Biopharmaceutical Process Development: Good Manufacturing Practices or Breaki...Chris Willmott
These are the slides from a presentation "Biopharmaceutical Process Development: Good Manufacturing Practices or Breaking Bad?" given by Andrew Warr as part of the 2015 Careers After Biological Sciences programme at the University of Leicester UK
Biosimilars are biological generics drugs.They undergo a rigorous evaluation to get approved.How to prove biosimilariy from analytical comparability is explained using a recently approved US FDA bio-similar monoclonal antibody.
USFDA Approval Process For Drug Products & Biological Product i.e NDA Vs. BLA
Comparison of NDA and BLA application process in USA. IND, NDA, ANDA & BLA dossier submission procedure.
Production and purification of Viral vectors for gene and cell therapy appli...Dr. Priyabrata Pattnaik
Presentation at "2016 Osong BioExcellence - Renaissance in Immunotherapy" at South Korea, an event jointly hosted by Kbio Health and Merck on 6th October 2016.
Biopharmaceutical Process Development: Good Manufacturing Practices or Breaki...Chris Willmott
These are the slides from a presentation "Biopharmaceutical Process Development: Good Manufacturing Practices or Breaking Bad?" given by Andrew Warr as part of the 2015 Careers After Biological Sciences programme at the University of Leicester UK
Biosimilars are biological generics drugs.They undergo a rigorous evaluation to get approved.How to prove biosimilariy from analytical comparability is explained using a recently approved US FDA bio-similar monoclonal antibody.
USFDA Approval Process For Drug Products & Biological Product i.e NDA Vs. BLA
Comparison of NDA and BLA application process in USA. IND, NDA, ANDA & BLA dossier submission procedure.
Production and purification of Viral vectors for gene and cell therapy appli...Dr. Priyabrata Pattnaik
Presentation at "2016 Osong BioExcellence - Renaissance in Immunotherapy" at South Korea, an event jointly hosted by Kbio Health and Merck on 6th October 2016.
This presentation mainly deals with clinical development of biosimilar products. It also gives enough on non-clinical development so that the audience is well oriented.
GxP is a general abbreviation for the "good practice" quality guidelines and regulations. These slides provide an overview of current regulations, with a focus on pharmaceuticals and healthcare.
Biosimilar a biological drug evaluation includes the biopharmaceutical families, the difference between small molecules and bio-pharmaceutical products, the regulatory requirements for biosimilars and the fact about biosimilars and biologic / bio pharmaceuticals the competent authorities and the key component of successful pharmacovigilane programs
MARKETING AUTHORISATION, LICENSING AND QUALITY ASSESSMENT OF VACCINES IN INDI...Swapnil Fernandes
- European pharmaceutical legislation provides a comprehensive framework for the marketing authorisation of vaccines.
- In contrast to the European scenario, the Indian scenario for vaccines is relatively less regulated and follows the same process of approval as other biologics in spite of having a National Handbook for Vaccine Policy.
- Vaccine authorisation in the US, as is the case in EU, is a more straightforward process than in most other markets as the USFDA has provided vaccines with a distinct set of regulations in concerned areas of safety and quality.
Journey in the Development of Biologics Through End of Phase 3
Our Goals
To better understand the FDA’s CMC requirements and expectations for biologic manufacturing and product testing
To better visualize a cost-effective, risk-managed approach to manage these manufacturing processes and products through clinical development into market approval
To better appreciate the challenges involved with controlling safety, potency, and impurity profiles for these products
Bioavailability and Bioequivalence StudiesPranav Sopory
BA and BE studies.
Seminar presented in All India Institute of Medical Sciences (AIIMS - New Delhi).
Focus in Pharmacokinetic parameters (Cmax, AUC)
Single dose PK study, Steady state PK study, Modified drug release PK study, In vivo mechanisms, invitro mechanisms, Pharmacodynamic Study, Comparatice Clinical Trials. Biowavers and Biosimilimars.
Reference: CDSCO guideline, USFDA guideline, ICH guidelines
Biologics (eg, vaccines, blood and blood components, somatic cells, gene therapy, tissues, therapeutic proteins) are regulated by the US Food and Drug Administration (FDA). Biologics/Biosimilars/Biobetters are widely used to diagnose, prevent, treat, and cure diseases and medical conditions.
