BLOOD PRODUCTS ADVISORY COMMITTEE

90^th Meeting – August 16, 2007

Bethesda, MD

Informational Presentations: FDA/WHO Biological Standards

A. Summary of January 29-30, 2007 WHO Meeting with WHO Collaborating Centres for Biological Standards and Standardization to Support the Development of WHO Biological Reference Preparations for Blood Safety-related in vitro Diagnostic Tests, Paul A. Mied, Ph.D., DETTD, OBRR, FDA

WHO Collaborating Centres for Biological Standards and Standardization:

National Institute for Biological Standards and Control (NIBSC)
Paul-Ehrlich-Institut (PEI)
Center for Biologics Evaluation and Research (CBER)

Meeting Convened by:

The Quality Assurance and Safety: Blood Products and Related Biologicals (QSD) team, Department of Medicines Policy and Standards (PSM), World Health Organization (WHO)

Location of the Meeting:

FDA/CBER, Bethesda, Maryland

Objectives of the Meeting:

To foster cooperation among the WHO Collaborating Centres for Biological Standards and Standardization.
To strengthen the development of WHO International Biological Reference Preparations for the control of in vitro diagnostic tests related to blood safety.

Intended Use of the WHO Biological Reference Preparations:

Validation, quality control, assessment of comparability, and regulation on a global basis of blood safety-related in vitro diagnostic tests, contributing to a harmonized regulation of blood and blood products.

Priority Projects Identified:

Replacement of Existing WHO Biological Reference Preparations near exhaustion:

1. Anti-HBs immunoglobulin (proposed 2^nd International Reference

Preparation)

2. HCV RNA (proposed 3^rd International Standard)

3. Parvovirus B19 DNA (proposed 2^nd International Standard)

4. Anti-Syphilitic Standard (proposed 2^nd International Standard)

New WHO Biological Reference Preparations Needed:

5. HIV-1 Genotype Panel (proposed 2^nd International Reference Panel)

6. HIV-2 RNA International Standard

7. Anti-HIV Panel (proposed 2^nd International Reference Panel)

8. HBsAg and HBV DNA Genotype Panels

9. Anti-HBc International Standard

10. Anti-HCV Panel

11. Anti-HTLV-I/II Panel

12. Anti-Plasmodium species Panel

13. Anti-Trypanosoma cruzi Preparation/Panel

C. Proposed WHO Biological Reference Preparations that need further discussion:

14. HIV-2 RNA Genotype Panel

15. HCV Genotype Panel

16. Parvovirus B19 Genotype Panel

17. Anti-CMV Standard

18. WNV RNA Preparation/Pan Panel for arthropod-borne flaviviruses RNA

19. HCV Core Antigen Preparation

20. Anti-HHV-8 and HHV-8 DNA Preparations

21. TSE Blood Preparations

22. Blood-borne Bacteria Panel

23. Anti-Leishmania Panel

Additional Agreements among WHO Collaborating Centres:

· A need for collection and exchange of epidemiological information with an impact on blood safety.

· The established WHO Biological Reference Preparations and those to be developed are suitable to cover the forthcoming new technologies for detection of infectious agents.

· A need for improved collaboration among WHO Collaborating Centres and between the WHO Collaborating Centres and WHO. Annual face-to-face meetings and teleconferences are necessary to monitor progress.

· A need to establish a network of WHO Collaborating Centres for in vitro diagnostics-related biological standardization representing all WHO Regions to ensure complementary and focused expertise at the global level.

Plan of Action:

The Priority Projects to establish WHO Biological Reference Preparations to support international regulations for blood and blood products safety will form a five-year In Vitro Diagnostic strategic plan. This plan will be submitted to the ECBS for endorsement in October, 2007. The In Vitro Diagnostic strategic plan will be used to support resource mobilization activities.

B. Potency and Safety Standards for Plasma Derivatives, Mei-ying W. Yu, Ph.D., DH, OBRR, FDA

The Division of Hematology (DH) in CBER/FDA has the primary responsibility for the scientific evaluation of manufactured biologic products derived from blood or plasma and their analogs derived from recombinant DNA technology. Examples of these products include clotting factors, immune globulins, and albumin. To ensure their safety and effectiveness, DH personnel have actively participated in developing and establishing CBER, WHO or global potency and safety standards through close collaboration with WHO collaborative centers (e.g., NIBSC and PEI), EDQM (Ph Eur), and industry. CBER standards are available upon request to product manufacturers for lot release testing of final-container products or for in-process control testing.

