Monoclonal antibodies: functional improvements at SPC shelf life limits
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Monoclonal antibody (mAb) therapeutics are one of the fastest growing sectors in the pharmaceutical industry and have already established themselves as frontline therapies in oncology.
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Monoclonal antibodies (mAbs) have complex structures that are susceptible to degradation through various mechanisms. Their structures consist of primary, secondary, tertiary, and quaternary levels that give them their shape and biological functions. Common degradation pathways for mAbs include aggregation, oxidation, hydrolysis, and denaturation. Many steps involved in preparing and handling mAbs, such as temperature changes, shaking, dilution, and interaction with containers, can accelerate degradation by introducing factors like metal ions, oxygen, shear forces, and adsorption to surfaces. Care must be taken to minimize degradation risks through practices like avoiding excessive temperature changes and forces during preparation, handling, and storage.
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3) Important experimental techniques discussed are x-ray crystallography and NMR spectroscopy that provide structural information for target biomolecules essential for structure-based drug design.
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1. Drugs can bind to plasma or tissue proteins through hydrophobic interactions or self-association. The two most important plasma proteins for binding are albumin and alpha-1-acid glycoprotein.
2. Binding affects drug distribution, activity, and clearance. It can facilitate distribution through transport or inactivate drugs by preventing sufficient free concentrations.
3. Factors that influence binding include the drug's properties, protein concentrations, binding affinities, and competing substances. Disease states can also impact protein levels and binding.
4. Binding kinetics and constants can be determined experimentally to understand a drug's behavior and potential for interactions
Konversi steroid
This document provides a table comparing different glucocorticoids including their approximate equivalent dose in milligrams of hydrocortisone, their biological half-life in hours, and whether they are considered short-acting, intermediate-acting, or long-acting. Short-acting glucocorticoids like cortisone and hydrocortisone have half-lives of 8-12 hours while intermediate-acting drugs such as methylprednisolone, prednisolone, prednisone and triamcinolone have half-lives of 18-36 hours. Long-acting glucocorticoids betamethasone and dexamethasone have the longest half-lives of 36-54 hours.
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Product characterization is key to successful biological drug development. Comprehensive characterization of new therapeutic monoclonal antibodies requires a deep understanding of their structural and functional critical quality attributes (CQAs) which may impact product potency, stability and safety. Various analytical approaches can be used to characterize the effects of changes during the process of generating a biological drug.
This webinar will review some of the approaches to N-glycan profiling of monoclonal antibodies using Mass Spectrometry (MS), including Hydrogen Deuterium Exchange (HDX-MS) analytics. Using the Humira monoclonal antibody, the effect of glycosylation on the Fc-region mediated effector function was assessed with binding and CDC and ADCC activity assays. This review will give the listener an understanding of how the molecular structure, and the different ways they can be measured, influences binding and affects potency of a therapeutic biologic.
In this webinar you will learn:
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- Glycosylation effects assessment by activity assays
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Here are the matches between the pharmacologic terms and their definitions:
1. Efficacy - C) This is the maximal response obtainable by a drug treatment
2. Potency - E) This is the amount of drug required to produce a desired effect
3. Tolerance - A) Decreased response to the same dose of the drug.
4. Therapeutic index - D) This is the ratio of the toxic dose to the therapeutic dose
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Drug product performance
This document discusses drug product performance and bioequivalence studies. It defines drug product performance as the release of the drug substance from the product leading to bioavailability, which relates to clinical safety and efficacy. Bioequivalence studies compare formulations and are used to assess the impact of changes to the drug substance, formulation, or manufacturing process. They can be conducted in vivo using pharmacokinetic or pharmacodynamic endpoints or in vitro using dissolution studies.
1.preformulation concept in Modern pharmaceutics.pptx
Preformulation is defined as the investigation of physical and chemical properties of a drug substance alone and when combined with excipients. The goal is to generate information to help formulators develop stable and safe dosage forms with good bioavailability. Some key tests include determining the drug's solubility, stability, and compatibility with various excipients using techniques like DSC, TLC, and HPLC. This provides critical data to guide the rational selection of dosage form and formulation components.
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Biorelevant ppt
The document discusses biorelevant dissolution media, which aims to simulate conditions in the gastrointestinal tract in vitro in order to predict in vivo drug performance. It notes the development of biorelevant media was necessary because compendial media did not adequately simulate in vivo dissolution. The summary discusses key points about biorelevant media simulating conditions in the stomach, small intestine, and colon. It also mentions factors considered in developing biorelevant media like fluid composition, hydrodynamics, drug properties, and their use in predicting plasma profiles and developing IVIVCs.
Preformulation Guide
This document provides guidance on preformulation studies for new drug substances. It outlines the key steps in preclinical testing including pharmacology, toxicology, and preformulation. Preformulation involves characterizing the physicochemical properties of the drug, including solubility, pKa, partition coefficient, stability, and crystal properties. The goal is to design an optimal drug delivery system through understanding the physical and chemical attributes of the new molecule.
