The analysis of particulates has been a longstanding challenge in biopharmaceutical drug product development and quality control because the active constituents themselves may form particulate matter as a degradation product that may be difficult to quantify. Entegris manufactures a range of particle characterization instrumentation for both the laboratory and online monitoring. A comparison of background membrane imaging versus flow. Subvisible particle analysis shouldnt require milliliters of precious sample volume.
New applications for the flowcam to be used for particle analysis in general industry are constantly developed. Microflow imaging imagebased particle analysis for biopharmaceuticals. Ranking your formulations based on a quantitative count of proteinaggregates shouldnt take weeks. Subvisible particles, visible particles, light obscuration, flow imaging, particle identification. The calibration records are retained by the software and can be retrieved for subsequent uses. How does dynamic imaging particle analysis allow identification of subvisible particles. Light obscuration is the method of choice listed in the pharmacopoeias for the analysis of subvisible particles in parenteral products. Subvisible particle analysis in parenteral formulations.
The uncertainties around subvisible particles svps may warrant their being controlled as a critical quality attribute, fda office of biotechnology products division of therapeutic proteins dtp deputy director barry cherney stressed at a. The accusizer tm line of instruments are based on the principle of single particle optical sizing spos. The flowcam captures highresolution, digital images of particles suspended in a fluid. Particle analysis can feel like finding a needle in a haystack, especially when youre dealing with subvisible particles. Variable threshold method for determining the boundaries. The software can also be used to validate particle counters. Achieving reliable particle count and size analysis of.
And youll have visual verification on the spot, as images are displayed in realtime. Every particle in every image is then analyzed to create a database of particle count, size, transparency and morphology or shape. Visible and subvisible particles in the bcg immunotherapeutic. Archimedes subvisible particle detection, counting. Application software permits the precise evaluation of visible mobile and immobile particles in each unit. The field of particle analysis is highly dynamic and various emerging techniques are available for this purpose. Why simply counting shadows leaves you in the dark about us the downstream column is a blog and community for scientists and others involved in downstream biomanufacturing. Combining the highest specification technology with advanced software and automation options make these the most advanced instruments available for usp particle testing. Commonly a single threshold defines the level for a pixel in the image. Variable threshold method for determining the boundaries of. Usp chapter, subvisible particulate matter in therapeutic protein injections, became official august 1, 2014 and provides specific guidance for proteinbased formulations. Subscribe to cleanroom technology magazine for incisive analysis of the latest news and developments in hitech industries manufacturing in controlled environments.
Variable threshold method for determining the boundaries of imaged subvisible particles r. Learn how to measure protein aggregation and analyze subvisible particles, two of the key challenges in the development of biotherapeutics. The bmi technology allows customers to image the particles on top of a coated membrane as if it were a conventional microscope slide. Each particle image is saved to a userbuilt reference library and used to improve the software s pattern recognition algorithms and improve particle identification. The production of mab therapeutics can be highly challenging due to various chemical degradation processes and aggregation. Mvas software is also used to identify the sample particles morphology and shape attributes that traditional light obscuration lo and size exclusion. Once a successful assay has been developed and validated, the resulting protocol, including run parameters, software. The horizon system can run 200 stability test samples from your formulation screen in less than a day, with just 25 l per test. Analysis of images begins with the definition of particle boundaries. Subvisible particle analysis the potential immunogenicity of particles ranging from nanometer to micron sizes in biotherapeutics has been a growing area of discussion between regulators and industry. Quality of bevacizumab compounded for intravitreal administration. A comparison of background membrane imaging versus flow technologies for subvisible particle analysis of biologics. Particle counting and analysis techniques are used to measure particle contamination and ensure adherence to specified limits. Coriolis has received cgmp accreditation by the local regulatory authority and since then we have been reinspected by the authority and audited by several clients successfully.
Protein aggregate and subvisible particles analysis information thermo fisher scientific us. Mfi gives you more insight into the world of subvisible particlesway more than just size and count. Usp, therapeutic protein injections beckman coulter. Usp related products and solutions beckman coulter. Particulate testing solutions for contamination control. For particle concentration, derived diameters d10 and d50, the coef.
