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PHARMACEUTICAL AND CHEMICAL SECTORS| 36 |The powder containedin these capsules andtablets is probioticsthat were microencapsulatedusinga supercriticalCO 2process.‘Green’ ways toup the survival rate of probioticsA study 1 found that the survival rate of probiotics in, for instance, probiotic supplements,is generally extremely low. These micro-organisms simply cannot withstand the storage process.Is there a way to help them survive and to do so in an environmentally friendly way?Active pharmaceuticalingredients (APIs) such asprobiotics are, in general, verysensitive to high temperaturesand solvents. Conventionalmicro-encapsulation methodsare therefore unsuitable touse for APIs, as they typicallyrequire high temperaturesand/or solvents during theencapsulation process.“One would encapsulate an APIto protect it against elementssuch as moisture or light in itsenvironment; from gastric acidsthat can destroy it and also toallow for its controlled delivery inthe intestines,” explains Dr PhilipLabuschagne, a researcher at theCSIR’s encapsulation and deliveryresearch group.Labuschagne has been workingon a way to safely encapsulatesensitive actives, particularlyprobiotics, using a new ‘green’processing method. This methodentails the use of supercriticalcarbon dioxide (CO 2) as a processmedium.“The supercritical CO 2processoccurs at mild temperatures(not more than 40 ˚C) and isnon-toxic. In addition, unlikeconventional solvents, the CO 2canbe completely removed simply bydepressurisation so that the endproductcontains no traces of it,”explains Labuschagne.He used this process to developa polymer matrix that is basedon inter-polymer complexation– a process that mixes twocomplementary polymers withdistinct properties in order toobtain a polymer matrix withunique characteristics. Forinstance, the inter-polymercomplex developed byThe study found that:… only five out of ninecommercial probiotic products inSouth Africa contain sufficientlevels of organisms to haveprobiotic potential. One of the mainreasons for this is the sensitivenature of these micro-organisms toheat, light and moisture.Probiotics are livemicro-organisms (in most cases,bacteria) that are similar tobeneficial micro-organisms foundin the human gut. They are alsocalled ‘friendly bacteria’ or ‘goodbacteria’. Probiotics are availableto consumers mainly in the formof dietary supplements and foods.An example ofinter-polymer complexation:The most common interpolymercomplex is between polyacrylicacid and polyvinylpyrrolidone.They are both hydrophilic(attracts water), but oncecomplexed they becomehydrophobic (repels water).Microencapsulation,in materials science,is the coating ofmicroscopic particleswith another material.Labuschagne is pH responsive,which means that it willprotect the probiotic fromgastric acid attacks and ensureits release in the more alkalinepH-environment of the largeintestine. In addition, it protectsthe probiotics from moistureand oxygen during storage.The end-product is a powderwith particle sizes of between50 and 500 microns (microparticles).Any probiotic straincan be encapsulated usingthis technology, and it can alsobe used for other APIs – evenvitamins and possibly vaccines.“We have already proved thatthis encapsulation methodshows significant improvementin the shelf life of probiotics, aswell as greater protection fromgastric acids and improvedrelease in the intestines,”says Labuschagne. “Thistechnology has been patentedand the results published.”Micro-encapsulation usingsupercritical CO 2holdsimmense promise for theentire API manufacturingindustry. The project wasoriginally funded by a coinvestmentfrom the IndustrialDevelopment Corporation,and a company called Ellipsoidwas created through which thecommercialisation will takeplace.1 An evaluation of nine probioticsavailable in South Africa, August2003, E Elliott, K Teversham– Petro LowiesEnquiries:Dr Philip Labuschagneplabusch@csir.co.zaDr Philip Labuschagne adds the raw materialsto the supercritical CO 2reactor to preparemicro-encapsulated probiotics.| 37 |
PHARMACEUTICAL AND CHEMICAL SECTORS| 38 |Dr Stoyan StoychevThe CSIR is currently buildingcapacity for large-scalerecombinant production ofbiopharmaceuticals. At present,there are a number of suchproducts at various stages in thedevelopment pipeline, includingtherapeutic peptides such asExenatide (diabetes treatment),Enfurvitide and Griffithsin (HIVinhibitors) as well as anti-rabiesmonoclonal antibodies (mAbs).Production of biologicsBiopharmaceuticals areconventionally produced insterile fermentation facilitiesusing mammalian cellcultures. A drawback of suchsystems is that they have aUsing biologics totransform the drugmarketplaceBiologic products now provide important therapeutic options for a range of serious clinical conditions.Therapeutic biologics such as genetically engineered recombinant proteins and monoclonal antibodies representa large portion of newly-approved therapies for conditions such as chronic inflammatory diseases and cancer.limited production capacity,and setting up such facilitiesrequires a huge capitalinvestment. Biologics mayalso be produced by usingrecombinant micro-organismsor plants engineered to