PART II

Planning and management ofvaccine production

Veterinary vaccines have to be consideredas medicinal products and, therefore,should be included in a framework ofregulations for marketing. Since theseregulations are related to technicalrequirements, they alone are capable ofguaranteeing to potential users the quality,safety and efficacy expected of suchproducts.

Such a guarantee is absolutely- necessaryfor the protection of the livestock popu-lation against infectious diseases, and alsoto ensure, ultimately, the high standardsof hygiene required of food products thatare to be marketed.

REGULATIONS FRAMEWORK

Regulations relating to veterinary vaccineshave to define, as precisely as possible, theconditions required for the registration ofveterinary immunobiological products,directions on how to file an application forregistration of a product, the conditionsunder which it is permissible tomanufacture a product and the issuing ofmarketing authorizations (licences).

The conditions under which theinspection of manufacturing premises areto be carried out need to be defined in theregulations relating to immunologicalveterinary medicinal products (IVMPs).

The regulations should be sufficientlyprecise to take into account the variousstandards of manufacture and methods ofworking with such products throughoutthe country concerned. Consideration hasalso to be given to the human and financialresources associated with the industry. If

Re0s. 17(orHon5 ncenzring9 controls and praLmues related to vetevri my vaccines

P. Vannier

regulations demand standards that aretoo high being based on theoreticalconsiderations and are inappropriate tothe socio-economical conditions obtainingin a country, they will very probably neverbe applied.

Under such circumstances, it would bepreferable to formulate regulations of aless demanding nature, which wouldtherefore be more likely be recognizedand would lead to improvements in thestandard of IVMPs used in that country.

LICENSING AUTHORITIES AND PROCEDURES

It goes without saying that it is necessaryto define the conditions and procedureswhich will be used by the registrationauthority clearly. Such definitionsguarantee to national and foreignmanufacturers the independence andimpartiality of the registration authority.

Normally the applicant submits to thenational authority (which could be theministry of agriculture or an agency, but isalways a government department), anofficial application to obtain a licence tomarket a particular IVMP. With theapplication, several copies of the product'sdocumentation file, giving essential data,are also sent, to enable the authority tocompile a dossier relating to that particularproduct. In addition, samples from typicalbatches of the product are sent to controllaboratories for official testing. Generally,the authority acknowledges receipt of theapplication and allocates an officialregistration number to the product. Fees,which vary in amount, have to be paid.

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156 Registration, licensing, controls and practical issues related to veterinary vaccines

The official registration number will laterbecome the marketing authorization(licence) number of the registered product.

The regulations should define a timeperiod for the examination of theapplication file by the official technicaladvisers responsible to the nationalauthority. However, in many countries theauthorization to market the product isbased on an assessment made by anindependent committee, working fromthe results of an investigation made bytechnical experts.

The work of the committee should bestrictly confidential. Members of thecommittee should include representativesof the national authority and recognizedexperts in the field of veterinary immuno-biologicals. Impartiality, objectivity,confidentiality, technical assessment andscientific competence are the essentialaspects of the procedure to be followed inassessing the suitability of a product forlicensing prior to marketing.

DATA TO BE INCLUDED IN AN APPLICATION

(REGISTRATION) FILE

The following information is taken fromEuropean Commission Directive 81 / 852(amended as 92 / 18 and published on 20March 1992).

The file is composed of six sections: i) asummary, ii) expert reports, iii) analyticaldetails, iv) descriptions and results ofsafety and v) efficacy (potency) trials andvi) documentation relating to safety testingand efficacy trials.

Summary of the dossier of informationThe IVMP which is the subject of theapplication should be identified by thenames of the active ingredients, togetherwith their pharmaceutical formats and thequantities used in the product, the methodand route of administration and a de-scription of the final sales presentation ofthe product.

The name and address of the applicantshould be given together with the nameand address of the manufacturer and thesites involved in the different stages ofmanufacture as well as, where relevant,the name and address of the importer.

Annexed to the administrative data thereshould be copies of a document (e.g. alicence) showing that the manufactureris authorized to produce IVMPs. Theapplicant should submit a list of countriesin which such authorization has beengranted. The applicant should also submita summary of the product's characteristics.

Experts' reports

Reports must be provided on all the testsand investigations made. Each reportshould consist of a critical evaluation ofthe various tests and / or trials and shouldpresent all the relevant data for detailedevaluation. The expert(s) involved shouldgive their opinions as to whether sufficientguarantees have been provided as to thequality, safety and efficacy of the productconcerned; a brief summary is notsufficient.

Each report should be prepared by asuitably qualified and experienced person,who may be a company employee. Thereport should be signed and dated by theexpert and should also include briefinformation about the educationalbackground, training and occupationalexperience of the expert. The professionalrelationship of the expert to the applicant(i.e. the company) must be declared.

Analytical sectionThis section should give descriptions ofall the physico-chemical, biological ormicrobiological tests carried out tocharacterize the IVMP. All test proceduresused should correspond to the most up-to-date scientific methods available andshould be validated procedures; results ofthe validation studies must be provided.

Qualitative and quantitative particularsof constituents. Qualitative particulars ofall the constituents of an IVMP should givea complete description of the constituentsof the final product, as administered toanimals, including the designation ordescription of: the active ingredients; thecomposition and constituents of adjuvants,excipients etc. (whatever their nature);and the quantities used, including pre-servatives, stabilizers, emulsifiers andcolouring matter.

In giving the quantitive particulars ofthe active ingredients of an IVMP, it isnecessary to specify, wherever possible,the number of organisms, the specificprotein content, the mass, the number ofinternational units (TU) or units of biol-ogical activity (either per dosage unit orvolume) and, with regard to the adjuvantand the constituents of excipients, the massor volume of each.

Where an TU of biological activity hasbeen defined, this should be used.

Description of the preparation of the finalproduct. The description of the method ofpreparation accompanying the applicationfor marketing authorization should bedrafted in such a manner as to give anadequate description of the nature of theoperation employed. This descriptionshould include the various stages ofmanufacture; in the case of continuousmanufacture, full details concerningprecautions taken to ensure the homo-geneity and consistency of each batch ofthe finished product; and details ofblending, etc.

Production and control of starting materialsThe starting materials are all the com-ponents used in the production of theIVMP. It is recommended that an officialmonograph such as the EuropeanPharmacopoeia should be consulted whenthese substances are listed.

The routine tests carried out on eachbatch of starting materials must be as statedin the application for a marketing licence.If tests other than those described in thepharmacopoeia are used, proof must besupplied that the starting materials meetthe quality requirements of the phar-macopoeia.

In the application (registration) file, theorigin and provenance of starting materialsshould be described and documented.

For genetically engineered startingmaterials, the information given shouldinclude descriptions of: the starting cellsor strains, the construction of theexpression vector (name, origin andfunction of the replicon, promoterenhancer and other regulator elements),the control of the sequence of DNA or RNAwhich has been inserted, oligonucleotidesequences of the plasmid vectors in cells,the plasmid used for transfection, addedor deleted genes, the biological propertiesof the final construct and the genesexpressed, copy number and geneticstability.

Information should also be provided onall the substances of biological origin usedat any stage in the manufacturingprocedure. Such information shouldinclude: details of the source of thematerials; details of any processing,purification and inactivation applied,together with data on the validation ofthese processes and in-process controls;details of any tests for detecting con-tamination that have been carried out oneach batch of the substance.

When the starting materials are not ofbiological origin, the information shouldprovide a detailed description of thematerials, together with their function,methods of identification and purity. Abrief description should also be providedof the tests undertaken to establish thepurity of each batch of the startingmaterials.

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Control tests during productionComplete information should be providedof the control tests that are carried out onintermediate products, with a view toverifying the consistency of the productionprocess and the final product. Forinactivated or detoxified vaccines,inactivation or detoxification should beconfirmed during each production run andimmediately after the inactivation ordetoxification process.

Control tests on the final productThe registration file should list the teststhat are carried out on representativesamples of each batch of the final product.The frequency of tests which are notroutinely carried out on each batch shouldalso be stated and expiry dates should beindicated.

Certain tests of the general characteristicsof a product should be included amongthe tests of the finished product, even ifthey are only carried out in the course ofthe manufacturing process.

These tests should, wherever applicable,be concerned with establishing typicalvalues and the maximum deviations tobe expected in relation to mechanical,physical, chemical or microbiologicalcharacteristics, as well as special physicalcharacteristics such as density, pH andrefractive index. For each characteristic,average values, with appropriateconfidence limits, should be establishedby the applicant for each particularproduct.

For all tests, descriptions of thetechniques for assessing the final productshould be set out in sufficiently precisedetail, such that they can be readilyreproduced.

When appropriate testing proceduresare available, the quantity and nature ofthe adjuvant (i.e. its activity) and itsconstituents should be confirmed by meansof tests with the final product and, when

necessary, the excipient(s) used should besubject to identification tests described indetail in the file.

Safety tests prior to batch release have tobe described in the registration file inaddition to appropriate tests to dem-onstrate the absence of contamination byadventitious agents or other substancesand, where applicable, a test to verifycomplete inactivation should be carried outon the product in its final container andthe results given.

Potency tests. Potency tests also have tobe described. These tests are carried out todemonstrate conformity with specifi-cations and to ensure that the efficacy ofthe product is reproducible from batch tobatch and is of an acceptable minimumstandard.

Stability tests. A description should begiven of the tests undertaken to supportthe shelf-life proposed by the applicant.The results of analyses, justifying theproposed shelf-life under all likely storageconditions, should also be given.

Safety tests. The particulars anddocuments in the registration file shouldinclude a description of all the safety testscarried out on the target species.

Laboratory tests. Trials should beundertaken in which the IVMP isadministered at the recommended dose,and by each recommended route ofadministration, to animals of each speciesand category in which it is intended foruse. The conditions of these trials shouldbe described in detail together with theobjective criteria to be used (such as rectaltemperature and performance measure-ments) to assess the safety of a product.Safety tests need to be performed and theresults described in terms of possibleeffects following:

the administration of one dose;the administration of an overdose;the repeated administration of onedose;

0 the reproducibility of the results ofrepeated tests.

For live vaccines, special safety tests arerequired to establish:

the putative spread of the vaccinestrain;its dissemination in the vaccinatedanimal;the possibility of reversion to virulenceof attenuated vaccines;the biological properties of the vaccinestrain (e.g. neurotropism);the recombination of elements of thegenome and the possibility of theemergence of new strains by genomicreassortment.

Field studies. The file should includesupportive data from field studies tosupplement the results of laboratorystudies.

Potency testsThe particulars and documents in the re-gistration file should include descriptionsof tests to demonstrate the potency(efficacy) of the product administered toeach category of each target species, by therecommended route(s) and using theproposed schedule of administration.

The demonstration of potency shouldbe undertaken under well-controlledlaboratory conditions, by challenge, afteradministration of the IVMP to the targetanimal according to the recommendedconditions of use. So far as possible, theconditions under which the challenge testis carried out should mimic the naturalconditions for infection with regard to thenumber of challenge organisms and theroute of administration of the challenge.

In general, detailed results of all safetyand potency tests need to be presented in

the file and the report of each test shouldinclude the test protocol, records of actualdata, analysis of recorded results and theconclusions drawn from the data.

Controls must be included in all assaysand must be clearly identified in thereports. Bibliographical references shouldbe given where additional scientific dataare required to explain some of thearguments put forward by the manufact-urer in support of the product.

CONTROLS TO BE UNDERTAKEN BY NATIONAL

AUTHORITIES

These controls depend on national policiesand on the human and financial resourcesavailable in the country.

Controls must be carried out at thenational level, by the appropriate author-ities both before marketing authorizationand before the release of batches.

Controls carried out before marketingauthorization are not routine but may benecessary to confirm the data and resultsobtained by the manufacturer. Thesecontrols can be very simple, such assterility tests and titrations of organisms,but more complex controls, such as efficacyand safety tests on target species, may alsobe necessary. Obviously, complex controlscan only be carried out where the author-ities have the technical means sufficient toobtain proper, fully validated results whichcannot be contested by the manufacturer.

Efficacy and safety controls may becarried out routinely or not. In most cases,the nature of the control tests undertakenis dependent on the data given in theregistration file. If some data appearunclear or insufficient, further tests maybe necessary to confirm the results obtain-ed by the manufacturer. Under thesecircumstances the tests undertaken are, tosome extent, determined by the dataproduced by the manufacturer.

National authority control tests onbatches prior to release are carried out on

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160 Registration, licensing, con rols and practical issues related to veterinary vaccines

some vaccines that have strategic im-portance for specific vaccination or diseaseeradication programmes, for examplerinderpest and foot-and-mouth diseasevaccines. Such vaccines are produced by apublic or recognized private manufacturerand batches are released only if the resultsof control tests carried out by the officialauthorities are satisfactory.

These tests are expensive in time andmoney and need to be carried out asquickly as possible to avoid delays inmarketing the product. Such pressures cancontribute to improvements in the qualityof the products if the tests are carried outby an efficient and competent organization.In developing countries, it is essential tohave a regional policy involving strongcooperation among countries to saveresources and to promote the developmentof more efficient laboratories.

It may not be reasonable or possible tohave one national control laboratory percountry and it would be more appropriateto avoid duplication by sharing theexpenses of maintaining one efficientlaboratory among several countries withmutual acceptance of the results obtainedby such a laboratory. In practice, however,such an approach has remained, up to now,difficult to achieve.

Official authorities should consider thatin many developing countries the nationallaboratories are themselves producingseveral vaccines and, in such cases, it isessential that the laboratories in charge ofproduction and those in charge of controltests are completely separate. If not, theindependence and impartiality of thecontrol laboratories will be compromisedand disputes may arise as to theacceptability of the test results obtained.

INSPECTION

When vaccines are produced locally, thenational authorities have to take measuresto obtain guarantees concerning the

standards of manufacturing practice.Guidelines have been established invarious countries and regions such as theUnited States and Europe to define goodmanufacturing practices (GMPs). Qualityassurance (QA) is increasingly defined asbeing all the planned and routine actionsnecessary to provide adequate confidencethat a product or service will satisfy givenrequirements for quality (Soulebot, 1992)rather than demanding the overintensivetesting of final products. The implicationof this is that the quality of the finishedproduct is largely determined by thequality of the raw materials and manu-facturing processes used.

If, in addition to the quality of the rawmaterials, the various stages in themanufacturing process are controlled inan appropriate way, the probability of adefect or contamination in the finishedproduct would be very low. The methodsand standards of inspection required maybe developed according to this concept.

An authorization to permit productionon a trial basis, in the first instance, needsto be made by the official authorities beforeroutine manufacturing of any product cancommence and the product receive theappropriate licence. Authorization shouldonly be given if the premises and manu-facturing processes meet the technicalrequirements that will ensure a good-quality product. Technical requirementsneed to be defined at the national level(even if they have been developed anddefined in other countries) and made knownto manufacturers as soon as possible.

A compromise has often been madebetween the minimum standards requiredto ensure high quality of products and theeconomic situation of a country. Indeed, insome situations, if the national authoritiesintend to guarantee the quality of aparticular marketed product, it may evenbe necessary not to authorize itsmanufacture in the country.

It is essential that manufacturing pre-mises be inspected regularly but at variableand random intervals to check on theconsistency of manufacturing practices.

If products are not manufactured locally,the problem becomes a little more complexbecause the standards required of manu-facturing practices have to be the same inthe exporting country as in the importingcountry. Inspection certificates providedby the authorities from the country oforigin will be required by the authoritiesof the importing country and must beincluded in the registration file. Anagreement between countries willoften be necessary to ensure that theadministrative and technical values ofthese certificates are the same. Sometimesit may be necessary to harmonize theconditions of inspection in differentcountries to ensure mutual recognition ofcertificates issued by different nationalauthorities.

