Overview of the Regulation of Blood and cGMPs

1. Overview of the Regulation of Blood and cGMPs Sheryl A. Kochman Deputy Director, DBA, OBRR, CBER September 15, 2009

2. Outline • General Principles • Overlapping Layers of Blood Safety • Regulatory Terms • Regulation of Blood • Current Good Manufacturing Practices (cGMPs) • Licensure and What to Submit • Contacts at OBRR

3. General Principles • Ensure the safety, effectiveness, and availability of blood and blood products • Protect the health of the donor and recipients • Ensure that the blood collected is safe for transfusion or further manufacture • Regulation/requiring screening tests cGMPs

4. 5 Overlapping Layers of Blood Safety • 1st Donor screening - Potential donors are provided educational materials and asked specific questions by trained personnel about their health and medical history • 2nd The blood is tested for transfusion transmissible agents • 3rd Blood establishments must keep current a list of individuals who have been deferred as blood or plasma donors • 4th Blood products are quarantined until the products have been thoroughly tested and the donation records have been verified. • 5th Blood establishments must investigate any breaches of these safeguards and correct system deficiencies

5. Regulatory Terms • Statute • Regulation • Recommendation • Authorities

6. Laws, Acts Passed by Congress Highest level of authority Binding on both agency and industry No flexibility Statutes

7. Regulations • 21 CFR 10.3 • Regulations are an agency rule of general or particular applicability and future effect issued under a law administered by the Commissioner or relating to administrative practices and procedures. In accordance with 10.90(a), each agency regulation will be published in the Federal Register and codified in the Code of Federal Regulations.

8. Regulations (cont) • Announced in Federal Register (FR) & Codified in Code of Federal Regulations (CFR) • 21 CFR 10.80 & 21 CFR 10.90(a) • Promulgated by an agency • Carry the force of law • Binding on both agency and industry • Allow for some flexibility • May become obsolete and need to be periodically reviewed, updated or revoked; takes time to accomplish

9. Recommendations • Guidance documents • FDA’s recommendations (current considerations) on how to comply with statutes and regulations • Developed under Good Guidance Practices 21 CFR 10.115 • Level 1 or Level 2 document • Not binding on FDA or regulated industry • Found on FDA website http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Blood/default.htm

10. Recommendations (cont) 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.  If you cannot identify the appropriate FDA staff, call the appropriate number listed on the title page of this guidance.

11. Other Information Also found on the website in: • CBER SOPPs and Office-specific SOPs http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/ProceduresSOPPs/default.htm • Memorandums http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/OtherRecommendationsforManufacturers/MemorandumtoBloodEstablishments/default.htm

12. Regulatory Oversight for Blood • Food, Drug, and Cosmetic Act (FD&C Act) • Public Health Service Act (PHS Act) • Section 351 • Title 21 Code of Federal Regulations (CFR)

13. FD&C Act Some sections important to blood • Section 201 - Definitions • Section 301 – Prohibited Acts • Section 501 - Adulteration • Section 502 - Misbranding • Section 510 – Registration • Section 704 – Factory Inspection http://www.fda.gov/RegulatoryInformation/Legislation/FederalFoodDrugandCosmeticActFDCAct/default.htm

14. PHS Act • Requires licensure for some biological products, i.e. those in interstate commerce • No person shall introduce or deliver for introduction into interstate commerce any biological product unless: • A biologics license is in effect • Each package of biological product is plainly marked • Biological product is safe, pure, potent and effective • Facility where product is manufactured meets standards • Applicant consents to inspection • Secretary establishes requirements for approval, suspension and revocation of biologics license http://www.fda.gov/RegulatoryInformation/Legislation/ucm148717.htm

15. Significance of Licensure • Signifies FDA approval of product(s) and facility • License number appears on label of product(s) approved in application • Allows shipment of product(s) in interstate commerce

16. cGMP Regulations • 21 CFR 210 & 211s - Finished Pharmaceuticals • First published in FR in 1963 (26 FR 6385) • 21 CFR 606s – Blood and Blood Components • Final Rule published in 1975 (40 FR 53532)