Naveen Kumar Singh received his B.Sc. in Biotechnology (2007) at University of Pune (Pune, India), M.Sc. in Biotechnology (2009) at Jaipur National University (Jaipur, India), and Ph.D. in Biochemical Engineering (2016) at Jacobs University Bremen (Bremen, Germany).
During his Ph.D., Naveen worked under the supervision of Prof. Marcelo Fernández-Lahore. His research dealt with designing experiments for developing fiber-based and cryogel-based adsorbents for capturing large therapeutic biomolecules (proteins, plasmids, and monoclonal antibodies). He had successfully evaluated the in-house fiber- and cryogel-based chromatographic adsorbents with the commercially available adsorbents and the in-house adsorbents had shown similar or higher productivities compared to the commercial adsorbents.
In February 2017, Naveen joined the group of Prof. Merlin L. Bruening in the Department of Chemical and Biomolecular Engineering at the University of Notre Dame as a Postdoctoral Research Associate. His current research focuses on developing novel bioseparation processes by introducing polyelectrolyte multilayer films onto membranes/monoliths for the purification of biotherapeutics like monoclonal antibodies.
Publications:
N. K. Singh, et al, “Preparation and Characterization of Grafted Cellulosic Fibers and their Applications in Protein Purification“, Sep. Purif. Technol., 143 (2015) pp. 177–183. https://www.sciencedirect.com/science/article/pii/S1383586615000714
N. K. Singh, et al, “Direct Capture of His6-tagged Proteins Using Megaporous Cryogels Developed for Metal-ion Affinity Chromatography“, inAffinity Chromatography (Ed.: S. Reichelt), Spinger, New York, USA, Methods in Molecular Biology, 1286 (2015) pp. 201–212. http://link.springer.com/protocol/10.1007/978-1-4939-2447-9_16
N. K. Singh, et al, “Gamma ray mediated functionalization of monolithic cryogels for macro-biomolecule purification“, N. Biotechnol., 31, Supplement (2014) pp. S127. http://www.sciencedirect.com/science/article/pii/S1871678414019906
N. K. Singh, et al, “High capacity cryogel-type adsorbents for protein purification“, J. Chromatogr. A, 1355 (2014) pp. 143–148. https://www.sciencedirect.com/science/article/pii/S0021967314008899
N. S. Bibi, N. K. Singh, et al, “Synthesis and performance of megaporous immobilized metal-ion affinity cryogels for recombinant protein capture and purification“, J. Chromatogr. A, 1272 (2013) pp. 145–149. https://www.sciencedirect.com/science/article/pii/S0021967312017670
Blog articles:
What are cryogels? https://www.biochemadda.com/cryogels-monolith-ion-exchange-affinity-chromatography/
“The Evolution of Pharmaceutical Biotechnology – Science, Strategies, Products, and Regulations”
Shows the latest developments in pharmaceutical biotechnology and provides a broad overview of biotherapeutic & biosimilar regulations globally and in the EU
This presentation mainly deals with clinical development of biosimilar products. It also gives enough on non-clinical development so that the audience is well oriented.
GxP is a general abbreviation for the "good practice" quality guidelines and regulations. These slides provide an overview of current regulations, with a focus on pharmaceuticals and healthcare.
Biosimilar a biological drug evaluation includes the biopharmaceutical families, the difference between small molecules and bio-pharmaceutical products, the regulatory requirements for biosimilars and the fact about biosimilars and biologic / bio pharmaceuticals the competent authorities and the key component of successful pharmacovigilane programs
MARKETING AUTHORISATION, LICENSING AND QUALITY ASSESSMENT OF VACCINES IN INDI...Swapnil Fernandes
- European pharmaceutical legislation provides a comprehensive framework for the marketing authorisation of vaccines.
- In contrast to the European scenario, the Indian scenario for vaccines is relatively less regulated and follows the same process of approval as other biologics in spite of having a National Handbook for Vaccine Policy.
- Vaccine authorisation in the US, as is the case in EU, is a more straightforward process than in most other markets as the USFDA has provided vaccines with a distinct set of regulations in concerned areas of safety and quality.