PHARMACO-VIGILANCE

It is important to set up a system whichallows an exchange of information onmarketed IVMPs between users andofficial authorities. Such an exchange ofinformation, which may be informal, formspart of a pharmaco-vigilance network andcontributes to the detection of problems inrelation to the use of a marketed product.Such a system can be very useful,particularly when the economic situationdoes not permit important controls onfinished products or routine and frequentinspections of premises. Very simplesystems can be set up by authorities toinform the main users of IVMPs, forexample veterinarians, including, forinstance, a telephone line connected to aspecial unit which can give information onproblems occurring after the use of certainproducts. The main difficulty will be todifferentiate between real problems thatrequire immediate action and occasional

events in which the suspected productplays no role at all.

More complex systems can be usedincluding a computerized database ofinformation from users, inquiries andepidemiological surveys. At present thereare very few such systems operationalworldwide.

Pharmaco-vigilance is usefulassessing, in the most expeditious way,the real effects of a vaccine in the field.Side-effects and lack of efficacy can oftenbe observed after the introduction of a newproduct, which may have been used undernormal or abnormal field conditions.Occasionally small alterations in themanufacturing process can affect thequality of the finished product and nothave been detected by tests carried outby the manufacturer and the officiallaboratory.

Pharmaco-vigilance is also useful for thecollection of data on the effects of vaccinesused under conditions that are somewhatdifferent from those described in theregistration file. In developing countries,for instance, the number of target speciesto which a vaccine can be administeredmay increase considerably. When vaccinesare imported or when assays are expensiveit is often difficult to carry out tests onparticular species, such as camels and gameanimals for registration purposes and theuse of vaccines may, therefore, have to beadapted to very specific and particularconditions. In such cases pharmaco-vigilance can contribute to the datarequired for registration files, even if itcannot provide it all because the exchangeof information is insufficient and theresults of serological surveys and / orclinical records are needed to provideobjective and quantifiable data. In addition,when products are imported and wherelocal conditions are not totally appropriatefor the setting up of regular and importantcontrol tests on finished products,

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162 Registration, licensing, controls and practical issues related to veterinary vaccines

pharmaco-vigilance has an important roleto play in assessing the effects of a vaccinein an animal population, particularly withregard to its efficacy.

At present, in several developingcountries, there are agreements andcontracts between avian and pig product-ion cooperatives and research and controllaboratories to carry out field trials forstudies of, for example, the developmentof protective antibodies and clinical resultsafter vaccination. Such trials make possiblea better understanding of the performanceof vaccines applied under specificconditions.

PRACTICAL ISSUES

To be credible, the organization set up bythe national authority has to be foundedon technical competence and experience.All of those involved in the different stagesof the registration process have to beproperly trained in the methods of officialinspection, examination of data andlaboratory tests. In addition, veterinaryimmunobiological products have certainspecificities and the problems related tothe manufacture and control of theseproducts are totally different from those ofchemical ones. Specialists and specializedteams are needed to manage the wholeregistration procedure of IVMPs. To savefinancial resources, it may sometimes bepossible to involve the same people inthe administrative procedures for theregistration of both chemical and biologicalproducts but, in both cases, all technicalmatters have to be the responsibility of theappropriate specialists.

In developing countries, such problemsoften become greater because the economicsituation does not permit the establishmentof an operational, efficient organization.Regional cooperation among countries istherefore needed. Cooperation can includethe exchange of test reagents and materials,information about the investigation of new

applications for registration and the resultsof tests and licences which have beengranted.

At present, it appears essential todevelop a strong collaboration amongcountries based on good complementarytechnical competence. The poorer thefinancial resources of the countries in aregion, the greater the need for suchcollaboration.

It is essential that a licensing systemshould be both rigorous and demandingand, at the same time, flexible and easilyapplicable. The system must allow anequitable treatment of all the marketableproducts which are to be assessed, by usingthe same technical criteria and standards;this is the sole guarantee for freecompetition among manufacturers.

If the above conditions are not in place,the system will favour the development ofa black market with the opposite results tothose desired. The development of a blackmarket becomes more likely when themeans and conditions for controlling thedistribution of products are weal< andinadequate. In all cases, the penaltiesimposed against those involved in blackmarket activities should be very severe.

The national authorities may haveanother problem in relation to issuinglicences, namely, how to define thethreshold of acceptability in regard toquality, safety and efficacy, so as to be ableto accept or reject a particular vaccine. Ingeneral, a vaccine will be rejected if itappears to be insufficiently safe or lackingin efficacy, there is insufficient scientificdata available on file or the qualitative orquantitative composition of the vaccine atthe time of testing does not correspond tothe data given in the registration file.

It is impossible to generalize about allthe possible cases that may justifiy therejection of a product and, therefore, therefusal of a licence. However, nationalauthorities have to elaborate a policy that

can be properly understood and acceptedby manufacturers and this policy shouldbe founded on technical requirements andguidelines developed from presentscientific understanding and from therequirements set up in other countries,adapted to local conditions.

Whatever the efforts to develop goodtechnical guidelines, some problems willremain and, at some point, the competenceand experience of the official inspectorswill be required to intervene to make adecision. Under these circumstances it isessential that the legal requirements of thelicensing procedure be such as to limit thesubjective element in the interpretation oftest results and in the judgement ofinspectors on the merits of a particularapplication for a licence.

BIBLIOGRAPHY

Commission of the European Communities.(1992). The rules governing medicinalproducts in the European Community, Vol.V A. Directorate General for InternationalMarket and Industrial Affairs.

International Association of BiologicalStandardisation. 1992. Symposium on theFirst Steps Towards an InternationalHarmonization of Veterinary Biologicals:1993 and the Free Circulation of Vaccineswithin the EEC. Developments inBiological Standardisation, No. 79.

Soulebot, J.P. 1992. Fedesa's point of view:quality application to IVMPs. InInternational Association of BiologicalStandardisation. Symposium on the FirstSteps Towards an InternationalHarmonisation of Veterinary Biologicals:1993 and the Free Circulation of Vaccineswithin the EEC, p. 201-211. Developmentsin Biological Standardisation, No. 79.

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VACCINE TECHNOLOGY EXPERTISE WITHIN

PRIVATE INDUSTRY

Commercial vaccine producersCompanies that produce vaccine are inbusiness to generate profit from the sale oflicensed products. In certain circumstancessome are prepared to sell technologytransfer packages to state or parastatalbodies and deals of this nature may befinanced by government or agency aid inthe form of a soft loan.

In such cases it is very important that acontract is signed which clearly definesthe objectives to be met by the companyand the performance criteria which mustbe acheived for the company to dischargeits obligation including a defined follow-up period of support consultancy withspecified responsibilities.

A feasibility study may be necessary toestablish a project outline and broadspecification to facilitate a costing and theformulation of a contract that both partiescan sign. The cost of the feasibility studymay also be funded by government oragency soft loan.

The developing country must be satisfiedthat the commercial company is capable ofmeeting the commitments it is proposingto undertake and that it does in fact ownthe technology it is proposing to sell. Thedeveloping country is advised to engagean independent consultant with theappropriate technical background andexpertise to advise it and act on thecountry's behalf in the formative,implementation, handover and supportconsultancy stages.

role of private industry in the travic er ofvaccine technology to devaloping countries

A.J.B. Haigh

Engineering and bioengineering companiesThere is a large range of engineering andbioengineering companies available frommanufacturers of equipment (e.g. pressurevessels, filters, process modules) to processdevelopment contractors. While thesecompanies are specialists in their ownspecific fields, their role is really one ofsupport and supply to the existing vaccineproduction and development industry;they generate solutions to engineeringand/ or processing problems againstspecifications defined by the customer.

ConsultantsConsultants range from individuals withparticular expertise in one or more areasof vaccine technology to consultingcompanies with teams of specialistsconstituted to meet the particular technicalaspects of a project at various stages.Consulting companies are unlikely to havethe required biological process technologyexpertise but can usually provide the otherexpert inputs required.

Takeovers and mergers within thepharmaceutical and veterinary biologicalindustry have for some time resulted inthe availability of a number of individualswith extensive experience in veterinarybiologicals production and control whooffer their services as self-employedconsultants. These independent con-sultants have much to offer not only asnoted in the section Commercial vaccineproducers, above, but also as an alternativeto commercial vaccine producers as asource of technology expertise.

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166 The role of private industry in the transfer of vaccine technology to developing countries

THE PROCESS OF ACQUIRING TECHNOLOGY

Prior to contractRegardless of the size of the proposedbusiness, the stages to be worked throughby the purchaser and vendor are similarand differ only in scale and the range ofskills and specialized inputs required.

The purchaser must first define his orher needs. Ideally a document should beprepared which sets out the requirementsand includes any particular conditions orconstraints the purchaser may wish toimpose or bring to the attention ofprospective vendors. This document maybe submitted to potential vendors and/ orprovide the supplementary information toa published tender invitation. The servicesand assistance of an expert consultant inpreparing the basic terms of reference andin selecting the vendor are advisable.

Potential vendors should submit out-line proposals and cost estimates. Then,following further evaluation andnegotiation, a detailed contract should bemade with a selected vendor. Dependingon the size and scope of the project,vendors may need to do extensive detailedwork, which may include feasibilitystudies, both to satisfy the purchaser andto establish detailed costings. This can beboth time-consuming and costly and willnot be undertaken lightly.

Ultimately the purchaser needs to knowwhat is going to be supplied, how much itwill cost and the stages at which paymentsare due. The vendor must be satisfied thatthe obligations can be discharged withinthe agreed time-frame and that the way ofdoing this has been understood andaccepted by the purchaser. These pointsshould be embodied within a contractwhich clearly states who will do what andby what time, what the acceptance criteriaare and what will happen in the event ofnon-compliance. The contract shouldprovide for binding arbitration in the eventof an inability to agree. By and large the

clauses in the contract which define theobligations and specify what must happenwhen either party fails to fulfil itsobligations are the most important. Whileeverything is going smoothly the con-tractual details tend to assume a lessersignificance.

Post-contractImplementation of the contract maydemand nothing more than the vendoraccepting a number of the purchaser's staffat the vendor's production facility andproviding specified training. The terms ofthe agreement (contract) to do this willstate how many staff, how and by whomthey will be funded, for how long, thespecific techniques they will be trained in,how they will be evaluated, the fee to becharged by the vendor, how manypayments are to be made by the purchaser,when they are to be made, etc.

Alternatively, implementation of acontract may involve the erection of avaccine production unit on a greenfieldsite and its handover in working order,fully staffed by local personnel. Obviouslythe scope and scale of this requires amultidisciplinary project team anddedicated project management to ensuredefinition of, and coordinated adherenceto, the critical path.

Even large commercial vaccinecompanies are unlikely to have therequired range of expert staff on hand toimplement such an undertaking. Projectsof this size are usually implemented byteams composed of experts from more thanone company. The contractors may be aconsortium of the key technology sources,such as process, civil and mechanicaland electrical technicians, and projectmanagement may be provided from oneor a combination of these, or by aconsultancy group. The purchaser shouldinsist that the managing contractorcarrying overall responsibility be the

vendor responsible for providing theprocess technology and that all otherinputs, from whatever source, be arrangedthrough subcontracts with that vendor.

Project implementation can beconsidered as a series of phases whichoverlap. The efficient management of thisoverlap offers savings in time which canmean a considerable saving in cost. Anoutline of each of the phases involvedfollows.

Design. A great deal of design work willhave been carried out pre-contract toenable contractors to establish the financialcommitments and obligations they areundertaking. This work initiates thepreparation of the master design documentwhich lays down criteria and tolerancesfor all aspects of the project such astechnology criteria, operating methods andquality standards. An important aspect ofthe master design document is the settingof overall design tolerances. Biologicalsystems are, by their nature, relativelyunpredictable and very susceptible tooperator error. Excess capacity above thatspecified by the purchaser must be"designed in" to provide the purchaserwith a reasonable expectation of meetingspecified capacity. This capacity is inaddition to that allowed for predictablefactors arising from planned maintenance,public and religious holidays, etc.

Design involves detailed drawings,isometrics, models, etc. Models not onlyassist in three-dimensional design but alsofacilitate the preliminary validation of theprocess operating manual. Detailedspecifications for the purchase of plant andequipment are issued. The site is usuallyselected pre-contract since its suitabilityand availability and the quality of majorutilities have an enormous impact on thecivil and mechanical and electrical costs.Further visits to the site by design staffmay be necessary depending on the

quantity and quality of the data acquiredpreviously. Evaluations of locally availableequipment, materials and skills (e.g.stainless steel fabricators, welders) will benecessary. Time and money spent at thisstage save far heavier costs later.

The design stage includes:civil design (buildings, site, etc.): plansand specifications, models;

0 mechanical and electrical engineeringdesign (air-handling and treatment,process services, effluent treatment,utilities, etc.): plans, flowsheets,layouts, models, specifications;

0 process design (the biologicalproduction and handling element):preparation of operating and qualitycontrol manuals, plans, flowsheets,layouts, models, specifications;

0 spares and spare parts quantificationand specification;consumables quantification andspecification;

o supp or t and ancillaries (refrigeratedtrucks, regional cold stores, serumprocessing plants): layouts, specifi-cations, models.

Procurement. Project management inconjunction with design will, so far as it ispossible, ensure that the plant andequipment with the longest procurementlead times are specified first and placed onorder as soon as possible. These key itemsand their place in the installation schedulehave a major influence on the imple-mention critical path.

To minimize future problems withimportation, vendors should use localsources of supply where possible.However, process plant and equipmentand key mechanical and electrical plantwill usually have to be imported if thevendor has to guarantee performance;biological processes are quirky and twoapparently equivalent pieces of plant maynot offer the same biological performances.

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168 The role of private industry in the transfer of vaccine technology to developing countries

Ordering is phased against stated leadtimes to place equipment on-siteadequately in advance of the needs of theinstallation programme.

Installation. The first element of on-siteactivity is site preparation and civilconstruction. Mechanical and electricalinstallation commences soon after theinstallation of process plant and equipmentinstallation commences well beforecompletion of mechanical and electricalinstallation. There should be "milestones"in the contract and critical path at whichcontractors receive a phased payment. Anytraining of the purchaser's staff at thevendor's facility should commence at timesappropriate to returning them to the siteas soon as they can usefully contribute tothe completion of the project. The futuresite maintenance engineer should com-mence training as soon as the contract issigned so as to be back on-site as soon asinstallation starts.

Commissioning. Commissioning is theinitiation of data collection for justificationof handover acceptance. All items of plantand equipment are tested and operated toensure they perform to specification. Itemsfirst undergo engineering commissioningto check that the mechanical and electricalparts function and perform within thecriteria specified. These tests are certifiedand become a cumulative record forhandover. All measuring, monitoring andcontrol equipment is tested, calibrated andcertified.

Commissioning of the air-handling andfiltration system is crucial. This system isthe key to biological containment andsecurity. Its capacity to perform reliably tothe specified design parameters in the faceof both extreme environmental conditionsand process loadings must be demon-strated. This should be the responsibilityof the specialist contractor.

Finally all plant and equipment with abiological function is tested and certifiedfor performance and, where relevant,sterilizability (e.g. filters, culture vessels,valves, transfer lines, centrifuges,autoclaves). Seed banks are set up withcertified stock and scale-up cultures areestablished. At this point plant is ready tomove to the preproduction stage.