17. 21 CFR Part 210cGMP In Manufacturing, Processing, Packing, Or Holding Of Drugs; General • 210.1 - Status of current good manufacturing practice (cGMP) regulations • 210.2 - Applicability of cGMP regulations • 210.3 - Definitions

18. 21 CFR Part 211 cGMP For Finished Pharmaceuticals • Subpart A - General Provisions • Subpart B - Organization and Personnel • Subpart C - Buildings and Facilities • Subpart D - Equipment • Subpart E - Control of Components, Containers, Closures • Subpart F - Production and Process Controls • Subpart G - Packaging and Labeling Control • Subpart H - Holding and Distribution • Subpart I - Laboratory Controls • Subpart J - Records and Reports • Subpart K - Returned & Salvaged Drug Products

19. Why Follow Drug cGMPs? • 43 FR 18614 (May 28, 1974) • Blood and blood components are used in diagnosis, cure, mitigation, treatment, or prevention of disease in man • Therefore blood meets definition of drug in section 201(g) of FD&C Act • Blood products, including Source Plasma, must meet all statutory requirements of FD&C Act

20. Title 21 CFR Subchapter F(Biological Product Regulations) • 600 - General • 601 - Licensing • 606 - Current Good Manufacturing Practices • 607 - Registration • 610 - General biological product standards • 630 - General requirements for blood • 640 - Additional standards for blood and blood products

21. Quality Guidance Documents • Guideline of General Principles of Process Validation (May 1987) http://www.fda.gov/drugs/guidancecomplianceregulatoryinformation/guidances/ucm124720.htm • Guide to Inspections of Quality Systems (QSIT) (August 1999) http://www.fda.gov/iceci/inspections/inspection guides/ucm074883.htm

22. Licensure

23. Some Definitions • BLA – Biologics License Application • Application - Original submission requesting a U.S. license • Supplement - Submission to request change to an existing approved license application • Amendment - Information submitted to an unapproved application or supplement to revise or modify the submission • Submission – Application, supplement, amendment, labeling, product correspondence

24. How Do I Know What to Submit? • 21 CFR 601.2 • 21 CFR 601.12 • Form FDA 356h • Broad Guidance 5/10/1999 CMC guidance for blood and blood components • Product-specific Guidance

25. What to Submit for a New BLA 21 CFR 601.2 • An application on forms prescribed for such purposes • Data which demonstrate that the manufactured product meets prescribed requirements of safety, purity, and potency • A full description of manufacturing methods • Data establishing stability through the dating period • Samples representative of the product for introduction or delivery for introduction into interstate commerce;

26. 21 CFR 601.2 (cont) • Summaries of results of tests performed on the lots represented by the submitted samples • Specimens of the labels, enclosures, and containers • The address of each location involved in the manufacture • A claim for categorical exclusion under 25.30 or 25.31 or an environmental assessment under 25.40 of this chapter

27. 21 CFR 601.2 (cont) An application shall not be considered as filed until all pertinent information & data have been received by FDA

28. What to Submit • Guidance for Industry For the Submission of Chemistry, Manufacturing and Controls and Establishment Description Information for Human Blood and Blood Components Intended for Transfusion or for Further Manufacture and For the Completion of the Form FDA 356h "Application to Market a New Drug, Biologic or an Antibiotic Drug for Human Use"  5/10/1999

29. What to Submit (cont) • http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Blood/ucm077087.htm • See also Product-specific Guidance • http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Blood/default.htm

30. What to Submit for Supplements • 21 CFR 601.12 • Guidance for Industry: Changes to an Approved Application: Biological Products: Human Blood and Blood Components Intended for Transfusion or for Further Manufacture  8/07/2001 • http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Blood/ucm076729.htm

31. What to Submit for a Prior Approval Supplement (PAS) 21 CFR 601.12(b)(3) • (i) A detailed description of the proposed change; • (ii) The product(s) involved; • (iii) The manufacturing site(s) or area(s) affected; • (iv) A description of the methods used and studies performed to evaluate the effect of the change on the identity, strength, quality, purity, or potency of the product as they may relate to the safety or effectiveness of the product; • (v) The data derived from such studies; • (vi) Relevant validation protocols and data; and • (vii) A reference list of relevant SOPs.

