  15. 15.  CPV is an ongoing program and could be applied to  New Products : ◦ Developed through FDA process validation stages 1 and 2 and entering routine commercial manufacturing. ◦ Implemented immediately following successful PPQ ◦ FDA guidance recommends  “ Monitoring and sampling of process parameters and quality attributes at the level established during PPQ stage until sufficient data is available to estimate variability estimates”. 8/6/2015 15 Drug Regulations : Online Resource for Latest Information
  16. 16.  CPV is an ongoing program and could be applied to ◦ Existing or Legacy Products: ◦ Existing validated products in commercial manufacturing. ◦ A monitoring plan should be established or enhanced for existing products. ◦ Define the scope of the CPV ◦ Identify parameters and attributes for CPV ◦ Conduct evaluation of Process performance based on the historical manufacturing data/ routine manufacturing data 8/6/2015 16 Drug Regulations : Online Resource for Latest Information
  17. 17.  Implement  A systematic approach to maintenance of the facility, utilities and equipment  Periodic review of the equipment and facility qualification status.  Can be referenced to Quality systems for CPV monitoring plan. 8/6/2015 17 Drug Regulations : Online Resource for Latest Information
  18. 18.  CPV will also help to  Identify improvement areas ◦ Adjustment to the control strategy , specifications ◦ Support evaluation of the proposed post appoval changes ◦ Facilitate investigations ◦ Support Technical Transfers ◦ Confirm that the changes / process improvements have had the desired impact. 8/6/2015 18 Drug Regulations : Online Resource for Latest Information
  19. 19.  CPV concepts can be applied to  Small & large molecules  Sterile & Non-sterile products  Finished products  Active Pharmaceutical Ingredients  Combination products 8/6/2015 19 Drug Regulations : Online Resource for Latest Information
  20. 20. 8/6/2015 20 Drug Regulations : Online Resource for Latest Information Stage 1 : Process Development Document Process understanding , control strategy , CQAs, CPPs Stage 2: Process Performance Qualification Verify Control Strategy Stage 3 CPV Establish monitoring & sampling plan for each CQA
  21. 21.  CPV: Establish monitoring & sampling plan for each CQA  Assess need for enhanced understanding based on ◦ Criticality level of Quality Attribute ◦ Unit Operation & parameter variability impact to the Quality attribute & current capability. ◦ Range of experience of material variability impact on the quality attribute ◦ Robustness of any predictive models. 8/6/2015 21 Drug Regulations : Online Resource for Latest Information
  22. 22. 8/6/2015 22 Drug Regulations : Online Resource for Latest Information Data Collection Data Analysis and Review Determination whether CAPA needed Continuous Improvement & Change Management Update Process understanding
  23. 23.  Plan for CPV should address ◦ Input and out parameters/attributes ◦ Data collection methods ◦ Statistical methods to be used ◦ Frequency at which data will be evaluated ◦ Plan could be product specific covering all unit operations, raw materials, equipment settings ◦ Products could also be grouped 8/6/2015 23 Drug Regulations : Online Resource for Latest Information
  24. 24.  Plan for CPV should address ◦ Roles & Responsibilities ◦ Management reviews ◦ Mechanisms to trigger changes requiring redesign & re-qualification. ◦ Leveraging existing data of the Quality System including APR 8/6/2015 24 Drug Regulations : Online Resource for Latest Information
  25. 25. ◦ Determine based on the current understanding of the manufacturing process and systems in relation to quality attributes ◦ This can be based on ◦ First principles ◦ Prior knowledge ◦ Statistical Models based on DOE ◦ Empirical Models ◦ Understanding based on manufacturing experience 8/6/2015 25 Drug Regulations : Online Resource for Latest Information
  26. 26. ◦ Generate significant estimates of variability ◦ Adjustments to the control strategy may be warranted ◦ Potential changes in process/ raw material attribute or parameter criticality may be warranted ◦ Initial monitoring may  Involve grater number of parameters  Heightened sampling and testing ◦ Some CQA’s may require separate validation studies ( Viral Clearance) 8/6/2015 26 Drug Regulations : Online Resource for Latest Information
  27. 27. ◦ Number of parameters and/or extent of testing may increase or decrease as  Knowledge is gained  Specific residual risks are reduced or  New risks identified 8/6/2015 27 Drug Regulations : Online Resource for Latest Information
  28. 28. ◦ Decision to discontinue testing should be based on  Confidence achieved in the stage 1 and stage 2 and throughout stage 3  Robustness of the control strategy  Ability of the control strategy to manage variation  Rationale for change or discontinuance should be documented 8/6/2015 28 Drug Regulations : Online Resource for Latest Information
  29. 29.  Developed according to QbD principles  Control Strategy identified during development  Based on process understanding & QRM  Consider parameter & enhanced sampling of stage 2 for CPV  Consider Intra batch & inter batch variability for establishing monitoring plan  If this has been done during PPQ then sampling and testing can be reduced to routine levels.  Justify routine level scientifically and statistically 8/6/2015 29 Drug Regulations : Online Resource for Latest Information
  30. 30.  Complete establishing the capability of the process  Look at process performance across many batches  Build overall picture of inter batch variability  More batches may be needed if the variability of the input affects final product quality  Establish statistically based control limits to evaluate atypical variation of inputs  Process capability analysis can be performed with groups of samples.  Process capability can be calculated by considering batches in all three stages of validation 8/6/2015 30 Drug Regulations : Online Resource for Latest Information