The horizon instrument is the industrys first system designed specifically to address the demand for quantitative subvisible particle analysis at every stage of biologic drug formulation. The instructional chapter usp mentions mfi as a possible orthogonal technique for subvisible particle analysis in addition to light obscuration. Astm e3060 16 standard guide for subvisible particle. Nanoparticle tracking analysis nta is one such technique. Smallvolume parenterals having a volume of 25 ml or more may be tested individually. Subvisible particulate matter testing achieving reliable particle count and size analysis of injections, ophthalmic solutions, and lipid emulsions the united states pharmacopeia usp and other agencies such as ep, jp, and chp have established test methods to assure the minimization of particle counts in intravenous injections paren. Uncertainties in subvisible particulates need to be. The laboratory instruments svss and sbss are now compatible to the pharmacopoeia usp 787 subvisible particulate matter in therapeutic protein injections. Particle size was calculated based on equivalent circular diameter using the mfi software. In case of ri influences, we recommend also using a lightindependent technique such as resonant mass measurement rmm archimedes for subvisible particle analysis in protein formulations. The guide will address the following components of particle analysis using dynamic imaging microscopy. In this study adeno associated virus aav particles contaminated by host cell proteasomes are analysed with direct versus indirect methods performed in. The presence of subvisible particles svps in parenteral formulations of biologics is a major challenge in the development of therapeutic protein formulations. The comfortable software supports several particle measuring devices.
Mfi has become an established technique for subvisible particle analysis, though no monographspecifications in the pharmacopoeias exist so far. Powders for parenteral use are reconstituted with particle free water or with an. In this study adeno associated virus aav particles contaminated by host cell proteasomes are analysed with direct versus indirect methods continued. Analysis of the particle size distribution for all samples s1s5 and the reference bevacizumab revealed that, in general, the number of subvisible particles between 10 and 24. Postprocessing analysis provides the ability to create image libraries, identify and exclude certain types of particulates silicone oil for one example and create more accurate particle counts. The digital images of the particles present in the sample are processed by image morphology analysis software that allows their quantification in size and count.
Monoclonal antibodies mab and related products are widely used as therapeutic agents to treat various cancers and autoimmune diseases. Dynamic image analysis to evaluate subvisible particles during continuous drug infusion in a neonatal intensive care unit. Collaborative study for analysis of subvisible particles using flow. Viavi micronir pro software provides data acquisition and chemometric model building, and assures compliance with title 21 cfr part 11, usp chapter 1119 and ep chapter 2. Within this section, a brief overview of emerging or less routinely used techniques for subvisible particle analysis is provided.
Oct 22, 2015 nanoparticle tracking analysis nta as the submicron fraction of the subvisible particle size range comes under greater scrutiny, techniques that enable the enumeration and sizing of nanoparticles are also increasingly vital additions to the characterisation toolkit. Typically, these particles are quantified by counting the number of particles in given size ranges. With a strong focus on analysis of subvisible particles svp we feature the. So the user can see at one glance whether the analysed sample meets the requirements of the selected standard. Innovative methods and instruments are key parameters for analysis and characterization of particles. Subvisible and visible particle analysis in biopharmaceutical.
Particle count test and method 2 microscopic particle count test, are specified hereinafter. Part 2, experience with the application of subvisible particle analysis. The technical parameters and system settings of the. When examining injections and parenteral infusions for subvisible particles. With walkaway automation, the horizon instrument helps you screen up to 96 formulation samples in under 2 hours with far superior particle image analysis than current methods. Subvisible particles particulate contamination of injections and infusions consists of extraneous, mobile undissolved particles, other than gas bubbles, unintentionally present in the solutions. Dynamic image analysis to evaluate subvisible particles. The horizon system can run 200 stability test samples from your formulation screen in less than a. The subvisible and visible particles present in a solution are often classified based on size, and are quantified by the actual number of particles present rather than by weight or molar amounts. From the characterization of superabrasives, chemicals, petroleum, and fruit juice, to yeast and fragrance encapsulation if its a fluid, or can be suspended in a fluid, flowcam it.
Highresolution images of subvisible particles between 1. Imagebased particle analysis for biopharmaceuticals. By enabling low volume and high throughput subvisible particle analysis, the horizon system makes it. A gsk team member with expertise in particle analysis reasoned an imaging particle analyzer that takes digital images of each individual particle detected in a. Analysis of images begins with the definition of particle boundaries from the captured. Archimedes is an innovative, highperformance system which harnesses the technique of resonant mass measurement in order to detect and count particles in the size range 60nm 5m and to measure particle mass and size. Astm e306016, standard guide for subvisible particle measurement in biopharmaceutical manufacturing using dynamic flow imaging microscopy, astm international, west conshohocken, pa, 2016, back to top.
Characterization of visible and subvisible particles. Subvisible particles are usually defined as particles that are too large for analysis by size exclusion chromatography sec e. Due to the complex milieu of subvisible particles, sample preparation and the method of analysis can affect the accuracy of. Uncertainties in subvisible particulates need to be understood, fda tells biotech cmc strategy forum. The ability to see the actual particles in parenteral formulations, to see their morphology, and to automatically differentiate one type from another marks an important advance in parental drug particle analysis. Archimedes is uniquely positioned to quantitatively measure protein aggregates in biotherapeutics in the size range 200nm. Excessive particulate contamination in proteinbased drug products may lead to adverse health outcomes.
