If you continue browsing the site, you agree to the use of cookies on this website. Although much has been written about protein formulation, relatively little literature exists about how to formulate peptide drug products. Third edition, the global challenge, edited by richard a. To mitigate against protein degradation, drug companies employ formulation development. Topp em, zhang l, zhao h et al, chemical instability in peptide and protein pharmaceuticals, formulation and process development strategies. Thus, if interfacial stress is a stability concern for a particular protein molecule, then use of a nonionic surfactant is a good first step in mitigating this problem. Pegylation is currently a well established technique for improving the pharmacokinetics and pharmacodynamics of protein drugs because of its in vivo stabilization effects. Enzyme specificity trypsin arg, lys chymotrypsin phe, tyr elastase als, gly, ile, leu, val, ser carboxypeptidase tyr, phe, ile, thr, glu, his, ala enzyme inhibitors. The key role of protein based nanostructures has recently revolutionized the nanomedicine era. Mountain view, california plenum press new york and london. The development of long acting protein formulations must maintain protein stability and be able to deliver a large enough dose over a prolonged period. To screen formulations morequickly it is common to subject the samples to extreme conditions. Formulation, characterization, and stability of protein drugs case histories edited by rodney pearlman megabios corporation v burlingame, california i and y. Effect of cyclodextrins on the thermal stability of.
The challenge for biopharmaceutical companies is that degraded proteins create ineffective and potentially harmful therapeutics for their customers. On this page we highlight various whitepapers on topics in protein formulation. Insulin, gammaglobulin and protein containing vaccines have been routinely employed for decades. Understanding the impact of methionine oxidation on the. The focus in the development stage of recombinant protein drugs is the production and puri. Pharmaceutical dissolution testing a handson course. It is well recognized that protein product development is far more challenging than that for smallmolecule drugs. When a new protein is in the development phase, one would ask what should be the most effective and efficient process to identify a formulation given the resource, budget, and timeline. Once a dried formulation has been developed, we can also work toward identifying a lyophilization cycle that is intended to provide pharmaceutical elegance and efficiency as well as ensure the stability of the drug product.
One oftenoverlooked aspect of these peptide products is formulation development. Injectable formulations include protein,antibody, vaccine, and peptide. Stability and characterization of protein and peptide drugs case histories edited by. The major challenges include inherent sensitivity to different types of stresses during the drug product manufacturing process, high rate of physical and chemical degradation during longterm storage, and enhanced aggregation andor viscosity at high protein concentrations. Effects of formulation, interfaces and drug product manufacturing operations. Enzyme inhibitors enzyme specificity trypsin arg, lys chymotrypsin phe, tyr elastase als, gly, ile, leu, val, ser carboxypeptidase tyr, phe, ile, thr, glu, his, ala enzyme inhibitors. Costeffective scaleup of the cell culture or fermentation process, and puri. Leading scientists offer detailed profiles of ten protein drugs currently in development. Slideshare uses cookies to improve functionality and performance, and to provide you with relevant advertising. Once a dried formulation has been developed, we can also work toward identifying a lyophilization cycle that is intended to provide pharmaceutical elegance and efficiency as well as ensure the stability of the drug. Analysing protein stability for drug formulation using vroc.
Morgan notes that if it is possible to formulate the biologic to within the traditional stability in liquid form, and with a reasonable viscosity, an autoinjector may be a suitable option for a combination product. Sorry, we are unable to provide the full text but you may find it at the following locations. Protein stabilization by a stabilizers can be achieved through the traditional preferential interaction mechanism 16 andor other proposed mechanisms such as nonspecific interaction with surface hydrophobic pockets 17 or charged amino acids, 18 specific. Stability of protein formulations and their importance. Formulation, characterization, and stability of protein drugs. Protein formulation development linkedin slideshare. Differential scanning calorimetry a method for assessing. Manning mc, patel k and borchardt rt, stability of protein pharmaceuticals, pharm res, 6, pp903918, 1989 2. Protein formulation and delivery, edited by eugene j. Transport processes in pharmaceutical systems, edited by gordon l. Due to complexity of proteins bioassay are required to assess potency of the formulation. This ready reference also features recent data and an abundance. Wang yj, pearlman r eds stability and characterization of protein and peptide drugs. Protein stability is essential for drug efficacy and storage shelf life.