Journey in the Development of Biologics Through End of Phase 3
Our Goals
To better understand the FDA’s CMC requirements and expectations for biologic manufacturing and product testing
To better visualize a cost-effective, risk-managed approach to manage these manufacturing processes and products through clinical development into market approval
To better appreciate the challenges involved with controlling safety, potency, and impurity profiles for these products
Bioavailability and Bioequivalence StudiesPranav Sopory
BA and BE studies.
Seminar presented in All India Institute of Medical Sciences (AIIMS - New Delhi).
Focus in Pharmacokinetic parameters (Cmax, AUC)
Single dose PK study, Steady state PK study, Modified drug release PK study, In vivo mechanisms, invitro mechanisms, Pharmacodynamic Study, Comparatice Clinical Trials. Biowavers and Biosimilimars.
Reference: CDSCO guideline, USFDA guideline, ICH guidelines
Biologics (eg, vaccines, blood and blood components, somatic cells, gene therapy, tissues, therapeutic proteins) are regulated by the US Food and Drug Administration (FDA). Biologics/Biosimilars/Biobetters are widely used to diagnose, prevent, treat, and cure diseases and medical conditions.
Naveen Kumar Singh received his B.Sc. in Biotechnology (2007) at University of Pune (Pune, India), M.Sc. in Biotechnology (2009) at Jaipur National University (Jaipur, India), and Ph.D. in Biochemical Engineering (2016) at Jacobs University Bremen (Bremen, Germany).
During his Ph.D., Naveen worked under the supervision of Prof. Marcelo Fernández-Lahore. His research dealt with designing experiments for developing fiber-based and cryogel-based adsorbents for capturing large therapeutic biomolecules (proteins, plasmids, and monoclonal antibodies). He had successfully evaluated the in-house fiber- and cryogel-based chromatographic adsorbents with the commercially available adsorbents and the in-house adsorbents had shown similar or higher productivities compared to the commercial adsorbents.
In February 2017, Naveen joined the group of Prof. Merlin L. Bruening in the Department of Chemical and Biomolecular Engineering at the University of Notre Dame as a Postdoctoral Research Associate. His current research focuses on developing novel bioseparation processes by introducing polyelectrolyte multilayer films onto membranes/monoliths for the purification of biotherapeutics like monoclonal antibodies.
Publications:
N. K. Singh, et al, “Preparation and Characterization of Grafted Cellulosic Fibers and their Applications in Protein Purification“, Sep. Purif. Technol., 143 (2015) pp. 177–183. https://www.sciencedirect.com/science/article/pii/S1383586615000714
N. K. Singh, et al, “Direct Capture of His6-tagged Proteins Using Megaporous Cryogels Developed for Metal-ion Affinity Chromatography“, inAffinity Chromatography (Ed.: S. Reichelt), Spinger, New York, USA, Methods in Molecular Biology, 1286 (2015) pp. 201–212. http://link.springer.com/protocol/10.1007/978-1-4939-2447-9_16
N. K. Singh, et al, “Gamma ray mediated functionalization of monolithic cryogels for macro-biomolecule purification“, N. Biotechnol., 31, Supplement (2014) pp. S127. http://www.sciencedirect.com/science/article/pii/S1871678414019906
N. K. Singh, et al, “High capacity cryogel-type adsorbents for protein purification“, J. Chromatogr. A, 1355 (2014) pp. 143–148. https://www.sciencedirect.com/science/article/pii/S0021967314008899
N. S. Bibi, N. K. Singh, et al, “Synthesis and performance of megaporous immobilized metal-ion affinity cryogels for recombinant protein capture and purification“, J. Chromatogr. A, 1272 (2013) pp. 145–149. https://www.sciencedirect.com/science/article/pii/S0021967312017670
Blog articles:
What are cryogels? https://www.biochemadda.com/cryogels-monolith-ion-exchange-affinity-chromatography/
“The Evolution of Pharmaceutical Biotechnology – Science, Strategies, Products, and Regulations”
Shows the latest developments in pharmaceutical biotechnology and provides a broad overview of biotherapeutic & biosimilar regulations globally and in the EU
This presentation contains recommendations and requirements for the design of bioanalytical testing used in comparibility studies for biosimilar drug development using rituximab as an example
Global Biopharmaceutical Contract Manufacturing Market - Qualitative and Quan...Aiswariya Chidambaram
This presentation which highlights the key market and technology trends in the global biopharmaceutical contract manufacturing market was delivered as a lecture at the In-Focus Seminar session at CPhI Worldwide 2013 held at Frankfurt, Germany.
