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National Institute of BiologicalsMinistry of Health & Family WelfareGovernment of India
Dr. J. P. Prasad
Scientist & Head, Blood Products
NIB, NOIDA
Email: [email protected]
National Institute of BiologicalsMinistry of Health & Family WelfareGovernment of India
PRESENTATION PLAN
• Global Market of Plasma Derived Products
• Indian Market
• Quality Control evaluation at NIB
National Institute of BiologicalsMinistry of Health & Family WelfareGovernment of India 3
The global plasma fractionation market is estimated to grow at a CAGR of 6.7% from 2016 to 2021 to reach USD 26.07 Billion by 2021.
The immunoglobulin segment accounted for the largest share of the market in 2015
Growing aging population, rising incidences of bleeding and immune disorders, and growing use of immunoglobulin and alpha-1-antitrypsin are expected to propel the growth of this market.
Global market for Plasma Derived products
Source: Markets & Markets: Global Forecast to 2021
National Institute of BiologicalsMinistry of Health & Family WelfareGovernment of India
The Worldwide Plasma Fraction Market
4
10%
46%
9%
4%2%
29%
Worldwide Plasma Fractions market by Product- $11.7 billion
Albumin IVIG Factor-VII Sp.IG factor-IX All others
The Marketing Research Bureau
National Institute of BiologicalsMinistry of Health & Family WelfareGovernment of India 5
0.01
1.64
3.44
5.74
0 1 2 3 4 5 6
Factor VIII per capita consumption
USA
INDIA
JAPAN
SWEDEN
0.1
23.6
29.3
57.5
0 5 10 15 20 25 30 35 40 45 50 55 60
IVIG grams/ thousand population
USA
INDIA
JAPAN
SWEDEN
1
281
367
534
0 50 100 150 200 250 300 350 400 450 500 550
Albumin Kgs./ million population
USA
INDIA
JAPAN
SWEDEN
National Institute of BiologicalsMinistry of Health & Family WelfareGovernment of India 6
Needs about 900,000 liters of plasma proteins 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)
National Institute of BiologicalsMinistry of Health & Family WelfareGovernment of India 7
Indigenous Manufacturers licensed on Form-28E to manufacture for sale and distribution of Blood
Products
M/s. HemarusTherapeutics Ltd., Telengana
M/s. Reliance Life Sciences Pvt Ltd.
Navi Mumbai
M/s. Bharat Serums and
Vaccines Ltd., Mumbai
M/s. Intas Pharmaceuticals,
Ahmedabad
M/s. Virchow Biotech Pvt Ltd.,
Telengana
National Institute of BiologicalsMinistry of Health & Family WelfareGovernment of India 9
Source: ppta.org
Plasma Derived Products
are inherently complex
and variable, a vigilant
monitoring is required to
ensure the quality as well
as safety of such
products.
National Institute of BiologicalsMinistry of Health & Family WelfareGovernment of India 10
NIB OVERVIEW
National Institute of BiologicalsMinistry of Health & Family WelfareGovernment of India
CERTIFICATION
ISO 17025 : 2005 CERTIFICATION BY NABL
Initiation of ISO:9001, ISO:14001 & OSHAS 18001
MONOGRAPH DEVELOPMEN
T
PUBLICATION OF 23 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)
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 remarkb) 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 ESTABLISHEDDEVELOPMENT OF
INDIGENOUS SOFTWARES
*HEMO-VIGIL-Haemovigilance *AKS SOFTWARE –Drug Survey*e-BLOOD BANKING-Blood Banks
MAJOR SCIENTIFIC ACHIEVEMENTS OF NIB
12
National Institute of BiologicalsMinistry of Health & Family WelfareGovernment of India
NIB SCIENTISTS DECLARED AS GOVERNMENT ANALYSTS
Name of NIB Scientist and Lab notified as CDL
Products
Dr. J. P. Prasad, Scientist Grade-II,Blood Product Lab
(i) Human Albumin; (ii) Human Normal Immunoglobulin (IV & IM); (iii) Human Coagulation Factor VIII; (iv) Human Coagulation Factor IX; (v) Plasma Protein Fraction; (vi) Fibrin Sealant Kit; (vii) Anti-Inhibitor Coagulation Complex.
