What is a Variation…?
Variation regulations and guidelines
Types of variations
Type-IA
Type-IB
Type-II
Extension
Unforeseen variations (Z category)
Grouping of variations
Work sharing of variations
Fee
eAF
Renewals
Biosimilars
A biosimilar is a biological medicine highly similar to another already approved biological medicine (the 'reference medicine'). (A medicine whose active substance is made by a living organism.)
Biologicals
Biological medicines contain active substances from a biological source, such as living cells or organisms and are often produced by cutting-edge technology.
Biological medicinal product
Biological Medicinal Products, also known as biologics or biologicals, are medicinal products that are manufactured using biotechnology processes and derived from living organisms or their products. They can include vaccines, blood products, gene therapies, monoclonal antibodies, recombinant proteins, and other complex biological substances.
Biological Investigational Medicinal Product
Refer to biological products that are being investigated in clinical trials or research studies to evaluate their safety, efficacy, or pharmacokinetic properties. These products have not yet received marketing authorization and are still in the experimental phase.
In the European Union, A biological substance is referred as the active ingredient in biological products.
A "biological substance" is defined as "a substance that is produced by or extracted from a biological source
That requires a combination of physico-chemical-biological testing, along with the production process and its control, for its characterization and the determination of its quality.“
Examples: Immunologic medicines
Medicines derived from human blood and plasma
Medicines developed by means of recombinant DNA technology
Hybridoma and mAb methods
Advanced therapy medicinal products
The requirements of the EU centralized procedure.
The approval standards for biotechnology products are the same as for chemically synthesized medicines.
Both types of products must be safe and effective and have appropriate quality.
MAA for a biotechnology product must meet the standard dossier submission requirements
MAA must generally comply with the CTD format, including with respect to
Module I (administrative information, including labelling)
Module 2 (various summaries)
Module 3 (chemical, pharmaceutical, and biological information)
Module 4 (nonclinical reports)
Module 5 (clinical study reports)
The EU has approved the highest number of biosimilars worldwide, and consequently has the most extensive experience of their use and safety.
EMA has issued scientific guidelines to help developers conform to the strict regulatory requirements for approving biosimilars.
The guidelines have evolved to keep pace with rapid advances in biotechnology and analytical sciences, and they take on board increasing experience of clinical use.
All medicines produced using biotechnology and those for specific indications must be approved in the EU through EMA
Some biosimilars may be approved at national level, such as some low-molecular weight heparins derived from porcine intestinal mucosa.
What is a Variation…?
Variation regulations and guidelines
Types of variations
Type-IA
Type-IB
Type-II
Extension
Unforeseen variations (Z category)
Grouping of variations
Work sharing of variations
Fee
eAF
Renewals
Biosimilars
A biosimilar is a biological medicine highly similar to another already approved biological medicine (the 'reference medicine'). (A medicine whose active substance is made by a living organism.)
Biologicals
Biological medicines contain active substances from a biological source, such as living cells or organisms and are often produced by cutting-edge technology.
Biological medicinal product
Biological Medicinal Products, also known as biologics or biologicals, are medicinal products that are manufactured using biotechnology processes and derived from living organisms or their products. They can include vaccines, blood products, gene therapies, monoclonal antibodies, recombinant proteins, and other complex biological substances.
Biological Investigational Medicinal Product
Refer to biological products that are being investigated in clinical trials or research studies to evaluate their safety, efficacy, or pharmacokinetic properties. These products have not yet received marketing authorization and are still in the experimental phase.
In the European Union, A biological substance is referred as the active ingredient in biological products.
A "biological substance" is defined as "a substance that is produced by or extracted from a biological source
That requires a combination of physico-chemical-biological testing, along with the production process and its control, for its characterization and the determination of its quality.“
Examples: Immunologic medicines
Medicines derived from human blood and plasma
Medicines developed by means of recombinant DNA technology
Hybridoma and mAb methods
Advanced therapy medicinal products
The requirements of the EU centralized procedure.
The approval standards for biotechnology products are the same as for chemically synthesized medicines.
Both types of products must be safe and effective and have appropriate quality.
MAA for a biotechnology product must meet the standard dossier submission requirements
MAA must generally comply with the CTD format, including with respect to
Module I (administrative information, including labelling)
Module 2 (various summaries)
Module 3 (chemical, pharmaceutical, and biological information)
Module 4 (nonclinical reports)
Module 5 (clinical study reports)
The EU has approved the highest number of biosimilars worldwide, and consequently has the most extensive experience of their use and safety.
