IG Production and Safety Platelet Disorder Support Association July 20, 2013 Mary Gustafson, Vice President, PPTA Global Regulatory Policy
Presentation Outline Introduction - PPTA Plasma Collection Final Therapy Manufacturing Recent Regulatory Concerns PDSA Meeting July 20, 2013 Page 2
PPTA Plasma Protein Therapeutics Association (PPTA) Global industry association representing manufacturers and source plasma collectors in the U.S., Canada and the EU Key Areas: Standards setting Advocacy PDSA Meeting July 20, 2013 Page 3
PPTA Members Plasma derived therapies and Recombinant therapies; Manufacturing sites in USA, Austria, Belgium, Switzerland and Italy Plasma derived therapies; Manufacturing site in Germany and USA Plasma derived therapies and Recombinant therapies; Manufacturing sites in USA, Switzerland and Germany Plasma derived therapies; Manufacturing sites in Spain and USA Plasma derived therapies; Manufacturing sites in Italy and USA PDSA Meeting July 20, 2013 Page 4
Source Plasma Members Access Plasma LLC ADMA Biologicals BioLife Plasma Services Biomat USA Biotest Pharmaceuticals Blood and Plasma Research BloodSource Cangene Corporation CSL Plasma DCI Biologicals Haema AG Interstate Companies KEDPlasma, LLC Kedrion SpA Octapharma Plasma Ortho-Clinical Diagnostics Europlasma GmbH Plasmapunkt Favoriten GmbH Ruhr-Plasma-Zentrum Bochum GmbH Scantibodies Biologics Southern Blood Services UNICAplasma PDSA Meeting July 20, 2013 Page 5
Two Standards Programs Covers plasma collection Manufacturer based standard Both are in addition to compliance with regulatory requirements PDSA Meeting July 20, 2013 Page 6
Plasma Protein Therapies What are plasma protein therapies? How are therapies made? What safeguards are employed in the manufacturing process? Photo of manufacturing process PDSA Meeting July 20, 2013 Page 7
What are Plasma Protein Therapies All therapies replace proteins that are missing or deficient in an patient s plasma Plasma protein therapies treat rare, chronic, often genetic diseases and disorders Immune globulins (Ig) (ITP, PIDD, CIDP) Alpha-1 proteinase inhibitor (A1AD) Blood clotting factor (hemophilia A and B, von Willebrand disease) Specialty Ig products (Rho(D), tetanus, hepatitis, rabies, RSV) Albumin (severe burns, shock, trauma, surgery) PDSA Meeting July 20, 2013 Page 8
How are therapies made? Plasma-derived therapies Starts with the collection of high-quality plasma from healthy donors Plasma is a protein-rich blood component Plasma is collected from healthy, committed donors PDSA Meeting July 20, 2013 Page 9
Donor Eligibility PDSA Meeting July 20, 2013 Page 10
The procedure through which plasma is collected 1. Enclosed sterile system by which blood is drawn into a machine 2. The plasma is separated from the red blood cells and platelets» The red blood cells and platelets are returned to the donor» Source Plasma is harvested 3. Source Plasma is the starting material for plasma protein therapies Plasmapheresis PDSA Meeting July 20, 2013 Page 11
Starting Material Source plasma is donated in ~400 centers in the U.S. FDA licensed o Adhere to FDA regulations o cgmp compliant IQPP-certified o Adhere to PPTA voluntary stds o Independent audits All donors are screened Qualified no one time donors All plasma is tested PDSA Meeting July 20, 2013 Page 12
U.S. Collection Centers Map produced by Dr. Adelbert James, Epidemiologist at Emory University School of Medicine, Atlanta, GA PDSA Meeting July 20, 2013 Page 13
How are therapies made? Plasma is pooled, purified and processed to extract specific proteins Purification methods, viral inactivation, viral removal used in extraction process Plasma Proteins and the Diseases They Treat PDSA Meeting July 20, 2013 Page 14
Fractionation Term for production of plasma protein therapies Complex Manufacturing Process Purification and Pathogen Reduction Substantial investment in equipment, training and quality control Highly regulated process U.S. FDA facility inspections, international government inspections PPTA Quality Standards of Excellence, Assurance and Leadership (QSEAL) third-party audits PDSA Meeting July 20, 2013 Page 15