Applications, problems and solutions pawan dulal 1 1university of nottingham, uk it has always been an aspiration for a pharmaceutical company to create a drug that would be ideal with high specificity, high affinity, solubility and safety. Many strategies are being pursued to improve the formulation and dosage forms of antibodies to improve ef. Protein and peptide drug delivery systems authorstream. In this report we show that the increase in protein thermodynamic stability was accompanied by a reduction of protein structural dynamics. Inverse relationship of protein concentration and aggregation. Effects of formulation, interfaces, and drug product manufacturing operations, aggregation of therapeutic proteins, 3031, 2010. However, they take long periods of time and use large amounts of material. Aggregated proteins incur immune responses that cause serious side effects, which makes protein stability an integral part of protein formulation. Liquid formulation an overview sciencedirect topics. Protein and peptide drug delivery system authorstream. The name protein is coined from the greek word protos, meaning first or foremost. This is a daunting challenge because proteins can readily aggregate, even under solution con. Development of stable protein formulations may require even more resources and effort than conventional small molecule pharmaceuticals.
The case histories of these important new compounds are described from the perspective of their formulation, characterization, and stability. The science and practice of pharmacy, and is the editor of pharmaceutical chemistry and pharmaceutical testing, analysis and control sections of the book. This ready reference also features recent data and an abundance of previously unpublished information. Biological drugs offer high specificity and potency, but their formulation and delivery pose substantial challenges. A comprehensive guide to protein stability assay platforms.
Results obtained are used to assess the thermal stability of protein antigens in vaccine formulations. Here, the authors highlight recent advances in formulation strategies, describe. New technologies for protein delivery pose significant challenges for formulation development. A close look at protein aggregation, deamidation, and oxidation. Protein stability depends on temperature, ph, concentration. Nonionic surfactants are often used in protein formulations to reduce interfacial stress and prevent protein denaturation, aggregation, and adsorption loss lee et al. Gaining insight into protein stability is critical in protein drug formulation as protein stability plays a key role in the efficacy and shelf life of the drug. One could envision achieving this goal by developing a formulation with perfect stability, i. Aug 15, 2015 although the large number of stability tests and analyses required for the development of stable protein formulation present difficulties for biopharmaceutical companies, one of the biggest challenges for formulators is the limited number of known and approved excipients for protein stabilization, according to kemter. Protein formulation an overview sciencedirect topics. Different process parameters during each of these operations can affect the purity, activity and efficacy of the final product. Chemical and physical pathways of protein degradation pharmaceutical biotechnology series vol. Differential scanning calorimetry dsc is an important tool in studying protein structural stability. Carpenter, protein aggregation and particle formation.
Engineering challenges of protein formulations randolph. Rational design of lyophilized high concentration protein. Development of formulations for protein drugs requiring high dosing in the order of mgkg may become challenging for solubility limited proteins and for the subcutaneous sc route with 100 mgml protein concentrations. Longterm studies of formulated protein samples can provide information on the stability of the drug under various conditions. Legacy is equipped to develop all types of lyophilized freezedried protein formulations. The design of manufacturing systems for the controlled release of proteins and peptides from polymers requires, therefore, a fundamental knowledge the erosion mechanism of a biodegradable polymer.
Pharmaceutical aerosols, dry powder inhalation systems and nasal delivery devices. Latest advances in the stabilisation and formulation of protein and peptide drugs. A formulation method to improve the physical stability of macromolecularbased drug products. Peptide and protein drug analysis, edited by ronald e. When proteins become unstable, molecules unfold and aggregate. Nov 02, 2012 integrity bio is a protein formulation development, fill finish, and drug delivery cmo. Jan 20, 2016 stability studies of proteins and peptides slideshare uses cookies to improve functionality and performance, and to provide you with relevant advertising. Opalescence in a therapeutic protein formulation may be determined per the european pharmacopoeia 5. Stabilization and release effects of pluronic f127 in protein. But the most promising protein based drug will not be of bene. Characterization of monoclonal antibody formulations.
