The document provides an overview of biopharmaceuticals. It discusses that biopharmaceuticals are biologically significant compounds derived from living cells that are used to treat various human health disorders. It then covers classification of biopharmaceuticals, examples of different types including antibodies, cytokines, hormones, enzymes, vaccines, and monoclonal antibodies. The document also discusses production processes, quality control, and future trends in the biopharmaceutical industry.
4. Biopharmaceuticals!!!
ī¯ Biopharmaceuticals or Biotherapeutics or Biologicals
ī¯ Biologically significant compounds like Hormones,
Proteins (eg.antibodies) & Nucleic Acids (DNA & RNA)
ī¯ Biopharmaceutical drugs are large, complex molecules
derived from living cells.
ī¯ Obtained from biological source and produced through
industrial biotechnology
ī¯ Useful for treatment of variety of human health
disorders, fight cancer, viral infections, diabetes,
hepatitis and multiple sclerosis
5. Biopharmaceuticals!!!
ī¯ These are medical drugs produced using
biotechnology especially
īŽ genetic engineering or
īŽ hybridoma technology or via
īŽ biopharmaceutical techniques such as
recombinant DNA technology, gene transfer
īŽ antibody production methods
īŽ Conventional vaccines
ī¯ Insulin-
īŽ First Recombinant Biopharmaceutical pdt
6. Classification of
Biopharmaceuticals
ī¯ First Generation Biopharmaceuticals
īŽ unengineered murine monoclonal antibodies or simple
replacement proteins displaying an identical amino acid
sequence to a native human protein.
ī¯ Second Generation Biopharmaceuticals -
engineered, products.
īŽ alteration of amino acid sequence, glycocomponent of a
glycosylated protein,
īŽ covalent attachment of chemical moieties such as
polyethylene glycol.
īŽ alter immunological or pharmacokinetic profile of protein,
or in order to generate novel fusion products
8. Types of Biopharmaceuticals
ī¯ Enzymes â
ī¯ Activase, alteplase, TPA (dissolves blood clots)
ī¯ Pulmozyme, dornase alfa , (a recombinant DNAse I that
digests DNA in the mucous secretions in lungs)
ī¯ Cerezyme, imiglucerase, (a recombinant glucocereborsidase
for GaucherÃģs disease, bone destruction and enlargement
of the liver and spleen)
īą Alphanine SD, Benefix, Bebulin VH, Profilnine SD, Proplex T
Factor IX, belonging to peptidase family S1, is one of the
serine proteases of the coagulation system. Deficiency of this
protein causes hemophilia B
10. Types of Biopharmaceuticals
ī¯ MONOCLONAL ANTIBODIES
īŽ Produced by using Hybridoma Technology
īŽ Popularly known as âMagic bulletsâ
īŽ Used for the treatment of Rheumatoid
Arthritis , cancers
īŽ Antibody produced by a single clone of
cells
11. Types of Biopharmaceuticals
ī¯ VACCINES
īŽ Biological preparation that improves
immunity to a particular disease
īŽ They can be prophylactic or therapeutic
īŽ e.g. HBV vaccine--a Subunit Vaccine
composed of only surface proteins, produced
in the yeast
12. ī¯ to respond to a human influenza
pandemic.
ī¯
to respond to a human influenza pandemic.
13. Biopharmaceuticals
USAN/INN Trade
Name
Indication Technology Mechanism of
Action
abatacept Orencia rheumatoid arthritis immunoglobin CTLA-
4 fusion protein
T-
cell deactivation
adalimumab Humira rheumatoid
arthritis, ankylosing
spondylitis, psoriatic arthritis,
psoriasis, Ulcerative
Colitis, Crohn's disease
monoclonal antibody TNF antagonist
alefacept Amevive chronic plaque psoriasis immunoglobin G1
fusion protein
incompletely
characterized
erythropoietin Epogen anemia arising from
cancer chemotherapy, chroni
c renal failure, etc.