Developed by Edwin Cohn during WW2 Alcohol (Cohn) Fractionation Proteins are purified by adding alcohol to plasma in steel tanks at low temperatures The resulting precipitates are further purified into the main therapeutic plasma proteins albumin, immunoglobulin, etc Has stood the test of time relatively little modification and supported by 60 years of clinical experience Proteins can also be separated by chromatography based on size, electrical charge PDSA Meeting July 20, 2013 Page 16
Fractionation Process Pooling Cryo Eff. Supernatant I or Supernatant II+III Supernatant IV-1 Supernatant IV-4 Cryo Separation Fr I Separation Fr II+III Separation Fr IV-1 Separation or Fr IV- 4 Separation Fr V Separation Cryo Paste Fr. I Paste Discard Fr. II - III Paste Fr. IV-1 Paste Fr. IV-4 Paste Fr V Paste Factor VIII I G A 1 P I Albumin PDSA Meeting July 20, 2013 Page 17
Plasma-Derived Therapies Collection of Human Plasma Frozen storage & transport Protein Manufacturing 60-day Fractionation Steps inventory hold Source Donor selection Donor deferral Donor testing Plasma testing Viral marker rates Recovered FDA Regs. Clotting factors IgG A1PI Albumin Specialty Therapies In I process controls Purification Viral reduction/ inactivation 7 to 12 0 months PDSA Meeting July 20, 2013 Page 18
Industry Safety Initiatives PDSA Meeting July 20, 2013 Page 19
IG-associated Thrombosis Thrombosis long-recognized complication of IVIG infusion Serious events infarction, stroke, pulmonary embolism Causes uncertain (viscosity, platelet aggregation, coagulation factor contaminant) Precautionary labeling for past decade Cluster with one product in 2010 Coagulation factor XIa bad actor Procoagulant activity explains some but not all thromboembolic events PDSA Meeting July 20, 2013 Page 20
Risk Mitigation Identify most likely causes Identify promising test methods Discuss risk mitigation manufacturing strategies Provide information i on standards d development PDSA Meeting July 20, 2013 Page 21
IG-associated Thrombosis Increased surveillance via FDA s Sentinel Initiative Manufacturing processes extensively studied for procoagulant activity Critical parameters identified Processes controlled Tests implemented to detect procoagulant activity International reference material available PDSA Meeting July 20, 2013 Page 22
June 2013: FDA requiring boxed warning for thrombosis for all IG products More prominent placement Uniform approach for communicating risk Recommendations for patients and health care professionals PDSA Meeting July 20, 2013 Page 23
IG-associated Hemolysis Hemolysis long-recognized complication of IVIG infusion Addressed in current product labeling Attributed to IgG anti-a/b agglutinins US/EU product specifications set antibody limit level of <1:64 in direct hemagglutinin assay Recent concerns that hemolysis occurs although h products meet regulatory specifications PDSA Meeting July 20, 2013 Page 24
Risk factors High doses: > or = 2 g/kg IG-associated Hemolysis Recipient blood type A, AB or B Possibly patient t risk factors (e.g., inflammatory diseases) Complications Severe anemia/transfusion requirement Renal failure PDSA Meeting July 20, 2013 Page 25
ABO Immunology Image Credit: InvictaHOG PDSA Meeting July 20, 2013 Page 26
ABO Distribution Dean L. Blood Groups and Red Cell Antigens [Internet] PDSA Meeting July 20, 2013 Page 27
Hemolysis Risk Mitigation Workshop Planned to review situation and explore risk mitigations Co-sponsors: FDA, PPTA, NIH January 2014, Bethesda, MD Four sessions, 1.5 days Epidemiology, Pathogenesis, Pt Risk Factors Product-related related Risk Factors Manufacturing and Risk Mitigation Workshop Summary PDSA Meeting July 20, 2013 Page 28
IPAW Purpose Raise global awareness about source plasma collection Recognize the contributions of plasma donors to saving and improving lives Increase understanding about lifesaving plasma protein therapies and rare diseases PDSA Meeting July 20, 2013 Page 29 ALL member companies with IQPP-certified centers planning events (U.S. and Europe)