ARTIFICIAL INTELLIGENCE IN HEALTHCARE.pdfAnujkumaranit
Artificial intelligence (AI) refers to the simulation of human intelligence processes by machines, especially computer systems. It encompasses tasks such as learning, reasoning, problem-solving, perception, and language understanding. AI technologies are revolutionizing various fields, from healthcare to finance, by enabling machines to perform tasks that typically require human intelligence.
Ethanol (CH3CH2OH), or beverage alcohol, is a two-carbon alcohol
that is rapidly distributed in the body and brain. Ethanol alters many
neurochemical systems and has rewarding and addictive properties. It
is the oldest recreational drug and likely contributes to more morbidity,
mortality, and public health costs than all illicit drugs combined. The
5th edition of the Diagnostic and Statistical Manual of Mental Disorders
(DSM-5) integrates alcohol abuse and alcohol dependence into a single
disorder called alcohol use disorder (AUD), with mild, moderate,
and severe subclassifications (American Psychiatric Association, 2013).
In the DSM-5, all types of substance abuse and dependence have been
combined into a single substance use disorder (SUD) on a continuum
from mild to severe. A diagnosis of AUD requires that at least two of
the 11 DSM-5 behaviors be present within a 12-month period (mild
AUD: 2–3 criteria; moderate AUD: 4–5 criteria; severe AUD: 6–11 criteria).
The four main behavioral effects of AUD are impaired control over
drinking, negative social consequences, risky use, and altered physiological
effects (tolerance, withdrawal). This chapter presents an overview
of the prevalence and harmful consequences of AUD in the U.S.,
the systemic nature of the disease, neurocircuitry and stages of AUD,
comorbidities, fetal alcohol spectrum disorders, genetic risk factors, and
pharmacotherapies for AUD.
Report Back from SGO 2024: What’s the Latest in Cervical Cancer?bkling
Are you curious about what’s new in cervical cancer research or unsure what the findings mean? Join Dr. Emily Ko, a gynecologic oncologist at Penn Medicine, to learn about the latest updates from the Society of Gynecologic Oncology (SGO) 2024 Annual Meeting on Women’s Cancer. Dr. Ko will discuss what the research presented at the conference means for you and answer your questions about the new developments.
The prostate is an exocrine gland of the male mammalian reproductive system
It is a walnut-sized gland that forms part of the male reproductive system and is located in front of the rectum and just below the urinary bladder
Function is to store and secrete a clear, slightly alkaline fluid that constitutes 10-30% of the volume of the seminal fluid that along with the spermatozoa, constitutes semen
A healthy human prostate measures (4cm-vertical, by 3cm-horizontal, 2cm ant-post ).
It surrounds the urethra just below the urinary bladder. It has anterior, median, posterior and two lateral lobes
It’s work is regulated by androgens which are responsible for male sex characteristics
Generalised disease of the prostate due to hormonal derangement which leads to non malignant enlargement of the gland (increase in the number of epithelial cells and stromal tissue)to cause compression of the urethra leading to symptoms (LUTS
MANAGEMENT OF ATRIOVENTRICULAR CONDUCTION BLOCK.pdfJim Jacob Roy
Cardiac conduction defects can occur due to various causes.
Atrioventricular conduction blocks ( AV blocks ) are classified into 3 types.
This document describes the acute management of AV block.
Flu Vaccine Alert in Bangalore Karnatakaaddon Scans
As flu season approaches, health officials in Bangalore, Karnataka, are urging residents to get their flu vaccinations. The seasonal flu, while common, can lead to severe health complications, particularly for vulnerable populations such as young children, the elderly, and those with underlying health conditions.
Dr. Vidisha Kumari, a leading epidemiologist in Bangalore, emphasizes the importance of getting vaccinated. "The flu vaccine is our best defense against the influenza virus. It not only protects individuals but also helps prevent the spread of the virus in our communities," he says.