  31. 31.  Determine impact of each process variable/material attribute on CQA by risk/criticality analysis  Criticality analysis may have been done in Stage 2 but cause and effect relation between inputs and outputs may not have been established.  Where variability has not fully assessed ◦ Evaluate potential sources of variability ◦ Determine their impact on CQA or process performance ◦ Confirm / establish input vs VQA correlations. 8/6/2015 31 Drug Regulations : Online Resource for Latest Information
  32. 32.  Products are developed by traditional process  Critical quality attributes and process parameters are not defined  Perform criticality and risk assessment  Include raw and in process material attributes & manufacturing systems that may affect the safety, efficacy and product quality.  Perform this assessment based on ◦ Current process understanding ◦ Experience of the commercial manufacturing process ◦ Quality system events like deviations and COC ◦ Product performance on stability 8/6/2015 32 Drug Regulations : Online Resource for Latest Information
  33. 33.  Use data of existing routine monitoring of the defined critical attributes and parameters.  Initial evaluation could be retrospective review of existing process performance data.  As data is collected additional aspects may need evaluation  Monitor additional parameters across all batches  Implement intensive sampling of an output within a batch until desired level of process understanding is achieved. 8/6/2015 33 Drug Regulations : Online Resource for Latest Information
  34. 34.  This monitoring could ◦ Provide data to develop correlations ◦ Establish cause effect relations ◦ Identify inputs requiring better control ◦ Help reduce out put variability 8/6/2015 34 Drug Regulations : Online Resource for Latest Information
  35. 35.  Review the plan periodically during the commercial phase of the lifecycle  Review can be after a defined phase : after number of batches  Review the plan if there is a process change which may affect the quality or process performance  Data in stage 3 focuses on material or process data  Data from other quality systems could be used to review process performance  Other systems which may provide information on product quality ◦ Performance on stability ◦ Periodic review ◦ Complaints ◦ Deviations ◦ Atypical events 8/6/2015 35 Drug Regulations : Online Resource for Latest Information
  36. 36.  Develop a process to collect, analyze, report and store obtained data.  Use appropriate technology tools  Use statistical tools of various complexities ◦ Time series plot ◦ Histograms ◦ Box Plots ◦ Process capability  Cp, Pp, CpK, Ppk 8/6/2015 36 Drug Regulations : Online Resource for Latest Information
  37. 37.  Consider distribution of the data : Normal vs. Non normal  Define how the results will be reported ◦ Process capability : Index or Defects per million opportunities  Cross refer applicable GMP documentation for excursions outside approved procedures, formulas, specifications, standards or parameters. 8/6/2015 37 Drug Regulations : Online Resource for Latest Information
  38. 38.  Set limits to provide an indication to indicate change and attention.  These limits represent voice of the process ◦ Common cause variation inherent in the process  Different from specifications, proven or studied boundaries or in process control limits. 8/6/2015 38 Drug Regulations : Online Resource for Latest Information
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  40. 40. 8/6/2015 40 Drug Regulations : Online Resource for Latest Information
  41. 41. 8/6/2015 41 Drug Regulations : Online Resource for Latest Information
  42. 42.  SPC limits are determined in different ways.  Control chart limits ◦ Establish temporary control limits ◦ Once sufficient data is available establish permanent / locked limits  Time series run charts may be used for parameter attribute assessment until a statistically significant data set is available.  Alternatively initial limits can be set based on historical data or other sources of process understanding. 8/6/2015 42 Drug Regulations : Online Resource for Latest Information
  43. 43.  Review control limits when intentional changes are introduced  If as part of an “out of control” assessment a special cause is identified suspend control limits till more data is obtained.  Where special cause events these values should be removed from calculations for the establishment of control limits 8/6/2015 43 Drug Regulations : Online Resource for Latest Information
  44. 44.  Review control charts at predetermined frequency  Identify in as real time as possible ◦ Process excursions : out of statistical control ◦ Data points which fall out side of locked statistical limits ◦ Shifts : Out of statistical trend events  Assess statistical out of control events based on the quality concern of the event.  Clearly define what will constitute OOST event in monitoring plan  Review the Eight Western Electric rules to establish guidelines for identifying OOST events. 8/6/2015 44 Drug Regulations : Online Resource for Latest Information
  45. 45.  Capability analysis links ◦ Voice of the process : routine or common cause process variation ◦ With ◦ Voice of the customer : Attribute / parameter acceptance criteria  Perform capability analysis ◦ Once the process is in statistical control ◦ When Data is normally distributed  If desired level of process capability is not achieved implement process improvement plans. 8/6/2015 45 Drug Regulations : Online Resource for Latest Information
  46. 46.  Indices measure how well the data fits into the specification limits.  Frequently used process capability indices include Cp and Cpk.  Cp is used to evaluate the variation of the process.  Cpk is used to evaluate the centering of the process.  Normally the Cp / Cpk values be targeted at 1.33 or above
  47. 47. USL = Upper Specification Limit, LSL = Lower Specification Limit.