Measuring the size and concentration of subvisible particles within a. The results obtained in examining a discrete unit or group of units for particulate matter cannot be extrapolated with certainty. Analysis of subvisible particles and aggregates in gmp. Halo labs subvisible particle analysis instrumentation. Archimedes, an innovative system for detection and counting of subvisible particles including protein aggregates and for particle mass and size measurement. Expert knowhow in aggregate and subvisible particle analysis as a gmp compliant service. Evaluation of particle techniques for the characterization of. For the determination of particulate contamination 2procedures,method1lightobscuration particle count. Direct imaging particle measurement technologies have.
Nov 20, 2018 subscribe to cleanroom technology magazine for incisive analysis of the latest news and developments in hitech industries manufacturing in controlled environments. Horizon subvisible particle analysis instrument halo labs. These analytical challenges were met with success as long as the definition of particulate matter remained well within the. Before sample analysis, system suitability was confirmed for accurate sizing using a 1. Due to the morphology of the particles, modern application software makes it possible to determine particle characterization by number and size. By enabling low volume and high throughput subvisible particle analysis, the horizon system makes it possible to perform particle screening as early as. Analysis of subvisible particles pharmaceutical technology. The accusizer system is used for usp,, and subvisible particulate matter testing. Transfer to the filtration funnel the total volume of a solution pool or. In addition to the particlespecific analyses, a forensic case study was performed as an example of how a forensic lab may begin to incorporate subvisible particles into current schemes of analysis.
Aug 24, 2017 dynamic image analysis to evaluate subvisible particles during continuous drug infusion in a neonatal intensive care unit. By contrast, the human eye can only count up to a limited number of particles figure 2. Subvisible and visible particle analysis in biopharmaceutical research and development this chapter gives an overview of methods for the analysis of subvisible and visible particles within. Mvss software is used to process the captured images and determine the particle size and count within a desired particle size range. Mfi software gives you the ability to dive deep into a single sample or examine a. New tools and opportunities presented by danny chou, president and founder at compassion biosolution, llc followed by an industry perspective presented by mark bumiller, technology manager at particle sizing systems, an entegris company. Images of the sample are captured as it passes through the flow cells sensing zone. Analytical methods to characterize aggregates and subvisible. Variable threshold method for determining the boundaries of imaged subvisible particles. An accurate assessment of particle characteristics and concentrations in pharmaceutical products by flow imaging requires accurate particle sizing and morphological analysis. This chapter gives an overview of methods for the analysis of subvisible and visible particles within biopharmaceutical products. Paswin particle analysis software the particle analyzing software paswin has been developed for particle measuring devices and analyzes particle size distributions of dispersed materials in liquids and gases and runs under windows. The instructional chapter usp mentions mfi as a possible orthogonal technique for subvisible.
New tools and opportunities danny chou, president and founder at compassion biosolution, and mark bumiller. Sub visible particle analysis shouldnt require milliliters of precious sample volume. The images collected are used by the software to create an extensive database of information size, shape. To achieve unparalleled subvisible particle analysis, the horizon system employs halo labs proprietary analytical technique backgrounded membrane imaging bmi.
The case study involved the investigation of a subvisible paint particle. Separation, characterization and discriminant analysis of. Gustaf kylberg, rickard nordstrom and idamaria sintorn vironova ab, stockholm, sweden characterization and analysis of subvisible particles of biological origin can be challenging or give insufficient information. How the flowcam works for characterization of visible and subvisible particles turning data into insight. Subvisible particulate matter in therapeutic protein injections. Protein aggregate and subvisible particles analysis information. Because its imagebased, you can add quantifiable morphological parameters to your analysis. The horizon system is powered by a novel and highly sensitive backgrounded membrane imaging bmi technology. Protein aggregation, proteinaceous particles, nonproteinaceous particles, subvisible particles, mfi, mvas, lumetics link, discriminant analysis. Particulate matter and particle size testing eurofins. Overlooking subvisible particles in therapeutic protein products. The derived diameters and particle concentrations for the 20 lots of bcg it are summarized in table 5, and were consistent across the 20 lots analyzed.
Protein aggregate and subvisible particles analysis. At gsk, imaging particle analysis using flowcam has been integrated into its testing program for development of proteinbased. Critical gaps in the analysis and control of subvisible particles. In this study adeno associated virus aav particles contaminated by host cell proteasomes are analysed with direct versus indirect methods performed in a standard. Reasons for the selection of each of these particle types are explained. Overlooking subvisible particles in therapeutic protein. The flow imaging method of particle size analysis relies on the definition of the particle. Particle morphology, captured by images, can be used to determine whether the svp is inherent, intrinsic, or extrinsic. Subvisible particle analysis protein antibody integrity bio. Quality of bevacizumab compounded for intravitreal. The green circle illustrates a large particle that the software clipped into many small particles.
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