Training. Local staff of a suitablebackground and education are selectedvery early in the project and subjected toboth classroom and practical training in aworking environrnent using the sametechnology as that of the project. Thetrainees return to the site to assist in thebiological commissioning and to preparethe specific standard operating proceduresfor the plant to be approved by the vendor.

Preproduction. An agreed series of trialbatches are prepared in the new installationby the local staff under the supervision ofthe vendor, to prove the operability of theplant within the performance criteriaspecified and, at the same time, to validatethe new standard operating procedures.

Handover. The final handover of the plantis dependent on the preproduction batchesmeeting the target criteria.

Consultancy. Failures of plant, equipmentand structures occur even in the mostefficiently organized projects. Contractorindemnities for a specified period to coversuch events must be written into thecontracts / purchasing agreements.

Performance problems of a biologicalnature may be beyond local expertise. Theconsultancy phase is designed to place theexpertise of the vendor at the disposal ofthe new facility for a specified period, forinstance, three years. Biological technologyis constantly being improved and it is veryimportant that the original contract clearly

defines the purchaser's rights with respectto improvements in the process technologybeing purchased, particularly over theperiod of the follow-up consultancy andany subsequent extension to that period.Ideally, the contract should require thevendor to notify the purchaser of im-provements to the technology over thisperiod and the purchaser should have theright of acquisition at a reasonable price.

The vendor should make an armual auditinspection of the facility and provide thepurchaser with a written report togetherwith recommendations for implement-ation. The inspecting team should beappropriately staffed for the target facilitiesto be properly inspected. Additionalvendor support should be available onrequest. This may be provided at thevendor's facilities or on-site as appropriatefor the particular problem. The formalannual inspection and recommendationsshould command a consultancy fee. Adhoc support should be available on requeston a time charge plus expenses basis.

The purchaser should have the option toextend the consultancy phase againstrenegotiated rates.

TRADITIONAL TECHNOLOGY ACQUISITION

BY DEVELOPING COUNTRIES:

POINTS FOR AND AGAINST

The single most quoted justification fortechnology acquisition by developingcountries is self-sufficiency followedclosely by a cheaper product which saveshard currency by avoiding the import ofcommercial vaccine.

Unfortunately the facts do not generallysupport this justification (although everyindividual case must be evaluated on itsmerits). The benefits of scale are lost. Theinitial capital investment is enormous andthe bulk of this investment (about 70percent) is in civil and mechanicalengineering, i.e. the creation of theenvelope and environment in which the

process plant and associated equipmentand resources are located and operated.Most of the process plant and many of themechanical and electrical plant spares aswell as many process liquor componentsand control reagents must still be imported,requiring hard currency. This is frequentlysubject to bureaucratic delay. Major utilitysupplies, especially water and electricity,are unreliable in developing countries,resulting in frequent production crises anddisasters. The provision of effectivestandby sources is expensive both toprovide and to operate. Trained staffsalaries are rarely competitive, resulting incontinuous losses of staff which furtherendangers production reliability. The needto operate to international good manufac-turing practice (GMP), good laboratorypractice (GLP), quality and environmentalstandards adds further to unit costs.

Self-sufficiency requires that certifiedquality- and potency-tested vaccinemeeting the standards (with long leadtimes in many cases) will be available whenthe demand arises. The points given aboveare only a few of the more common causesof failure to achieve this and, un-fortunately, the management of vaccineplants in developing countries is rarelysufficiently experienced or powerful in thehierarchy to influence the situation for thebetter.

A further consideration is that ofemerging new technologies. The possibilityof multiple antigen vector vaccinesadministered orally, possibly even via thefeed, is quite real. Against such a possibilitythe validity of investing in traditionalvaccine technology, rather than continuingto import until the position clarifies,becomes very doubtful.

The above remarks should not in anyway deter those seeking to improveexisting production facilities particularlywith respect to meeting GMP / GLPstandards or upgrading quality assurance.

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Generral oe ign and opevating voquirennentsor vaccine rflanuiactuving establishments

The design and operation of facilitiessuitable for the manufacture of veterinaryvaccines depend on many factors,including the nature of the organisms fromwhich the vaccines are to be prepared, thespecific manufacturing processes used andthe particular economic, technical andgeographical situation in which the facilityis to operate.

This chapter will give only a broadoutline of the principles which should beborne in mind for the design andconstruction of new facilities or theupgrading of existing installations. Manyof the design features are relativelyuncomplicated and should therefore notbe prohibitively expensive to incorporateinto a new building design although it maybe difficult and expensive to make changesto existing buildings which did not takeinto account these factors at the designstage. Similarly, when facilities are beingupgraded or modified for other purposes,it is often appropriate to review basicdesign and operating parameters to ensurethat, wherever possible, improvementswhich permit the most satisfactoryfunctioning of the plant are incorporated.

The essential requirement for a manu-facturing plant is that it should produce asufficient quantity of good-quality, safeand effective product in an economicmanner as required. The objectives ofoptimum plant design and the concepts ofgood manufacturing practice and totalquality management are intended toensure that these requirements are met ona routine basis.

P.J. Radlett

In a number of countries, generalguidelines for the manufacture ofveterinary products have been in place forsome time. In particular, manufacturewithin the United Kingdom has beensubject to compliance with publishedguidelines (Sharp, 1983; Government of theUnited Kingdom, 1983) and a set ofguidelines for the manufacture ofveterinary immunological products withinthe European Union (EU) has also beenpublished (Commission of the EuropeanCommunities, 1992). These guidelines setout the general requirements for facilitiesand their operation and are based on anappreciation of the problems that can occurin the manufacture of veterinary vaccinesand of how such problems can be avoided.

Although these guidelines are notmandatory in other parts of the world,most of the principles they contain areapplicable to any manufacturing situationand, where they can be effectivelyintegrated into the design and operationof other units, it is frequently advantageousto do so. Incorporation of some specificdesign features at the start of a project maynot be practicable or cost-effective, butcareful design with thought to futurepossible needs when setting down the basicdesign and layout is likely to proveworthwhile and may save expensivemodification work as and when thesefeatures become important.

The following sections describe the mainprincipies governing the general layout oflaboratories, the major factors which needto be considered in their operation and the

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specific needs of particular manufacturingareas.

GENERAL ARRANGEMENT OF BUILDINGS

Buildings should be constructed of good-quality materials, with impervious finisheswhich can be easily cleaned and main-tained and constructed in such a way thatadjacent areas can be effectively sealed andseparated from one another and from theoutside. In today's manufacturingenvironment wood is not regarded as idealand, where used, needs to be thoroughlypainted and regularly maintained.

In many situations it will be necessaryor desirable to hold individual areas underan air-pressure differential, which may benegative or positive to the outside and toadjacent areas. The materials and methodof construction should be such that thiscan be achieved easily.

In the construction and fitting out of allmanufacturing areas, consideration shouldbe given to the avoidance of ledges andcrevices and unnecessary internal pro-trusions such as surface water downpipesor other architectural features. Whereverpossible, windows should be fitted flushto internal wall surfaces and coving usedto create smooth, easily cleaned corners.

Areas where the product or its sterileconstituents are directly exposed duringmanufacture will require greater attentionto these details than those in which theproduct is manipulated within totallyenclosed containers. However, the prin-cipal aim remains to create the cleanestpossible manufacturing environment andone which is easily maintained.

Attention paid to the logistics of productand material flow and staff movementsduring manufacture will ensure thatsequential manipulations may be carriedout in adjacent areas and will promote anefficient flow of materials into and out ofeach area.

To maintain cleanliness and the integrity

of the manufacturing environment,facilities need to be provided for thetransfer of materials into and out ofmanufacturing areas in such a way thatthe environment of the room is protectedand infectious agents (either to bemanufactured or adventitious) arecontained. In general these access pointsshould be separate from those used for theentrance and exit of staff.

Materials, in particular live organisms,that are handled in quality control (QC)laboratories are considered by mostregulatory authorities to present a risk tothe manufacturing operation. Suchlaboratories should therefore be situatedin a building separated from that used formanufacturing. Where this is not practicalor feasible there should be at least a solidwall between the two different activities.Again, care taken at the design stage willensure that features can be accommodatedthat will make possible the smooth flow ofsamples from the manufacturing areas tothe QC laboratory and of the results ofanalyses from QC back to manufacturing.

The sizing of manufacturing facilities isa complicated operation. Areas need to belarge enough for the operations which willbe carried out in them but such facilitiesare expensive and excess space isunnecessarily costly. Conversely, as willbe clear from the above, if logical flowpatterns are to be established andmaintained, the later expansion ofindividual areas may be difficult toachieve. In consequence, it is usuallyprudent to make allowance for any futureexpansion of activities while the project isstill at the design stage.

EQUIPMENT

The detailed equipment requirements fora vaccine manufacturing establishmentwill depend on the scope and capacity ofthe particular unit, but some general pointscan be made.

Many facilities will require stainless steelfermenters, inactivation and blendingvessels which may vary in volume from afew to several thousand litres. Manymanufacturers can provide fermenters andother vessels of satisfactory design but itshould be noted that the control packagewhich accompanies the vessel may bemuch more sophisticated than is actuallyrequired resulting in unnecessary costs.In most of the situations covered by thescope of this manual, process operationswill be essentially hand controlled and,while a degree of automatic environmentalcontrol will be required, it would be wiseto ensure the vessel manufacturer providesonly that which the process needs and notthe ultimate of which it is capable.

At the other end of the spectrum, it issometimes considered appropriate tominimize capital costs by fitting mild steeljackets insulated with cheap lagginginstead of using good-quality stainlesssteel. In many cases this is a false economysince, once installed, such fermenters arefrequently required to function over anindefinite lifespan in a hot humidatmosphere, which soon results indeterioration of the lagging and ultimatelythe jacket. Effecting repairs is then difficult,disruptive and expensive.

Great care needs to be taken at the designstage to ensure that fermentationequipment is installed with due regard toboth process and service flows andparticularly that drainage from both vesseland pipework during steam sterilization iseffective. Open drainage channels in floorsare frequently con sidered undesirablebecause of the resultant contamination riskand the efficient draining of steamcondensate to ensure the sterility ofpipework and vessels is made considerablymore complicated where valves cannotsimply be purged.

In addition to fermentation equipment,the facility will need autoclaves and

sterilizing ovens, designed in such a waythat the minimum requirements forsterilization can easily be met (ParenteralDrug Association, 1978 and 1981), and arange of other equipment such as freeze-driers, filling machines, centrifuges, filtersand antigen concentration equipment.Again, there is a wide range ofsophisticated commercial equipmentavailable from which to choose and it isimportant to balance the right level ofsophistication against the needs of theprocess and the situation in which it isbeing operated. Simple systems arefrequently more labour-intensive but tendto require less maintenance and are easierto put right when they go wrong.

AIR-HANDLING SYSTEMS

Most manufacturing facilities require afairly sophisticated air-handling system.In the interests of the operators, theirefficiency and the product itself, it willbe necessary to maintain equitabletemperature and humidity levels in thefacility. In addition, a principal objectiveshould be to maintain as clean a workingenvironment as possible. This will entailsegregation, both internally and externally,from other areas, which may pose somerisk to the maintenance of a satisfactorymanufacturing environment.

The methods normally employed topromote a clean working environmentinclude the provision of air filtered throughsterilizing high-efficiency particle adsorp-tion (HEPA) filters and the maintenance ofpressure differentials between adjacentareas. In situations where live organismsare handled within the manufacturing areathere will also be a requirement to filterexhaust air. In small installations it ispossible to achieve these requirements withsimple individual "through the wall" fan/filter units. The balancing of such a system,however, can become an extremely com-plex problem, since the pressure drop

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across, and the flow of air through, eachunit may cause detrimental effects on theatmosphere of the next one.

In practice it may prove more satisfactoryto use a separate fan unit to supply eachrelated group of rooms. The same prin-ciples apply to the extraction side of thesystem and great care should be taken toensure that potentially contaminated airextracted from a unit handling liveorganisms cannot be recirculated into cleanproduction areas.

The detailed airflow rates and pressuredifferentials required depend on theparticular functions and layout of thefacility. In general, a minimum pressuredifferential of 1.5 mm water gauge betweenadjacent areas is normally used. Care mustbe taken with the layout to ensure thecumulative effect of this does not result invery large pressures on windows anddoors which connect with or are related tonearby areas. This could cause problemswith the sealing of windows or the openingof doors.

For general manufacturing or enclosedprocessing areas, an air exchange rate ofseven to eight changes per hour is usuallyconsidered adequate, but for sterile areasexchange rates of at least 20 changes perhour are required if the low particle andbacterial counts specified in the Europeanand United States guidelines are to be met.These are undoubtedly necessary to ensurethat satisfactory working conditions aremaintained.

It is important that inlet and outlet ductsare carefully positioned to provide a goodsweeping action in workrooms. Typically,inputs are terminally filtered into the areaat a high level and balanced with low-level extractors on the opposite side of theMOM.

STAFFING

It is essential that any manufacturingfacility should be staffed with personnel

who are of the right calibre and sufficientlytrained to perform the tasks required ofthem. This will almost invariably meanthat a nucleus of qualified and / orexperienced senior staff will need toimplement an ongoing training pro-gramme to ensure that all staff are fullyconversant with the tasks required of them.To make the latter possible all personnelwill benefit from an overview of the entirefacility, its functions and the rationalebehind the operating regimes imple-mented. It must be remembered thattraining will need to cover not only thetechnical methods employed but also thebasis of good manufact-uring procedures,safety and quality assurance in thebroadest sense.

To be confident that live agents andmaterials, including both those used formanufacture and the adventitious agentsthat are inevitably present on the site, donot gain access to manufacturing areasother than those in which they originate, itis good practice, and in many situations amandatory requirement, to restrict the freeaccess of staff to all areas of the site. Acommonly used rule of thumb restrictsoperations to one type of productorganism, per operator, per air space, perday. The restrictions on staff, especiallythe time period, will depend on theparticular manufacturing operation, butsuch restrictions should prevent the directmovement of personnel between QCfacilities and manufacturing areas andbetween manufacturing areas handlinglive organisms and those in whichinactivated antigens or products arehandled.

These restrictions, however desirablefrom the manufacturing standpoint,inevitably tend to create and amplifybarriers to effective communication. Thisplaces an even greater emphasis on theimportance of adequate and continuingstaff training and dialogue among the

various groups on site. It is essential toensure the unit works as one and not as aseries of disparate groups.

WATER

Manufacturing facilities require a reliablesupply of good-quality water for generalpurposes and for direct use in themanufacturing process. Important factorsinfluencing the quality of water are themicrobial content and the total quantityand nature of both organic and inorganicimpurities.

Traditionally, the water used in tissueculture or bacterial fermentation processeshas been produced by distillation, usuallyfollowing a desalting or ion-exchangepurification stage. More recently, excellentresults for both tissue culture and bacterial-based products have been obtained usingwater produced by the method of reverseosmosis instead of distillation. This is anextremely energy-efficient process and,in some situations, plants which haveswitched to reverse osmosis fromdistillation have been known to recovertheir capital costs in a matter of months.

Whatever the method used for themanufacture of pure water, the equipmentused for its production and storage requirecareful management. Bacterial growth instorage tanks and purification columns,whether ion-exchange or reverse osmosis,is a constant hazard and toxins may per-sist even if the live contaminants areeliminated. As yet, the columns availablefor purification stages cannot be steam-sterilized and regular chemical disinfectionmust be carried out. The problem of waterstorage can largely be overcome by heatingthe storage vessel, and preferably thedistribution system, to at least 65°C andmaintaining that temperature until thewater is required for manufacture. Carefulattention needs to be paid to the layout ofthe distribution system itself to avoid"dead ends", poorly designed valves and

other points at which water may remainstagnant.