  48. 48.  Cp and Cpk are statistical tools  Ensures that a production process has met the specification limits defined for a particular process or products.  Cp measures the process capability with respect to its specification using Upper Specification Limit (USL) and Lower Specification Limit (LSL)
  49. 49.  Cpk measures the process variation with respect to its sample mean, which is also considered to be the process mean.  Process capability is determined by taking periodic samples from process under controlled conditions and calculating its standard deviation and sample mean.  Standard deviation determines how far a sample is from the sample mean  sample mean is the average of the samples taken under consideration.
  50. 50. Cp < 1: The process output exceeds specifications. The process is incapable. Cp = 1: The process barely meets specifications. There is a probability that at least 0.3% defects will be produced and even more if the process is not centered. Cp > 1: The process output falls within specifications, but, defects might be produced if the process is not centered on the target value. Cp = 2: Represents the short-term objective for process capability. Since Zst = 3 x Cp, we achieve 6 sigma when Cp = 2.
  51. 51. Cpk = Cp: The process mean is on target. Cpk = 0: The process mean falls on one of the specification limits, therefore, 50% of the process output falls beyond the specification limits. Cpk < -1: The process mean is completely out of the specification limits, therefore, 100% of the process output is out of specification limits.
  52. 52. 8/6/2015 52 Drug Regulations : Online Resource for Latest Information
  53. 53. ◦ Cp and CpK measure Potential process capability ◦ Typically referred to as Short Term Process variability indicators  Within variability based on the control chart sigma value ◦ Pp and PpK are referred to as long term process indicators ◦ Rely upon overall process variability  Based on sigma for the n-1 points 8/6/2015 53 Drug Regulations : Online Resource for Latest Information
  54. 54.  For Data assessment smaller of the capability indices is typically used as a conservative measure.  Larger the Index more capable is the process of meeting the specification limit  Usually CpK / PpK of > 1.33 is desirable.  If CpK < 1 variability of the process is greater than the specification limits  CpK > 1.33 corresponds to 4 sigma ◦ 99.99 % of the data will be within specifications 8/6/2015 54 Drug Regulations : Online Resource for Latest Information
  55. 55.  Capability analysis ◦ Performed on existing process to establish baseline ◦ To determine if an improvement had an impact ◦ Monitor or control process as in case of a stage 3 data ◦ Can be applied to a new process as part of Qualification and approval process ◦ Reliability engineering metrics can be used as a means of monitoring equipment wear and tear. 8/6/2015 55 Drug Regulations : Online Resource for Latest Information
  56. 56. ◦ Outline actions to follow for investigation out of control/alert values and occurrence of trends ◦ Extent of investigations should depend on  Proximity of results to specifications  Perceived risk of the process shifting & leading to future OOS ◦ Investigate Instances where the values are within control limits but control limits lie out side specifications  Try to identify root cause and implement corrective actions. ◦ For very low variability processes outliers lie very close to control limits and a sufficient safety margin versus the specification.  For such outliers conduct lesser degree of investigations 8/6/2015 56 Drug Regulations : Online Resource for Latest Information
  57. 57. ◦ Statistical control limits  are tighter than acceptance criteria  Should to be considered acceptance criteria themselves  Used to alert process SME’s and management to potentially unacceptable process variability which may lead to future batches not meeting specifications ◦ Out of statistical control limit value  Should not impact batch release decision  Consider impact prior to next manufacturing campaign 8/6/2015 57 Drug Regulations : Online Resource for Latest Information
  58. 58.  Desired State ◦ Potential issues are identified as soon as data are entered in the process analysis tool.  Could be direct from the process in real time  Could be performed after the batch has been completed ◦ An automated alert system can be used to inform responsible persons of issues as soon as they are detected ◦ When evaluation against control / alert limits is manual establish appropriate interval for process analysis. 8/6/2015 58 Drug Regulations : Online Resource for Latest Information
  59. 59.  Management Review ◦ Cross functional team meetings ◦ Operational excellence / Continuous improvement programme ◦ Conduct for all processes currently running at the site 8/6/2015 59 Drug Regulations : Online Resource for Latest Information