32. What to Submit for a “Changes Being Effected in 30 Days” Supplement (CBE30) 21 CFR 601.12(c)(3) • The information listed in paragraph (b)(3)(i) through (b)(3)(vii) of this section shall be contained in the supplement • Include statement: “Supplement – Changes Being Effected in 30 Days”

33. What to Submit for a “Changes Being Effected” Supplement (CBE) 21 CFR 601.12(c)(3) & (c)(5) • The information listed in paragraph (b)(3)(i) through (b)(3)(vii) of this section shall be contained in the supplement • Include statement: “Supplement – Changes Being Effected”

34. What to Submit for an Annual Report (AR) 21 CFR 601.12(d)(3) • (i) A list of all products involved; and • (ii) A full description of the manufacturing and controls changes including: the manufacturing site(s) or area(s) involved; the date the change was made; a cross-reference to relevant validation protocols and/or SOPs; and relevant data from studies and tests performed to evaluate the effect of the change on the identity, strength, quality, purity, or potency of the product as they may relate to the safety or effectiveness of the product. • (iii) A statement by the holder of the approved application or license that the effects of the change have been assessed.

35. What to Submit for a Comparability Protocol (CP) 21 CFR 601.12(e) • Describe: • Specific tests • Validation studies • Acceptable limits to be achieved • Demonstrate lack of adverse effect of manufacturing changes on the identity, strength, quality, purity, or potency of the product as related to the safety or effectiveness of the product

36. What to Submit for a Labeling Change 21 CFR 601.12.(f)(1) • Description of the proposed change • Information necessary to support the proposed change • See also 21 CFR 601.12 (f)(2) & (f)(3)

37. What to Submit (cont) • See also Product-specific Guidance • http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Blood/default.htm

38. Contact Information • Mailing Address Director, Division of Blood Applications OBRR, CBER, FDA HFM-370 c/o Document Control Center, HFM-99 1401 Rockville Pike, Suite 200N Rockville, MD 20852-1448 • Telephone – (301) 827-3543 • Fax – (301) 827-3534 • Blood and Plasma Branch Consumer Safety Officers

39. Brenda Bell Karan Blum Judy Ciaraldi Marla Cohen Lore Fields Michael Gorman Diane Hall Jennifer Jones Rosia Nesbitt Hoi May Wong Blood and Plasma BranchChiefLeslie Holness, MDBlood Registration CoordinatorJan O’BrienConsumer Safety Officers

40. Division of Blood Applications • Division Director – Richard J. Davey, MD • Deputy Director – Sheryl A. Kochman • Chief, Blood and Plasma Branch – Leslie Holness, MD • Chief, Regulatory Project Management Branch – Jeffrey Anderson • Chief, Devices Review Branch – Teresita Mercado

41. Director Jay S. Epstein, M.D. Deputy Director Ginette Michaud, M.D. Acting Assoc. Director for Medical and Scientific Affairs Basil Golding, M.D. Assoc. Director for Regulatory Affairs Alan E. Williams, Ph.D. Associate Director for Research C.D. Atreya, Ph.D. Associate Director for Policy Jennifer Scharpf   Policy and Publication Staff Division of Emerging & Transfusion Transmitted Diseases Director Hira L. Nakhasi, Ph.D. Deputy Director Paul Mied, Ph.D. Division of Hematology Director Basil Golding, M.D. Deputy Director Susan Abbondanzo, M.D. Division of Blood Applications Director Richard J. Davey, M.D. Deputy Director Sheryl A. Kochman CBER, OFFICE OF BLOODRESEARCH ANDREVIEW