1. CBER 1 Normal Source Plasma Donor Program Rosia E. Nesbitt, BS, SBB(ASCP), CQA(ASQ) Consumer Safety Officer CBER, OBRR, DBA September 16, 2009

2. CBER 2 Outline Source Plasma Regulations Normal Source Plasma Donor Categories and Criteria Donor Questionnaire Informed Consent Requirements and Recommendations

3. CBER 3 Outline (cont.) Source Plasma Collection Plasmapheresis – Procedure Specific Requirements Source Plasma Testing Submission Content Review of Submission

4. CBER 4 Source Plasma The fluid portion of human blood collected by plasmapheresis and intended as a source material for further manufacturing use [21 CFR 640.60] Primarily collected by automated methods May be collected manually

5. CBER 5 Regulations Donor Suitability and Testing – 21 CFR 610s, 630s, and 640.60 – 65 Donation Records for SP – 21 CFR 640.72 Informed Consent – 21 CFR 640.61

6. CBER 6 Normal Source Plasma Intended Use – Injectable Products (e.g., plasma derivatives) – Noninjectable Products (e.g., reagents) – Research Source Plasma can only be distributed in interstate commerce if collected in a facility approved in a BLA [21 CFR 601.2]

7. CBER 7 Normal Source Plasma (cont.) Storage temperature: -20 C or colder [21 CFR 640.69(b)] Expiration Date: 10 years [21 CFR 610.53(c)]

8. CBER 8 Donor Categories Source Plasma can be obtained from the following donor types: – Normal, non-immunized – Immunized – Normal donor with an existing disease antibody (IgG only) – Donor in a disease state with an antibody (IgG and/or IgM) – Donor with a high risk status – Donor participating in an IND

9. CBER 9 Normal Source Plasma Donors Normal donor – must meet all donor suitability criteria Donation Interval: – Frequent Donation: every 2 days with no more than 2 times in 7 days [21 CFR 640.65 (b)(8)] – Infrequent Donation: every 28 days or less frequently FDA Memorandum: Revision of FDA Memorandum of August 27, 1982: Requirements for Infrequent Plasmapheresis Donors (March 10, 1995)

10. CBER 10 Donor Criteria [21 CFR 640.63(a)] The suitability of a donor for Source Plasma shall be determined by a qualified licensed physician or by persons under his supervision and trained in determining donor suitability. Determination shall be made on the day of collection from the donor by means of: – Medical history – Tests – Physical examination as appears necessary to the qualified licensed physician.

11. CBER 11 Donor Criteria Examined by a qualified licensed physician [21 CFR 640.63(b)] – On the day of the first donation – No more than one week prior to the first donation – At subsequent interval of no longer than one year Adequately trained physician substitutes may perform some of the routine functions of a physician FDA Memorandum: Physician Substitutes (8/15/88)

12. CBER 12 Donor Criteria (cont.) Documentation: Each donor shall be certified to be in good health by the examining physician. The certification … shall indicate … the suitability of the individual to be a plasmapheresis donor… [21 CFR 640.63(b)(3)]

13. CBER 13 Donor Criteria [21 CFR 640.63(c)] Donor must be in good health as indicated by: – Normal temperature – Blood Pressure within normal limits – Hemoglobin ≥ 12.5 g/dL or hematocrit > 38%

14. CBER 14 Donor Criteria (cont.) [21 CFR 640.63(c)] – Normal pulse rate – A total protein ≥ 6.0 g/dL per 100 milliliters of serum – Donors must weigh at least 110 pounds

15. CBER 15 Donor Criteria (cont.) [21 CFR 640.63(c)] Freedom from acute respiratory diseases Freedom from infectious skin disease at the site of phlebotomy Freedom from any disease, other than malaria, which is transmissible by blood Freedom of the arms and forearms from skin punctures or scars indicative of drug addiction Freedom from a history of viral hepatitis after age 11

16. CBER 16 Donor Criteria (cont.) [21 CFR 640.63(c)] Freedom from a history of close contact within 12 months of donation with an individual having viral hepatitis Freedom from a history of having received, within 12 months, blood or blood products Any donor who appears to be under the influence of any drug, alcohol, or does not appear to be providing reliable answers to medical history questions, should not be considered a suitable donor