  60. 60.  Ongoing review of process performance increases process understanding for ◦ Attributes and parameters which are in control ◦ Special and common cause variation through investigations.  Use this information to update process understanding and process design 8/6/2015 60 Drug Regulations : Online Resource for Latest Information
  61. 61.  Knowledge management system should support ◦ End to end : Raw materials to impact on finished product ◦ Site to site  Knowledge management tools ◦ Documentation sharing software ◦ Global Product meetings ◦ Review metrics  Periodic Product performance reviews should include all stake holders to leverage increased process understanding for similar products and process platforms. 8/6/2015 61 Drug Regulations : Online Resource for Latest Information
  62. 62. ◦ Define responsibilities in the monitoring plan document ◦ Activities include  Data collection , evaluation and analysis  Escalation mechanisms  Management reviews ◦ Personnel should have understanding of statistical tools being used. 8/6/2015 62 Drug Regulations : Online Resource for Latest Information
  63. 63. ◦ Actions  Identify to Eliminate / control special cause variation  Limit / remedy impact in the short term  Timely  Based on the understanding of the event  Long term actions to prevent recurrence of the special cause events 8/6/2015 63 Drug Regulations : Online Resource for Latest Information
  64. 64. ◦ Special cause variations  Outside approved procedures, formulas, acceptance criteria, standards or parameters  Requires investigations, CAPA through the site deviations management process ◦ Common cause variation  Requires a more fundamental approach to understand the sources of variation  Identification of ways to reduce variation 8/6/2015 64 Drug Regulations : Online Resource for Latest Information
  65. 65.  Improvement actions  Evaluate for impact on ◦ Product Quality ◦ Compliance to regulations ◦ Prior regulatory submissions ◦ Technical feasibility ◦ Process efficiency 8/6/2015 65 Drug Regulations : Online Resource for Latest Information
  66. 66.  Confirm all CAPA through a monitoring plan  Document in CAPA system  Use change management system  Agreed actions may require ◦ A change to process design ( stage 1 of FDA process) or ◦ Process Validation ( Stage of the FDA process) 8/6/2015 66 Drug Regulations : Online Resource for Latest Information
  67. 67.  When special cause variation : OOSC or OOST or Low process capability is identified conduct root cause analysis.  Use statistical techniques ◦ Hypothesis testing ◦ Principle component analysis ◦ Linear regression ◦ ANOVA / MANOVA ◦ Multiple regression tools  Based on the outcome take measures ◦ Tighten parameters : Unit operation , environmental ◦ Tighten incoming material specifications 8/6/2015 67 Drug Regulations : Online Resource for Latest Information
  68. 68.  Example is based on ◦ A science and risk Based approach ◦ Selection of subset of CQA and Process Parameters for for CPV ◦ Similar levels of monitoring and sampling as stage 2 , process qualification  Heightened monitoring and sampling compared to the eventual routine situation. 8/6/2015 68 Drug Regulations : Online Resource for Latest Information
  69. 69. 8/6/2015 69 Drug Regulations : Online Resource for Latest Information 1 •Assess criticality of Quality Attribute •Assess each unit operation and parameter impact to the Quality Attribute •Assess Material Variability Impact to the Quality Attribute •Assess Process operations impact on the Quality Attribute 2 •Amend Monitoring plan for Stage 3 using Risk Based Approach 3 •Collect sufficient data to demonstrate control and capability and that all sources of variability is understood. 4 •Move to routine monitoring programme.
  70. 70.  Example ◦ Utilize the assessment in previous slide for each CQA of the out put drug product or drug substance ◦ This process will be utilized for Oral Solid Dosage form CQA for Content Uniformity of Dosage Units and dissolution. 8/6/2015 70 Drug Regulations : Online Resource for Latest Information
  71. 71.  Step 1 : Assessment of Drug Product CQA’s to monitor. 8/6/2015 71 Drug Regulations : Online Resource for Latest Information Critical Quality Attribute Criticality Rating Rationale & Comments Assay High Over dose : Side effects; Under dose : Lack of efficacy; however dose response curve is not precipitous Uniformity of Dosage Units High Variability in plasma levels may lead to side effects or poor clinical response; however, dose response curve is not precipitous. Dissolution High Poorly soluble ( BCS class 2) drug substance- dissolution characteristics important for bioavailability; linkage of bioavailability to dissolution is not known. Water Content High Moisture may affect degradation of dosage form performance, i.e. dissolution. AP stable; however in API in drug product requires further investigation. Could also impact microbiology.