Whatever process and procedures areadopted, the quality of both "feed" andpurified water will require regularmonitoring and equipment will requireregular sterilization or sanitization.

LIQUID EFFLUENT

Manufacturing facilities almost inevitablyproduce large amounts of liquid effluentwhich need to be discarded in a safe andsatisfactory manner. The appropriatenecessary procedures depend on localregulations and the nature of the agentshandled in the facility but should take intoaccount the possible presence of liveagents, their inactivation and the chemicalcontent of the material to be discarded.

Total segregation of live from non-infective areas within the facility willminimize the volume of the more difficultmaterials that arise from the former areas.

Small quantities of liquid effluent cannormally be rendered innocuous byautoclaving, but larger quantities requirea dedicated collection and treatmentfacility. Heat treatment of contaminatedeffluent is commonly practised, either as abatch or a continuous process. Care needsto be taken to ensure that there is sufficientstorage capacity for untreated material,both to balance the throughput of thesterilizer and to provide storage duringequipment failures and accidents withinthe facility.

WASTE DISPOSAL

If the risks of environmental contaminationand cross-contamination are to be avoided,solid wastes arising from areas handlinglive agents require decontamination priorto removal from the area in which theywere generated. This can be accomplishedeither by fumigation (e.g. withformaldehyde) or heat-sterilization (e.g.autoclaving). This in turn requires the

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provision of suitable facilities for theseactivities at, or close to, the perimeter ofthe area in which the agent is handled.With careful design one sterilization/fumigation facility can serve more thanone area and, depending on the natureof the agent handled, an acceptablecompromise can sometimes be found bysurface decontamination of materials at thetime of removal from the infected area andsubsequent sterilization in an adjacentfacility. It should be pointed out, however,that suitable sterilization/ fumigationfacilities are frequently required for thetransfer of materials into manufacturingareas and, where this is so, the samefacilities can serve for the removal of wastematerials.

Waste materials should not be allowedto accumulate ort the site or to becomedispersed around the site. Theidentification of a single deposition pointat the perimeter of the site, combined withregular collections by the appropriatewaste disposal authority, should serve tominimize problems with solid waste.

MANUFACTURING MATERIALS

If a high degree of assurance is to beobtained in relation to the quality ofroutinely manufactured products, it isimportant that all materials used formanufacture are of a suitable quality.This does not necessarily require theimportation of expensive high-puritycomponents, provided a reliable source ofsatisfactory materials can be found locally.

Where a pharmacopoeial standard fora particular component exists, there isfrequently a requirement to meet it andthis can be accomplished either bypurchasing ready tested material or byarranging for the appropriate tests to becarried out. Where there is no requirementto meet a pharmacopoeial standard themanufacturer needs assurance that thesupplier can routinely supply material

which will result in the production of asatisfactory product. Such assurance needsto take into account both the satisfactoryyield and the efficacy of the final productand its safety.

In many cases it is advisable to set uproutine tests on batches of raw materialsprior to their use for manufacturingoperations. It could also be important inthe subsequent investigation of productiontrends and in solving the inevitableproduction problems, which arise fromtime to time in all biological manufacturingoperations, that the individual batches ofraw materials used for each operation canbe traced. It is therefore advisable to batch-label each consignment of raw materialson arrival, to introduce some formal QCrelease procedure to confirm that thematerials are considered acceptable foruse and to record the batch identificationas materials are used, thus ensuringtraceability throughout the productionprocess.

SEED PRODUCTION AND STORAGE

Under most circumstances the productionof seeds, including both the live agent and,where appropriate, the substrate on whichit is to be grown, will require the provisionof facilities for the handling of relativelysmall amounts of materials underconditions in which these materials are atsome stage exposed to the air in theworkroom or cubicle. This will necessitateclose attention to the quality of the air andthe maintenance of clean conditions in theroom itself.

Manufacturing operations in which liveagents are handled under conditions inwhich sterile materials are exposed, albeittransiently, to the environment, representone of the most difficult challenges in thedesign of facilities which satisfy all aspectsof modern manufacturing requirements.The principles described here for seedproduction can be modified and extended

for other aspects of the manufacturingoperation and will be cross-referenced inother sections of this chapter.

The European guidelines (Commissionof the European Communities, 1992)recommend that sterile operations of thetype described here are carried out in alaminar airflow cabinet (meeting theguidelines' Grade A classification) whichhas been installed in a "clean" room(meeting the guidelines' Grade Bstandard). Such a facility would require asupply of HEPA-filtered air, at a rate thatprovides at least 20 changes per hour tothe room itself, and a similarly filteredextractor system. A full garment changefacility for operators would also berequired. This too, would need its ownsupply and extractor of HEPA-filtered airproviding the same level of air replacementas for the laboratory. A pressuredifferential of at least 1.5 mm water gaugeshould be maintained between thechanging room and the laboratory. Thelaboratory will also need some form oftransfer lock, preferably capable offumigation, for the movement of materialsinto and out of the seed production facility.

With the introduction of appropriatequality assurance procedures and asuitable arrangement of pressure differ-entials between corridors, anterooms,changing rooms and laboratories, such afacility provides an effective barrier againstthe ingress of contamination from externalsources (including the environment, theoperators and materials brought into theunit) and an effective barrier ensuringcontainment of the live organisms handledwithin the facility. A convenient way ofachieving this is to hold the workroomunder negative pressure, make thechanging room more strongly negative andprovide an anteroom at a positive pressure.In this way the changing room acts as aplenum or "sink" and provides a barrieragainst air movements from either side.

Recently, totally enclosed isolation unitshave been developed, in which operatorswork through glove ports. The units arefitted with "pass-through" hatches, whichcan be fumigated, and sometimes eveninclude environmental control facilities.Such units, although expensive, can behighly effective, enabling differentorganisms and/ or operations to behandled in adjacent units withoutcompromising either the environment orthe operator.

A "master" seed bank should beestablished, based on an isolate of thematerial from which the vaccine is to beprepared and, in the case of viral vaccines,the substrate (or cell line) on which theagent is to be cultivated. The manufacturerwill need to be assured that these materialsare free from all adventitious agents whichmight cause contamination losses in themanufacturing process or untowardeffects, or even disease, in animals onwhich the vaccine is subsequently used oron others which are in contact with suchvaccinated animals.

In addition to an assurance of the purityof the material, the manufacturer alsoneeds to be assured that the seed materialwill routinely produce high, and thereforeeconomically acceptable, yields in theproduction system and that it produces asafe, reliable and effective end product.Examples of these requirements can befound in the series of documents issuedby the European Union's EuropeanCommittee for Veterinary MedicinalProducts (EC, n.d.a and n.d.b).

Aliquots of suitable material need to bestored for long periods under conditionsappropriate for the particular entity.Depending on the organism, storage overliquid nitrogen, storage at -70°C, freeze-drying or, occasionally, storage atcool-room temperatures may all beappropriate. The essential requirements arethat the organism should not lose titre or

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undergo any change in its characteristicswhile in storage for long periods. Fromthis material it is customary to set up oneor a number of working seed banks, whichcan be stored under similar conditions tothe master bank and used to initiate eachproduction cycle or series of cycles. Bycareful use of the seed banks in this waythe original master bank becomes almostimmortal and can be used to supportproduction over long periods without theserial passaging of the organism to a levelwhere the characteristics of the seedmaterial itself might become modified.

MEDIA PRODUCTION

The media used for the cultivation of theagents under manufacture can bepurchased ready prepared or as sterileconcentrates from reliable sources. Theycan also be prepared on-site from com-ponent materials. In most casesconsiderations of cost and the volumesrequired dictate that media are producedon-site.

By their very nature, the componentsand media used for manufacture usuallytend to encourage the growth of adventit-ious contaminants, and care needs to betaken to ensure the components themselvesand the facilities in which they are pre-pared are as free from such contaminantsas possible. It is usual to provide adedicated media production facility, closeto but separated from other manufacturingareas on the site. This unit should be wellordered, free from materials not immedi-ately required for the process and amenableto routine and methodical cleaning. It maybe considered appropriate to provide aworking environment of HEPA-filteredair and it is preferable that staff working inthe area should not enter other manu-facturing areas on the same day.

The components used for mediaproduction should meet the generalrequirements outlined in the section

Manufacturing materials (p. 176) andparticular care should be taken overmaterials of biological origin which forman essential part of many culture media. Insome countries there are specific regulatoryrequirements governing the use and testingof such materials (Medicines ControlAgency, n.d.). These are intended to ensurethat no disease-causing agent is introducedto the manufacturing process and, as aminimum, the manufacturer needs to besure that the animals from which thematerials, for example serum, wereobtained, were healthy and from a disease-free herd and that the method of collectionand processing was unlikely to haveadversely affected the quality of suchmaterials.

Depending on the nature of the manu-facturing process, once prepared, themedium may be sterilized and put intostorage containers or vice versa.Alternatively, the medium may betransferred directly into the productionvessel before or after the sterilization cycle.The dispensing of sterilized media intomultiple storage containers may requiresterile handling facilities similar to thosedescribed in the section Seed productionand storage (p. 176).

ANTIGEN PRODUCTION

The facilities required for antigenproduction will depend on the nature ofthe organisms from which the vaccine is tobe prepared, the manufacturing methodsto be employed and the proposed scale ofthe operation. Manipulations in whichsterile materials are effectively exposed tothe operator and / or the local environmentduring manufacture will require facilitiesthat are essentially similar to, but obviouslymay need to be larger than, those describedfor the production of seed materials. Incases where the utilization of facilities (andtherefore volume throughput) is low, thesame unit may be used for both functions,

with the provision of suitable safeguardsbetween operations.

Where all operations are carried outwithin totally enclosed vessels, pumps,pipework, etc. the inside of the equipmentmay be considered as the manufacturingenvironment and a somewhat less rigor-ous environment is usually consideredacceptable for the location of themanufacturing equipment. Nevertheless,it is important to pay attention to the designand operation of these areas in order tominimize the likelihood of adventitiouscontamination arising or persisting withinthem. Important features to consider willbe: easily cleaned surface finishes,drainage, the ventilation system, the meansby which materials enter and leave thearea and operator access.

Where practicable it is desirable toprovide enclosed processing areas with asupply of HEPA-filtered air and for antigenproduction (where by definition live agentsare handled) it will be preferable to holdthese areas at a pressure negative to thesurrounding areas. As described for seedproduction areas, the careful planning oflayouts and pressure differentials can beused to create a situation in which the workarea is protected from possible externaladventitious contamination, and yet thereis still a containment barrier at the point ofentry through the changing room.

To provide safeguards during enclosedmanufacturing operations for the integrityof both the contents of the vessels andequipment and of the environment in theroom, consideration should be given tothe means by which samples are taken,and additions made, during processing.

Most equipment used for large-scalemanufacturing operations can and shouldbe sterilized in situ with steam. Equipmentwhich cannot be steam-sterilized presentsa more difficult problem, and care shouldbe taken to ensure any procedures usedfor chemical sterilization are validated

under the actual conditions of the opera-tion beforehand. Assuming that facilitiesare available for the in situ steam-sterilization of major equipment, it shouldbe a relatively simple matter to ensure thatthe cormections used for sampling, addi-tions and vessel-to-vessel transfers are alsosteam-sterilized in situ before and aftereffecting transfers.

Where some items of equipment mustbe chemically sterilized it is preferable toarrange the plant in such a way that asmuch of the equipment, pipework andvalves as possible is steam-sterilized andreliance is placed on chemical sterilizationonly for the essential components thatcannot be subjected to steam underpressure.

ANTIGEN INACTIVATION

Unless the vaccine undergoing manu-facture is a live attenuated one, the nextstage in vaccine preparation is inactivationof the antigen. The major dilemma in thisprocedure from the viewpoint of facilitydesign and operational convenience isthat the process, by definition, starts withlive material and after the commencementof its inactivation every effort should bemade to ensure there is no possibility ofits being contaminated with other livematerial.

These constraints have implications forboth the inactivation vessel and theworkroom itself. To overcome the possiblerisk of droplets from within the inactiva-tion vessel (which may not have come incontact with the inactivant) reinfecting thevessel contents, it is considered goodpractice to transfer the mixture of liveantigen and inactivant to another sterilevessel after a period of mixing. Theseprocedures are usually carried out in thearea in which the antigen was producedand the closed vessel containing theinactivating material is either isolatedwithin the facility or transferred to a

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separate holding room while the inactiva-tion process is completed. During thisprocess it is often found preferable not tosample or open the vessel for any reason.Conversely, there is a good argument formonitoring the progress of each inactiva-tion cycle, and this can only be done bysampling. The most appropriate approachin each situation may well depend on theregulatory environment or pharmaco-poeial requirement for the product inquestion. In either case, it would beprudent to introduce some form of formalquality assurance clearance procedurebefore material that has completed theinactivation cycle is transferred for down-stream processing or vaccine blending.

DOWNSTREAM PROCESSING

The requirements for any downstreamprocessing depend on whether the productis live or inactivated and on the needs ofthe manufacturing process itself. Whileinactivated, innocuity tested antigens ofdifferent types may, with reasonablesafeguards, be handled in the same area, aseparate area will be needed for liveantigens. Different live organisms canusually be handled in the same areaproviding it can be cleared, cleaned andfumigated between successive productioncycles. If production throughput is high,however, it may be preferable to haveseparate areas for different products.

The most common type of downstreamprocessing operation is probably con-centration of the antigen, but othernecessary procedures may include variouspurification or separation stages. Whereverpossible it is preferable to carry outdownstream processing of inactivatedproducts after the inactivation stage hasbeen completed in order to avoid thecomplication of handling the live material.Such processing should, whereverpossible, be carried out in a separate areato that in which the live material was

produced. Where this is not practicable,further innocuity tests should be carriedout on the completion of operations andmaterial should not be passed on forblending until satisfactory results areobtained from these tests.

As emphasized previously, the work-rooms in which inactivated antigens arehandled should be free from other liveorganisms and preferably held under apositive overpressure of HEPA-filtered air.If the manufacturing operation necessitatestransient exposure of the product to theatmosphere of the room, the room shouldmeet the standards defined for seedproduction but at positive pressure inrelation to its surroundings. Enclosedprocessing operations may be carried outin a less rigorous environment, but apositive pressure of HEPA-filtered air isdesirable. The same considerations relatingto cleanliness, material and operator accesswill apply as were indicated in the sectionAntigen production (p. 178).

Where live attenuated vaccines areproduced, the manufacturing area shouldbe held under negative air pressure andoperations may be carried out effectivelyin areas similar to those described for seedand antigen production.

The equipment required for downstreamprocessing should preferably be sterilizedin situ by steam under pressure but, wherethis is not possible, chemical sterilizationusing a fully validated process is likely toprove satisfactory. The remarks relating tochemical sterilization in the antigenproduction area also apply to this situation.

Whether or not separate rooms will berequired for the downstream processingstages of manufacture depends on thenature and complexity of these operationsin relation to other activities. In manysituations, however, it will be appropriateand sufficient to perform these stages in apart of the room used for blending thevaccine.

VACCINE BLENDING

Vaccine blending is usually a mixingoperation based on the combination of oneor more antigens each of which has beenshown to conform to the manufacturer'squality requirements together with theother components of the vaccine, such asadjuvant, preservative and frequently adiluent.

