Product quality review

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Product quality review

  1. 1. Presentation prepared by “Drug Regulations” a not for profit organization. www.drugregulations.org
  2. 2.  This presentation will cover ◦ Regulations ◦ Objectives ◦ Comparison of objectives: WHO/EMA / FDA/ ICH ◦ How to perform ◦ How to perform: Comparison of WHO/EMA/FDA/ICH ◦ Procedure for review :Comparison of WHO/EMA/FDA/ICH ◦ Data Analysis ◦ Responsibility : Comparison of WHO/EMA/FDA/ICH This presentation has been prepared form publicly available material on the World Wide Web.
  3. 3.  Required to be completed annually  Incorporates a review of multiple aspects  Determines impact on the quality of the finished product and active ingredients.
  4. 4.  Powerful quality management tool  Covers all aspects of the supply chain ◦ Starting materials ◦ Process ◦ Process environment ◦ Process output (product)
  5. 5.  WHO ◦ Good manufacturing practices for pharmaceutical products: main principles , Annex 2 , 1.10  EMA – Part 1 of EU GMP , Chapter 1, 1.10 ◦ Draft published in November 2005 ◦ Effective from January 2006
  6. 6.  FDA: 21CFR 211. 180(e) ◦ Requirement published in September 1978 ◦ Effective March 1979 ◦ Commonly referred as “Product Annual Review”.  ICH : Q7A – section 2.5 and 12.6 ◦ Adopted by FDA in August 2001 ◦ Adopted by EMA in October 2005 , part II EU GMP covering Basic Requirements for Active Substances used as starting materials.
  7. 7. Objectives EMA FDA Q7A WHO Verifying the consistency of the existing process Specified x Specified Specified Verifying the appropriateness of current specifications for starting materials Specified x x Specified Verifying the appropriateness of or need for change in current specifications for Finished Products Specified Specified x Specified Need for changes in Manufacturing or control procedure x Specified x x To highlight any trends Specified x x Specified
  8. 8. Objectives EMA FDA Q7A WHO To identify product improvements Specified x x Specified To identify process improvements Specified x x Specified To evaluate the need for Corrective and preventive actions Specified x Specified Specified To evaluate the need for Revalidation of production process Specified x Specified Specified
  9. 9.  Normally annually  Deviation from p.a. basis possible but has to be justified(cf. objectives of the PQR) ◦ e.g. when number of batches produced is too small for trending  Periodic or rolling - both acceptable  Previous reviews should be taken into account
  10. 10.  Procedure should be described in an SOP in order to ensure that: ◦ Report is available soon after end of respective period ◦ All batches are considered (no gaps) ◦ Report concludes with assessment, whether / to what extent CAPA or revalidation should be undertaken
  11. 11.  Especially those from new sources.  Summary of all batches received in a year and their approval status;  Summary of the suppliers/manufacturers of the materials;
  12. 12.  Compilation and analysis of  Analytical tests for key quality attributes  Description  Identification  Loss on drying/water content by Karl Fisher  Particle size  Related substances  Assay;
  13. 13.  Compilation and analysis of  Certificate of analysis (COA) results obtained from Supplier/manufacturer  Details significant deviations observed such as rejection of vendor lots
  14. 14.  Compilation(s) and analysis of  In-process test results obtained from the total number of batches manufactured in that particular year e.g.  Weight variation,  Dimension,  Friability,  Hardness,  Disintegration time,  Fill volume variation (such as for ampoules, vials, bottles), pH, etc
  15. 15.  Compilation(s) and analysis of  Finished product test results  Description/appearance  Identification  pH  Loss on drying/Water by KF  Viscosity  Dissolution test  Impurities and related substances  Degradation product (if any) and  Assay.
  16. 16.  Compilation(s) and analysis of  Summary of the number of failed batches/products.  Identify the batches that failed specifications  root cause for this failure, if identified  Summary of the reasons for failure  Assignable causes  Non-assignable causes  Summary of the completed investigation report(s)  Corrective actions taken.
  17. 17.  Compilation(s) and analysis of  Significant deviations  Non-conformances  Related investigations  Effectiveness of resultant corrective and preventive actions taken  Causes of the non-conformance, sorted based on data trending  Trend analysis of corrective and preventive actions (CAPA) taken
  18. 18.  Compilation(s) and analysis of  All changes carried out to the processes  Mixing time  Blending time  Drying time  Coating process  Compression speed/time  Filling speed  Review/report of the impact of the changes on the quality of the product.