  72. 72.  Step 1 : Assessment of Drug Product CQA’s to monitor. ◦ Product : Oral Tablet ◦ Dose : daily 30 mg ◦ Example focused on 2 CQA’s that are assigned high severity  Uniformity of dosage units  Dissolution 8/6/2015 72 Drug Regulations : Online Resource for Latest Information
  73. 73.  Step 2 : Assessment of each unit operation and parameter impact to the CQA’s ◦ The cause and effect matrix after formulation development and before process development is given in next table. 8/6/2015 73 Drug Regulations : Online Resource for Latest Information
  74. 74.  Step 2 : Assessment of each unit operation and parameter impact to the CQA’s 8/6/2015 74 Drug Regulations : Online Resource for Latest Information Drug Product Dispense Blend Lubricate Compress Coat Package Appearance M Identity M M Assay M M M Impurities UDU H M M Dissolution H H Micro
  75. 75.  Step 2 : Assessment of each unit operation and parameter impact to the CQA’s  Selection of UDU and dissolution  Highest risk quality attributes before process development  Development PV stage 1 studies lead to an understanding of Assay CQA  Extensive studies result in introduction of important elements of control strategy. ◦ In-line NIR testing for blend homogeneity ◦ At line testing of uniformity of dosage units ◦ Algorithm as an important element of the dissolution control strategy. 8/6/2015 75 Drug Regulations : Online Resource for Latest Information
  76. 76.  Step 2 Cause and effect matrix after process development studies and application of control strategy. 8/6/2015 76 Drug Regulations : Online Resource for Latest Information Drug Product Dispense Blend Lubricate Compress Coat Package Appearance C C C C C C Identity C C+E C C C C Assay C C C C+E C C Impurities C C+E C C C C UDU C C C+E C+E C C Dissolution C C C+E C+E C C Micro C C C C C C
  77. 77.  Step 2 : Assessment of each unit operation and parameter impact to the CQA’s  Types of control strategy applied  C = Conventional strategy elements including cGMP  C+E = Conventional strategy elements including cGMP + Elements of enhance / QbD approaches.  Using the risk assessment criteria applied during development shows that the impact on all drug product CQAs is low risk when a comprehensive control strategy is applied. 8/6/2015 77 Drug Regulations : Online Resource for Latest Information
  78. 78.  Step 2 : Assessment of each unit operation and parameter impact to the CQA’s ◦ Evaluate the residual risk using a different risk assessment tool. ◦ Evaluate the residual risk strategy ◦ Theoretically all of the unit operations have been mitigated to predicted green for each unit operations impact on each CQA. ◦ However variability across wide range of input material attribute variability in combination with operational conditions may not have been demonstrated. 8/6/2015 78 Drug Regulations : Online Resource for Latest Information
  79. 79.  Step 2 : Assessment of each unit operation and parameter impact to the CQA’s ◦ For the purpose of this example the focus will be on the impact of compression on dissolution and content uniformity. ◦ A summary of the control strategy risk assessment for UDU and dissolution after stage 2 process validation is seen subsequent table leading to proposed PV stage 3. 8/6/2015 79 Drug Regulations : Online Resource for Latest Information
  80. 80.  Control Strategy Assessment Summary after Stage 2 Process Qualification 8/6/2015 80 Drug Regulations : Online Resource for Latest Information Uniformity of Dosage Units Acceptance criteria applied to drug substance particle size Extensive studies performed to understand homogeneity during blending and lubrication operations. In-Line NIR applied to blending and lubrication unit operations At line NIR individual tablet assay UDU provides high level of confidence using stratified sampling. Each tablet indirectly evaluated for weight ( pressure monitoring) Control strategy established and confirmed
  81. 81.  Control Strategy Assessment Summary after Stage 2 Process Qualification 8/6/2015 81 Drug Regulations : Online Resource for Latest Information Uniformity of Dosage Units Considerations for Stage 3 Process Validation CPV based on step 2 Consideration of reduced testing compared to Stage 2 for routine monitoring based on control strategy. Reduced frequency of at-line testing of individual tablet for assay.