Dr. Renu Jain, Scientist Grade-I,Recombinant Product Lab
(i) r- Insulin and Insulin analogues; (ii) r-Erythropoietin (EPO); (iii) r-Granulocyte Colony Stimulating Factor (G–CSF)
Dr. Reba Chhabra, Scientist Grade-I, Immunodiagnostic kit Lab
(i) Human Immunodeficiency Virus; (ii) Hepatitis B Surface Antigen;(iii) Hepatitis C Virus
Ms. Ajanta Sircar, Scientist Grade-III,Biochemical Kit Lab
(i) Glucose Test Strips;(ii) Fully automated analyser based glucose reagents
Dr. J. P. Prasad, Scientist Grade-II,& Ms. Kanchan Ahuja, Scientist Grade-III,Blood Grouping Reagent Lab
Blood Grouping reagents
National Institute of BiologicalsMinistry of Health & Family WelfareGovernment of India
Monograph : book of Standards and Specifications
Genesis of IP Blood Products Monographs
2014
IP 2016
Participatingas expertmemberfrom BPL forreview ofBloodProductsMonographsand GeneralChapter.
CONTRIBUTED IN REVIEW OF 7 MONOGRAPHS:
1. Human albumin,
2. Plasma Protein Fraction,
3. Human Normal Immunoglobulin for intravenous use,
4. Human Normal Immunoglobulin,
5. Dry Anti-Hemophilic Factor-VIII,
6. Coagulation Factor-IX and
7. Fibrin Sealant kit
National Institute of BiologicalsMinistry of Health & Family WelfareGovernment of India
Plasma Derived SamplesRegulatory Functions at NIB
1- Human Albumin
2- Human Plasma Protein Fraction
3- Human Normal Immunoglobulin (IV)
4- Human Normal Immunoglobulin (IM)5- Human Normal Immunoglobulin (IV) Bulk6- Human Normal Immunoglobulin (IM) Bulk7 Hepatitis B Immunoglobulin8 Rabies Immunoglobultin
9- Anti –D Immunoglobulin (IV) 10- Anti –D Immunoglobulin (IM11- Human Tetanus Immunoglobulin (IM)12- Human Tetanus Immunoglobulin (IM) Bulk
13- Human Coagulation Factor VIII plasma derived14- Human Coagulation Factor VIII recombinant
15- Human Coagulation Factor IX
16- Fibrin Sealant Kit
17- Anti-Inhibitor Coagulant complex
18- Anti-Thrombin III concentrate
19-Human Fibrinogen
National Institute of BiologicalsMinistry of Health & Family WelfareGovernment of India 16
Sample receipt SRRD Unit, coding of samples
Laboratory: sample entry, sample transfer
Laboratory testing
Test report compilation
Test report(s) verification
Test report approval
Report compilation
COA for decoding
Decoding by SRRD file
sent to the lab
Protocol scrutiny by the lab
Final COA
Approval by the DD(QC)
SRRD UNIT Report
dispatch
Turn Around Time- 45 DAYS
Referred by CDSCO/State Drug Offices/Port Offices
4
e –Mail to Referred body
& copy to Manufacturer
By Post to Referred body
& copy to Manufacturer
NIB Website
TESTING PROCESS : FLOW CHART
321
5
6
7
891011
13
12
National Institute of BiologicalsMinistry of Health & Family WelfareGovernment of India
Sl. No. Requirement Document submitted by the manufacturer/ importer
Comments
1 Batch release from country of origin
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 tointernational standards
4 Name of three countries
5 Method of viral inactivation
6 Certificate of analysis with name ofpharmacopoeia complied
Scrutiny of 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:
Signature:……………..