  19. 19.  Compilation(s) and analysis of  All changes carried out to the analytical methods  Solvents  Buffers  Reagents  pH  Composition of mobile phase  HPLC/GC method parameters  i.e. flow rate, temperature, wavelength, run time, and change of HPLC/GC column  Review/report of the impact of the changes on the quality of the product.
  20. 20.  Compilation(s) and analysis of  Marketing Authorization variations submitted/granted/refused, including those for third country (export only) dossiers.  Number of products registered with local and overseas authorities that were covered in the review document, if grouping by product type are done.  Changes made to the product specification and their status of approval. Document the regulatory decision.  Number of products submitted but not approved/refused by the local and overseas authority
  21. 21.  Compilation(s) and analysis of  Results of the stability monitoring programme and any adverse trends.  Number of batches included for stability studies during the review period and the reasons for their selection.  Stability study report and results, i.e.  Out of specifications for each conditions (real time/long term and accelerated studies),  Review of the results obtained for stability indicating analytical tests.
  22. 22.  Compilation(s) and analysis of  Quality-related product returns, complaints and recalls  Investigations performed at the time.  Batches returned due to potential quality defects, together with the reasons.  Market complaints received in a year, together with the nature of complaints.  Batches recalled, together with the reasons.  Investigation reports prepared following market complaints and the actions taken to prevent recurrence.
  23. 23.  Compilation(s) and analysis of  Summary of all corrective actions from previous product quality review reports  Implementation status of each of the corrective actions  Their effectiveness in addressing the problems.
  24. 24.  Compilation(s) and analysis of  FOR New marketing authorizations and variations to marketing authorizations,  Review of post-marketing commitments.  Changes, in terms of the specifications  registered with drug regulatory authority, including overseas drug regulatory authorities.  Post-marketing commitments  Review of status of these commitments
  25. 25.  Compilation(s) and analysis of  The qualification status of relevant critical equipment and utilities,  e.g. HVAC, water, compressed gases, etc.  Number of equipment / instruments  production and laboratory department.  Qualification/re-qualification status of equipment / utilities  production processes and QC laboratory
  26. 26.  Compilation(s) and analysis of  The actual results of qualification, maintenance and calibration etc. would not be required in the PQR.  The Product Quality Report should cross reference to the respective validation reports.  Information available in the validation report need not be repeated in the PQR.
  27. 27.  Compilation(s) and analysis of  Review of Technical Agreements to ensure that they are up to date.  Review of written contract covering the technical requirements on periodic maintenance of production and laboratory equipment between the manufacturer and supplier.  A summary report would be sufficient.
  28. 28.  Compilation(s) and analysis of  Review of written contract covering the technical requirements between contract giver and contract acceptor (if any).  A summary report would be sufficient.  Determine whether there is a need to revise/update the technical agreements.
  29. 29. Items for Review EMA FDA Q7A WHO A review of a representative number of batches, whether approved or rejected, and, where applicable, records associated with the batch X Specified X x Review of starting /packing materials especially from new sources Specified X X Specified Review of supply chain traceability for active substances Specified X Specified Specified Review of critical in-process & finished product results. Specified X Specified Review of all batches that failed to meet specifications & their investigations Specified X Specified Specified
  30. 30. Items for Review EMA FDA Q7A WHO A review of all significant deviations or non-conformances, their related investigations, and the effectiveness of resultant corrective and preventive actions taken Specified X Specified Specified A review of all changes carried out to the processes or analytical methods Specified X Specified Specified A review of Marketing Authorisation variations submitted, granted or refused, including those for third country (export only) dossiers. Specified X X Specified A review of the results of the stability monitoring programme and any adverse trends. Specified X Specified Specified
  31. 31. Items for Review EMA FDA Q7A WHO A review of all quality-related returns, complaints and recalls and the investigations performed at the time. Specified Specified Investigations under under 211.192 Specified Specified A review of adequacy of any other previous product process or equipment corrective actions Specified X X Specified For new marketing authorisations and variations to marketing authorisations, a review of post- marketing commitments Specified X X Specified Review of qualification status of relevant equipment and utilities, e.g. HVAC, water, compressed gases, etc Specified X X Specified A review of any contractual arrangements as defined in Chapter 7 to ensure that they are up to date Specified X X Specified
  32. 32. Procedure EMA FDA Q7A WHO Frequency Annually Annually x Annually Account for previous reviews Should be taken into account X X Should be taken into account Groupings by product type Specified X X Specified Products All authorised medicinal products, including export only products, X X All products including export only products. Written Procedure Not specified Specified. X Specified Written Report Specified X Specified Specified Completion of corrective action in a timely manner Specified X Specified Specified Ongoing management review of follow up actions as part of self inspection specified X x Specified
  33. 33.  Should not be a meaningless listing of data.  Should review of all required components including:  Appropriate summary; evaluation and interpretation of the information available on the manufacturing process.  Should have the capability of detecting long term trends.  Should not be considered in isolation and should be linked to the findings of previous reviews.