EMA has issued scientific guidelines to help developers conform to the strict regulatory requirements for approving biosimilars.
The guidelines have evolved to keep pace with rapid advances in biotechnology and analytical sciences, and they take on board increasing experience of clinical use.
All medicines produced using biotechnology and those for specific indications must be approved in the EU through EMA
Some biosimilars may be approved at national level, such as some low-molecular weight heparins derived from porcine intestinal mucosa.
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.
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.
Presentation by NEPAD Agency on the African Medicines Regulatory Harmonisation made at the Euro-Africa Health Investment Conference, March 26 - 27, 2013, London, United Kingdom.
ISO IDMP: Practical considerations from XEVMPD experienceQdossier B.V.
ISO IDMP (Identification of Medicinal Products) is coming! What lessons can we learn from our practical exprience with XEVMPD in preparation for IDMP? Topics include data cleaning, managing inconsistencies across product registrations and countries and controlled vocabularies
PAREXEL Principal Consultant Angela McGillivary discusses commercial considerations, clinical development, regulatory requirements, submission and post approval strategies in emerging markets
Complementary medicines MMDR reforms: Assessment pathwaysTGA Australia
An overview of the reform initiatives relevant to complementary medicines. Topics include the implementation of recommendations from the Review of Medicines and Medical Devices Regulation.
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.
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.
Presentation by NEPAD Agency on the African Medicines Regulatory Harmonisation made at the Euro-Africa Health Investment Conference, March 26 - 27, 2013, London, United Kingdom.
ISO IDMP: Practical considerations from XEVMPD experienceQdossier B.V.
ISO IDMP (Identification of Medicinal Products) is coming! What lessons can we learn from our practical exprience with XEVMPD in preparation for IDMP? Topics include data cleaning, managing inconsistencies across product registrations and countries and controlled vocabularies
PAREXEL Principal Consultant Angela McGillivary discusses commercial considerations, clinical development, regulatory requirements, submission and post approval strategies in emerging markets
Complementary medicines MMDR reforms: Assessment pathwaysTGA Australia
An overview of the reform initiatives relevant to complementary medicines. Topics include the implementation of recommendations from the Review of Medicines and Medical Devices Regulation.
Presentation: Regulation of autologous cells and tissuesTGA Australia
This presentation provides an overview of the regulation of autologous cells and tissues in Australia, including a discussion on emerging examples of practices that have the potential for increased risk.
The TGA Pharmacovigilance Inspection Pilot Program: 2015-2016TGA Australia
Firsthand overview of the TGA's Pharmacovigilance Inspection programme from the perspective of both the TGA and companies that have participated in the 'Pilot Inspection Programme'.
Presentation: Regulation of autologous cells and tissuesTGA Australia
This presentation provides an overview and describes the recent TGA public consultation on the exclusion of some autologous cell therapies from regulation.
Presentation: What's trending in medicines regulation? A January 2017 reflectionTGA Australia
This presentation provides a local perspective on recent developments in the medical technology and pharmaceutical landscape, and the future of the TGA in a global context.
Update on regulatory reforms from the Scientific Evaluation BranchTGA Australia
Presentation on the latest on variations, Generic Medicines Reform Program, Human cells and tissue regulation (excluded goods), Faecal Microbiota Transplantation and 2D DataMatrix codes for medicines
Update on regulatory reforms from the Scientific Evaluation BranchTGA Australia
Presentation on the latest on variations, Generic Medicines Reform Program, Human cells and tissue regulation (excluded goods), Faecal Microbiota Transplantation and 2D DataMatrix codes for medicines
How to Submit Non-Clinical Data to CBER Using SEND : Understanding New FDA Re...MMS Holdings
What You Will Learn
The FDA’s CBER will begin requiring electronic submissions of nonclinical data to be submitted using the 3.1 and 3.1.1 versions of CDISC SENDIG on March 15th, 2023. With these requirements taking effect soon, Sponsors need to understand how to meet the new rules and regulations provided by SEND, as failing to meet them could result in FDA refusal.
In this webinar, a cross-functional team of statistical programmers and regulatory experts will share actionable insights to help study teams prepare for the new requirements.
Attendees will learn how to:
Understand nonclinical study data submissions to CDER and CBER
Differentiate biologics from drug submission in non-clinical studies
Prepare for this change to ensure a successful submission.
Solve the challenges of a SEND package
Ensure compliance with both SEND 3.1 and 3.1.1 for submission of nonclinical data to CDER and CBERHo
Separate SEND IG DART 1.1 from SEND IG
Manage legacy studies and studies that already meet requirements
Differentiate between submission packages
Use the FDA’s data standard catalog, technical conformance guide and controlled terminology
Who Will Benefit from Attending?