The mixing operation may be simple ormay involve the use of specialized mixingequipment, as for example in the prepara-tion of oil-emulsion vaccines. Antigens forblending have a high financial valueresulting from the materials and labourwhich have been expended in theirpreparation and testing. It is therefore ofparticular importance that all the othercomponents used, including both addition-al antigens and the blending materials, areof suitable quality and integrity and willresult in the production of a satisfactory,sterile, safe and effective vaccine.

The blending of vaccine will usuallyrequire the same type of facilities as arerequired for any of the downstreamprocessing stages and, as indicatedpreviously, it is frequently appropriate tocarry out both activities in the same areaand in some cases even to use the sameequipment.

VACCINE FILLING

At each successive manufacturing stagethe investment in labour and materialsincreases and the manufacturer shouldintroduce safeguards to ensure that onlysatisfactory materials are passed on for thenext stage. This is certainly true for thefilling operation, where the inconvenienceand loss associated with discarding finalfilled product is considerable.

Filling operations almost inevitablyexpose the final product to the atmosphereat the actual dispensing point, so theseoperations are best carried out under alaminar curtain of HEPA-filtered air within

a sterile room. Because of the large volumeand number of containers involved inmost filling operations, sterile rooms ofconsiderable size are frequently required.As has been described elsewhere in thischapter, the facility will need its own sterilechanging rooms, a satisfactory means ofgetting sterile materials (including finalcontainers and product) into the room anda means of moving the filled containersout of the room all without harmingthe filling operation itself. The basicrequirements of the filling room will besimilar to those described in the precedingsections for rooms in which sterile productis transiently exposed to the atmosphere.The air pressure within the room shouldbe either positive or negative relative tothe surrounding area, depending onwhether the facility is for a live orinactivated product.

Final vaccine containers which can beheat-sterilized are best introduced directlyinto the filling room by means of asterilization cycle through a double-ended"pass-through" sterilizer Other types offinal container, such as those sterilized byradiation, should be sterilized double-wrapped and in such a way that the outerpackaging can be removed outside thefilling room and the inner wrappingsurface decontaminated or fumigated in atransfer lock prior to being introduced intothe filling room proper.

Removal of filled containers can be doneeither on a batch basis at the conclusionof filling operations or continuouslythroughout the process. For large batchesthe latter tends to be preferable and this isfrequently accomplished by means of aconveyor belt. The belt should not emergedirectly from the sterile room and subse-quently re-enter it.

In the case of live filled products, manywill require a freeze-drying stage after thefilling operation. It will be very convenientif the freeze-drier can be loaded directly

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182 General design and operating requirements for vaccine manufacturing establishments

from the filling area. If the freeze-drier isdouble-ended the product may then betransferred for storage without re-enteringthe filling area. For single door machines,however, it will be necessary to pass thevials back into the filling facility whenunloading the machine. This tends toreduce the flexibility of the filling unitwhich could otherwise be decontaminatedand set up for processing the next batch(which could involve a different antigen).

In all cases where live products arehandled it should be remembered that thefilled containers may be contaminated onthe outside and some form of surfacedecontamination will need to be con-sidered once the final container seals havebeen applied.

QUALITY ASSURANCE

For the purposes of this chapter, qualityassurance will be taken to encompassthe elements of quality control (QC),environmental monitoring, validation anddocumentation leading to batch release.Each manufacturing site will require theservices of a QC unit, which shouldpreferably be located in a different buildingto that of the production facilities. It ishighly convenient if the QC unit is situatedon the manufacturing site, but specializedtests, especially those requiring sophisti-cated equipment, may have to be carriedout by external organizations or units.

QC facilities on a manufacturing siteshould be operated in such a manner thatthe risk of agents being transmitted fromthe QC unit to the production facilities isminimized. This may be effected by meansof the HEPA filtration of extract air frointhe QC unit together with restrictions onthe movement of personnel and materials.Movement of samples and documentationbetween units may give rise to particularproblems, but arrangements which permitsafe and effective transfer of materials fortest and the two-way transmission of

appropriate documentation are notdifficult to establish.

It will be important to distinguishbetween those test procedures that relatedirectly to the quality of the manufacturedproduct (for which there should be clearlydefined acceptance criteria) and those thatcontribute towards an overall under-standing of the manufacturing process. Thelatter, when considered individually,would not normally be used to condemn aproduction batch.

Apart from both quality control and in-process tests on materials and productduring the manufacturing process, theproducer should also continuouslymonitor the manufacturing environment,in terms of both its physical and biologicalperformances. In this way potentialproblems can be identified before theybecome critical and corrective action maybe taken before production losses areexperienced.

The range of environmental monitoringthat might be considered is too broad tolist here in detail, but it should cover atleast all of the following: environmentalbacterial levels in both sterile and generalmanufacturing areas; the quality of processfluids (particularly water); airflow pressuredifferentials and filter integrity; andequipment performance (particularly ofsterilizers). To establish that processequipment and operating procedures arecapable of performing the tasks requiredof them on a routine basis and under theconditions of normal use, it is necessary tohave them validated. This is usually carriedout as part of the initial commissioningprocess and, although time-consuming,thorough testing of each stage of theprocess at the outset can save major losseslater on. Furthermore, the regular revalida-tion of equipment will not only increaseconfidence in the operation but help toidentify problem areas before they becomecritical.

All of the above procedures should beformally documented and the docu-mentation rnade available for review, sothat in considering either the factorymanufacturing record or the production ofan individual batch the results ofmandatory QC tests, in-process controltests, environmental and validation studiescan all be taken into account. In this iAray,the manufacturer can have a far greaterdegree of confidence in the products thanwould otherwise be possible from theresults of statutory QC tests alone and,when difficulties occur, the possible causescan more easily be identified andeliminated.

CONCLUSIONS

Careful adherence to the principles of goodfacility design and manufacturing practiceshould help to ensure that productionplants function at a high level of efficiencyand that losses are a rare event. Althoughthere is undoubtedly an element ofadditional expenditure related to the issuesraised here, much can be done withoutsignificantly increasing installation costs.Where additional expenditure is involved,the analysis should take into account thesavings associated with greater productionefficiency and reduced losses and alsothe greater confidence in the productof customers and the relevant controlauthorities.

In a similar way, attention should bepaid to quality throughout the manu-facturing operation and every effort shouldbe rnade to build quality into the product,rather than relying on testing for it.

With the appropriate design of facilities,high levels of productivity can be achievedand in-process losses can be minimized.There will also be a high degree ofprobability that the filled vaccine will passall required final product tests and performin a safe and effective manner when usedin the field.

BIBLIOGRAPHY

Commission of the European Communities.1992. The rules governing medicinal products

in the European Community, Vol. IV, Goodmanufacturing practice for medicinalproducts. Directorate General forInternational Market and IndustrialAffairs.

EC. (n.d.a) General requirements for theproduction and control of live mammalianbacterial and viral vaccines for veterinaryuse. Committee for Veterinary MedicinalProducts of the European Community.

EC. (n.d.b) General requirements for theproduction and control of inactivatedmammalian bacterial and viral vaccines forveterinary use. Committee for VeterinaryMedicinal Products of the EuropeanCommunity.

Government of the United Kingdom. 1983.Compendium of guidelines on the qualitycontrol of veterinary immunologicalproducts. Weybridge, UK, BiologicalProducts and Standards Department,Central Veterinary Laboratory, Ministryof Agriculture, Fisheries and Food.

Medicines Control Agency. (n.d.) Use ofsubstances of animal origin in themanufacture of veterinary vaccines.Document MAL 67. London.

Parenteral Drug Association. 1978. Validationof steam sterilization cycles. TechnicalMonograph No. 1, Philadelphia, Pa.,USA.

Parenteral Drug Association. 1981. Validationof dry heat processes used for sterilizationand depyrogenization. Technical Mono-graph No. 3, Philadelphia, Pa., USA.

Sharp, J.R. 1983. Guide to good pharmaceuticalmanufacturing practice. London, HerMajesty's Stationery Office.

Vaccine manual 183

sign, irepcii L

anufacturingGCIU

DESIGN

During the initial stage of designing avaccine manufacturing establishment(VME) the following factors must be takeninto consideration:

national and international legalrequirements;site location;general building layout;utilities and services;building construction and finishes;processes;equipment;maintenance and repair of premises,plant and equipment;maintenance records.

NATIONAL AND INTERNATIONAL LEGAL

REQUIREMENTS

A VME is obliged to comply with legalrequirements which may not be the samein every country. Taking the most stringentfrom different countries and compilingthem in a theoretical international standardrequirements for VMEs gives someindication of the most severe conditionswhich a VME would have to comply with.

The first question to be asked is whetherthe VME is to supply the national orinternational market. The costs ofconstruction, equipment and the manu-facturing process will depend on this.

SITE LOCATION

When planning and siting a VME thefollowing points need to be considered:

aintenahc( of vacci etCbNjshi1cflts and

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altitude, accessibility, terrain, neighbours,climate, security, noise, future devel-opments, pollution and local regulations.

AltitudeAltitude affects the efficiency of, forexample, internal combustion engines,standby electricity generator sets andtractors. It also affects the boiling point ofwater in steam boilers, etc. Engines andboilers are normally rated at sea level,therefore it is important to know whatefficiency is to be expected at differentaltitudes and, when commissioning suchplants, this factor has to be considered.

Terrain

VMEs should be sited in areas that are freefrom flooding and easily accessible. Theground has to be such that the foundationsof the building are on a sound solid surface.It should also be in an area where suchservices as drainage and sewage disposalare accessible and, in cases where thesehave to be discharged into the ground, theground should be such that it can accept orabsorb the effluent so disposed of.

ClimateWeather conditions influence several of therequirements to be considered in thedesign, with regard to the construction anduse of the premises. Hot and dry weatherimplies that the VME has to have air-conditioning and air filters will probablybe required where dust is a constant

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186 Design, repair and maintenance of vaccine manufacturing establishments and equipment

problem. With hot, wet weather, increaseddrying capacity will be necessary, par-ticularly for air under pressure, and aspecific type of roof and windows will haveto be used.

Noise

If the VME is adjacent to such high-noiseareas as major motorways, industrialsites or airports the noise level couldaffect the working atmosphere within thelaboratory.

PollutionThe VME should be protected from theenvironment and the environment fromthe VME. It should be sited where there isno pollution from the surrounding area,but as this can never be guaranteedcompletely, means for water and airfiltration/purification should be installed,to ensure their appropriate quality forindustrial use, otherwise contaminationproblems may arise.

The VME itself must be designed so asto ensure that no gaseous, liquid or solidwaste disposal contaminates the soil, waterstreams or atmosphere. A VME can causeaerial pollution by oil-fired boilers andincinerators, if these are not wellmaintained.

The health and safety of personnel canalso be a problem unless buildings andequipment are designed to protect boththe workers and the products and are wellmaintained to ensure that they perform tothe required standards.

Local regulationsEach country has its own regulations onthe construction of buildings. Theserequirements must conform to thepublished regulations pertaining to issuessuch as sewage and effluent discharge, thedrilling of water boreholes and wells andthe standard of electric installations in theestablishment.

AccessibilityThe site should be accessible by road andshould be such that strict entry restrictionscan be enforced.

NeighboursThe establishment should be located on asite where public buildings such ashospitals, farms (especially those withlivestock) and factories which could causepollution are at some distance. This is notalways possible so, as noted before, thedesign should have provision for theinstallation of purification systems for airand water supplies if needed.

Security

The VME should guarantee that no diseaseoutbreak will occur as a result of itsmanufacturing activities. This means theprovision of adequate installations, strictadherence to good manufacturing practices(GMPs), an adequate security system forthe entry and exit of personnel, staff,visitors and contractors and a goodperimeter fence.

Future developmentsThe site should be so designed that there isroom for future expansions. Buildingsshould be arranged so that central servicessuch as electricity and steam generatingplant and administration blocks will notbe affected during future expansions.

GENERAL BUILDING LAYOUT

Consideration has first to be given to therequirements of the different areas of aVME.

General areas are those where there isno reciprocal threat between product andenvironment and no special requirementsother than order, cleanliness (standardGMPs) and possible temperature condition-ing for personnel comfort or productconservation. These are: administrationoffices, general stores, material washing and

preparation areas and areas for labelling,packing, storage and dispatch of the finalproducts.

Restricted areas are those where livepathogens are handled and may impose athreat to the environment. These are:laboratories where field samples arehandled, areas where seeds are prepared,areas where large-scale production takesplace, areas where live vaccines are freeze-dried and areas where challenge tests takeplace.

In all these areas, air, liquid and solideffluents must be decontaminated andpersonnel leaving the area must, at least,change their clothes. Depending on thepathogen handled, showering may also berequired. Access should be strictlyrestricted to those working in the area.

Air pressure should be negative to theambient by air extraction through absolute,high-efficiency particle adsorption (HEPA)filters. When live pathogens are handledin open processes (e.g. freeze-drying),provisions for the supply of sterile air tothe area, together with the use of safetycabinets to protect the personnel and theproduct are important. Liquids and solidsmust go through chemical and/ or physicaldecontamination processes to avoidcontamination of the environment beforedisposal.

Clean areas where the product must beprotected from the environment include:media production, inactivated antigenprocess and storage, inactivated vaccineblending and inactivated vaccine fillingareas. The air pressure in these areasshould be positive with respect to ambientand, where sterile products are handled inopen processes (e.g. sterile fillin.g), sterileambient conditions should be provided.

During the initial stages of designing aVME, the following are some of the manyfactors that should be considered:

o what vaccines are required to beproduced;

what types of laboratories are required;0 what types of animal isolation unitsare required;

o what equipment is required for eachspecific task;

o how many people are required;o what recreational facilities arerequired;are some of the employees to beaccommodated on-site;

o what services are required in thewhole establishment or in specificlaboratories;

o how effluents are to be treated anddischarged;

o what storage facilities are required.Once agreement on these points has been

established, those concerned with thedesign should go through every detail andconsult those who are to use the facilities,so that at this initial stage nothing isomitted.

Owing to the lack of such coordination,some establishments have had problemsmodifying their original plans and in manycases this has resulted in more moneyhaving to be spent.

UTILITIES AND SERVICES

Essential services are understood to be:water, furnace oils, electric power,automotive fuels, air, communications,gases, effluent treatment and steam.

WaterThere should be an adequate source ofwater for the establishment to runsmoothly. In laboratories two types ofwater are normally used: mains water (forcooling and heating) and purified water.

The quality of mains water is veryimportant as this will dictate the cost ofrunning steam boilers and waterdistillation plant. Where mains water issoft, say up to 23 parts per million (ppm)of hardness, scaling becomes only a minorproblem and the chemicals required to

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188 Desikn, repair and maintenance of vaccine manufacturing establishments and equipment

descale the boilers and water stills are notexpensive. Where water is available froma borehole, it is usually hard. Treatment isexpensive when a water-softening plantbecomes necessary.

Adequate water storage is also veryimportant. Ideally the VME would havean elevated water reservoir from whichwater will flow under gravity to all waterpoints in the establishment. The reservoirshould be accessible for regular cleaning.It should also be noted that it is importantto check the quality of water and, ifnecessary, the water in the reservoir shouldbe treated according to normal healthrequirements.

Mains water must be free of pathogens,pesticides and heavy metals since traces ofany of these coming into contact withproduction material and equipment maylead to altered production conditions.

Cooling or heating water is used for culturevessels, process equipment or ambienttemperature conditioning. It must becontrolled to ensure that it will not imposea threat of chemical or biological con-tamination to the production process.

Purified water is obtained by de-mineralization followed by distillation orreverse osmosis. It should be sterilized andkept sterile or in such conditions (80°C)that will prevent the growth of conta-minating organisms. It should be pyrogenfree.

