CURRENT CONSIDERATION FOR INTRAVENOUS IMMUNOGLOBULIN IN NIB INDIA

Transcription

1 CURRENT CONSIDERATION FOR INTRAVENOUS IMMUNOGLOBULIN IN NIB INDIA Dr. J. P. PRASAD HEAD, BLOOD PRODUCTS LABORATORY

2 Presentation Plan Regulation of Blood & Blood Products in India Evolution of Blood safety measures PDMPs : Demand and availability in India Introduction to Testing of plasma derived products at NIB Proposed initiatives to upgrade the QC testing of IVIG 2

3 Regulation of Blood and Blood Products India Central Drugs Standard Control Organization (CDSCO) Ministry of Health & Family welfare (Govt. of India) Drugs Controller General of India is Central License Approving Authority (CLAA) State Licensing Authority (SLA) Ministry of Health & Family welfare (State Govt.) Licenses are issued by SLA after approval of CLAA based on joint inspection of blood banks / manufacturing facilities by Central and State Drugs Inspectors along with experts National AIDS Control Organization (NACO) Ministry of Health & Family welfare (Govt. of India) Responsibility of planning and management of Blood Transfusion Services / Blood Safety Program Indian Pharmacopoeia Commission (IPC) Ministry of Health & Family welfare (Govt. of India) Preparation of Monographs and Reference Standard National Institute Biologicals (NIB) Ministry of Health & Family welfare (Govt. of India) Quality control testing of All Biologicals including Blood Products Haemovigilance 3

4 Standards for assuring viral safety of blood donations 4

5 EVOLUTION OF BLOOD SAFETY MEASURES Establish NBTC & SBTC Eliminate professional donors Drug& Cosmetic act, Syphilis test 1972 HBsAg Test 1989 HIV 1& 2 antibodies 2002 HCV antibody Enact legislation for Blood bank operations Mandatory Licensing of all blood banks Strengthen Enforcement machinery Develop Trained manpower Compendium National Blood Policy & Guidelines

6 Screening for Hepatitis B surface antigen and Hepatitis C Virus antibody, HIV I and HIV II antibodies, Syphilis and malarial parasites shall be mandatory for every blood unit before it is used for the preparation of blood components. VIRAL INACTIVATION PROCESS : The procedure used by the licensee to inactivate the pathogenic organisms such as enveloped and nonenveloped virus, especially infectivity from HIV I & HIV II, Hepatitis B surface antigens and Hepatitis C Virus antibody, the viral inactivation and validation methods adopted by the licensee, shall be submitted for approval to the Licensing Authority and Central Licence Approving Authority 6

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8 Total market for plasma products in India is estimated to be >$100 million with overall demand growing about 10-15% annually Albumin Estimated to be the largest component contributing kg. A quarter of the world s haemophilic patients IVIG Estimated immunoglobulin total quantity contribution is ~15000 kgs Plasma derived factor VIII Estimated total served market ~40 mn IUs. Annual Report HFI 8

9 PLASMA DERIVERD PRODUCTS - MAUNFACTURERS IN INDIA Plasma for fractionation mostly from recovered plasma High Yield technology for Coagulation factors yet to be adopted Major production for Human albumin followed by IVIG Intas Pharmaceuticals Reliance Life Sciences Bharat Serums & Vaccines Ltd Hemarus Virchow 9

10 Needs about 10,00,000 liters of plasma per year largely import dependent for plasma protein therapies and is depending on few domestic fractionation plants for self-sufficiency in plasma medicines. Has about 1 % self sufficiency Index by global norms for Albumin and IVIG. Factor VIII is still worse (The Source - PPTA-2014) 10

11 IMPORT OF BLOOD PRODUCTS TO INDIA NIB 1. USA 2. ITALY 3. SOUTH KOREA 4. GERMANY 5. HUNGARY 6. SWITZERLAND 7. BELGIUM 8. UKRAINE 9. AUSTRIA 10. UK 11. ISRAEL 12. SPAIN 13. CHINA 14. DENMARK 15. CANADA Indigenous batches % Imported batches %

12 ASSURING QUALITY OF PLASMA DERIVED PRODUCTS 24

13 NIB LABORATORIES & ANIMAL HOUSE State-of-the-Art facility designed by NIH, Maryland, USA Total area : Sq m (3.71 Acres) Operationalization: year 2007 Cost of Lab & Animal Facility: Rs. 128 crores (27.82 M USD) 100% power back-up with 7.5 MW in-house generators LABORATORIES Total Area: 10,300 Sq m (2.55 Acres) ANIMAL HOUSE Total area: 4700 Sq m (1.16 Acres) 42 Laboratory modules: Biosafety level 2 01 Laboratory module: Biosafety level 3 06 Laboratory module: Biosafety level 2 01 Laboratory module: Biosafety level 3 Complies the requirements of animal welfare regulations & guidelines of CPCSEA (Committee for the Purpose of Control & Supervision of Experiments on Animals) 25