Proteins have the tendency to unfold and aggregate depending on the environment. Different conditions can affect different aspects of protein stability. Protein and peptide protein are the most abundant macromolecule in the living cells. Twoday short course with the emphasis on formulation and dosage form design strategies, mechanisms of degradation and excipient choices course background and objectives to provide attendees with. Nguyen th, ward c 1993 stability characterization and formulation development of alteplase, a recombinant tissue type plasminogen activator. Proteins chains of same 20 amino acids but in different combinations and sequences, each joined together by a specific type of covalent bond. Challenges in the development of high protein concentration. As is the case with other pharmaceuticals, formulation development is one of the critical steps in developing a protein as a therapeutic product. Aggregated proteins gain immune response which results in adverse side effects. Integrity bio is a protein formulation development, fill finish, and drug delivery cmo. Proteins generally require a formulation excipients as a protein stabilizer in a liquid state. Aggregated proteins gain immune response which results in. If a protein drug has the stability and enzyme resistance necessary to survive transit through the. Unique challenges, such as long reconstitution time for a lyophilized high protein concentration drug product, can limit practical usage and commercial marketability of the product.
A formulation is one solution condition in a multidimensional therapeutic trade space. Rising to the challenge of biologic drug formulation. Protein nanoparticles have turned out to be the major grounds for the transformation of different properties of many conventional materials by virtue of their size and greater surface area which instigates them to be more reactive to some other molecules. The formulation must be resistant both to physical and chemical degradation. His teaching responsibilities include courses in solubility, controlled drug delivery and drug stability at the graduate level. Structural basis for cyclodextrins suppression of human growth hormone aggregation. In this paper, a systematic approach is presented to develop a lyophilized high concentration protein formulation. Pdf the development of stable protein formulations. The challenge is to maintain the integrity of the complex and the often highly sensitive 3d structure of biopharmaceutical drug substances by designing an ideal environment of stabilizers, buffers, and detergents. The result of phase ii trial of judson et al groups research shows that there has been significant response of.
Practical approaches to protein formulation development. Bulk drug substance goes through a series of formulation, fill and finish operations to provide the final dosage form in the desired formulation and container or delivery device. The increasing use of recombinantly expressed therapeutic proteins in the pharmaceutical industry has highlighted issues such as their stability during longterm storage and means of efficacious. Oct 27, 2016 please use one of the following formats to cite this article in your essay, paper or report.
Parenteral formulation 6 buffers to stabilize ph, hold a drug in solution and obtain an acceptable shelf life part of the decision of which buffer to use to control the product ph to improve stability improve solubility of protein modify viscosity later reduce pain arginine buffer vs other. Detection of prion protein using a capillary electrophoresisbased competitive immunoassay with laserinduced fluorescence detection and cyclodextrinaided separation. Such a characteristic immediately suits it to protein drug stabilization and release effects of. This instrument increases the temperature linearly and measures the amount of energy required to attain the temperature. Stability and characterization of protein and peptide drugs. Stability of protein formulations and their importance proteins are essential for life. Protein stability and formulation testing proteinsimple. Conformational stability describes the ability of protein to maintain its native structure, to be properly folded. For pdf copies of older articles, please go to the whitepapers section of the. Monitoring charge variants during formulation development gives you critical information on drug stability and efficacy.
May 01, 2015 use of complex or uncommon stabilizers. The basic problem in the delivery of protein and peptide drug delivery systems is the degradation of the proteins by the metabolic enzymes present in the body. Measuring protein aggregation and particulates during formulation and stability testing gives you valuable info on formulation suitability. Microflow imaging mfi lets you measure particle size, concentration and a host of morphological parameters so youll easily be able to differentiate between protein aggregates, air bubbles, silicone oil.
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