This year, the flu season is expected to coincide with a potential increase in other respiratory illnesses. The Karnataka Health Department has launched an awareness campaign highlighting the significance of flu vaccinations. They have set up multiple vaccination centers across Bangalore, making it convenient for residents to receive their shots.
To encourage widespread vaccination, the government is also collaborating with local schools, workplaces, and community centers to facilitate vaccination drives. Special attention is being given to ensuring that the vaccine is accessible to all, including marginalized communities who may have limited access to healthcare.
Residents are reminded that the flu vaccine is safe and effective. Common side effects are mild and may include soreness at the injection site, mild fever, or muscle aches. These side effects are generally short-lived and far less severe than the flu itself.
Healthcare providers are also stressing the importance of continuing COVID-19 precautions. Wearing masks, practicing good hand hygiene, and maintaining social distancing are still crucial, especially in crowded places.
Protect yourself and your loved ones by getting vaccinated. Together, we can help keep Bangalore healthy and safe this flu season. For more information on vaccination centers and schedules, residents can visit the Karnataka Health Department’s official website or follow their social media pages.
Stay informed, stay safe, and get your flu shot today!
Couples presenting to the infertility clinic- Do they really have infertility...Sujoy Dasgupta
Dr Sujoy Dasgupta presented the study on "Couples presenting to the infertility clinic- Do they really have infertility? – The unexplored stories of non-consummation" in the 13th Congress of the Asia Pacific Initiative on Reproduction (ASPIRE 2024) at Manila on 24 May, 2024.
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2. - Biologics – definition & applications
- Process is the Product
- Monoclonal antibodies & vaccines as growth opportunities
- Changes in global biopharmaceutical industry
- Paradigm shift in development process for bioloigcs
- Effective process development and manufacturing strategy
- Integrated CMC team
- Select/establish cell line(s) critically
- Establish knowledge-based process for commercialization
- Pursue revolutionary manufacturing technologies
- Summary
3. Biologics
• Include a wide range of medicinal products such as vaccines,
blood/components, allergencis, somatic cells, gene therapy,
tissues & recombinant therapeutic proteins created by biological
processes (as opposed to chemically)
• Composed of sugars, proteins or nucleic acids or complex
combinations of all, or living entities such as cells and tissues
• Isolated from a variety of natural sources – human, animal or
microorganism, or produced by biotechnology methods and
other technologies (e.g. recombinant DNA)
Gene-based and cellular biologics promise to treat a variety of
medical conditions for which no other treatments are available
Quotes from Wikipedia 6 July 2009
4. Glucophage® 166
Rituxan®
Taxol® 854 145,000
Chemical Biologics
Size (M.W.) < 500* 20,000 - 200,000+*
Complexity Low High
Process Conditions (T/P) High Ambient
In-Process Concentration Concentrate (~100g/L) Dilute (.5 -5g/L)
Reactor Volume < 8,000 L ~20,000+L
Reaction Steps Multiple chemical Complex product
reactions/isolations made by living cells
Production Solvents Organic Aqueous
Isolation/Purification Crystallization Chromatography
Product Definition Few simple assays Many complex assays
Process Changes Equivalency Comparability
maybe clinical trials
Patent/IP Molecules Process Knowhow
IP Expiration Threat Generics dominant Biosimilars evolving
PROCESS is the product
5. • Global pharmaceutical market Before global financial crisis…
Revenue US$ 773 bn in 2008
Projected growth rate of 5%
• Global biopharmaceutical market
Revenue US$75 bn in 2008
Projected growth rate 12%
• Growth in biopharmaceutical market
to reach US$138 bn by 2014
dominated by products from
mammalian cell cultures (>75%)
• Opportunities in biopharmaceuticals
Novel & biosimilar r-proteins
Vaccines
Source: Global Trends and Drivers of Biopahrmaceutical
Manufacturing, Frost & Sullivan, Asia Biomanufacturing Summit
28 October 2009
6. Therapeutic Proteins = Biopharmaceuticals
• 75 FDA approved therapeutic proteins
• > 500 additional proteins under development
• Broad applications:
Cancers & autoimmune diseases (treated by
monoclonal antibodies and interferons)
Heart attacks, strokes, cystic fibrosis and Gaucher's disease (treated by
Enzymes and blood factors)
Metabolic diseases: diabetes (treated by insulin)
Blood diseases: anemeia (treated by erythropoietins), hemophilia
(treated by blood clotting factors).