  82. 82.  Control Strategy Assessment Summary after Stage 2 Process Qualification 8/6/2015 82 Drug Regulations : Online Resource for Latest Information Dissolution Understanding of process to produce an acceptance criteria applied to drug substance particle size • Prediction algorithm developed from DoE’s dependent on : • Drug substance particle size • Specific surface area of lubricant • Lubrication mixing time • Tablet crushing force Model developed at small scale and limited conformation during stage 2, process qualification Stratified sampling applied for testing of tablet cores
  83. 83.  Control Strategy Assessment Summary after Stage 2 Process Qualification 8/6/2015 83 Dissolution Control strategy established and confirmed Continue stratified sampling at same level as above for a pre-defined number of batches Measurement of material attributes of drug substance • Particle size • Specific surface area of the lubricant • Tablet crushing force • Process parameter of lubrication time Maintain end product testing Verify Multivariate model and demonstrate robustness Provide comparative data between prediction and measurement to support movement to RTRT
  84. 84.  Step 3 : Assess Material Variability Impact ◦ Summary out put of Risk Evaluation after Formulation Development and IVIVC studies using FMEA 8/6/2015 84 Drug Regulations : Online Resource for Latest Information CQA (Severity)/F ailure Mode App Fri Hard Impurities Water CU Disso Micro Magnesium Stearate Surface Area Particle Size
  85. 85.  Step 3 : Assess Material Variability Impact  CU: Low level of risk remains for the API particle size.  Disso: A high level of residual risk remains for Magnesium Stearate specific surface area and API particle size.  Two raw materials with the potential to have significant impact on dose uniformity and dissolution.  Based on prior knowledge API particle size could have significant impact on content and dose uniformity.  Due to the particle size of the API; however, tablet strength and testing during development, this has been migrated to a low risk level. 8/6/2015 85 Drug Regulations : Online Resource for Latest Information
  86. 86.  Step 3 : Assess Material Variability Impact  Conversely , due to the feed forward control strategy model, limited development data and the desire to eliminate routine testing of dissolution as part of batch release testing, the CQA of dissolution is considered an excellent candidate for heightened testing as part of CPV plan.  The variability of within batch results should be be considered in determining the number of samples and locations which will be tested for each batch. 8/6/2015 86 Drug Regulations : Online Resource for Latest Information
  87. 87.  Step 3 : Assess Material Variability Impact  Although the powder blend is designed to be free flowing, variability is estimated during early phases of production with different batches of excipients.  Continued monitoring of dissolution and material attributes and process parameters impacting dissolution is justified during the first part of CPV to confirm that the model and predictions are acceptable. 8/6/2015 87 Drug Regulations : Online Resource for Latest Information
  88. 88.  Step 4 : Assess Operational Practices Impact  Following operations practices could impact content uniformity or dissolution.  Multiple Operators  Multiple Shifts  Multiple Equipment sets  Process interruptions ( Breaks, lunches, weekends, equipment malfunction etc.) 8/6/2015 88 Drug Regulations : Online Resource for Latest Information
  89. 89.  Step 4 : Assess Operational Practices Impact  A review of the level of process understanding and the design of the control strategy indicates that these factors are very low risk.  UDU :Many control strategy elements which are operator independent ◦ In-line monitoring of blend homogeneity linked to an automatic system to stop blending ◦ An easy to read revolution counter.  Homogeneity is confirmed after the lubrication unit operation, therefore reduced testing is justified during Stage 3 CPV. 8/6/2015 89 Drug Regulations : Online Resource for Latest Information
  90. 90.  Decision Process : Risk assessment summary  Dissolution is largely dependent on ◦ Drug substance particle size ◦ Magnesium stearate surface area ◦ Tablet crushing force ◦ Lubrication time  Operators can have impact to the equipment set-up and resulting process parameters and crushing force. 8/6/2015 90 Drug Regulations : Online Resource for Latest Information
  91. 91.  Decision Process : Risk assessment summary  Although the powder blend is designed to be free flowing, variability is estimated during early phases of production with different batches of excipients and use of operational personnel.  Continued monitoring of the dissolution, material attributes and process parameters impacting dissolution is justified during the first part of the CPV to confirm that the model and predictions are acceptable. 8/6/2015 91 Drug Regulations : Online Resource for Latest Information
  92. 92.  Summary of PV stage 3, part 1 Evaluation  Summary of science and risk based evaluation for the four step CPV risk assessment as applied to content uniformity and dissolution of oral tablets. 8/6/2015 92 Quality Attribute Content Uniformity Dissolution Risk Patient Unit Operations Material Operations Practices Residual Overall risk
  93. 93.  Summary of PV stage 3, part 1 Evaluation  CU ◦ Based on the analysis no additional monitoring is required post PPQ  Dissolution ◦ Based on the analysis further evaluation is needed ◦ Additional sampling and testing for dissolution should be included for period of time until control and capability are established. 8/6/2015 93 Drug Regulations : Online Resource for Latest Information
  94. 94.  PV stage 3 , art 1 , Monitoring plan Summary and Criteria  Pre–defined to determine what testing could be reduced ◦ process capability  e.g. CpK>1with 99 % confidence 8/6/2015 94 Drug Regulations : Online Resource for Latest Information