recombinant protein stimulation of red
blood cell
production
etanercept Enbrel rheumatoid arthritis,
ankylosing spondylitis,
psoriatic arthritis, psoriasis
recombinant human
TNF-receptor fusion
protein
TNF antagonist
infliximab Remicad
e
rheumatoid arthritis,
ankylosing spondylitis,
psoriatic arthritis, psoriasis,
Ulcerative Colitus, Crohn's
disease
monoclonal antibody TNF antagonist
trastuzumab Herceptin breast cancer humanized monoclon
al antibody
HER2/neu (erbB2
) antagonist
ustekinumab Stelara psoriasis humanized monoclon
al antibody
IL-12 and IL-23
antagonist
denileukindiftito
x
Ontak cutaneous T-cell lymphoma
(CTCL)
Diphtheria toxin
engineered protein
combining Interleukin-
2 and Diphtheria toxin
Interleukin-
2 receptor binder
golimumab Simponi rheumatoid arthritis, psoriatic
arthritis, ankylosing
monoclonal antibody TNF antagonist
16. Indian Scenario
ī¯ 2,345 crore rupees -- 2002-2003
ī¯ 20,441 crore rupees --2011-2012
ī¯ Domestic sales have exceeded the export revenues.
17. Indian Scenario
Company Segment Revenue 2011-2012 (crore rupees)
Serum Institute of India Biopharmaceutical 1708
Biocon Biopharmaceutical 1676.40
Nuziveedu seeds Bio-agriculture 745
Reliance Lifesciences Biopharmaceutical 693
NovoNordisk Biopharmaceutical 647.28
18. Future Trends
ī¯ Regulatory Trends
īŽ Increasing Government Support
īŽ IP Protection Enforcement
īŽ Regulatory Reforms (innovation, restrict
imitation, outsourcing, VC)
īŽ Drug Price Cuts
ī¯ Technology Trends (novel tchnologies/pdts)
ī¯ Enterprise Development Trends
īŽ Strategic Alliances
īŽ Cluster Development
īŽ Increasing R & D investment (Estb Pdt Pipeline)
īŽ More International Clloaboration
īŽ Mammalian Cell Expression Drug Development
19. Key Factor
The main driver for FUTURE GROWTH
The key factor to compete and proper in the
21st century GLOBAL ECONOMY
INNOVATION
23. Venom !!!
ī¯ Biotoxins - highly complex or relatively
small protein. Two functions
ī¯ Vary greatly in functions& mechanism
ī¯ Predation âsnakes, spider, scorpion,
jellyfish, wasp
ī¯ Defense â bee, ant, honeybee, frog, termite
ī¯ Typically injected into prey or aggressors by
biting or stinging or other sharp body
feature.
24. Snake Bite
ī¯ Snake bite is a acute life threatening
time limiting medical emergency a
occupational hazard often faced by
farm labourers and farmers. It is in
endemic form all over tropical
countries like India.
ī¯ WHO -Snake bite Neglected Tropical
Disease.
25. GRAVITY
ī¯ 2.5 lakh snake bites per year in India.
ī¯ 35,000 to 50,000 deaths per year due to
snake bite in India.
ī¯ High mortality in Maharashtra, up to 5000
deaths per year
ī¯ High mortality in rural population.
ī¯ Death figure may be high.
ī¯ 3000 species of snakes are distributed
worldwide. 500 are venomous species. 52
venomous species are found in Indian
subcontinent.
33. Medically Important Snakes
ī¯ Dangerousness of snake species
īŽ Venom Characteristics
īŽ Lethality of the venom
ī¯ Key Variables
īŽ Frequency of medical attention after a bite
īŽ Local or systemic envenomation
īŽ Fatal Bites
īŽ Long term consequences
īŽ Availability of antivenoms
īŽ Size of population at risk
34. Snake Venoms
ī¯ Complex mixture of proteins and
peptides
ī¯ 80-100 or more proteins
ī¯ Small number of superfamilies
īŽ Enzymes
īŽ Nonenzymatic proteins
35. Snake Venom
ī¯ Contains number of toxins and enzymes. It is a clear
transparent, amber tinted fluid and contains.
ī¯ 1. Neurotoxin (Predominant in Elapids)
ī¯ 2. Cholinesterase (Predominant in Elapids)
ī¯ 3. Haemolysins (Predominant in Viper)
ī¯ 4. Thromboplastin (Predominant in Viper)
ī¯ 5. Fibrinolysins
ī¯ 6. Proteolysins
ī¯ 7. Cardiotoxin
ī¯ 8. Agglutinins
ī¯ 9. Coagulase, Hyaluronidase etc.