• Worldwide sales approximately $57 billion in 2006 with projected growth of
13% , or >$90 bn by 2010.
• Monoclonal antibodies (Mabs) ~32bn in 2008, growing rapidly to 30% global
biologics market
Piribo, “Global Protein Therapeutics Market Analysis", ProLOG Feb 13, 2008
8. • Global vaccines market will grow to over a USD $23.8 bn by 2012,
growing at ~11% per year
• Novel and improved vaccines growing at 58% p.a.
Traditional and combinations
Include mostly pediatric & partially
adult vaccines
Novel and therapeutic vaccines
include both adult & therapeutic
Global Vaccine Market US$ bn
Source: Global Trends and Drivers of Biopahrmaceutical Manufacturing,
Frost & Sullivan, Asia Biomanufacturing Summit 28 October 2009
9. • Pandemic & seasonal Flu vaccines: to reach $7.1 bn in 2010 with
19.8% growth rate, driven by pandemic flu vaccine global supply
shortage (H5N1, H1N1)
• Driven by bird flu (2005) and swine flu (2009), government spending
worldwide on Pandemic Influenza Preparedness tripled to $7 bn in
2009 ($2.2 bn in 2004, 17% CAGR), reaching ~ $10 bn by 2015 (5%
CAGR)
• Global Pandemic Influenza Preparedness Market: estimated @$52
bn in 2010-2015 (5% CAGR)
Novel cell-based process & manufacturing technology reaching the
market:
Baculovirus system/Insect cells (Protein Sciences, Novavax)
Mammalian cells: Vero (Baxter), MDCK (Novartis)
Per.C6 (Sanofi/Crucell); in serum-free media
Avian cells: EB66, duck embryonic stem cell line by Vivalis
DNA vaccines: VGX Pharma (IND) early development
Global Pandemic Influenza Preparedness Market Forecast 2010-2015, Publication: 04/2009 by Market Research Media.
10. • Concerns over global Economy Increasing global price regulations
Implement a protectionist and nationalist policies
Strengthen the local pharmaceutical industry by implementing more
stringent price regulation on foreign manufacturers
• Shift in growth from mature markets to emerging markets
Emerging economies could generate up to a fifth of global
pharmaceutical sales by 2020
Changing growth dynamics from the West to emerging economies shift
developer interest in patient groups
Increasing trend in outsourcing manufacturing and R&D cost-effectively
• Cost containment pressures in major markets worldwide
Escalating healthcare costs have put pressure on payers to contain
pharmaceutical expenditure
Multiple stakeholders in the R&D/Product Development process
including payers, patients and pharmacists (for pricing considerations)
Source: Global Trends and Drivers of Biopahrmaceutical Manufacturing,
Frost & Sullivan, Asia Biomanufacturing Summit 28 October 2009
11. Global Pharmaceutical Sales
Global Pharmaceutical: 2009 Market Sizes*
Growth Rate
4.5-5.5% Emerging, 115
US, 302
Japan, 88
* All values
2008 2009 are in US$,
EU, 172 Billions
15%
Growth Rate in Sales (%)
10% Growth in emerging country markets:
Far outstrip growth in the US & EU
5%
US EU Japan Emerging
Source: Global Trends and Drivers of Biopahrmaceutical Manufacturing,
Frost & Sullivan, Asia Biomanufacturing Summit 28 October 2009
12. Discovery Phase Development Phase Commercialization Phase
(3-6 years) (5-10 years) (8-12 years - Patent Expiration)
Basic Manufacturing
Full Early Stage Late Stage - Full Product
Research Sales
Discovery Development Development Management
Distribution
ECN IND BLA LAUNCH Generics
Biosimilars
10,000
-30,000 ~250 5-10 2-5 2 1
Preclinical
Phase I Phase IIa, IIb Phase III
Testing
Clinical Trial Clinical Trial Clinical Trial
(lab & animal testing)
Small
Biologics Molecules
Drug Development
Outsourcing to CROs, CMOs Process Tech Transfer earlier
Manufacturing Outsourcing to External Facilities
13. Molecular Biology Preclinical Filing, Regulatory
& Clinical Launch &
Cell Line & Process Review & Approval
Development Commercialization
Development
2-3 years 3-4 years 1-2 years
Full Drug Development Capabilities and Infrastructure Required
- CMC: Process development & biologics Manufacturing
- Preclinical and Clinical: Toxicity, Phases 1 and III, comparability studies
- Filing and regulatory challenges
High Barriers to Entry
- $50M – $500M long term investment required
- Competition with existing brands (low price differentials)