17. CBER 17 D onor Criteria (cont.) Donation Interval for Red Blood Cell Loss 8 weeks if Red Blood Cells (RBC) are not returned to donor [21 CFR 640.63(e)] Recommendations: > 200 mL RBC loss defer donor for 8 weeks < 200 mL RBC loss can continue to donate – If the donor has a second Red Blood Cell loss in 8 weeks then defer the donor for 8 weeks from the most recent loss. FDA Memo: Donor Deferral Due to Red Blood Cell Loss During Collection of Source Plasma by Automated Plasma Pheresis (December 4, 1995)

18. CBER 18 Donor Questionnaire – The facility shall provide adequate space for the private and accurate examinations of individuals to determine their suitability as blood donors [21 CFR 606.40(a)(1)] – Suitability must be determined on day of donation [21 CFR 640.63(a)]

19. CBER 19 Donor Questionnaire (cont.) Donors are asked a series of questions about: – Medical history – High risk behavior – Potential exposure to transfusion transmissible diseases

20. CBER 20 Donor Questionnaire (cont.) HIV signs and symptoms FDA Memo: Revised Recommendations for the Prevention of HIV Transmission by Blood and Blood Products (April 23, 1992)

21. CBER 21 Donor Questionnaire (cont.) – Travel in endemic areas HIV-1 Group O vCJD

22. CBER 22 HIV-1 Group O Deferral: References FDA Memo: Interim Recommendations for Deferral of Donors at Increased Risk for HIV-1 Group O Infection, (December 11, 1996) http://www.fda.gov/downloads/BiologicsBloodVaccines/Guid anceComplianceRegulatoryInformation/OtherRecommendati onsforManufacturers/MemorandumtoBloodEstablishments/U CM062591.pdf Recommendations for Management of Donors at Increased Risk for Human Immunodeficiency Virus Type 1 (HIV-1) Group O Infection (August 2009) http://www.fda.gov/BiologicsBloodVaccines/ GuidanceComplianceRegulatoryInformation/Guidances/defau lt.htm

23. CBER 23 vCJD Risk Deferral: References Guidance for Industry: Revised Preventive Measures to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob Disease (CJD) and Variant Creutzfeldt-Jakob Disease (vCJD) by Blood and Blood Products (January 2002) http://www.fda.gov/BiologicsBloodVaccines/SafetyAvailabili ty/BloodSafety/ucm095143.htm Questions and Answers on FDA Guidance: Revised Preventive Measures to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob (CJD) Disease and Variant Creutzfeldt-Jakob Disease (vCJD) by Blood and Blood Products http://www.fda.gov/BiologicsBloodVaccines/SafetyAvailabili ty/BloodSafety/ucm095140.htm

24. CBER 24 Informed Consent Requirements The written consent of a prospective donor shall be obtained after a qualified licensed physician has explained the hazards of the procedure to the prospective donor. [21 CFR 640.61] You must maintain the donor's written informed consent in the donor's record. [21 CFR 606.160(b)(1)(i) & 640.72(a)(3)] The explanation of hazards must consist of such disclosure and be made in such a manner that intelligent and informed consent is given and that a clear opportunity to refuse is presented [21 CFR 640.61].

25. CBER 25 Informed Consent Recommendations Guidance for Industry: Informed Consent Recommendations for Source Plasma Donors Participating in Plasmapheresis and Immunization Programs (June 2007) http://www.fda.gov/BiologicsBloodVaccines/Guida nceComplianceRegulatoryInformation/Guidances/B lood/ucm073433.htm http://www.fda.gov/BiologicsBloodVaccines/Guida nceComplianceRegulatoryInformation/Guidances/B lood/ucm073433.htm

26. CBER 26 Informed Consent Recommendations (cont.) Donor should be given an opportunity to ask questions Participation is voluntary, donor may withdraw at anytime Acceptability is determined by physical examination, medical history, laboratory testing Informed consent should be signed by donor and physician

27. CBER 27 Informed Consent Recommendations (cont.) Potential consequences if results of test for communicable disease agents are reactive, positive, or outside of normal limits – Donor will be notified [21 CFR 630.6] – Temporary or permanent deferral [21 CFR 610.41] – Entry of the donor’s identification information in a deferral registry [21 CFR 606.160(e)] – Reporting of positive test results to public health officials