Electric powerIn many developing countries the electricpower supply is not reliable. There arepermanent and serious electrical fluctua-tions which harm electrical equipmentinstalled in the establishment. It is advisa-ble to install voltage stabilizers to preventthe malfunctioning of sensitive electricaland electronic equipment, such as controlpanels and centrifuges, and also a powerfactor correction facility at the main powerdistribution point, as this will reduce

electricity consumption and protectelectrical equipment such as motors.

An electricity standby generator plantshould be considered as a standard pieceof equipment. To determine the size of thestandby generator the following factorsshould be taken into consideration:

the total electrical load installed;the type of fuel used in the generatorengine;

e the essential electrical power demandin the VME, as this will indicate theminimum size of the generating plant;future load expansion.

The generating plant must be able tostart up automatically under any of thefollowing situations:

there is no power from the mainsupply;phase failure;short circuit;

e low voltage.

AIR

A VME needs various ventilation systems.An adequate rate of ventilation is essentialto protect the plant personnel and theproduct from solvents or fermentationgases and from particulate or biologicalcontamination. Up to 20 air changes perhour may be required to maintain properprocess conditions, under a positive ornegative pressure differential with respectto ambient.

It may be necessary to sterilize the airsupplied and / or extracted from aparticular area or to heat, cool or dry thisair, in which case energy will be saved byrecycling it as much as possible. Specificexhaust systems may be necessary toremove dangerous gases (toxic, flammable,etc.) to prevent them from diffusing intothe working space.

Gases

Generally, the gases used in vaccinemanufacturing establishments include: air

under pressure, carbon dioxide, liquidnitrogen, methane, oxygen, acetylene andrefrigeration gases such as R12, R22 andR502.

The availability of these gases is im-portant because the operations of theestablishment can be seriously handi-capped if they are in short supply.

Air under pressure must be obtainedfrom a clean source, should be filtered andshould be dried before and after thecompression process. This will prevent rustformation and the blockage or damage ofprefilters and sterilizing filters by con-densates or particles of rust scale. Most othergases will probably be obtained fromspecialized suppliers according to spec-ifications.

It is important to note that severalrefrigeration gases are being phased outbecause of the harm they cause to the ozonelayer of the earth's atmosphere. Whenchoosing refrigeration equipment, thispoint should be considered and newtechnologies in this area should befavoured in spite of their probable initialhigher costs.

Steam

In a VME, steam is used in small amountsfor heating purposes in stills, temperatureconditioners for ambient air and infermenters, and in large amounts forsterilizing purposes in autoclaves, sterilelines, fermenters, process equipment andvaccine blending and filling vessels.

Generally, saturated steam is used,overpressurized at 6 to 10 kg / cm' in thegenerator and reduced to working pressureat the points of use. Steam can be producedfrom individual electrically heated boilersor from a central fuel-fired steamgeneration plant.

The availability of electricity and oil fuelvaries from country to country but, ingeneral, fuel-fired steam generators arecheaper to run than electrical ones. The

steam supplied to steam receivers shouldbe clean (free of undesirable chemicals"dragged" from the boiler) and filteredthrough 0.1-micron sintered 316 gradestainless steel filters. The pipework has tobe of non-corrosive material, ideally 316grade stainless steel. Safety devices shouldbe fitted on the receivers. Condensate fromsteam lines should be returned to the boilerwater feed tank. Steam and condensatepipelines should be lagged (insulated). Ifthe steam is obtained from tap or industrialwater, great attention must be given toimpurities in the water and addedsofteners. "Dragging" of water from theboiler is possible on occasions of suddenhigh peak demand of steam but standardprocedures should minimize these peakdemands, as they will also condition thesize of the boiler. The use of clean steamobtained from purified water is mostadvisable, but its high investment cost maynot be compensated by the possibleimprovement of performance of theprocess.

It is also advisable to maintain steampressure in the system for 24 hours a day.Vibrations provoked by the steam"hammering", which occurs when steamlines are warming up, impose a great stresson the integrity of'sterile process lines andequipment.

Furnace oils

Where used the reliability of supply shouldbe considered.

Automotive fuelThis commodity is nearly always availablein developing countries but at high cost.Automotive fuel is normally used onelectricity standby generating sets andvehicles.

CommunicationsGood communications are essential for theeffective operation of any enterprise.

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eo Design, repair and maintenance of vaccine manufacturing establishments and equipment

Effluent treatmentWhere disease security has to be controlled,the treatment of gaseous, liquid and solideffluents must be considered. Laboratoriesand animal isolation units working withhigh-risk pathogens (e.g. foot-and-mouthdisease or anthrax vaccine) should have:

° c o nt i nu ou s air extraction throughabsolute filters to maintain negativepressure with respect to ambient at alltimes, thus preventing the escape ofcontaminated air from the unit throughpersonnel or materials entry and exitpathways;

0 discharge of liquid effluents chemicallytreated in a confined secure area, underan absolute air extraction system (thepH of the effluent is increased to 11.5[0.25 percent free alkali] by the additionof concentrated sodium hydroxidesolution, and maintained at this levelfor at least 24 hours before neutraliza-tion and discharge into the normalsewage treatment) or heat-treated in apressure vessel located below groundlevel (so that the effluent can flow intoit by gravity). The heat treatment of theeffluent should be carried out underpressure, preferably by direct injectionof steam or by electric heaters. Thetemperature has to be held at 121°C forabout two hours, depending to someextent on the volume to be treated. Thetreated effluent may be discharged intothe main city drainage / sewage systemor, in areas where this is not available,into soak pits.all solid materials (glassware, paper,empty containers, tools, spares, theexterior of containers of inactivatedantigen, etc.) decontaminated by oneof the following means: autoclaving(heating up to 121°C for 30 minutes),hypochlorite, mild acid or strong alkalisoaking treatment and / or form-aldehyde fumigation before leaving therestricted area.

UILDING CONSTRUCTION AND FINISHES

The building construction and finishesshould ensure protection of the vaccineduring manufacture from contaminationand should permit efficient cleaning andavoid the accumulation of dust and dirt.

The construction design must be such asto prevent the entry or harbouring ofinsects, birds or rodents. Surfaces shouldbe smooth, robust, non-porous, easy toclean and easy to maintain. They shouldbe free from cracks, crevices and ledges.

The finishes of walls, floors, ceilings anddoors should be of good quality and shouldnot allow the accumulation of particulatematter. There should not be recesses thatcannot be cleaned.

Where floors may come in contact withchemicals such as diluted acid or alkalisolutions, the floor must be protected withchemical-resistant covering. This is veryimportant since, if it is not done in time,serious damage can be caused to the floorand consequently to the foundation of thebuilding. Expansion joints and cracksshould be sealed with a suitable resilientcompound.

There have been major problems withleaking roofs in many VMEs. Most flatroofs leak and in countries where rainfallis high and climatic changes are significantit is suggested that pitched roofs are usedrather than roof slabs. Sometimes flat roofsare necessary where specific equipment forsupply services to the establishment has tobe mounted. If this is the case, properdesign should be made to cover the roof asmuch as possible.

The ceilings in the building should beconstructed and finished so that they aresolid, capable of being completely sealedand easy to clean. Doors and windowsshould have a smooth impervious finishand should close tightly. Where theproduction room is under a controlledenvironment, the windows should be fixedand the doors should have seals. If the

building is maintained under controlledenvironmental conditions, say negative orpositive pressure, airlocks must beprovided in manufacturing areas.

The paint used on walls and ceilingsshould be of a quality that can be cleaned.

Where there is a lot of dust, entrances tothe VME should have airlocks to minimizeits entry into the building. The inlet for thesupply of air to the ventilation systemshould be sited in a position that willminimize the amount of dust blown intothe building and it should be providedwith filters of a large dust-holding capacity.

Process

Work must be done according to goodlaboratory practices (GLPs) and goodmanufacturing practices (GMPs). After athorough study of the process, thenecessary equipment and proceduresshould be defined and validated anddetailed, precise descriptions of allprocedures must be written.

There is a great variety of productionprocesses. Mammalian cells, bacterial cells(aerobic and anaerobic), mycoplasma andvirus cultures all share some commonrequirements, but each also imposesspecific conditions related to the productthat has to be manufactured.

The final product may be a live or aninactivated vaccine. Inactivation can takeplace before or after purification steps(such as centrifugal separation, filtration,precipitation, ultrafiltration, affinitychromatography and immunoaffinitychromatography) and it is necessary toblend active components and excipientsunder sterile conditions, before bottling thefinal product.

EquipmentAll the equipment used in the productionprocess must be validated and a manual ofoperating procedures should be prepared.All the procedures involving the use of the

process equipment have performanceparameters (pressure, agitation, temp-erature, pH, dissolved oxygen,oxidation-reduction potential, flowcontrol, etc.) which require monitoring/controlling equipment.

The ageing of equipment tends toincrease the possibility of failure and mayreduce the efficiency of the process, unlessa good maintenance programme isfollowed.

REPAIR AND MAINTENANCE OF PREMISES,

PLANT AND EQUIPMENT

Maintenance demands large resources oflabour and money but it is absolutelyessential if facilities such as plant,machinery, equipment and buildings areto remain in an acceptable operatingcondition ready for maximum utilization.

Many developing country VMEs haveno maintenance facilities. This is a veryimportant issue since, without trainedmaintenance personnel, the successfulrunning of the establishment will bejeopardized. There should be amaintenance department comprising: anengineer / technician, a fitter / plumber /welder, a refrigeration mechanic, acarpenter, an electronic/ electricaltechnician and a mason/bricklayer).

Basic tools and equipment required in arepair and maintenance workshop

The following is the recommended list ofbasic tools and equipment required to carryout standard repair work on processequipment, machines, buildings, etc.

Fitter/welder/plumber's tools comprising:o various sizes of metric spanners (ringand open-ended);

o box spanners from 6 to 22 mm;0 a set of screwdrivers;o a measuring tape;o a brass drift;el punches;

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192 Design, repair and maintenance of vaccine manufacturing establishments and equipment

e a filter gauge,e pliers;e a ball peen hammer;e pipe wrenches of various sizes;o a portable electrical drill.

Refrigeration mechanic's tools comprising:various metric spanners (both ring andopen-ended);

o a set of refrigeration spanners;e an Avometer;0 a refrigeration charging manifold;o a portable refrigerant cylinder;e a set of electrical screwdrivers;o insulated cutter pliers;o a thermometer.

Electronicl electrical technician's toolscomprising:

a set of electrical screwdrivers;o an Avometer;

a diode tester;electronic test/ check apparatus (volt-ampere meter, etc.);

e a vacuum pump.

Carpenterlmason's tools comprising:basic general tools.

General workshop equipment comprising:oxygen/ acetylene welding cylinders,regulators and complete torches withhosepipes;a tungsten or metal inert gas arcwelder;a pedestal drilling machine;a bench grinder;a pressure gauge testing/ calibrationstand;thread cutting tools,pipe vices;bench vices;a pipe bender.

When selecting equipment or machinesit is important to consider their complexityof maintenance, the availability of sparesand the knowledge and expertise of

maintenance staff. There have been caseswhere a VME has acquired equipment thatwas so sophisticated that nobody was ableeither to operate or maintain it. When anestablishment acquires an expensivemachine or piece of equipment, it shouldbe ensured that whoever is to take care ofthe machine is properly trained by thesupplier or manufacturer in its operationand maintenance. Planned preventivemaintenance is the best method to adoptbut it requires that spares be available atall times, and this is a major problem formany VMEs in developing countries.

Preventive maintenance is carried outon plant equipment or machines to preventbreakdowns. It is done on a scheduledbasis and also when required, especially ifmachine performance is seen to bedeteriorating.

To determine when a machine shouldundergo preventive maintenance it isnecessary to know the machine'sbreakdown characteristics and also toadhere to the manufacturer's recom-mended schedules.

The stocking of spare parts is difficult indeveloping countries owing to a lack offinances and spares not being availablelocally when required. It is advisable,therefore, that when a machine or piece ofequipment is bought a reasonable numberof the spares recommended by themanufacturer should be kept in stock andsupplied regularly under contract, for atleast three or more years, to ensure theproper operation of the equipment.

INSPECTION

Each step of the production process shouldhave a written inspection procedure to befollowed and recorded. Equipmentinspections can be carried out by differentindividuals as long as they are allspecialists for the objects of the inspection.Easy access and correct illumination areimportant for inspection procedures, as

poor working conditions lead to careless,inefficient work.

The following tests should be performedon process or controlling equipment forvalidation, when the equipment is to beused for the first time, after a modificationor for verification within a maintenanceroutine, when applicable.

Leak tests

Leak tests should be performed on culturevessels, process and blending vessels,associated pipelines and, in general, on allpressurizable equipment. Such equipmentshould be filled with liquid (usually wateralone or with detergent to promotepenetration) in order to check the integrityof the system. These tests should be carriedout under both positive and negativepressure (vacuum) as leaks may show upunder only one situation.

Temperature mappingIt is necessary to ensure that the sterilizingor working temperatures are achieved atall required points of the equipment andassociated pipelines. Multipoint recordingequipment fitted with thermocouples willfacilitate this test.

The following equipment should havetemperature maps to confirm that it workscorrectly and that the procedures achievethe results expected:

liquid nitrogen containers for seeds orproduct storage (-190°C);deep freezes and freezers for seeds andproduct storage (-120°C, -80°C, -30°C,-20°C);refrigeration cabinet or cold rooms(4°C);autoclaves and ovens with differentsterilizing temperatures and workloadconditions;culture vessels, intermediate processvessels and associated pipelines forsterilizing, working and storageconditions.

Depending on the size of the equipmentand process conditions, between six and30 recorded points will provide sufficientinformation to assess or confirm whetherthe equipment is working correctly andwhether the procedures followed areachieving the expected results.

SterilizationSterilization parameters are establishedaccording to temperature mapping andreaction times. There is a tendency toincrease sterilization time to ensure that ithas been effective. This is misguided; acorrect procedure should sterilize for theminimum length of time required, thusprolonging the working life of sensors andequipment. If steam traps are being used,they must be periodically tested duringsterilization with an external contactthermometer.

Washing

Dirt, particularly protein, must beeliminated from the process equipmentand associated lines, before the nextprocess takes place. Careless washing leadsto protein coat build-up, increased contam-ination rates, earlier instrument andequipment deterioration and, in general,poorer process conditions. This becomesparticularly critical in centrifugal separ-ation equipment.

Membrane integrity testingSterilizing (HEPA) air filters for

ventilation and laminar flow units (LFUs)and sterilizing air filters for processequipment should have their integritytested regularly by means of: specificparticle-size oil aerosol penetration tests(applicable to all filters); or other tests, suchas the water intrusion test applicable tohydrophobic air filters, which are generallyused in small filtration units installed inprocess equipment.

Aerosol penetration detection equipment

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194 Design, repair and maintenance of vaccine tnanufacturing establishments and equipment

is expensive and a contract service with aspecialized company may be the bestsolution to having filters tested regularly.

Process equipnnent

Culture vessels and associated pipelines.Usually, standard culture vessels arebought from a specialized firm, butsometimes they are built to match therequired purpose. The culture vesselshould be insulated (lagged) and thestirring system should be magneticallydriven whenever possible this is the mostreliable, long-term, leak-proof system.

The slope (gradient) of the associatedpipelines is of great importance for theproper cleaning and sterilization of thesystem. The system must be equipped withvent or drain valves to prevent air orcondensate accumulation in piping duringsteam-sterilization. Special care must begiven to welded joins as these may causefailure by developing minor cracks.Contact with steam or chilled water isparticularly critical for welded joins. Weldsmay also suffer great tensile stress owingto great and sudden changes intemperature.