  95. 95.  Summary of a monitoring plan for PV stage 3 , continued process verification is given in subsequent table with dissolution testing at heighted level  This plan focuses on product CQA testing  However plan can also include ◦ Heightened material CQA’s testing ◦ Process parameter monitoring. ◦ Frequent trending of any and all results 8/6/2015 95 Drug Regulations : Online Resource for Latest Information
  96. 96.  Monitoring summary for CPV 8/6/2015 96 CQA HMP Rationale Sampling Acceptance Criteria Target min CpK # of batches RATIONALE Appearance No Routine sampling & inspection uses AQL acceptance sampling Routine Meets release criteria NA NA NA Identity No Identity confirmed by multiple tests ( Assay, dissolution, UDU) Routine Meets release criteria NA NA NA Impurities No Impurities controlled in API. Formulation & process produce stable drug products Routine Meets release criteria for D P > 1 NA NA Friability No Adequate in process control Routine Meets in process criteria NA NA NA Hardness No Adequate in process control Routine Meets in process criteria NA NA NA
  97. 97.  Monitoring summary for CPV 8/6/2015 97 CQA HM P Rationale Sampling Acceptance Criteria Target min CpK # of batc hes RATIONALE ASSAY No In-process NIR provides confidence in assay Routine Meets release criteria > 1 NA NA Uniformity of Dosage units No At line NIR for individual tablet assay and in pine weight control data provides high level CU will meet quality requirements Routine Meets release criteria > 1 NA NA Dissolution Yes Complex multivariate relationship requires more data to assess robustness. 60 tablets/batc h using stratified sampling Mean > 85 % . MA’s for API particle size, magnesium stearate surface area and crushing force and lubrication time monitored. > 1 NA NA Microbiolog y No Oral ingestion and low water activity if the drug product formulation mitigates microbial quality issues. Routine NA Annual Verification Routine Release requirements NA NA
  98. 98.  Monitoring summary for CPV ◦ Acceptance criteria for dissolution follows ASTM E 2709 using 90 % confidence interval ◦ AQL : Limiting Quality Level ◦ CS : Control strategy ◦ MA : Material Attributes ◦ CAP : Capability Analysis ◦ HMP : Heightened Monitoring Plan 8/6/2015 98 Drug Regulations : Online Resource for Latest Information
  99. 99.  Proposed Routine Monitoring Programme  When pre defined capability measures are achieved as part of Stage 3 , CPV , the levels of testing may be adjusted to statistically routine levels, which in the case of dissolution involves real time release testing.  This level of testing is applied as part of application of statistical evaluation e.g. capability.  If RTRT is implemented, frequent monitoring of some of the direct process measurements, such as blender revolutions, should be considered. 8/6/2015 99 Drug Regulations : Online Resource for Latest Information
  100. 100.  Proposed Routine Monitoring Programme  Pre-defined criteria could be set, such as a defined confidence interval of process capability CpK > 1 with 99 % confidence which when achieved would drive a review to decide of and what testing could be reduced to the routine monitoring level, and what elements of the control strategy could be considered for a change.  A summary of the monitoring plan for stage 3 Continued Process Verification is given in previous table.  This focuses on Product CQA’s testing  Monitoring plan could also include heightened material CQA’s testing , process parameter monitoring and frequent tending of any and all results. 8/6/2015 100 Drug Regulations : Online Resource for Latest Information
  101. 101.  Process under review  Legacy product : Oral Dissolving tablets  Process design phase did not include evaluations of the full range of excipient attributes  Their possible contribution to variability  No detailed control strategy developed for the process  Historical performance review ◦ Potential excipient variability ◦ Impact to assay and and stability 8/6/2015 101 Drug Regulations : Online Resource for Latest Information
  102. 102.  Initial Stage 3 Monitoring Plan  Conduct expanded assessment of product and process input  Identify potential process parameters and/or process and material attributes for monitoring and and/or enhanced testing.  Use conventional risk assessment tools to identify those most likely to impact process variability and performance. 8/6/2015 102 Drug Regulations : Online Resource for Latest Information
  103. 103.  Initial Stage 3 Monitoring Plan  Engage Technical, Quality, development, and Manufacturing personnel  Apply the plan to a manufacturing campaign  Obtain statistically valid set of data which includes process variability conditions and compile. 8/6/2015 103 Drug Regulations : Online Resource for Latest Information
  104. 104.  Initial Stage 3 Monitoring Plan  Conduct assessment of the ◦ Initial parameters/Attributes ◦ Level and frequency of testing  Determine if parameters will be ◦ Maintained ◦ Removed ◦ Added 8/6/2015 104 Drug Regulations : Online Resource for Latest Information
  105. 105.  Initial Stage 3 Monitoring Plan  First step ◦ Review data from release attributes and known CQA’s over a given period ◦ Determine current level of variability in the attributes ◦ Review if inputs for the attributes may benefit from enhanced monitoring. 8/6/2015 105 Drug Regulations : Online Resource for Latest Information
  106. 106.  Product CQA’s ◦ Assay ◦ Disintegration ◦ Dissolution ◦ Impurities ◦ Content Uniformity 8/6/2015 106 Drug Regulations : Online Resource for Latest Information
  107. 107.  Conduct a statistical assessment of the the Product CQA’s 8/6/2015 107 Drug Regulations : Online Resource for Latest Information Product CQA PpK’s Assay 0.9 CU 2.66 Disintegration 2.16 Dissolution 2.34 Impurities 5.09
  108. 108. 8/6/2015 108
  109. 109. 8/6/2015 109
  110. 110. 8/6/2015 110