28. CBER 28 Informed Consent Recommendations (cont.) Information concerning the “window period” for infection A caution that the donor should participate in only one plasmapheresis program at a time Records are subject to inspection by FDA and other regulatory agencies A statement that the donor has read and understands the material on high risk groups and that he/she is not at risk for transmitting HIV infection to others

29. CBER 29 Informed Consent Recommendations (cont.) Description of possible donor reactions/hazards from procedure – Blood loss from the inability to return blood – Hematomas or localized infections at venipuncture site – Tingling of lips or finger or muscle cramping due to the citrate anticoagulant

30. CBER 30 Informed Consent Recommendations (cont.) Description of possible donor reactions/hazards from procedure (cont.) – Allergic reaction such as flushing, itching, hives, abdominal cramps, difficulty breathing, chest pain, or bronchospasm, which may be life threatening – Nausea, vomiting, light-headedness, fainting, seizures – Any other adverse reaction specified by the manufacturer of the automated collection device

31. CBER 31 Source Plasma Collection Donor Identification: Each Source Plasma unit must be identified by number or other symbol to relate it directly to donor. [21 CFR 640.64(d)] Prevention of the contamination of the plasma: Skin at site of phlebotomy should be cleaned thoroughly to give maximum assurance of sterility. [21 CFR 640.64(e)]

32. CBER 32 Plasmapheresis – Procedure Specific Requirements Syphilis and Serum Protein Electrophoresis (SPE) – tested initially at first examination and at least every 4 months thereafter

33. CBER 33 Plasmapheresis – Procedure Specific Requirements (cont.) Accumulated laboratory data must be reviewed by a licensed physician within 21 days after sample is drawn to determine if donor may continue in the plasmapheresis program. The review must be signed by the reviewing physician. [21 CFR 640.65 (b)(2)(i)] If the donor does not return to center within 6 months, he/she must be processed as a new donor [21 CFR 640.65(b)(1)(iii)]

34. CBER 34 Plasmapheresis – Procedure Specific Requirements (cont.) A donor identification system shall be established that positively identifies each donor and relates such donor directly to his blood and its components as well as to his accumulated records and laboratory data. Such system shall include either a photograph of each donor which shall be used on each visit to confirm the donor's identity, or some other method that provides equal or greater assurance of positively identifying the donor. [21 CFR 640.65(b)(3)]

35. CBER 35 Source Plasma Testing Each unit of Source Plasma must be tested using an FDA licensed test, for HBsAG, HCV, HIV-1, HIV-2 A sample of blood shall be drawn from each donor and tested for syphilis initially at first examination and at least every 4 months thereafter – [21 CFR 610.40] – [21 CFR 640.65(b)(1)]

36. CBER 36 Submission Content Submission should include sufficient information for FDA to determine if manufacturing is in compliance with FDA requirements and results in a product that is safe, pure and potent [21 CFR 601.2 & 601.12] Form FDA 356h Name of facility (address, registration number) Date collection began Include intended use – Injectable, noninjectable, research

37. CBER 37 Submission Content (cont.) Collection instrument (model, version no.) Description of operator training Computer system – 510(k) cleared Physician substitute program under 640.120

38. CBER 38 Submission Content (cont.) Description of medical oversight Description of quality oversight program Label and Form FDA 2567, if applicable Form FDA 2830 or reference an electronic one Contractors Testing lab Off-site storage

39. CBER 39 Submission Content (cont.) SOPs Donor suitability, including donor deferral Blood Collection, including the preparation of arm for phlebotomy High risk behavior, including AIDS information Donor history forms, including Informed Consent Quarantine and disposition of unsuitable products Physician Substitute training program

40. CBER 40 Submission Content (cont.) Submit as a PAS if operating under an existing license or as a new Biologic License Application (BLA) For PAS, may reference previously approved SOPs, forms and labeling (include STN)

41. CBER 41 Review of Submission Preliminary review for completeness and accuracy Assign Submission Tracking Number (STN) Applicant notified of STN by letter In-depth review of contents Communicate with applicant if additional information is needed Schedule pre-approval or pre-license inspection