  34. 34.  Controlling and improving processes and quality  Highlighting areas for focusing resource thereby:- ◦ Decreasing risk of out-of specification results. ◦ Decreasing downtime and increasing productivity. ◦ Decreasing the risk of product recall. ◦ Enhancing regulatory compliance. ◦ Improving communication across all areas including production, engineering, quality and regulatory functions.
  35. 35.  Enhancement of visibility where manufacturing operation are contracted out  (production, distribution, testing etc).  Improvement of product quality  Contributing to the protection of public and animal health.
  36. 36.  Trend data using appropriate statistical techniques to draw the conclusions. ◦ Time series plots ◦ Control charts ◦ Process capability study
  37. 37.  Facilitates corrective or preventive action should the process be out of control.  Determines if  (i) the process is in control; and  (ii) the process is capable.
  38. 38.  Establishes control limits through trending  Determines the appropriateness of the specifications for starting materials and Finished products.  Determines trends to identify product & process improvements.  Trigger to initiate action if process is out of control or has low capability.
  39. 39.  Shewhart Control Charts.  X-bar charts, R-charts and Moving Range charts etc.  Enables  Determination of upper and lower control limits  Identification of trends  upward trend of data, shift in mean etc  Appropriate actions may be taken before out-of specification occurs.
  40. 40. An Xbar chart is used to observe and evaluate the behavior of a process over time and take corrective action if necessary. The chart plots the average values of each of a number of small sampled subgroups. It is usually plotted in conjunction with the R (Range) Chart or the s (Standard Deviation) Chart A. Sample Mean B. Sample Number C. Lower Control Limit (LCL) D. Process Average E. Upper Control Limit (UCL) F. Plot of the individual sample Means vs sample number. Out of Control Point
  41. 41. A = Sample Range – B = Sample Number C= Lower Control Limit (LCL) D. Process Average Range – E. Upper Control Limit (UCL) – F. Plot of the Range values vs sample number. The R Chart plots the range values, or the difference between the highest and lowest values, for a series of subgroups. 
  42. 42. A. Sample StDev – B. Sample Number – C. Lower Control Limit (LCL) – D. Process Average – E. Upper Control Limit (UCL) F. Plot of the sample Standard Deviation values vs sample number. The chart plots the standard deviation of each of a number of sampled subgroups
  43. 43.  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
  44. 44. USL = Upper Specification Limit, LSL = Lower Specification Limit.
  45. 45.  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)
  46. 46.  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.
  47. 47. 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.
  48. 48. 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.
  49. 49.  Other types of statistical techniques may also be used ◦ Proper Interpretation of statistical analysis ◦ Conclusions to be drawn ◦ Determine whether the processes are in control and capable. ◦ Initiate action if process are out of control
  50. 50. Procedure EMA FDA Q7A WHO Responsibility to ensure accurate & timely review Specified X X Specified Contract manufacturer responsibility Specified X X Specified
  51. 51.  Important aspect of Good Manufacturing Practice.  Manufacturer and marketing authorization holder, (where different) should evaluate the results of this review  Assess if (CAPA) is required  Assess if revalidation is required  Complete corrective actions in a timely and effective manner.
  52. 52.  If M A holder is not the manufacturer, have a technical agreement to define responsibilities  Authorized person and marketing authorization holder should ensure that the Review is performed in a timely manner and is accurate.  Reviews should be signed by the authorized person and/or Marketing Authorization Holder.

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