All drain lines should be connected toan enclosed drain system to preventaerosol formation and increased con-tamination risks.

Air filters. The glass fibre "depth" type ofsterilizing air filter can deal with gases athigh rates of humidity, but is unable tosterilize filtered gas when it is wet and itis therefore essential to prevent the"dragging" of condensates into this typeof filter which is gradually being replacedby the hydrophobic membrane type. Thesenew filters are very reliable and resistantto sterilization. Their integrity can be testedeasily by means of water intrusion tests.Hydrophobic membranes may suddenlybecome clogged with humidity caused bymicrocondensation in the vicinity of the

membrane, but they do not lose theirsterilizing capacity when this occurs. Theworking procedures must be such that themoisture saturation point is not reached,in order to have a reliable gas filtrationprocess.

Laminar flow units. These are requiredwhenever sterile work has to be assured inan open process. Standard LFUs may haveeither horizontal (100 percent of the filteredair is run to waste) or vertical airflow (100percent of the filtered air is recycled) andare designed to protect the product. Safetyor security LFUs are designed for workwith pathogens and protect both theworker from the product and the productfrom contamination. They are fitted with asecond fan for the extraction of part of therecycled air (30 to 70 percent) throughHEPA filters to prevent the escape ofcontaminated particles from the secureenvironment of the LFU. The ambient air,driven by suction into the LFU, is keptaway from the sterile product by the designof the cabinet and there is therefore no riskof contamination if GMP procedures areobserved.

Liquid filters. These are used for coarse orfine clarification as a specific process or forprefiltration in a final sterilization process.Liquid filters must comply with the legalrequirements for pharmaceuticalsproduction. It is usually cheaper to usedepth filters for prefiltration, but thesterilizing filters should be of themembrane type. The whole system shouldbe provided with facilities for purifiedwater washing, in-situ steam-sterilization,liquid displacement by sterile air ornitrogen under pressure, draining, sterilesampling ports and the means of integritytesting of the final sterilizing filters.

Valves. Diaphragm valves are the mostreliable, although care must be given to

the diaphragm, as its working life isreduced by overtightening of the valve.Solids such as glass fragments from abroken electrode or metal particles releasedfrom the equipment can perforate thediaphragm. If only the first layer isperforated, a dirt pocket will be created, sovalves must be dismantled routinely andinspected for cuts or holes. Valves situatedon horizontal pipelines should be placedat a 45° angle from the horizontal toprevent the accumulation of condensateduring steam-sterilization.

Monitoring and controlling equipmentConnections for electronic equipment.Usually monitoring and controllingequipment is installed in panels located atsome distance from where the sensors areinstalled. The sensor transmits an electricsignal which is translated in terms of therequired parameter (pH, redox, dissolvedoxygen, temperature, pressure, etc.) in thereceiving monitor! controller. Electronicconnections may be welded or of the tightplug type. They must be moisture-proof.All connecting cables should be protectedfrom external electromagnetic interferenceand checks should be made to ensure thatno distorted signals are received by themonitor! controller.

Manometers. Manometers installed inprocess lines or equipment should beregularly calibrated against a standardcertified manometer.

Thermometers and thermostats. Thermo-meters should be calibrated against acertified thermometer in a water or oil bath.If the equipment is a controller it shouldhave a second alarm limit set at not morethan 1°C above and below the standardworking limits.

pH - pOR - D.O. - meters/controllers. It isvery important to check the wire con-

nections regularly and to ensure that theyare in good condition. It is also essential tocheck the condition of the wire mesh(shield). External induction parasiticsignals gain in power relatively as thespecific signal weakens, owing to poorconnections or a poor shield. Probes,particularly those for dissolved oxygen,should not be kept out of solution longerthan is strictly necessary, as this causesrapid ageing. Electrolytic solutions mustbe replaced regularly.

It is important to have electroniccalibration simulators to ensure that themonitor / controller is working well, butthe final calibration should be made byplacing the sensors in standard solutionsfreshly prepared for the purpose.Specialized advice should be sought fromequipment suppliers, as all the particularsituations that could arise cannot becovered in this chapter.

Flow meters. Flow meters for liquids andgases must be calibrated under differentworking conditions against certified ones.The testing process must be conducted insuch a manner as to prevent breakagesand operators must be protected againstsuch accidents, particularly when workingwith flow meters that measure gases underpressure.

Calibration can also be done bycomparing the theoretical volume thatshould be obtained at a fixed flow rate andtime against the volume actually obtained.This has to be done at different flow rates.

Dosing equipment. If dosing is carried outwith a peristaltic pump, it is important touse high-quality flexible tubing to avoidunexpected breakages.

Solution containers must not be allowedto run empty or dry out, since this willpromote the formation of crystals whichwill cause the dosing system to wear outprematurely.

Vaccine manual 195

196 Design, repair and maintenance of vaccine manufacturing establishments and equipment

Recorders. These have to be calibrated toregister precisely the figures that themonitors/ controllers show. These in turnshould be in strict agreement with the realfigures of the process. In critical processes,inspection and manual recording ofparameters must be performed at leastonce a day and the results noted onworksheets or on the recording chart itselfwhere this is necessary.

Timers. These are useful pieces ofequipment where reaction times are longor where it is necessary to control a lengthyprocess. Computer- or PLC-controlledprocesses have timers incorporated asstandard devices.

Maintenance records. It is important tohave a register of all the process equipmentand machines that are looked after by themaintenance department. For each pieceof equipment or machine the registershould comprise:

identification (model/make/serialnumber);modifications or repairs carried out sofar;the location of the equipment or plant;the total cost of the maintenance andrepairs carried out so far.

This information will assist in assessingeach individual piece of equipment and indeciding whether it is worth spendingmore money on it or whether a re-placement is required.

Each piece of equipment should have itsown logbook to record every inspection,calibration, repair job or changes ofdefective parts. This information will bevery useful in estimating the working lifeof the different components and willpermit the implementation of a main-tenance prevention routine, which willreduce production losses caused byunexpected failures of equipment.

BIBLIOGRAPHY

Barrer, P.J. 1983. Crucial factors for designof a pilot plant. Biotechnology, October1983: 661-666.

Commission of the European Communities.1992. The rules governing medicinal productsin the European Community, Vol. IV. Goodmanufacturing practice for medicinalproducts. Directorate General forInternational Market and IndustrialAffairs.

EC. (n.d.) General requirements for the productionand control of live mammalian bacterialand viral vaccines for veterinary use.Committee for Veterinary MedicinalProducts of the European Community.

EC. (n.d.) General requirements for the productionand control of inactivated mammalianbacterial and viral vaccines for veterinaryuse. Committee for Veterinary MedicinalProducts of the European Community.

Everett, K. 1984. Planning for a newlaboratory. Manuf Chem., April 1984:30-33.

Glacen, M.W., Fleischaker, R.J. & Sinskey,A.J. 1983. Mammalian cell culture:engineering principles and scale-up.Trends in Biotechnol., 1(4): 102-108.

Ríos, S. & Chaib, M. 1993. Sistemasintegrados de salas blancas o limpiaspara la industria farmaceutica. Ind. Farm.,November-December 1993: 27-42.

Sharp, J.R. 1983. Guide to good pharmaceuticalmanufacturing practice. London, HerMajesty's Stationery Office.

ects of financiry vac(,ine ma

ir. :AC din

Veterinary vaccine manufacturing, like anyother manufacturing process, can bereferred to as a product transformationprocess, that is a process in which a finitenumber of inputs (production factors) areconverted into a finite number of differentoutputs (products) (Naylor and Vernon,1969). An assessment of such a process ofproduct transformation is usually basedon the neoclassical production functionmodel whereby output is considered to bea function of fixed and variable factors inthe firm's production process (Naylor andVernon, 1969). This rnodel basically servesas a framework for the globally appliedcontemporary practices of cost accountingand financial management.

Veterinary vaccine manufacturers indeveloping countries often face a numberof specific problems including: macro-economic reforms, distorted markets,government interference and a poorfinancial investment basis.

In addition, in many developingcountries the production of veterinaryvaccines takes place in laboratories thatare either owned and run by governmentservices or at least have strong controllinglinks with government departments. Inthese government-controlled veterinarylaboratories, production, research andanimal health control functions areintermixed. In some rare cases, separatesubunits may be in charge of specificfunctions, for example vaccine productionunits are separate from serological services

P. de Greve

management ofuiact ring o. rations

coP d ties

or research. In most cases, however,veterinary laboratories lack the necessarytransparency in managerial (i.e. functional,commercial, financial and institutional)performance to allow a detailed financialanalysis of specific operations and / orfunctions. In other words, only seldom willa veterinary laboratory in a developingcountry be able to indicate the unit cost of,say, producing a specific type of animalvaccine or carrying out a specific sero-logical service.

In an era of structural adjustments inwhich government services are increas-ingly driven by the forces of marketdemand and supply, the management ofsuch services requires transparent pro-duction processes that yield products thatcan be valued against apparent demand inthe market.

This chapter aims at highlighting someof the important managerial and, morespecifically, financial aspects of theveterinary vaccine manufacturing processwith special emphasis on locally based,government-controlled production unitsin developing countries. The followingdiscussion will be of less relevance to theproduction and trading of vaccines byprivate companies.

Obviously, it is impossible to considerin great detail the issue of financialmanagement within the limits set for thismanual. The professional literature on thetopic of financial management and costaccounting is extensive but publications

Vaccine manual 197

veteri

198 Aspects of financial management of veterinary vaccine manufacturing operations in developing countries

that discuss this topic in relation to theproduction of veterinary vaccines indeveloping countries are all but non-existent. Field experience is limited andlittle has been published in this regard.The reflections found in this chapter arebased on a limited number of fieldexperiences in East, southern and WestAfrica in combination with the overallprinciples of applied economics andaccounting.

FINANCIAL MANAGEMENT

The management of a firm is a processof planning, controlling, organizing,communicating and motivating withthe ultimate goal of attaining theorganization's objectives in the mosteffective manner.

Financial management - which is partof the overall management task - servesthree main purposes: i) stock valuation forprofit measurement; ii) decision-making(including planning); and iii) control(accountability).

In the discussion of financialmanagement, some authors distinguishbetween management accounting and costaccounting (Drury, 1988):

Cost accounting relates to the process ofcalculating actual (unit) production costfor the purposes of stock valuation andprofit measurement (objective i) above).

e Management accounting relates to theprovision of information to helpmanagement make proper investmentdecisions (objectives ii) and, partly, iii)above).

Cost accounting makes use of historicaldata that are collected and categorized ona regular basis (accountancy) with theultimate purpose of assessing the per-formance of a firm and ensuring that it isprofitable and thus viable.

Management accounting relates to futurecosts (and benefits) with the aim ofplanning future activities and investments.

Strictly speaking, historical costs areirrelevant to the decision-maker but theyare used as the best available basis(although not the only one) for predictingfuture costs.

Business plans and financial controlFinancial statements are needed to projectand/ or analyse the functioning of a pro-duction unit and to allow an assessmentof the efficiency, creditworthiness andliquidity of the unit. For a veterinaryvaccine production unit (under public-sector control) three financial statementsshould be made: the balance sheet, theprofit and loss account and the sourcesand uses of funds statement, which mayalso be called the cash flow.

Balance sheet. Balance sheets give a viewof the assets and liabilities of the processingenterprise at the end of each accountingperiod, which is usually 12 months(Gittinger, 1982). The balance sheet is akind of static picture of the financial stateof the enterprise at a given moment.

The format in which balance sheets arepresented may vary from country tocountry, but the contents are always thesame. Example lis an example of a balancesheet (United Kingdom model) of animaginary vaccine production plant underjoint project/ government control,presented with equity and liabilities in theupper section and with assets given below.The figures are based on real data from anexisting plant.

In the case of Example 1, it was possibleto work out a balance sheet because thevaccine production unit was set upindependently from other governmentdepartments. Often, however, manufac-turing units are integrated in governmentdepartments that carry out variousfunctions, some of which belong to thepublic-sector mandate while others maybe more related to the private sector, for

Vaccine manual

EXAIV1PLE 1

Balance sheet for a vaccine productionplant (United Kingdom model)

31/12/1996(US$)

example viability testing for othermanufacturers.

It follows that in those cases wheregovernments are involved in vaccineproduction, certain constraints andpeculiarities may affect the managementof the manufacturing plant. Looking at thedata above, a number of observations canbe made.

Vaccine production units are oftengovernment-owned, i.e. capital is vestedwith the public sector and not in the handsof private-sector shareholders (whetherindividuals or holding companies). This isreflected in the balance sheet in Example 1by the somewhat unusual addition ofvested capital in the equity listing.Obviously, combinations of public- andprivate-sector ownership are possible aswell. In fact, under structural adjustment

or similar macroeconomic reformprogrammes, many developing countriestry to turn their public-owned servicesand/ or manufacturing organizations intocommercially oriented companies, at leastpartly owned by private-sector agents orholdings.

The balance sheet in Example 1 is a "stillphotograph" and does not indicate exactlyhow capitalization of the production unithas been realized. The inclusion of long-term loans in this particular example pointsat a financing construction in whichoutside sources (development agencies inthis case) have provided part of the capitalbase of the unit. The other part of thecapitalization presumably originates frompublic finance sources. Various scenariosare possible whereby the financing of newinvestments is done from public financesources, private investors (through theissue of new shares) or long-term finan-cing through funding agents (such asdevelopment organizations or the bankingsystem).

Retained earnings are a fourth importantsource of capital creation in a company. Inthe past, government-controlled vaccineproduction was based on policy guidelinesset out by the government and oftenstipulating exactly what had to beproduced and in what quantities - withoutany linkages to market forces. This kind ofuninspired management practice is slowlydisappearing, even in government-controlled manufacturing units. However,it may be difficult for the management ofsuch units to convince the owners of thecompany (in this case, the government) ofthe need to retain profits (if there are any)for reinvestment in the firm.

Valuation of stocks is a crucial factor infinancial management. This issue isdiscussed in more detail in the section Pricesetting and stock valuation (p. 203).

Suppliers' credit on the equity side anddebtors on the liabilities side of the balance

199

EquityShare capitalVested capital 7 000 000Retained earnings (800 000)

LiabilitiesCurrentshort-term loans 50 000suppliers' credit 50 000taxes payable

Long-termlong-term loans 400 000

8 300 000

AssetsFixedbuildings and equipment at cost 5 600 000less accumulated depreciation (1 100000)construction in progress

Currentcash and bank balance 200 000inventories (stocks) 3 300 000debtors (accounts receivable) 300 000less overdraff

8 300 000

200 Aspects of financial management of veterinary vaccine manufacturing operations in developing countries

sheet refer to temporary capital creationand culmination, respectively, because ofthe time lags between delivery and thepayment of invoices. A common concernof financial managers will be how to avoidtying up too many funds in short-termassets such as accounts receivable orinventories. Accounts receivable are oftena bottleneck, notably when governmentservices are a main customer of the firm inquestion. In fact, governments are oftennotoriously bad in paying their arrears,especially to companies or institutes whichthey cpntrol and own themselves. Thisoften leads to the cash needs of suchcompanies being seen as part of the annualoperation plan approved by governmentand, eventually, its designated bank andnot as a business-determined factor. Theproblem of accounts receivable fromofficial or semi-official sources may wellbe the single worst bottleneck for manysemi-governmental firms involved inmanufacturing for service sectors such asveterinary departments. In addition,whereas private customers can beblacklisted as bad debtors, this is oftenimpossible with governmental customers.This problem is even more acute in caseswhere the product concerns essentialservices to society such as forvaccinations against serious contagiousdiseases. In the case of outbreaks of such adisease, the delivery of vaccines is expectedto be immediate and frequently inrelatively large volumes. Payment is oftendelayed because substantial amounts ofmoney are involved, for which noallocation was made in the government'srecurrent budgets.