14 Laboratory Organisation and Structure- cont 26

15 NIB LABORATORIES: ACCREDITATION & GAZETTE NOTIFICATION Diagnostic Laboratories Therapeutic Laboratories Vaccine Laboratories Support Laboratories New Laboratory Blood Grouping Reagents Immunodiagnostic Kits Biochemical Kits Molecular diagnostic Blood Products Recombinant Products Enzymes & Hormones Therapeutic Monoclonal Antibody Bacterial Viral Sterility Animal Facility Allergen NABL accredited ISO 17025:2005 Both NABL Accredited & CDL Notified Not Accredited & Not Notified Total NABL Accredited laboratories: 10 Total CDL notified Laboratories: 08 15

16 MAJOR SCIENTIFIC ACHIEVEMENTS OF NIB CERTIFICATION ISO : 2005 CERTIFICATION BY NABL OSHAS Initiation of ISO:9001, ISO:14001 MONOGRAPH DEVELOPMENT PUBLICATION OF MONOGRAPHS ON BIOLOGICALS IN INDIAN PHARMACOPOEIA REFERENCE STANDARD PREPARATION OF NATIONAL REFERENCE STANDARD FOR INSULIN HIV, HBsAg & HCV PERFORMANCE PANEL Red Blood Cell Panel (35) Others under development COLLABORATION *WHO- NIBSC, UK, INTERNATIONAL COLLABORATIVE STUDIES FOR PREPARTION OF INTERNATIONAL REF. STD- PEG G-CSF & HBsAg *IIT- DELHI- CHEMOMETRIC ANALYSIS *DBT-BIOTECHNOLOGY, ADVANCED BIOLOGICALS & BIOPHRAMACEUTICALS *JAMIA HAMDARD- BIOINFORMATICS SUCCESSFUL PARTICIPATION IN PROFICIENCY TESTING PROGRAMME *EDQM- FRANCE: a) HCV RNA NAT TESTING-100% with excellent remark b) COAGULATION FACTOR VIII POTENCY ASSAY *NSRL AUSTRALIA: EQAS for HIV, HCV, HBV & SYPHILIS SEROLOGY *CMC VELLORE: EQAS FOR ANALYTES GLUCOSE & HbA1c ESTABLISHMENT OF IT- ENABLED SYSTEM PROCESS * e-publishing INCLUDING e- TENDERING * SAMPLE TRACKING * INVENTORY MODULE *e-office BEING ESTABLISHED DEVELOPMENT OF INDIGENOUS SOFTWARES *HEMO-VIGIL- Haemovigilance *AKS SOFTWARE Drug Survey *e-blood BANKING- Blood Banks 16

17 Testing of Plasma Derived Products at NIB 17

18 1 Human Albumin 2 Human Plasma Protein Fraction 3 Human Normal Immunoglobulin (IV) 4 Human Normal Immunoglobulin (IM) 5 Human Normal Immunoglobulin (IV) Bulk 6 Human Normal Immunoglobulin (IM) Bulk 7 Hepatitis B Immunoglobulin (IV & IM) 8 Rabies Immunoglobulin (IM) 9 Human Tetanus Immunoglobulin (IM) (Plasma derived) 10 Human Tetanus Immunoglobulin (IM) (Monoclonal) 11 Human Tetanus Immunoglobulin (IM) Bulk 12 Anti D Immunoglobulin (IV) 13 Anti D Immunoglobulin (IM) (Plasma derived/ Monoclonal) 14 Human Coagulation Factor VIII plasma derived 15 Human Coagulation Factor VIII recombinant 16 Human Coagulation Factor IX 17 Human Coagulation Factor IX Recombinant 18 Fibrin Sealant Kit 19 Anti-Inhibitor Coagulant complex 20 Anti-Thrombin III concentrate 21 Human Fibrinogen

19 METHODS FOR TESTING OF VARIOUS PLASMA DERIVED PRODUCTS AS PER INDIAN PHARMACOPOEA 2014 Identification Purity impurities Potency DID SDS-PAGE Assay HPLC Protein composition Anti-A Anti-B Anti-D Haem PKA IgA ACA Factor VIII Factor IX Specific potency assay IgG Total protein content Viral markers General safety General Tests Tests for limits HIV 1 & Ab Anti-HCV Ab HBsAg Sterility Pyrogen Abnormal toxicity BET ph Osmolality Moisture content Sodium Potassium Heparin Activated coagulation factors 19