ī¯ 10 out of 26 in each venom with seasonal & Regional
variations in potency.
37. Non-enzymatic snake venom proteins
ī¯ Other than enzymes, snake venom contains
numerous non-enzymatic proteins, which
play an important role in toxicity of the
venom.
ī¯ Examples of non-enzymatic snake venom
toxins are- 1. Neurotoxins 2. Cardiotoxins
3. Haemorrhagins 4. Myotoxins
5. Haemolysins
39. What is Antivenom ?
ī¯ Anti venoms are also known as
antivenenum, antivenine or antivenin
ī¯ Anti venoms are preparations of intact or
fragmented immunoglobulin G used for
treatment of human or animal suffering
from severe envenoming from the bites &
stings of various venomous animals.
40. IgG
īąLarge molecules -150 Kda
īąFour peptide chains. A tetrameric quaternary struct.
īąLinked by disulfide bonds.
īąThe Fc regions of IgGs bear a highly conserved N-
glycosylation site.
41. History
īą Anti venom is in existence for over a century.
īą Dr. Albert Calmette in 1894 demonstrated that
protection could be imparted against venoms
by immunising animals with low doses of
venom.
īą In 1895, he saved a life of a severely bitten
person by using anti venom raised in horses.
īą In India, Central Research Institute,Kasauli &
Haffkine Institute, Mumbai have been
producing snake anti venoms since 1925.
42. Are Antivenoms Safe
ī¯ Adverse Reactions
īŽ Early Anaphylactic reactions
ī¯ After 10-180 mins.
īŽ Pryogenic (endotoxic) reactions
ī¯ After 1-2 hrs
īŽ Late Anaphylaxis reactions
ī¯ After 1-12 days (mean 7 days)
45. WHY EQUINES ARE USED?
īąEasy to Handle
īąLarge volume of blood/plasma can be
collected at periodic intervals
īąWell established and validated purification
process for over 100 years
īąVery sensitive for venoms/toxins, hence
excellent immuno conversion
īą90% of commercial therapeutic sera are
equine origin
46. Anti venoms available in India
ī¯ Polyvalent Snake Antivenin,I.P.
Effective against the bites of Indian Cobra(Naja
naja), Russellâs Viper(Vipera russelli), Indian
Common Krait(Bangarus coeruleus) & Saw
Scaled Viper( Echis carinatus ).
ī¯ Monovalent Scorpion Venom Antiserum,I.P.
Effective against the stings of Red Scorpion
( Buthus tamulus ).
48. QUALITY CONTROL
ī¯ Definition
īŽ Process or system for monitoring the
quality of laboratory testing, and the
accuracy and precision of results
īŽ Routinely collect and analyze data from
every test run or procedure
īŽ Allows for immediate corrective action
49. QUALITY CONTROL
ī¯ Designing a QC Program
īŽ Establish written policies and procedures
ī¯ Corrective action procedures
īŽ Train all staff
īŽ Design forms
īŽ Assure complete documentation and review
50. QUALITY CONTROL
ī¯ Qualitative vs.Quantitative
īŽ Quantitative test
ī¯ measures the amount of a substance
present
īŽ Qualitative test
ī¯ determines whether the substance being
tested for is present or absent
52. QUALITY CONTROL (Chemical)
ī¯ Chemical and instrumental testing
īŽ Water analysis
īļ WFI, PW, Steam and Raw water testing
īŽ FP,RM,PM analysis
īŽ Inprocess Quality checks
īļ Protein Estimation
īļ Phenol testing
īŽ Stability testing
īļ Real time
īļ Accelerated studies
īŽ Process validation studies
53. QUALITY CONTROL
ī¯ Data Analysis
īŽ Select high quality controls
īŽ Experimental Analysis
īŽ Statistical analysis
īļ Central tendency (Mean, Median Mode)
īļ Variability (Range,Variance,SD, CV)
īŽ Develop Levey-Jennings chart
īŽ Monitor control values using the Levey-Jennings
chart and/or Westgard rules
īŽ Take immediate corrective action, if needed
ī¯Record actions taken
55. QUALITY CONTROL
ī¯ Quality Control is used to monitor both
the precision and the accuracy of the
assay in order to provide reliable results.