Potency Standards for Lot Release Testing for Clotting Factors:

Product	Standard	Potency per vial or ampoule	Ref. #
FIX Complex, FIX, rFIX	WHO 3^rd IS for FIX Concentrate (NIBSC 96/854)/Ph Eur/CBER	10.7 IU FIX	1
AHF, rAHF	CBER Mega 2/Ph Eur Batch 3 Standard for FVIII	10.4 IU FVIII (clotting assay) 8.6 IU FVIII (chromogenic assay)	2
AHF/vWF	WHO 1^st IS for vWF Concentrate (NIBSC 00/514)	9.4 IU vWF:Ristocetin Cofactor	3
Thrombin in Fibrin Sealant, bovine thrombin	WHO 2^nd IS for Thrombin (NIBSC 01/580)/CBER Lot K	110 IU Thrombin	4

Abbreviations: IS, International Standard; FIX Complex, FIX Complex (Human); FIX, Coagulation Factor IX (Human); rFIX, Coagulation Factor IX (Recombinant); AHF, Antihemophilic Factor (Human); rAHF, Antihemophilic Factor (Recombinant); AHF/vWF, Antihemophilic Factor/von Willebrand Factor Complex (Human)

Potency and Safety Standards for Immune Globulins or Albumin:

Product	Standard	Potency Requirement or Potency per mL (or when reconstituted)	Ref. #
IG, IGIV, IGSC	CBER Reference Immune Globulin, Lot 176, for Measles and Polio antibody levels	Required anti-measles potency: NLT 0.6 times the level of Lot 176 (42 IU/mL, recent data by a neutralization assay). Required anti-polio potency: NLT 0.28 for Type 1, 0.25 for Type 2, or 0.20 for Type 3, times the level of Lot 176 Lot 176: 2 IU anti-HBs/mL 95 IU anti-HAV/mL	5, 6
HBIG, HBIGIV	CBER Reference Hepatitis B Immune Globulin, Lot 2	220 IU anti-HBs/mL
Albumin, PPF, IGIV, IGSC, and some specific IGIV products	CBER Reference Prekallikrein Activator (PKA), Lot 3	100 IU PKA/mL Required limit for PPF: NMT 35.7 IU/mL Standard limit for IgG product: NMT 35 IU/mL 3% IgG
Rho(D) IG, Rho(D) IGIV	Global potency standard for anti-D immune globulin: WHO 2^nd IS (NIBSC 01/572)/Ph Eur 1^st BRP/CBER Lot 4	285 IU anti-D /mL Standard dose for use in preventing HDN: NLT 1500 IU (300 mg)	7, 8
IGIV, IGSC, specific IGIV products	WHO International Reference Reagents (IRRs) to standardize hemagglutination testing for anti-D: Positive IRR: NIBSC 02/228; CBER Lot 1A Negative IRR: NIBSC 02/226, CBER Lot 1N-a	Positive IRR: 0.0475 IU anti-D/mL 5% IGIV Nominal titer of 8 by a direct hemagglutination method	9
Same as above	NIBSC/Ph Eur 1^st BRP/CBER Reference reagents to set the maximum limit of anti-D in immune globulins: Positive RR: NIBSC 04/132; CBER Lot 1B Negative RR: NIBSC 04/140; CBER Lot 1N-b	Same titer as above except with more ampoules filled and shared among NIBSC, EDQM and CBER Maximum anti-D titer for 5% IgG : NMT the level in Positive RR (by the direct hemagglutination method)	10, 11

Abbreviations: IG, Immune Globulin (Human); IGIV, Immune Globulin Intravenous (Human); IGSC, Immune Globulin Subcutaneous (Human) ; HBIG, Hepatitis B Immune Globulin (Human); HBIGIV, Hepatitis B Immune Globulin Intravenous (Human); PPF, Plasma Protein Fraction (Human); BRP, Biological Reference Preparation; HDN, hemolytic disease of the newborn.

Safety Standards for In-Process Control:

Standard

Viral copies or IU per mL

Ref. #

CBER Parvovirus B19-positive plasma standard (genotype 1)

Use: Validating B19 NAT methods used for testing plasma pools (minipools and manufacturing pools) as analytical procedures to ensure the quality of starting plasma pools for all plasma-derived products.

10⁶genome equivalents (geq) or IU of B19 DNA per mL

CBER’s proposed maximum level of B19 DNA in the manufacturing pool:

10⁴ IU/mL

CBER Hepatitis A Virus-positive human plasma standard

Use: Validating HAV NAT methods used as described above.

