1. FDA Recommendations: Sampling Plans for Blood Establishments Lore Fields MT(ASCP)SBB Consumer Safety Officer OBRR/CBER/FDA October 19, 2012

2. Agenda Product Validation Regulations and Guidance Red Blood Cells by Apheresis Validation and QC Plans Platelet Pheresis Validation and QC Plans Red Blood Cells, Leukocytes Reduced Validation and QC Plans

3. Agenda (cont.) Binomial vs hypergeometric plans for quality control sampling How to submit an alternative approach for quality control

4. Regulations Guidance Documents

5. Process Validation process validation is defined as the collection and evaluation of data, from the process design stage throughout production, which establishes scientific evidence that a process is capable of consistently delivering quality products.

6. The CGMP regulations for validating pharmaceutical (drug) manufacturing require that drug products be produced with a high degree of assurance of meeting all the attributes they are intended to possess (21 CFR 211.100(a) and 211.110(a)).

7. Regulations Sec. 211.110 Sampling and testing of in- process materials and drug products. (a) “… Such control procedures shall be established to monitor the output and to validate the performance of those manufacturing processes…”

8. Regulations Sec. 211.110 Sampling and testing of in- process materials and drug products. b) “Valid in-process specifications for such characteristics shall be consistent with drug product final specifications…determined by the application of suitable statistical procedures…”

9. Regulations 21 CFR 606.60(a) “equipment be observed, standardized and calibrated on a regularly scheduled basis as prescribed in the Standard Operating Procedures Manual and must perform in the manner for which it was designed.”

10. Guidance Documents Guidance is intended to help you ensure donor safety and the safety, purity, and potency of the product.

11. Guidance Documents Process Validation: General Principles and Practices January 2011

12. Current Considerations Quality, safety, and efficacy are designed or built into the product. Each step of a manufacturing process is controlled to assure that the finished product meets all design characteristics and quality attributes including specifications.

13. Current Considerations This guidance describes the process validation activities in three stages Stage 1 – Process Design: The commercial 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 confirmed as being capable of reproducible commercial manufacturing. Stage 3 – Continued Process Verification: Ongoing assurance is gained during routine production that the process remains in a state of control.

14. Guidance documents (cont.) Three guidance documents SPC plans will be discussed during this presentation: –Guidance for Industry: Recommendations for Collecting Red Blood Cells by Automated Apheresis Methods - Technical Correction February 2001 –Guidance for Industry and FDA Review Staff: Collection of Platelets by Automated Methods December 2007 –Final Guidance for Industry: Pre-Storage Leukocyte Reduction of Whole Blood and Blood Components Intended for Transfusion September 2012

15. Red Blood Cells by Apheresis Validation and Quality Control Guidance for Industry: Recommendations for Collecting Red Blood Cells by Automated Apheresis Methods Technical Correction, February 2001 http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegula toryInformation/Guidances/Blood/ucm076756.htm

16. Red Blood Cell Quality Control is performed in two phases: Phase one QC (validation) is done at the implementation of the automated blood cell separator device manufacturing Red Blood Cells Phase two QC is monthly testing of a representative sampling of manufactured products for all devices

17. Phase One Evaluate 100 consecutive RBC units The 100 consecutive units should represent units collected from each device in use at the collection center and from all collection protocols (e.g., single RBC and double RBC).

18. Phase One Evaluate 100 consecutive RBC units (cont.) If the evaluation of the data collected during this phase indicates that the collection procedure can be performed with at least 95% of the units meeting the product specifications described in the device operator's manual or on the product labeling

19. Phase One If more than 5% of the units fail to meet the product specifications, the cause of the deviations should be investigated and corrected as part of the overall quality assurance program and the Phase One qualification process should be repeated. Units that do not meet the acceptable ranges specified in the device operator's manual or in the product labeling should be evaluated to determine their suitability for distribution.

20. Phase Two Collect 50 units of apheresis Red Blood Cells at each collection facility At least 95% of the product tested in the sampling should meet the product specifications described in the device operator’s manual or on the product labeling.

21. Phase Two If more than 5% fail to meet the product specifications, the cause of the deviations should be investigated and corrected as part of the overall quality assurance program and the process should be repeated.

22. Sampling Plan Although this is not one of the more recent plans proposed by FDA it is still a recommendation for these products and you may continue to use it. Blood centers who wish to harmonize their sampling plans may submit alternate approaches to this plan to FDA for review.

23. Guidance for Industry and FDA Review Staff Collection of Platelets by Automated Methods, December 2007 http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegula toryInformation/Guidances/Blood/ucm073382.htm

24. Validation of the Collection Process We recommend that establishing documentation of process validation include, but not be limited to, validation protocol development, installation qualification, process operator performance qualification, and product performance component qualification.