20 Scrutiny of Summary Production protocol NIB/BPL/PRO/DOC File No : SRRD Code : Name of the Product : Lot / Batch No. : Manufacturing date : Expiry date : Category of the product as per the lot release procedure: Sl. No. Requirement Document submitted by the manufacturer/ importer 1 Batch release from country of origin Comments 2 Plasma pool certificate from NCL/ manufacturer 3 Summary information of the plasma pool: A. Source of plasma B. Period of collection of plasma C: Certificate of plasma compliance to international standards 4 Name of three countries 5 Method of viral inactivation 6 Certificate of analysis with name of pharmacopoeia complied Signature:.. 34

21 Quality Control Testing of Various Blood Products at NIB in last 08 years Under testing, No. of Batches received for No. of Batches found NSQ, 1 No.of batches found SQ, Total batches tested = 3566 % of NSQ batches = 77 (2.2%) Number of Batches received and evaluated Number batches found SQ

22 Parameters found Out of -specification Immunoglobulin Protein composition Total protein Human albumin Total protein sodium content pre kallikrein activator Factor VIII/IX Potency assay 22

23 EDQM REFERENCE STANDARD EDQM Ref. Std. (Leaflet) Result of EDQM Ref. Std.

24 Molecular Size Distribution by HPLC

25 EDQM REFERENCE STANDARD EDQM Ref. Std. (Leaflet) Result of EDQM Ref. Std.

26 NIB SCIENTISTS DECLARED AS GOVERNMENT ANALYSTS Name of NIB Scientist and Lab notified as CDL Dr. J. P. Prasad, Scientist Grade-II, Blood Product Lab (i) (ii) (iii) (iv) (v) (vi) (vii) Products Human Albumin; Human Normal Immunoglobulin (IV & IM); Human Coagulation Factor VIII; Human Coagulation Factor IX; Plasma Protein Fraction; Fibrin Sealant Kit; Anti-Inhibitor Coagulation Complex. Dr. Reba Chhabra, Scientist Grade-I, Immunodiagnostic kit Lab Ms. Ajanta Sircar, Scientist Grade-III, Biochemical Kit Lab Dr. J. P. Prasad, Scientist Grade-II, & Ms. Kanchan Ahuja, Scientist Grade-III, Blood Grouping Reagent Lab (i) Human Immunodeficiency Virus; (ii) Hepatitis B Surface Antigen; (iii) Hepatitis C Virus (i) Glucose Test Strips; (ii) Fully automated analyser based glucose reagents Blood Grouping reagents

27 Contribution for Monograph Upgradation & Development in IP 2014 (n=7) 2018 (n=6) 1.Human Albumin 2.Human Normal Immunoglobulin (IM) Proposal for revision of method for total Protein estimation of 4 Blood Products 3.Plasma Protein Fraction 4.Dried-Anti-haemophilic Factor-VIII 5.Human Normal Immunoglobulin for Intravenous use 6.Coagulation Factor-IX 7.Fibrin Sealant Kit Proposal for revision of acceptance criteria for Fibrin Sealant Kit Development of a new monograph for Anti-D immunoglobulin (Monoclonal)

28 Research & Development Development of National reference Standards : Human Albumin for total protein Human coagulation factor VIII for potency assay Research project Comparison of various pharmacopeia methods with ionselective electrode potentiometry for measurement of Sodium content in human albumin preparation.

29 Recent Proposal for inclusion of haemolysis in the test for Anti A anti B haemagglutinin titer in the monograph Observed haemolysis till 1: 2 dilution Potential indication of serious adverse reaction Clinical impact of such batches to be investigated 29

30 SBOERVATIONS Batches: 8764 & 8765 with cell control Hemolysis observed in Neat and 1:2 Dilution with A and B cells

31 SBOERVATIONS Batch No

32 Anti complementary activity major challenges Validation of alternative methods Difficult to perform Time Consuming Not amendable to assessing large number of samples Difficult to standardize The different complement batches had a significant impact on the test result of the ACA assay Very high inter assay variability Ref: Plasma product Biotechnology meet 2011: 7 th Internaltional meeting, CSL Laboratories Andrea Buchacher et al (Octapharma, Austria) reported in Vox Sanguinis (2010) that different complement batches cause variations C1q Kit by M/s Quidel Total Haemolytic Complement Kit M/s Binding site 32

33 Harmonization of method for total protein estimation Kjeldahl method Most of the manufacturer perform Biuret method Variation in Kjeldahl protocols company to company Validation of Biuret Vs Kjeldahl to be done through international collaborative study Development of reference standard for Biuret assay NIB PROPOSES TO CORDINATE THE STUDY FOR DEVELOPMENT OF REFERENCE STANDARD FOR TOTAL PROTEIN ESTIMATION IN HUMAN ALBUMIN AND HUMAN NORMAL IMMUNOGLOBULIN IM/IV 33

34 Thank You 34