Regulatory Affairs and Submissions Professionals
Pharmaceutical Data and Programming Professionals
Nonclinical/Preclinical Development Professionals
“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
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
The regulation of biologicals in AustraliaTGA Australia
View this presentation for information on:
* what biologicals are, including classes and current uses
* the Australian biologicals framework
* new and experimental products
* clinical trials and risk management.
Pharmacovigilance and complementary medicines - Regulatory requirementsTGA Australia
Presentation on Pharmacovigilance basics – sponsor obligations, Complementary medicine safety – Regulatory perspective and Special considerations for complementary medicine pharmacovigilance
The challenges of regulating direct to consumer digital medical devicesTGA Australia
Presentation on digital medical devices, the role of the regulator, challenges in applying the framework to digital devices, international approaches and what is the TGA doing
Updates from the Pharmacovigilance and Special Access Branch TGA Australia
Presentation on using new sources of data in Pharmacovigilance, Pharmacovigilance Inspection Program (PVIP) update, International collaboration activities, Adverse Event Management System (AEMS)
Q and A
Manufacturing Investigational Medicinal Products - Legislative and GMP requir...TGA Australia
Presentation on Legislative requirements, specific risks for IMP manufacturing, manufacturing authorisations, PIC/S Guide to GMP PE009-13 and common issues
Presentation on the background of medicine shortages, definitions, reporting requirements, assessment and management, Section 19A and the compliance framework
Regulatory updates from the TGA Medical Devices Branch - Part 1TGA Australia
Presentation on the review of medicines and medical devices regulation, proposed changes to some definitions and regulation of some products without a medical purpose, reclassification of medical devices (not IVD), Unique Device Identification System and post-market monitoring
Regulatory updates from the TGA Medical Devices Branch - Part 2TGA Australia
Presentation on the regulation of software including software as a medical device, proposed regulatory scheme for personalised medical devices, including 3D Printed Devices, proposed changes to the Essential Principles, Conformity Assessment Procedures, and the requirements for devices used in clinical trials, and clarifying the requirements for systems and procedure packs
SME Assist: Help to navigate the regulatory mazeTGA Australia
Presentation to provide information on TGA’s SME Assist and what the service offers, details on upcoming SME Assist events and information on where to find more help
Presentation: Updates from the Pharmacovigilance and Special Access BranchTGA Australia
This presentation covers using new sources of data in Pharmacovigilance, Pharmacovigilance Inspection Program update, international collaboration activities and Adverse Event Management System.
Ozempic: Preoperative Management of Patients on GLP-1 Receptor Agonists Saeid Safari
Preoperative Management of Patients on GLP-1 Receptor Agonists like Ozempic and Semiglutide
ASA GUIDELINE
NYSORA Guideline
2 Case Reports of Gastric Ultrasound
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.
Factory Supply Best Quality Pmk Oil CAS 28578–16–7 PMK Powder in Stockrebeccabio
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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.
- Video recording of this lecture in English language: https://youtu.be/lK81BzxMqdo
- Video recording of this lecture in Arabic language: https://youtu.be/Ve4P0COk9OI
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
- Link to NephroTube website: www.NephroTube.com
- Link to NephroTube social media accounts: https://nephrotube.blogspot.com/p/join-nephrotube-on-social-media.html
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!
Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...Oleg Kshivets
RESULTS: Overall life span (LS) was 2252.1±1742.5 days and cumulative 5-year survival (5YS) reached 73.2%, 10 years – 64.8%, 20 years – 42.5%. 513 LCP lived more than 5 years (LS=3124.6±1525.6 days), 148 LCP – more than 10 years (LS=5054.4±1504.1 days).199 LCP died because of LC (LS=562.7±374.5 days). 5YS of LCP after bi/lobectomies was significantly superior in comparison with LCP after pneumonectomies (78.1% vs.63.7%, P=0.00001 by log-rank test). AT significantly improved 5YS (66.3% vs. 34.8%) (P=0.00000 by log-rank test) only for LCP with N1-2. Cox modeling displayed that 5YS of LCP significantly depended on: phase transition (PT) early-invasive LC in terms of synergetics, PT N0—N12, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), G1-3, histology, glucose, AT, blood cell circuit, prothrombin index, heparin tolerance, recalcification time (P=0.000-0.038). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early-invasive LC (rank=1), PT N0—N12 (rank=2), thrombocytes/CC (3), erythrocytes/CC (4), eosinophils/CC (5), healthy cells/CC (6), lymphocytes/CC (7), segmented neutrophils/CC (8), stick neutrophils/CC (9), monocytes/CC (10); leucocytes/CC (11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).