Bioequivalence biowaiver and ivivc studies 2014 new
The document discusses bioequivalence and biopharmaceutics classification system. It defines bioequivalence as the absence of a significant difference in the rate and extent to which the active ingredient becomes available at the site of drug action when administered at the same molar dose under similar conditions. It also defines pharmaceutical equivalents and alternatives. The document discusses approaches to determine bioequivalence including in vivo and in vitro methods. It provides details on bioequivalence study design, components, and considerations. Finally, it introduces the biopharmaceutics classification system and criteria for classifying drugs as highly soluble and highly permeable.
Drug excipients intraction
This document discusses drug excipient interactions and provides information on various types of interactions including physical, chemical, biopharmaceutical, and excipient-excipient interactions. It also describes analytical techniques used to detect interactions such as thermal methods, accelerated stability studies, chromatography, and others. Key factors that can affect drug stability are also covered such as temperature, moisture, and chemical interactions. Guidelines for stability testing from organizations like ICH are also summarized.
cara Baca SWISSADME-TargetPred.pdf
The document discusses key concepts in pharmacokinetics and drug design including:
- Pharmacokinetics (PK) describes what the body does to a drug through absorption, distribution, metabolism and excretion. Pharmacodynamics (PD) describes what the drug does to the body.
- For a drug to be effective it must reach its target in sufficient concentrations, but PK variability can impact efficacy and toxicity.
- Computational tools like SwissADME can predict physicochemical properties, absorption, and "drug-likeness" to help optimize properties during drug design and avoid late-stage failures.
Tsrl modified dosage forms august_non-confidential
This document discusses a patented formulation technology from TSRL that can modify the release properties of water-insoluble drugs to provide extended or delayed delivery. The technology is supported by an issued US patent that expires in 2033. Proof-of-concept studies in humans have demonstrated the ability to increase exposure and modulate the pharmacokinetic profile of simvastatin using a delayed release formulation. The technology offers a low-cost option for partners to test formulations and has the potential to improve therapies for conditions that follow circadian patterns or require lower and less toxic doses.
Preformulation
The document provides an overview of preformulation studies. It discusses the importance of characterizing the physical and chemical properties of new drug molecules during preformulation to aid in the development of stable dosage forms. Some of the key areas covered include drug-excipient compatibility studies, stability kinetics testing, and determining properties like solubility, partition coefficient, and polymorphism that can help dictate the suitable dosage form. The goal of preformulation is to gather necessary data to rationally develop safe and efficacious dosage forms.
various approaches in drug design and molecular docking.pptx
Various approaches used in rug design and drug discovery. The document discusses:
1. The process of drug discovery from 1900s to present, including use of chemical libraries, combinatorial chemistry, bioinformatics, and genome mining.
2. Challenges in drug discovery like high costs, failures, and lack of efficacy knowledge prior to synthesis.
3. Techniques in computer-aided drug design like docking, scoring functions, and flexible ligand docking to model drug-target interactions and identify potential drug candidates.
In silico lead discovery technique.pptx
This document discusses techniques for in silico lead discovery in drug development. It describes identifying a target and bioassay, finding a lead compound, isolating and purifying the compound, determining its structure, studying structure-activity relationships, and identifying the pharmacophore. Methods for identifying lead compounds include random screening, non-random screening, high-throughput screening, and structure-based drug design. After preclinical studies, compounds undergo clinical trials in four phases before potential release as an approved drug.
Bio availability and bio equivalence
The document discusses bioavailability studies, which determine the efficiency of drug absorption from different dosage forms and formulations. Key aspects covered include:
- Objectives of bioavailability studies such as determining the influence of excipients and other drugs on absorption during new drug development.
- Factors affecting bioavailability including drug properties, dosage form characteristics, and patient-related factors.
- Methods of measuring bioavailability including plasma concentration-time curves and urinary drug excretion.
- The importance of correlating in vitro dissolution tests to in vivo absorption through levels of in vitro-in vivo correlation (IVIVC).
Bioavailability and Bioequivalence detail.pdf
I am a pharmacist. These slides describe detail topic of biopharmaceutics topic. I hope pharmacy department students get more benefits about it.
Work Sample#1Regulatory_Requirements-BABE-Studies
The document discusses general considerations for conducting bioavailability and bioequivalence studies for orally administered drugs, including the regulatory objectives, methods used to evaluate bioavailability and demonstrate bioequivalence, and special topics like food effect and long half-life drugs. It provides background on key concepts like bioavailability, bioequivalence and their regulatory definitions as well as guidance on study design and requirements for different types of drug products and changes.
Regulatory requirements-BA/BE Studies
This slide show reflects general considerations of Bio-availability & Bio-equivalence studies for orally administered drugs. The presentation also accommodates US - FDA's approach and specific recommendations for such studies.
Preformulation guide
1. The document provides guidance on preformulation studies for new drug candidates. Preformulation involves characterizing the physical and chemical properties of a drug substance to aid in developing an optimal dosage form.