ī¯ Accuracy and Precision
īŽ The degree of fluctuation in the
measurements is indicative of the âprecisionâ
of the assay.
īŽ The closeness of measurements to the true
value is indicative of the âaccuracyâ of the
assay.
56. QUALITY CONTROL
ī¯ Summary
īŽ Establish written policies and procedures
īŽ Assign responsibility for monitoring and
reviewing
īŽ Train staff
īŽ Obtain control materials
īŽ Collect data
īŽ Set target values (mean, SD)
īŽ Establish Levey-Jennings charts
īŽ Routinely plot control data
īŽ Establish and implement troubleshooting and
corrective action protocols
īŽ Establish and maintain system for
documentation
59. QUALITY ASSURANCE
īą Quality assurance -Wide ranging concept
covering all matters that individually or
collectively influence the quality of a product.
īą It is the totality of the arrangements -ensure
that pharmaceutical products are of the quality
required for their intended use.
īą QA is the heart and soul of quality control
īą QA = QC + GMP /Other Quality Systems
FINE QUALITY INPUT ONLY CAN GIVE
YOU A FINE QUALITY OUTPUT.
60. QUALITY ASSURANCE
GMP
(Good Manufacturing Practice)
It works in favor of Manufacturer
Its focus is on Manufacturing
GMP consists of more technical operations
Mandatory
ISO
(International Organization for
Standardization)
It work in favor of customer
Its focus is on product Quality
ISO consists more Business operations
Optional
61. QUALITY ASSURANCE
ī¯ The Five Mâs of Quality
ī§ Man
ī§ Material
ī§ Machinery
ī§ Manuals/Methodology ( SOP)
ī§ Motivation
62. QUALITY ASSURANCE
ī¯ Activities of QA
ī§ Technology transfer
ī§ Monitoring Production
ī§ Validation
ī§ Documentation
ī§ Assuring quality of products
ī§ Quality improvement plans
ī§ Training
ī§ Quality Risk Management
63. QUALITY ASSURANCE
ī¯ Technology transfer
ī§ Checking and approval of documents
generated based on research centre
documents i.e. batch manufacturing record
ī§ Scale-up and validation of product
64. QUALITY ASSURANCE
ī¯ Monitoring Production
īŽ All the production activities
īŽ Utility Systems- HVAC, WFI, PSG, etc
īŽ Personnel
īŽ Equipment, Operational & Process Qualification
īŽ Validation & calibration
65. QUALITY ASSURANCE
īą Validation
ī§ Preparation of Validation Master plans for
facility/equipments/process Utility, Cleaning and all the
sections of the validation
ī§ Approval of protocol for validation of facility/
equipment/product/ process/Utility
ī§ Team member for execution of validation of
facility/equipment / product/ process
ī§ Final approval of the facility/ equipment/product/
process/Utility validation
66. QUALITY ASSURANCE
ī¯ Documentation
ī§ Standard operating procedures
ī§ Protocols of tests,
ī§ Results
ī§ Reports
ī¯ Standard Operating Procedures
ī§ An authorized written procedure giving instructions for
performing operations not necessarily specific to a given
process, product or material (e.g. equipment operation,
maintenance and cleaning; validation; cleaning of
premises and environmental control; sampling and
inspection).
67. QUALITY ASSURANCE
īą Assuring Quality of products
ī§ cGMP training
ī§ SOP compliance
ī§ Audit of facility for compliance
ī§ Line clearance
ī§ In-process counter checks
ī§ Critical sampling
ī§ Record verification
ī§ Release of batch for marketing
ī§ Investigation of market complaints
68. QUALITY ASSURANCE
īą Quality improvement plan
ī§ Feedback received from the compliance team
ī§ Customer complaint history
ī§ Proposals for corrective and preventive actions
ī§ Annual Products review
ī§ Trend analysis of various quality parameters for products,
environment and water
ī§ Review of the Deviations, Change Controls, Out Of
Specifications and Failures.