CONCLUSIONS: 5YS of LCP after radical procedures significantly depended on: 1) PT early-invasive cancer; 2) PT N0--N12; 3) cell ratio factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) LC characteristics; 9) LC cell dynamics; 10) surgery type: lobectomy/pneumonectomy; 11) anthropometric data. Optimal diagnosis and treatment strategies for LC are: 1) screening and early detection of LC; 2) availability of experienced thoracic surgeons because of complexity of radical procedures; 3) aggressive en block surgery and adequate lymph node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunoradiotherapy for LCP with unfavorable prognosis.
Title: Sense of Smell
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Ve...kevinkariuki227
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
The POPPY STUDY (Preconception to post-partum cardiovascular function in prim...
Module 3 requirements for Biologics (peptide/protein medicines)
1. Module 3 requirements for biologics (natural
peptide/protein medicines)
Biological medicines - what are they and how are
they different
Dr Scott Craig
Principal Adviser, Biological Science
Scientific Evaluation and Special Product Access Branch
Market Authorisation Division, TGA
ARCS Scientific Congress 2015
7 May 2015
2. Topics for today
• Background - what are biological medicines?
– Definition of a biological medicine and
regulatory frameworks
– What makes biological medicines different
– examples
• Registration information and evaluation process
– Type of data required to support registration
– Common misconceptions
– Variations to registrations
• Future directions
– Where is industry going
– How are regulators responding
Biological
medicines
Background
Registration
information
Future
directions
Biological medicines – what are they and how
are they different?
1
3. What are biological medicines
A TGA definition
• Are therapeutic goods that are derived from biological sources and are regulated as
registered medicines. They include proteins and polysaccharides such as:
– vaccines
– products of the fermentation of recombinant cell-lines
– medicines derived from the fluids and tissue of humans (where specified in the Therapeutic
Goods [Things that are not Biologicals] Determination No. 1 of 2011) and animals
– bacterially-derived proteins
– animal-derived polysaccharides like heparin
– biological medicines do not include antibiotics and small peptides or molecules <2500 Da
– biological medicines are distinct from 'biologicals' which are human cell and tissue products
Biological medicines – what are they and how
are they different?
2
4. Biological medicines – not biologicals?
• Biologicals are defined in Part 3-2A of the Therapeutic Goods Act 1989 (the Act)
as a thing made from, or that contains, human cells or human tissues ...
• This covers some human derived ‘medicine’ products
• Goods declared not to be biologicals - in the Therapeutic Goods (Things that are
not Biologicals) Determination No.1 of 2011 - include:
– biological prescription medicines (vaccines, plasma derivatives, recombinant
products)
– labile blood and blood components
– haematopoietic progenitor cells used for haematopoietic reconstitution (non-fresh
transplants)
Biological medicines – what are they and how
are they different?
3
5. Why are they different
• Size – difficult or impossible to construct using
chemical methods
• Complexity – rely on shape for function that comes
from interactions in 3-D
• Manufactured using living cells – bacteria, yeast,
mammalian cells
• Product quality and process – can’t test for quality, is a
function of control of manufacturing and final testing
• Labile – complexity of structure results in lack of
stability unless conditions are controlled
• Immunogenicity – proteins can stimulate a response
against the product
Biological medicines – what are they and how
are they different?
4
7. Benefits of biological medicines
• Ability to replicate naturally occurring targets
– harness normal physiological processes
– supplement clotting factors, enzyme replacement,
growth factors
• Target molecular pathways
– monoclonal antibodies precisely targeted, few off
target effects
– antibodies have binding and effector functions
– platform technology: leverage information from
previous products, shorter development cycle
– direct cargo to targets
• Engineer desired properties
– alter effector functions
– alter biopharmaceutic properties
– develop mimics
Biological medicines – what are they and how
are they different?
6
8. Common biological medicines
• Recombinant proteins
– Monoclonal antibodies such as anti-TNF in
inflammatory disease
– Growth factors such as epoetin
– Clotting factors such as factor VIII
• Naturally derived/extracted proteins and
polysaccharides
– Plasma derived proteins such as
immunoglobulins and factor VIII
– Heparin and its derivatives – enoxaparin,
dalteparin
– But not antibiotics or extracted small
peptides
• Vaccines, toxins and anti-venoms
Biological medicines – what are they and how
are they different?