National Institute of BiologicalsMinistry of Health & Family WelfareGovernment of India
METHODS FOR TESTING OF VARIOUS PLASMA DERIVED PRODUCTS AS PER INDIAN PHARMACOPOEA
18
Iidentification
• DID
• SDS-PAGE
• Assay
Purity
• HPLC
• Protein composition
impurities
• Anti-A Anti-B
• Anti-D
• Haem
• PKA
• IgA
• ACA
Potency
• Factor VIII
• Factor IX
• Specific potency assay IgG
• Total protein content
Viral markers
• HIV 1& Ab
• Anti-HCV Ab
• HBsAg
General safety
• Sterility
• Pyrogen
• Abnormal toxicity
• BET
General Tests
• pH
• Osmolality
• Moisture content
Tests for limits
• Sodium
• Potassium
• Heparin
• Activated coagulation factors
National Institute of BiologicalsMinistry of Health & Family WelfareGovernment of India
0
100
200
300
400
500
600
700
2010-11 2011-12 2012-13 2013-14 2014-15 2015-16
179
208 219
534
593609
177205 217
520
564593
2 3 2 1429 16
No
. of
bat
che
s
Trends of Various Blood Products Tested at NIB in last 6 Years
No. of batches received and evaluated No. of batches found SQ No. of batches found NSQ
National Institute of BiologicalsMinistry of Health & Family WelfareGovernment of India
Indigenous & Imported samples(2015 To 2016)
313298
Indigenous ImporterNumber of batches received Number of imported
batches receivedNumber of indigenous
batches receivedTotal SQ NSQ Total SQ NSQ Total SQ NSQ
609 596 16 296 294 02 313 299 14
SQ – Standard Quality NSQ – Not of Standard Quality
4.4%Not of Standard
Quality
National Institute of BiologicalsMinistry of Health & Family WelfareGovernment of India
PERFORMANCE EVALUATIONIN INDIGENOUS AND IMPORTED BATCHES OF PLASMA DERIVED PRODUCTS
21
Parameters found
Out –of -specification
Human albumin
Total proteinsodium contentpre kallikrein activator
Immunoglobulin
Protein composition
Total protein
Factor VIII/IX
Potency assay
National Institute of BiologicalsMinistry of Health & Family WelfareGovernment of India
5.00%6.00%7.00%8.00%9.00%
10.00%11.00%12.00%13.00%14.00%15.00%16.00%17.00%18.00%19.00%20.00%21.00%22.00%23.00%
1
12
23
34
45
56
67
78
89
100
111
122
133
144
155
Samples
Range as per I.P. 19.00 % -21.00%
Range of In-house Control-19.54%-20.50%
No. of Samples
5.00%6.00%7.00%8.00%9.00%
10.00%11.00%12.00%13.00%14.00%15.00%16.00%17.00%18.00%19.00%20.00%21.00%22.00%23.00%24.00%25.00%
1 3 5 7 9 11131517192123252729
In-HouseControl
Samples
Range as per I.P. 19.00 % -21.00
Range of Protein Std.8% ± 0.2
No. of
No. of Samples %
PERFORMANCE EVALUATION HUMAN ALBUMIN-TOTAL PROTEIN CONTENT
National Institute of BiologicalsMinistry of Health & Family WelfareGovernment of India
Thanks
Trend analysis of HAS batches of an Indigenous manufacturer for sodium content tested at National institute of Biologicals showing systematic error.
National Institute of BiologicalsMinistry of Health & Family WelfareGovernment of India
Comparative Results of Immunoglobulin Sample –Protein composition with HPLC & SDS-PAGE
Sample showing OOS Result
Sample showing within Specification Result
National Institute of BiologicalsMinistry of Health & Family WelfareGovernment of India
• Claimed 20%
• Actual content lower than the limits in the Certificate of Analysis
• Withdrawn from the supply
Protein standard from established manufacturer /
supplier of certified standards
• Imported batches of Human albumin having OOS result for total protein
• Standard used by the manufacturer/ Control laboratory found of higher value
• Product not recommended for marketing in India
In –House Protein standard of International Control
Laboratory
• Ploy specific AHG: Minimum potency preparation
• Withdrawn from the marketInternational Reference
standard NIBSC, UK
NIB’s Role in assessing the suitability of Reference standards / Certified Reference Materials
The Following standards found not suitable for use in test/ analysis of batches:
National Institute of BiologicalsMinistry of Health & Family WelfareGovernment of India
Conclusion
• Overall, the global consumption of plasma derived medicinal products has gone up over the last 20 years .
• Use of plasma derived medicinal products may vary from country to country .
• The Quality of the plasma derived products must checked for it quality to protect public health.
• The reference standard/ material and critical reagents should be tested before use.
29