  111. 111.  Product CQA’s ◦ Identify threshold for Statistical Assessment to trigger enhanced monitoring of additional inputs which may impact the attribute/parameter. ◦ In this example  assay data has a lower PpK  Statistical control limit lies slightly below the product specification.  Lower PpK indicates lower longer term capability.  Suggests a need to reduce variability and center the process. 8/6/2015 111 Drug Regulations : Online Resource for Latest Information
  112. 112.  Product CQA’s ◦ This analysis justifies parameters like tablet weight, excipient attributes, API particle size and others to be included in the monitoring plan to better understand their potential contributions to assay variability. 8/6/2015 112 Drug Regulations : Online Resource for Latest Information
  113. 113.  Product CQA’s ◦ Develop a priority matrix. Helps in ◦ Selection of optimal parameters/attributes to enhance the understanding of the process. ◦ Understanding the impact of input parameters ◦ Develop focus for higher risk elements. 8/6/2015 113 Drug Regulations : Online Resource for Latest Information
  114. 114.  Product CQA’s ◦ In this example ◦ Inputs were ranked for impact to process outputs ◦ Score used  1 = Low  3 = Marginal  5 = High priority 8/6/2015 114 Drug Regulations : Online Resource for Latest Information
  115. 115. 8/6/2015 115
  116. 116. 8/6/2015 116
  117. 117.  Product CQA’s ◦ Similar priority risk assessments were performed for ◦ all process steps & unit operations  Raw material input as unit operation ◦ Product Quality Drivers  CQA , Release parameters ◦ Impact to the patient  Complaints, mouth feel, appearance) ◦ Process Performance parameters  Yield , Packaging Impact 8/6/2015 117 Drug Regulations : Online Resource for Latest Information
  118. 118.  Product CQA’s ◦ In this example the particle size, bulk density and peroxide content of the excipient were selected ◦ These attributes correlated with product dissolution/disintegration and impurity levels at release and on stability, respectively. 8/6/2015 118 Drug Regulations : Online Resource for Latest Information
  119. 119.  Raw Materials ◦ An assessment of Raw Material attributes conducted. ◦ Based on process risk assessment ◦ Sources of variability were identified ◦ Following were identified for Excipient A  Particle size  Bulk Density  Peroxide content  Potential link to : Dissolution , Disintegration and Impurity levels 8/6/2015 119 Drug Regulations : Online Resource for Latest Information
  120. 120.  Raw Materials ◦ A review of specifications was conducted  “Use” value of peroxide content were significantly below Internal Specifications  Internal specifications were above CoA specifications  Incoming lots tested within specifications but well outside of typical experience with the product 8/6/2015 120 Drug Regulations : Online Resource for Latest Information
  121. 121.  Raw Materials ◦ Monitoring action plans were developed to  Review supplier capability  Establish a revised internal specification for peroxide content 8/6/2015 121 Drug Regulations : Online Resource for Latest Information
  122. 122.  In –process controls ◦ Review  Tablet hardness identified for enhanced monitoring  Linked to complaints : Broken tablets  Review hardness retrospectively  Tighten the control on the low end of the specification  Reduce tablet breakage  Maintain dissolution / disintegration properties 8/6/2015 122 Drug Regulations : Online Resource for Latest Information
  123. 123.  Quality System Elements ◦ Review  Stability  Warehousing/storage/sampling  Customer complaints  Equipment Preventive Maintenance/Calibration  Deviations ◦ Tablet hardness was selected for enhanced monitoring as mentioned earlier due complaints of broken tablets. 8/6/2015 123 Drug Regulations : Online Resource for Latest Information
  124. 124.  Process Performance Assessment ◦ Items identified for enhanced monitoring were evaluated via statistical control charts ◦ Identify actions when established control chart values are exceeded. ◦ At pre determined milestones conduct reviews to identify additional actions ◦ Summary of monitoring plan is given in subsequent slides. 8/6/2015 124 Drug Regulations : Online Resource for Latest Information
  125. 125. 8/6/2015 125 Drug Regulations : Online Resource for Latest Information
  126. 126. 8/6/2015 126 Drug Regulations : Online Resource for Latest Information
  127. 127. 8/6/2015 127 Drug Regulations : Online Resource for Latest Information
  128. 128. 8/6/2015 128 Drug Regulations : Online Resource for Latest Information
  129. 129.  This presentation is compiled from freely available resource like the website of FDA, EMA and publically available literature from websites of PDA, ISPE and DIA.  “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. 8/6/2015 12 9 Drug Regulations : Online Resource for Latest Information

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FDA Process Validation Guidance (Guidance for Industry: Process Validation- General Principles and Practices, Jan. 2011) outlines process validation activities in three stages - Stage 1: Process Design, Stage 2: Process Qualification and Stage 3: Continued Process Verification. Completion of Stage 2 subsequent to Stage 1 is a major milestone in the Process Validation Lifecycle as it confirms the process design and demonstrates the expected consistent performance of the manufacturing process. Knowledge and information gained from the design stage through the process qualification stage is used to complete this assessment. Stage 2 demonstrates suitability for successful commercial distribution where the data indicates that the process meets the conditions established in the protocol. Continued Process Verification is initiated for the subsequent commercial batches. Stage 3 assures that the process remains in a state of control during commercial manufacture. This presentation gives a practical approach to implement the stage 3 of the FDA Process Validation Guide.

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