7
9. What’s with the names
Golimumab or pertuzumab
Biological medicines – what are they and how
are they different?
8
10. Regulation framework – medicines
• Application through the prescription medicines registration process
• Submissions in CTD format
– require supporting quality, toxicology and clinical data
– quality requirements are different to small molecules
– hopefully now in eCTD
• Same guidelines as other medicines
– Australian Regulatory Guidelines for Prescription Medicines (ARGPM)
– adopted European Medicines Agency (EMA) and International Conference on
Harmonisation (ICH) scientific guidelines
– specific scientific guidelines for biological medicines
Biological medicines – what are they and how
are they different?
9
11. Evaluation for registration
• Regulated as any other medicine
– Prescription medicines registration
process (Cat1) for new products and
biosimilars
– 9D applications (Cat3) for variations
• Clinical and tox handled the same as
for other medicines
• Quality assessed in specialist areas
– Biological Science Section
– Vaccines in Laboratories Branch
– Secondary assessments for viral
safety, endotoxin, sterility, containers
Perjeta (pertuuzumab) and Herceptin (trastuzumab) binding to its target HER2
Biological medicines – what are they and how
are they different?
10
12. Quality evaluation – biological medicines
• Drug substance is the most critical part of manufacture
• Involves multi-step process:
– produce the target molecules
– separate it from the cellular production system
– refine it to the final spectrum of product characteristics
– formulate it for storage prior to filing
• Drug product usually minimal manipulation
– dilution with few excipients added
– sterile filtration
– filling and storage at final temp
Biological medicines – what are they and how
are they different?
11
13. Quality evaluations – process control
• Starting materials
– choice of cell lines
– molecular engineering of DNA
– development of cell lines, genetic
stability, viral safety
• Fermentation process
– controlled process - array of in process
controls to deliver consistent process
– closed process
• Purification process
– multiple steps of chromatography
– remove process related impurities
– reduce product related impurities
Multi-step manufacturing process for drug substance
Biological medicines – what are they and how
are they different?
12
14. Quality evaluations – key aspects
• Know your product
– extensive product characterisation
– extensive cell line characterisation
– stability studies are important
• Consistency of manufacturing
– critical quality attributes
– control strategy
– validation and verification
• Process development
– demonstrate process knowledge
– link to product knowledge
– demonstrate link through non-clinical to clinical
and commercial processes
Biological medicines – what are they and how
are they different?
13
16. Common misinterpretations
• Critical materials
– cell lines: full history and characterisation
– animal and human ingredients
• Process development and variations
– justification based only on manufacturing parameters
– changes need to be brought back to the patient context i.e. clinical implication
• Stability
– most biological medicines are effected by temperature – shipping conditions, deviations, variations
– extrapolation not accepted. More in ARGPM guidance 14.4 Specific requirements on stability of biological
medicines
– stability impact following variations
• GMP
– clearances required for critical steps in manufacture especially at drug substance including cell banks
Take home: look at the specific guidelines on the TGA website
Biological medicines – what are they and how
are they different?
15
17. Common questions
Do I need to put in a variation?
• Look at the minor variations guidance on the TGA website
– lists self assessable changes (different to chemical entities)
– guides on data requirements for other changes
– key scientific guideline is ICH Q5
• Evaluation approach
– what is the risk to the product control i.e. does it increase likelihood
– does the data control this risk
– the Secretary is satisfied that the variation requested does not indicate any reduction in the quality, safety
or efficacy of the goods for the purposes for which they are to be used
• Ask
– Biological.Medicines@tga.gov.au
Biological medicines – what are they and how
are they different?
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18. Post market assessment
• Complexity of manufacture and products attributes make them a high risk product
• New biological medicines are covered by a Risk Management Plan (RMP)
• TGA Laboratories Branch:
– undertakes batch release testing of all new biological medicines
– a survey program is in place to periodically check that quality is as expected
• GMP clearance
– Biological medicines require GMP clearances for more steps involved in
manufacturing than small molecule. Additional GMP requirement for biotech
manufacturers
Biological medicines – what are they and how
are they different?
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19. Future directions – industry and regulatory approach
Industry
• Platform technology
• Disposable technology
• In-line real time testing
• Increased product knowledge
• Biosimilars
Regulators
• ICH quality guidelines 8,9,10 and 11 (and12?)
– Improved product understanding leads to
more flexible regulatory controls?
– QbD
– Expanding risk based approach
• Evolving biosimilars approach
– FDA registration of 1st US biosimilar
– TGA review of biosimilars guideline
– World Health Organization (WHO) naming
Biological medicines – what are they and how
are they different?
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