- Complexity of products (not API) and manufacturing facilities
Highly Competitive Markets
- Large pharmaceutical companies moved in: Merck, Novartis, Aztrazeneca
- Major generics companies formed alliance: Teva & Lonza
14. Chemistry, manufacturing and control (CMC)
• Manufacturing Information “pertaining to the
composition, manufacture, stability and controls used
for manufacturing the drug substance and the drug
product”
• Information “ensure that the company can adequately
produce and supply consistent batches of the drug”
Early development stage
Evaluate current technology to produce product, begin
cell line and process development, and product
characterization
Supply GLP material for preclinical toxicology study &
produce GMP material for clinical trials
Begin developing process with end in mind
15.
16. New cell line? Process changes? Formulation changes?
Process Devt
Biologics Process Commercial
& Medium Scale
Research scale production Fill & Finish
production
<10L 2000lL – 20,000L
10L-500L
• New cell line • Process development, • Process scale up • Vial filling, packing
development optimisation, scale-up • DS Manufcturing • Lyophilization,
• Expression • Productivity enhancement facility operations • Supply chain operations
engineering • QbD, PAT implementation • COGS improvement • COGS improvement
• Media design • Product quality & stability • Lean manufacturing • Lean manufacturing
• Novel product
FUNCTIONAL EXCELLENCE
ONE CMC TEAM
CELL CULTURE ANALYTICS PURIFICATION FORMULATION
• Molecular Biologists • Analytical Biochemists• Chromatographers • Formulation chemists
• Microbiologists • Biophysical Chemists • Protein Biochemists • Protein Biochemists
• Cell Biologists • Protein Biochemists • Biochemical Engineers • Engineers
• Virologists
18. 1981 - HER2 gene cloned
1985 - Axel Ullrich and Art Levinson clone HER2 gene
1990 - Creates anti-HER2 monoclonal Antibody (Herceptin)
1992 - Files Herceptin IND, Phase I trials initiated (25-50
patients)
1993 - Herceptin Phases II trials begin (250-200 patients)
1995 - Initiates Phase III, 3 trials (500-1,000 patients)
1996 - Partners with DAKO for commercial diagnostic testing
kits
1997 - Completes Phase III enrollment
1998 - Presents Phase III data demonstrating effect with
chemotherapy and increase time to disease progression
1998 - Herceptin approved by FDA
Fully integrated high performance team delivers a mAb in <10 years
19. • All key expertise critical for product development available in country
• Government support for infrastructure and high risk investment
• Early development focus
Clinical Commercial
Regulatory hospitals Manufacturing
Consultant? or CMOs
Clinical
Institutes
Or CROs
Discovery Novel drug or
Marketing (internal & external)
Consultant? Biosimilars
Early Development
CMC Preclinical
Institutes Institutes
Legal/IP or CMOs or CROs
Consultants
Integrate in-country project team with core elements
Fill gaps in various support areas by appropriate consultants
Form oversight committee to support Project Team
20. Selection of cell lines – product specific & IP sensitive
Many matured cell line platforms to choose from (e.g. mAbs:
CHO, NSO, per.C6)
Cell line selection and construction in early basic research stage
without considering manufacturing may result in challenges/
delays in commercialization
Select cell line critically with END in mind: titer, stability,
product glycosylation & manufacturability
change of cell line post phase I clinical trials undesirable
process changes post phase II to be minimized
Process is Product Cell line dictates process
21. Selective to infection;
reduces risk to
adventitious agents
Swine cell lines: EB66 duck embryonic stem cell line by Vavilis shows promises
A-Bio notes: process information is gathered from EPAR sources and published literature; CELVAPAN information is from Baxter
22. • Product design & selection in early basic research stage without
considering manufacturing may result in challenges/delays in
commercialization
• Characterization of desired product driven by clinical needs
impacts significantly downstream
• Product characterization requires advanced analytics