25. Validation of the Collection Process You should conduct validation of the collection process using each type of device used in your establishment prior to implementing routine collections.

26. Validation of the Collection Process Validation Protocol An integral element of the performance and documentation of process validation is the development of a validation protocol. You should refer to FDA’s “Guideline on General Principles of Process Validation” as an outline for developing your validation protocol.

27. VALIDATION OF THE COLLECTION PROCESS Exceeding the allowable process failures of the collection process qualification may indicate that the process is not in control. You must investigate and correct the source of this failure (see 21 CFR 211.192, 606.100(c)) and should repeat validation.

28. Validation of the Collection Process You should select a statistically sound sample size for your product qualification.

29. Statistical Plans

31. If you select a sample size of 11 and find one failure, 11 additional samples would need to be tested with no additional failures.

32. Statistical Plans If you select a sample size of 60 and find one failure, 71 additional samples would need to be tested with no additional failures. If you select a sample size of 93 and find two failures, 163 additional samples should be tested with no failures. If you select a sample size of 124 and find three failures, 99 additional samples should be tested with no failures.

33. Quality Control Quality assurance (QA) is the sum of activities planned and performed to provide confidence that all systems and system elements that influence the quality of the component are functioning as expected. When this is demonstrated, the process is considered to be in a state of control.

34. Quality Control You must have a quality control (QC) unit that has the responsibility and authority to approve or reject all components… (21 CFR 211.22(a)).

35. Quality Control define a plan for non-selectively identifying collections to be tested. This should ensure testing of components collected on each individual automated blood cell separator device, each collection type, and each location.

36. Statistical Plan For Quality Control use either the binomial plan, hypergeometric plan, or another FDA approved scientifically sound plan.

37. Final Guidance for Industry: Pre- Storage Leukocyte Reduction of Whole Blood and Blood Components Intended for Transfusion, September 2012 http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegula toryInformation/Guidances/Blood/ucm320636.htm

38. Validation We recommend that establishing documentation of process validation include, but not be limited to, equipment installation qualification, validation protocol development, process operator performance qualification and product performance qualification

39. Validation Conformance to product standards must be assessed by a statistically valid method (see 21 CFR 211.160(b)). In the absence of a validation method (plan) provided by the manufacturer, you should develop a statistically valid plan based on 95% confidence that more than 95% of the components will meet the recommended results.

40. Leukocyte Reduction (LR) Performance Qualification Criteria for Blood and Blood Components

41. Statistical Plan TestRecommended ResultsTarget 1 Allowable Process Failures to achieve recommended results for a set of N tests 3 Percent component retention > 85% component95%/95%N=60N=93N=124 012 Residual WBC count ***** Single component: < 5.0 x 10 6 95% / 95%N= 60 collection s N=93 collectionsN=124 collection s 012

42. Quality Control Under 21 CFR 211.160(b), laboratory controls must include the establishment of scientifically sound and appropriate specifications, standards, sampling plans and test procedures. We will consider statistical plans that confirm a < 5% non- conformance rate with 95% confidence.

43. Quality Control One example of a scientifically sound statistical sampling and analytic plan is based on the binomial approach. Another example of a scientifically sound plan is based on the hypergeometric distribution. The hypergeometric plan is only for quality control sampling plans and cannot be used for validation.

44. Statistical Plans Other statistical plans may also be appropriate, such as the use of scan statistics will be considered if submitted to FDA

45. Statistical Plans For Validation and Quality control we recommend a binomial plan. This plan can be used for all blood products.

46. Statistical Plans For Quality Control you may use a hypergeometric plan

47. Statistical Plans

48. Putting It All Together, Using SPC Charts for Control SPC charts can be a critical part of achieving improvements, maintaining gains, and driving to a target. A controlled process should contain the following parts: –Specific statistical tools to track performance of important metrics and specifically identify when problems are occurring. –A written and specific procedure for how to deal with out of control problems before a failure occurs. –A process to follow up and verify that corrective action was effective and appropriate. –A closed loop process that continually assures the above parts are valid, up to date, and effective.

49. Example

50. Sampling Plans and SPC charts Two concepts can complement each other to reveal manufacturing variability and protect the patient. Data collected for sampling plan can be used to create SPC charts. Concept of Risk is tied to decision to select sampling plans and SPC charts.

51. Alternate Approach This guidance represents the Food and Drug Administration’s (FDA’s) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations. If you want to discuss an alternative approach, contact the appropriate FDA staff.

52. Alternate Approach Please submit your requests in writing to: Document Control Center Center for Biologics Evaluation and Research Richard Davey, M.D. 1401 Rockville Pike Suite 200N, HFM 99 Rockville, MD 20852-1448

53. Contacts Lore Fields MT(ASCP)SBB Consumer Safety Officer Blood and Plasma Branch Division of Blood Applications 301-827-6143 or your CSO at 301-827-3543