2. Key preformulation studies discussed include determining solubility, pKa, partition coefficient, chemical stability, and polymorphism. These studies provide important information on factors like bioavailability and dosage form design.
3. The guidance describes common techniques for conducting preformulation studies like equilibrium solubility methods and stresses the importance of stability testing under various conditions like temperature, pH and light exposure.
fda
This document summarizes a presentation given by Robert Lionberger on novel methods for demonstrating pharmaceutical equivalence and bioequivalence for complex drug products. It discusses the new Office of Research and Standards within the Office of Generic Drugs at FDA, which facilitates pre-ANDA development and conducts regulatory science research. It also describes challenges with evaluating generic versions of complex drugs like liposomes, inhalation products, and topical dermatological products. The presentation outlines FDA's research on evaluating these complex generics and developing new guidance through regulatory science approaches.
6405732.ppt
This document summarizes guidelines for developing biosimilar medicines. It discusses how biosimilars are defined as biological products that are similar but not identical to an approved reference product. The development of biosimilars follows a stepwise approach including analytical, nonclinical, and clinical studies to demonstrate similarity in quality, safety, and efficacy compared to the reference product. Key considerations include appropriate study designs and endpoints to sensitively determine potential differences. Immunogenicity is systematically evaluated throughout development.
Bioavailability and bioequivalance studies
This document discusses guidelines for bioavailability and bioequivalence studies. It defines key terms like bioavailability, bioequivalence, pharmaceutical equivalents and alternatives. It outlines when bioequivalence studies are necessary, such as for modified release drugs, and when they are not required, such as for parenteral solutions. It also describes the different types of studies including pharmacokinetic, pharmacodynamic and clinical endpoint studies. Finally, it provides details on study design, population, conditions and statistical evaluation for pharmacokinetic bioequivalence studies.
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1.preformulation concept in Modern pharmaceutics.pptx
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Monoclonal antibodies: functional improvements at SPC shelf life limits
- 1. Dr Andrew G Watts Associate Professor of Medicinal Chemistry Department of Pharmacy and Pharmacology University of Bath October 2014
- 2. 2 Monoclonal Antibodies Functional Improvements at SPC Shelf Life Limits
- 3. Introduction 3 Monoclonal antibody (mAb) therapeutics are one of the fastest growing sectors in the pharmaceutical industry and have already established themselves as frontline therapies in oncology. These drugs are often assigned short shelf lives once prepared for administration, typically 24 to 48 hours. However, SPC’s for some of these drugs recommend they be used immediately following preparation.
- 4. Aim 4 To evaluate the physical, chemical and functional stability of several mAb therapeutics used in oncology. - Pertuzumab - Rituximab - Trastuzumab - (Infliximab) Compare the (quality) characteristics of these drugs immediately after preparation with those at the limit of their SPC assigned shelf life.
- 5. Methods 5 Physical/Chemical/Functional analysis of each antibody was performed using: • visual inspection • SDS-page • pH • SE-HPLC, • circular dichroism (VT-CD) • dynamic light scattering (DLS) • LC-MS • Flowcam imaging (particle counting) • Functional activity (tailored assay) Each antibody was evaluated immediately following preparation as well as at its SPC designated shelf life.
- 6. Results - Pertuzumab 6 Sub-visible particles Functional activity
- 7. Methods 7 ‘Flowcam’ imaging (sub-visible particle counting) micro-air bubble silicone oil aggregated protein Quantification and characterisation of sub-visible particles Flow rate: 0.15 ml/min, efficiency: 30.2%, cell: FC100 100 µm x 2000 µm
- 8. Methods 8 Functional activity – Cell based assay 7.7 Biological activity Assessment of biological properties constitutes an essential step in establishing understanding of the stability profile under specific conditions. The technique should be relevant to the specific biological activity that enables the product to achieve its defined biological effect.
- 9. Results - Rituximab 9 Sub-visible particles Functional activity
- 10. Results - Trastuzumab 10 Sub-visible particles Functional activity
- 11. Results - Infliximab 11 Sub-visible particles Functional activity
- 13. Dilution Process 13 Dilution Preparation (reconstitution and dilution): - Rapid change in the chemical micro-environment of the drug - Dilution of A results in a dynamic mixture of B, C, D, E and F.
- 14. Summary 14 - Multiple stability studies on numerous monoclonal antibodies have been performed. - Higher levels of sub-visible particles and lower levels of functional activity are observed immediately following preparation, as compared to the product at the end of SPC assigned shelf-life. - Dilution of the drug into its ready-to-use form dramatically changes the micro-environment around the API. - Physical changes that occur are dynamic and will reach an equilibrium over time. This has been observed to result in lower particle numbers and improved functional activity.
- 15. Research team Dr Richard Parry • Principal Scientist • Functional Activity Terry Chapman Dr Monika Ali Khan Physical Stab Dr Andy Watts • Scientific Lead • Chemical Stability Maria Connolly • Programme Lead • Usability
- 16. mAbstalk.com Follow us, request article reviews, etc. at 16