1.2 x 10⁴copies/mL or 6000 IU/mL

No proposed limit of HAV RNA in the manufacturing pool yet.

Potency and Safety Standards under Development:

1. In collaboration with Dr. Elaine Gray of NIBSC, the 4^th International Standard for Factor IX Concentrate will be established.

2. In collaboration with Dr. Morag Ferguson of NIBSC, the 2^nd International Standard for Anti-HBs Immunoglobulin/CBER Lot 3 will be established to replace both the 1^st international reference preparation for anti-HBs Immunoglobulin (100 IU anti-HBs/mL when reconstituted) and CBER Reference Hepatitis B Immune Globulin, Lot 2. Nabi has kindly provided a candidate 5% HBIG preparation.

3. A new CBER Reference Immune Globulin, Lot 177, will be established to replace Lot 176. Baxter has kindly provided a candidate 10% IGIV preparation.

4. In collaboration with Dr. Susan Thorpe of NIBSC and Dr. Marie-Emmanuelle Behr-Gross of EDQM, new international reference reagents will be established to standardize hemagglutination testing for anti-A and anti-B hemagglutinins and to define the maximum levels of both in immune globulin products. Baxter has kindly provided a negative IGIV preparation derived from type AB plasma donations.

5. In collaboration with Dr. Sally Baylis of NIBSC, a parvovirus B19 genotype panel containing all three B19 genotypes will be established.

References:

1. Report to Biological Standardization Steering Committee. PA/PH/BIO (96) 18, R, August 1996.

2. Kirschbaum N, Wood L, Lachenbruch P, Weinstein M, Daas A, Rautman G, Spieser JM, Buchheit KH. Pharmeuropa Bio 2002; 1: 31-60.

3. Hubbard AR, Sands D, Chang AC, Mazurier C. Thromb Haemost 2002; 88: 380-6.

4. Whitton C, Sands D, Lee T, Chang A, Longstaff C. Thromb Haemost 2005; 93: 261-6.

5. 21 CFR 640.104 Potency.

6. Audet S, Virata-Theimer ML, Beeler J, Scott DE, Frazier DJ, Mikolajczyk MG, Eller N, Chen F, Yu MW. J Infect Dis 2006; 194: 781-9.

7. Thorpe SJ, Sands D, Fox B, Behr-Gross M-E, Schäffner G, Yu MW. Vox Sang 2003; 85: 313-21.

8. Thorpe SJ, Sands D, Fox B, Schäffner G, Yu MW, Behr-Gross M-E. Pharmeuropa Bio 2003; 2: 9-26.

9. Thorpe SJ, Fox B, Heath A, Dolman C, Virata ML, Yu MW, Thorpe R. Vox Sang 2005; 88: 278-87.

10. Thorpe SJ, Fox B, Heath A, Behr-Gross M-E, Virata ML, Yu MW. Biologicals 2006; 34: 209-12.

11. Thorpe SJ, Fox B, Heath A, Behr-Gross M-E, Virata ML, Yu MW. Pharmeuropa Bio 2006; 1: 579-85.

12. Saldanha J, Lelie N, Yu MW, Heath A, and the B19 Collaborative Study Group. Vox Sang 2002; 82: 24-31.

13. Saldanha J, Heath A, Lelie N, Pisani G, Yu MY, and the Collaborative Study Group. Vox Sang 2005; 89: 52-8.

C. Joint FDA/WHO Minimum Potency Standards for Certain Blood Grouping

Reagents, Sheryl Kochman, DBA, OBRR, FDA

Minimum Potency Standards for Blood Grouping Reagents

· Blood Grouping Reagent Anti-A minimum potency standard – replaces FDA lot 6A¹

· Blood Grouping Reagent Anti-B minimum potency standard – replaces FDA lot 7A-1¹

· Blood Grouping Reagent Anti-D minimum potency standard – replaces FDA lots 4a-1 and 9²

References:

1. Thorpe SJ, Fox B, Heath AB, Scott M, de Haas M, Kochman S, Padilla A.

International standards for minimum potency of anti-A and anti-B blood grouping reagents: evaluation of candidate preparations in an international collaborative study. Vox Sanguinis 2006; 91, 4: 336-344

2. Thorpe, SJ. Fox, B, Heath, AB, Scott M, de Haas, M, Kochman S, Padilla A. An International Standard for specifying the minimum potency of anti-D blood- grouping reagents: evaluation of a candidate preparation in an international collaborative study. Vox Sanguinis 2006; 90, 2: 131-139.