• Product complexity presents challenges in consistent supply to
patients (eg. blood factors, live virus vaccines)
Multiple cell hosts developed at early stage for strategic decision
including manufacturability
Process is Product Product quality challenges
process (eg. glycosylation pattern)
23. Glycan homogenity
• Large statistical population of variants
• Difficult to achieve due to macro and microhetergenity
• Achievable via process design and manufacturing consistency
Immunogenicity - injection site reactions/threat of anaphylaxis
Change in efficacy – ADCC response (Rituxin, tumor killing)
Product incomparability after scale up (Lumizyme, Genzyme)
• Myozyme (160L) = Lumizyme (2,000L)
• New BLA requested submission over carbohydrate structure
changes
CMC comparability issues (Erbitux, Imclone)
• pre-clinical PK issues: sBLA for non-small lung cancer withdrawn
• Additional PK requested by FDA for Erbitux 1st line head & neck
cancer
Biopharm Bulletin. March 13, 2009
24. Traditional Approach (fixed controls)
Failures; variation
detected late
Variability in
raw materials, High variability in
conditions product; Possible
recalls; Product
safety concerns
Dynamic Control Strategy (multidimensional) Rapid correction of
Characterized Space process parameters
Design Space
Variability in PAT Product
Adaptive
raw materials, Adaptive Control Space consistency;
conditions Control Space Lower failures
Acceptable Operating Space
25. Genentech has built a deep knowledge base for Quality by
Design (QbD) approaches:
• 5 licensed & 26 mAbs in active development
• 6 licensed sites for mAb DS production & 9 successful DS site transfers
• 7 successful major version changes
• 13 major Drug Substance Comparability Protocols approved
40 planned comparability efforts through 2010 based on QbD
Expanded Comparability Protocols: to bundle ‘like’ changes
within a single submission
Successful transfer to Singapore: Lucentis DS plant (microbial
1,000L) late 2006-2010 FDA license
Avastin DS plant (Cell culture, 80,000L)
Early 2007 -2010 FDA license (~37 mths)
“The Progress of Biotechnology manufacturing and Process Sciences”
Patrick Yang, Genentech, Inc., Nov. 5, 2007, APBioCheDSC, Taiwan.
26. High Cell Process Facility
Productivity Simplification Efficiencies
Current mAb platform Using disposable systems
improvement: Higher reduces SIP and CIP
capacity resins, One column requirements
TREND: process, No Protein A
Higher cell productivity and Reduction of Process
Chromatography Alternatives
process optimization result Equipment Size
Crystallization, Ppt, Q filters
in smaller and less complex
manufacturing facilities Chemical Process like - Process and facility
(20,000L vs. 2,000L) Continuous Processing modularization reduces
construction time
Automated sampling and
monitoring with new sensors
Moving of process
equipment into gray space
Equipment with Integrated reduces cleanroom space.
instrumentation for real time
control and release
“The Progress of Biotechnology manufacturing and Process Sciences”
Patrick Yang, Genentech, Inc., Nov. 5, 2007, APBioCheDSC, Taiwan.
27. Upstream Process
Downstream Process
Disposable Technology: Eliminates CIP, SIP, utilities
Controlled Environment Modules: Gowning ,
operator mobility , protects product & people
Advantages: 60%++ reduction in capital investment,
40% less space needed, 85% reduction in water and
waste, 32% reduction in COGS
Faster deployment: 12-18 months vs. 4+ years
28. For biologics, Process is the Product – effective process
development for manufacturing critical for product quality and
consistency, hence commercialization.
Monoclonal anitbodies and vaccines present significant
opportunities among future biologics being developed –
advanced manufacturing platform available to improve
productivity and reduce COGS.
Emerging market will enjoy significant growth in
biopharmaceuticals driven by global changes
Drug development process paradigm shift towards earlier tech
transfer around phase I for biologics – integrated cross
functional CMC team, formed early to guide process
development with END manufacturing ability in mind essential
for successful commercialization.