69. QUALITY ASSURANCE
īą Training
ī§ Induction training program
ī§ On the job training
īą Quality Risk Management
ī§ Assessment of risk analysis of every
process/activity in production QC
ī§ Quantifying or grading the probablity of
occurrence of activities
ī§ Taking measures to minimize the occurrence of
risks
71. Research areas in
Anti venom production
īą Chicken Egg Yolk Antibodies
īą High avidity antibodies
īą Reduced cross reactivity
īą Doesnât bind to rheumatoid factors
īą Applications mostly diagnostic rather than clinical.
īą Camelid Antibodies Antibodies
īą Antibodies devoid of Light Chains
īą Less immunogenic- least complement activation
īą Least anaphylactic & serum sickness reactions
īą High Titres & Avidity
īą Thermostable- supply chain
īą Universal Antivenom
73. Recent trends in
Anti venom production
īą VHH antibobies / Nanobodies
First single-domain antibodies were engineered
from heavy chain antibodies found in camelids;
these are called VHH fragments.
Advantages
genetic manipulation
Increased functional size of immune libraries
production of multivalent formats
production of oligoclonal preparations from
single cells
High physicochemical stability
High solubility
Recognition of hidden antigenic sites
Rapid tissue penetration, fast clearance
Well expressed
74. Research areas in
Anti venom production
ī¯ Equine Health
īŽ Mapping of CBC, LFT, KFT
īŽ Nutritional immunopotentiaters
īŽ Control of equine diseases R.equii, Glanders
īŽ Interlukine mapping studies
ī¯ Venomics
īŽ Study of venoms
īŽ Variability of venoms due to size, age, geographical
location
īŽ Design of effective antivenom (Mono / polyspecific)
īŽ Antivenoms may have paraspecific effects
--Cross neutralization
75. Research areas in
Anti venom production
ī¯ Immunization
īŽ Science + Art
īŽ Poorly immunogenic antigens â long immu. Sch.
īŽ Variability immune response
īŽ Toxic stress
īŽ Increased cost of production
īŽ Immunization protocols
īŽ Low Dose Low volume multisite pro.with adjuvants
īŽ Newer Adjuvants
ī¯ - Liquid, Emulsion, Nanoparticle
īŽ Safety & Immunogenicity
76. Research areas in
Anti venom production
ī¯ Plasma Processcing
īŽ Less Protein Aggregates
īŽ Pyrogen Free Antisera
īŽ Virus Free Antisera
īŽ Chromatographically purified antivenoms
īŽ Least protein & more neutralizing antibodies
īŽ Safety & Efficacy
ī¯ Formulations
īŽ Search of best stabilizers, preservatives
īŽ Lyohilization
77. Research areas in
Anti venom production
ī¯ Quality Control
īŽ Water Analysis â TOC, Rapid Tests
īŽ Enviromental Monitoring â Rapid Tests
īŽ Raw material analysis (Method val.)
īŽ Sterility âRapid tests
īŽ Endotoxin testing
īŽ Animal Testing 3 Râs (cytotoxic / ELISA/ LFA)
78. Research areas in
Anti venom production
Quality Control
īŽ Animal Testing 3 Râs (cytotoxic / ELISA/ LFA)
(European Centre for the Validation for Alternative Methods)
ī¯ Reduce
The number of animals used.
ī¯ Refine
In vivo test methods/ techniques by
Lessening or eliminating pain or distress to animal.
ī¯ Replace
Partially or totally the use of animals with in vitro
assays.
For Antirabies serum
ī¯ Two Tests Comply: ELISA and RFFIT
79. Summary of Research Areas
for Antivenoms
ī¯ Knowledge based composition design of venom
mixtures used for immunization
The number of animals used.
ī¯ Careful selection and adequate management of
animals used for immunizations.
ī¯ Well designed immunization protocols.
ī¯ Sound innovations in plasma fractionation â recovery,
tolerability & stability of antivenoms.
ī¯ Use of recombinant toxins as immunogens.
ī¯ Synthesis of engineered antibodies to substitute for
animal derived antivenoms.
80. Summary of Research Areas
for Antivenoms
ī¯ Scientific studies in existing manufacturing steps
towards inactivation or removal of viruses and
other zoonotic pathogens
ī¯ Introduction of novel quality control tests
ī¯ Devp. of invitro assays to substitute invivo assays
ī¯ Scientifically sound preclinical and clinical
assesment of antivenoms