Joint WHO/FDA Minimum Potency Standards for Blood Grouping Reagents 90 th Meeting of BPAC August 17, 2007 Sheryl A. Kochman Chief, Devices Review Branch DBA/OBRR/CBER/FDA

Background CBER minimum potency standards SPECIFICITYLOT Anti-A6A Anti-B7A-1 Anti-D (for IgG products)4a-1 Anti-D (for IgM products)9

Background (cont) Anti-C (rapid tube)10 Anti-C (saline tube)14 Anti-c (rapid tube)13 Anti-E (rapid tube)11a Anti-E (saline tube)15 Anti-e (rapid tube)12a Anti-Human Globulin (Anti-IgG)16A Anti-Human Globulin (Anti-C3d)17A

Background (cont) All manufactured in the early 1970s All polyclonal All potentially biohazardous

Why New Standards? Questionable relevance to current reagents derived form monoclonal antibodies Diminishing stocks European Union In-Vitro Diagnostics Medical Device Directive, 98/79/EC, implemented Some CBER standards found to be reactive for some tests for hepatitis.

Why Collaborate? Encourage international harmonization Elicit input from larger pool of experts –National Institute for Biological Standards and Control –International Blood Group Reference Laboratory –Sanguin CLB –CBER –WHO Provide replacement standards for both FDA and WHO

Materials & Methods Potency only Serial two-fold dilution titrations Hemagglutination Manual tube test Comparator reagents –45 low-protein Anti-D –10 high-protein Anti-D –22 Anti-A –23 Anti-B

Participants in Studies Anti-D Study 20 laboratories 13 countries US Licensed –American Red Cross –Gamma Biologicals, Inc –Immucor, Inc –Medion Diagnostics, AG ( formerly Medion Diagnostics GmbH) –Millipore (formerly Serologicals) –Ortho-Clinical Diagnostics Anti-A & Anti-B Study 17 laboratories 9 countries US Licensed –American Red Cross –Gamma Biologicals, Inc –Immucor, Inc –Medion Diagnostics, AG (formerly Medion Diagnostics GmbH) –Millipore (formerly Serologicals) –Ortho-Clinical Diagnostics

Results Wide-spread variability in end-point titer results across the laboratories for all standards and all reagents. A few outliers Complex analysis of the data required*

*References 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, Vol 90, 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 Vol 91,

Conclusions Anti-D standard 99/836 For low-protein Anti-D reagents Use a 1:3 dilution Replaces FDA Anti-CD, 9 For high-protein Anti-D reagents Use a 1:8 dilution Replaces FDA Anti-D, 4a-1

Conclusions Anti-A standard 03/188 Use a 1:8 dilution Replaces FDA Anti-A, 6A Anti-B standard 03/164 Use a 1:4 dilution Replaces FDA Anti-B, 7A-1

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