expressa particular therapeutic peptide,protein, monoclonal antibodyas well as vaccine sub-unit.The pharmaceutical industryis now being transformed dueto the emergence of biologics(biopharmaceuticals) whichoffer many advantages overconventional small-moleculedrugs. These include higherefficacy, reduced side effects,and the potential to curedisease, compared to treatingsymptoms.The size and complexity ofbiologics, in comparison tosmall-molecule drugs, havebrought a unique set ofchallenges to manufacturers.Therapeutic peptides,proteins and mAbs have tobe scrutinised at primary aswell as higher-order (native)conformation. Close attentionmust also be paid to anymodifications induced bythe recombinant expressionsystem. In addition, productand process-related substancesand impurities can affect boththe structure and functioningof biologics. Hence, it is criticalto be able to detect dimidiated,isomerised, oxidised forms,or protein aggregates as wellas host cell protein, DNA andculture components introducedduring cloning, production andpurification.In-depth characterisationof biologicsUnder these circumstances,manufacturers have to ensurethat their products undergorigorous characterisation tofacilitate transition throughdiscovery into development,eventual commercialisation,and their ultimate intendedtherapeutic use. Achievingthis goal is dependent on theavailability of appropriateanalytical tools to provide anarray of chemical and physicalinformation. Hence, a rangeof approaches has beendeveloped, optimised andsuccessfully implementedin-house for in-depthcharacterisation of biologics witha focus on meeting regulatoryand commercial specifications inorder to shorten time-to-marketas well as lower risk duringproduct development stages.The identity of recombinantlyexpressed peptides, proteinsand mAbs is scrutinisedusing a combination ofproteolytic digestion followedby multi-dimensional liquidchromatography peptidefractionation, directly coupledto tandem mass spectrometry.This workflow yields highresolutionpeptide sequencingdata that not only permit indepthcharacterisation of primarystructure, but also allow directdetection of post-translationalmodifications product as wellas process-related impurities.In addition, in-house developedmicrospheres (ReSyn TM ) arebeing used to manufactureimmobilised protease microreactorsfor fast and efficientprotein digestion that yieldshigh coverage primarystructure data.Cutting-edge ultrahigh-pressureliquidchromatography systemsProduct purity is monitoredusing electrophoresisas as wellas chromatography-basedtechniques, with separationbased on a range of molecularproperties such as size, charge,as well as hydrophobicity. Theuse of cutting-edge, ultra-highpressureliquid chromatographysystems in combination withcolumns packed with smaller,sub 2 μm size particles, allowsfor more efficient as well as faster separation of moleculesof interest.Since native structure dictatesfunction, the understanding ofstructure and its interplay withfunction is essential for developingeffective, safe, and cost-effectiveprotein biopharmaceuticals.The native conformation of largerpeptides, proteins and mAbsis examined on a global scaleusing circular dichroism, whichmonitors changes in secondarystructure, and fluorescencespectroscopy to monitor thetertiary and quaternary structurallevels of complex biologics. Futureefforts will also centre on thedevelopment and implementationof cutting-edge techniquesfor in-depth characterisationof native conformation on alocal scale. This will furthersupplement existing capabilitiesby allowing site-specificand detailed conformationalcharacterisation, that would beuseful throughout all stages ofprotein drug development, fromoptimisation of target binding andreceptor interaction(s) in research,to formulation, stability andcomparability studies in processdevelopment, where informationon changes in conformation couldplay an important role in thedevelopment and optimisationof complex biologics.In order to demonstrate thatmethods are appropriate for usein drug developmentprogrammes, substantial timeand resources are required. Inthe year ahead, our focus willbe on method qualification andvalidation so that the assayscurrently being used are deemedcompliant with internationalexpectations, and mostimportantly, that the analyticaldata derived from these methodsretain their full scientific value.– Dr Stoyan StoychevEnquiries:Dr Stoyan Stoychevsstoychev@csir.co.zaWhat are biologics?A biologic is a prophylactic, an in vivo diagnostic or atherapeutic substance that:• Is produced only by a living system, but is not simply ametabolite;• Is stated to contain a single substance that has documentedbiological activity or activities;• Has a relatively large molecular weight with a high structuralcomplexity compared with biologically active substancesthat can be made by chemical synthesis; is inherentlyheterogeneous in the molecular species present, and has animpurity profile that depends critically upon the processesused to make and test each batch; and• Has activity that is often very sensitive to physical conditions(i.e. temperature, shear forces, phase) and enzymatic action.| 39 |
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