Cash and bank balances could benegative if as happens far too often ingovernment-controlled organizationsoperations must be financed through bankoverdrafts because the government is latein channelling the necessary (andbudgeted) funds to the production firm it

owns and controls. Manufacturing unitsmust therefore try to create a sufficientrecurrent capital base to finance regularoperations. As indicated above, there mayalso be the problem that too much fundingis tied up in short-term assets, such asaccounts receivable or inventories. If thisis the case, the manager of themanufacturing plant should try to reducethe tied capital base.

Profit and loss account. The profit andloss account is the most widely usedfinancial statement. It is also the one whichis easiest to understand since it refers tothe common principle of profit analysis bycomparing revenue with cost. A fairlystraightforward model of profit and lossaccounts is shown in Example 2.

The profit and loss account is a financialreport that summarizes the revenues andexpenditure of an enterprise over anaccounting period (usually one year)

EXAMPLE 2

Profit and loss account

Profit and lossaccount 1996

(US$)

RevenueVaccine sales 1 450 000Antigen sales 150 000Cattle sales 600 000Serology services 100 000Donor support 500 000MiscellaneousTotal revenue 2 800 000

ExpenditureSalaries 900 000Production cost vaccines 650 000Production antigen 50 000Maintenance and repairs 200 000Office, communications and utilities 100 000Transport/travel 80 000Depreciation 100 000Loan repayment and interest 110 000Interest on overdraftBank charges 10 000Total expenditure 2 200 000

Net profit (loss) 600 000

EXAMPLE 3

Profit and loss account (revised format)

(Gittinger, 1982). It shows the results ofthe operations of the enterprise during thatperiod. The format shown in Example 2 isa very simple one which perfectly suits theneeds of smaller manufacturing units rununder government control. A morestandardized model might look as inExample 3.

Revenue can come from various sourcesbut basically relates to the sales of goodsand/ or services. In the case of veterinarylaboratories, sales of vaccine could be amajor source of revenue as shown inExample 2, but others might exist as well,for example payment for serologicalservices, antigen slides sales, veterinaryadvice against payment and sales ofanimals. Cash operating expenditureswould include all cash expenditureincurred to produce the output. Importantcosts in this category are labour and

material inputs. Selling and administrativecosts concern the so-called overheads,which also include training, ongoingresearch and development and training.

The non-cash operating expenses itemhas one major element depreciation.Depreciation refers to the process ofallocating a portion of the original cost ofan asset to each accounting period so thatthe value is gradually used up, or writtenoff, during the course of the useful life ofthe asset (Gittinger, 1982). Depreciationmay allow for a "rest value" which istreated as revenue at the time of write-offof the capital item. For example, a CO2incubator costing US$40 000 may have anexpected useful lifetime of ten years and arest value at the end of this lifetime ofUS$4 000. The annual depreciation wouldthus be:

(40 000 - 4 000)3 600

10

This amount would appear as a non-manufacturing or period cost in thefinancial statement and, consequently, itwould be used in deriving the unitproduction cost in the cost accountingexercise. The US$4 000 rest value wouldbe treated as revenue at the end of yearten.

The profit and loss account is anextremely important source ofmanagement information. Obviously,building up the database of summarizedprofit and loss accounts requires abreakdown of total revenue andexpenditure into its constituent parts, eachof which may require various subtableswith their own sets of assumptions andinputs. The following annual (or possiblyquarterly) statements are usually needed:

production and sales figures includingopening and closing stocks for factorinputs and product outputs withexpected losses and rejections;

° total revenues based on the production,

Profit and lossaccount 1996

(L/S$)

Gross revenue

- Cash operating expenses

= Gross income

- Selling and administrative costs

= Operating income beforedepreciation

- Non-cash operating expenses(depreciaton)

= Operating income (profit)

- Non-operating income andexpenses (interest, taxes otherthan on profit, subsidies, etc.)

= Net income (profit) beforeincome taxes

- Income taxes

= Net income (profit) after taxes

2

-1

800

880

920

-100

820

-100

720

-120

600

600

000

000

000

000

000

000

000

000

000

000

Vaccine manual 201

202 Aspects offinancial management of veterinary vacciae man facturing operations in developing countries

sales and stock figures and priceinformation;

o a detailed costing for specific(technical) cost centres, such asdifferent production departments,research department and advisory andresearch department;

G a detailed costing fór support centressuch as farm, rabbitry, breeding units,sales and distribution, administration,garage and workshop;

o input data for depreciation i.e.original cost, useful life and rest value;

o financial costs and bank charges;t h e capital expenditure budget(investment planning).

It is impossible to cover these input tablesin any detail in the context of this briefoverview so, because the key to successfulfinancial management lies in thedevelopment of correct and properfinancial statements, reference is made tohandbooks on financial management andcost accounting for further information.

It should be indicated that the profit andloss account also serves to bridge the gapbetween subsequent balance sheets. Thenet income (profit) from the profit and lossaccount, after the payment of dividend toshareholders (if there are any) is trans-ferred to the balance sheet as retainedearning and, if positive, will therebyincrease the owners' equity.

Financial indicators. The combination ofprofit and loss account and balance sheetallows the manager of a production unit toassess the financial viability of the plant.For this purpose, a number of financialindicators can be used. An outline of thecommon financial efficiency indicatorsfollows. For further information refer toGittinger (1982, p. 203-209).

Inventory turnover can be calculated bydividing the cost of goods sold by the valueof the inventory at year end. It measuresthe number of times that an enterprise

turns over its stocks each year and indicatesthe proportion of the inventory requiredto support regular sales levels throughoutthe year. This ratio also indicates theaverage length of time a firm keeps itsproducts in stock. A low inventoryturnover may mean difficulties in sellingthe product and / or poor stock controlpractices. Low inventory turnover alsomeans that a relatively large amount ofcapital is tied up in inventories. Forveterinary vaccine producers there is aspecific problem of safety stocks and non-continuous production processes.

As an example, a firm that sold US 2.8million worth of goods and was left with$3.3 million inventory at year end wouldhave an inventory turnover of 2 800 000/3 300 000 = 0.85, pointing to a low turnoverrate of on average around ten monthsbefore a vaccine or service is sold.

Operating ratio is calculated by dividingthe operating expenses by the revenue. Itis an indicator of the management's abilityto control operating costs, includingadministrative expenses. This ratio isespecially useful in a comparativeframework, i.e. when comparing onecompany's performance over several yearsor the performances of different com-panies. A ratio that increases over time is asign of imbalance between costs andrevenues, i.e. of disproportionately risingcosts or decreasing sales prices. In vaccineproduction, sales prices can reasonably becontrolled and the operating ratio will inthe first place be useful to give anindication of the relative cost ofproduction. In addition, if a firm has madea large investment, it will need a high cashflow in order to enable repayments. Thisrequires a low operating ratio.

In the example above the operating ratiowould be:

(1 880 000 + 100 000 + 100 000)= 0.74

2 800 000

Income ratios. The viability of a firmdepends greatly on its ability to generatefunds to repay investments, reinvest andcompensate owners for their capitalcontribution.

Some useful income ratios which reflectthe financial viability of a firm are: thereturn on sales, the return on equity andthe return on assets. The return on salesshows how large an operating margin thefirm has on its sales. Return on sales iscalculated as net income (revenue minuscosts) divided by revenue. The lower themargin (and thus the return on sales) themore the firm will have to sell in order toreach an acceptable return on investment.Return on equity is the ratio of net income(after taxes) to equity and is the mainguidance to owners of the firm in theirinvestment decisions. This applies equallywell where the government is the ownerof the firm. Return on assets is a moretheoretical income indicator reflecting theoverall return of the company on all theresources it engages. This ratio is thenearest to the internal rate of return anddiscounted measures of project worth(Gittinger, 1982, p. 206-207).

Financial ratios. Apart from efficiency andincome ratios, there is a third importantclass of financial indicators that reflects amanufacturing company's financialstrength, i.e. the creditworthiness ratios.These ratios concern the degree of financialrisk inherent in the enterprise (Gittinger,1982). Creditworthiness indicators are thecurrent ratio (current assets divided bycurrent liabilities), the debt-equity ratio(long-term liabilities divided by long-termliabilities plus eq-uity) and the debt servicecoverage ratio (net income plus de-preciation plus interest paid, divided byinterest paid plus repayment of long-termloans).

Sources and uses of funds statement. Thefourth financial statement that is used toassess the operations of manufacturing

units is the sources and uses of fundsstatement, or the cash flow table. As thelatter name indicates, the cash flow tableprovides an overview of the total flow offinancial resources into and out of anenterprise during an accounting periodand is useful for determining the likelyflow of financial resources in future.Reference is made to textbooks on financialmanagement for more information.

PRICE SETTING AND STOCK VALUATION

Price setting by (government-controlled)vaccine manufacturers is a difficult issue.In theory, the market should dictate pricelevels but in practice it does not. Marketsfor veterinary vaccines are far moreimperfect than those for, say, consumablesor inputs such as fodder. Quantitativeknowledge of "willingness to pay" bypotential customers (e.g. farmers) is oftenscarce and unreliable, if available at all.Moreover, in a number of cases, society iswilling to cover at least part of the costprice of a vaccine because of the potentialdisease threat to humans. In such cases,willingness to pay cannot be assessed ascustomers are more or less forced to acceptthe product and market demand cannottruly be established.

Nevertheless, the issue of price setting isclosely linked to cost accounting, in thatan estimation of unit output cost is aguideline in determining break-even salesprice levels. In more general terms, pricesetting is a less central issue than is theevaluation of stocks, being the input andoutput factors of the producttransformation process, and financialmanagement is concerned with thedetermination of the cost of all singleresources used in the transformationprocess, including non-physical resources,and the consequent value of single outputsof the process. Once these unit values areknown, management can determine properpricing policies.

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204 Aspects of financial management of veterinary vaccine manufacturing operations in developing countries

Period costs and product costIn the process of cost accounting,individual cost items that constitute thecost "chain" from basic inputs to finalproduct must be identified, quantified,valued and summarized in order to arriveat a unit product cost. In this process, adistinction is made between period costsand product cost as illustrated in Figure 3.

Product costs are directly related to themanufacturing process. Their treatment inthe financial statements, however, dependson whether the output produced is actuallysold or not. Non-manufacturing costs areperiod-related costs and thus alwaysappear in the profit and loss account asexpenses. Some of the directmanufacturing costs, on the other hand,may not appear as an expense unless theproduct is sold. The terms product costand period cost are thus interchangeablewith direct and indirect costs.

An example (based on an example byDrury, 1988) may clarify this issue:

A vaccine manufacturing laboratoryproduces 50 000 units of vaccine A duringyear 1. The costs for year 1 were (in UnitedStates dollars):

Manufacturing costs

Because only 40 percent of the producedvaccine was sold in the same accountingperiod, only 40 percent of the total productcosts appear in the profit and loss accountas an expense. The remaining 60 percent isincluded in the value of the closing stockwhich appears in the balance sheet but notin the profit and loss account. So thesecosts are not expenses but will becomeexpenses in the next accounting period(assuming that the remaining 30 000 dosesof vaccine will then be sold). On the otherhand, all period costs (non-manufacturing)will appear as expenses in the profit andloss account because they were incurred inthis period. The cost of goods sold isderived only from (part of) the productcosts and not from period costs.

Another notable effect is that, because ofthis allocation to different periods, the unitcost of a vaccine may differ from period toperiod if period costs are included. Forexample, from the first data it appears thatin order to produce 50 000 vaccines, totalexpenses are (in United States dollars):

But if related to year 1 the unit costappears to be different:

It is clear that only the second version

Manufacturing 40 000Non-manufacturing 40 000Total 80 000Number 20 000Unit cost 4.00

Labour costs 50 000Materials 20 000Manufacturing overheads 30 000

Total 100 000

Non-manufacturing costs 40 000

Less closing stock60 percent of total 60 000Cost of goods sold 40 000Gross profit 50 000Less non-manufacturing cost 40 000Net profit 10 000

Manufacturing 100 000Non-manufacturing 40 000Total 140 000Number 50 000Unit cost 2.80During year 1 the laboratory sold 20 000

units for US$90 000. The remaining 30 000units remained in stock at the end of year1. The profit and loss account for year 1would then look as follows:

Gross revenue (sales) 90 000Manufacturing costs

Labour costs 50 000Materials 20 000Manufacturing overheads 30 000

Total 100 000

Manufacturing cost

Non-manufacturing cost

Product cost

Period cost

Unsold

Sold

Recorded as an asset inthe balance sheet and

becomes an expense inthe profit-loss account

when the product is sold.

Recorded as an expensein the profit-loss account

in the currentaccounting period.

FIGURE 3

Comparison of manufacturing and non-manufacturing costs

Source: C. Drury, 1988.

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206 Aspects offinancial management of veterinary vaccine manufacturing operations in developing countries

(unit cost 4.00) is the correct one if, asassumed, only 20 000 vaccines are sold inyear 1. It should also be clear that the unitcost in year 2 could be different from year1 depending on the total number ofvaccines (of this particular batch) sold andthe exact period costs for year 2.

Sunk costs

Sunk costs are the costs of resources thathave already been acquired and that willnot be affected by present and futuremanagement decisions. In a way sunk costsare by definition irrelevant costs in theplanning process as the decision to incurthem has been taken before. Some authorsresist the use of the term sunk cost. Forthem, it simply applies to past expenseswhich may (or may not) have financialimplications. These implications could benew costs such as possible interestpayments on loans taken up to pay forpast investments.

In the case of vaccine production indeveloping countries, research anddevelopment (R&D) is typically a cost itemthat concerns management decisions of thepast. Strictly speaking there are two waysof dealing with R&D expenses in thefinancial statements.

In the first way, R&D expenses areconsidered to be investment costs and aretherefore depreciated over the usefullifetime of the investment. As a result, theprofit and loss account will contain an itemfor annual depreciation of R&D costs forthe various products put on the market. Inpractice, however, there may be difficultiesin assigning R&D costs to specific endproducts in a unit cost assessment.

Alternatively, R&D can be considered asperiod costs before the actual revenuestarted accruing. In this case, these costsshould have appeared in the profit andloss accounts of those years in which theywere incurred. This should still be reflectedin the balance sheet as R&D in early years

probably led to substantial negativeretained earnings being carried over fromthe profit and loss account to the balancesheet.

In practice, however, development costsare often regarded as sunk costs and arethus not recovered through sales of finalproducts. Often they are even disregardedin the profit and loss accounts and thebalance sheet, unless they concern materialassets.

Cost allocationVeterinary laboratories that are engagedin vaccine production often also providevarious other functions, such as serologyservices and veterinary advisory services.In order to improve the efficiency withwhich such laboratories carry out thesefunctions, a manager should ideally be ableto assess each function separately on a costand revenue basis. This means that revenueand expenses need to be allocated to sub-components of the overall organization. Infact, three types of cost centres can bedistinguished in a possible framework forcost control within a single manufacturingenterprise (Figure 4).

Practice shows that in the case ofgovernment-controlled veterinary labo-ratories, the allocation to cost centres ismore of an exception than the rule eventhough there are tremendous differencesin the kind of services offered by suchlaboratories, some of which belong to thepublic domain while others may well becommercially oriented. The establishmentof cost, profit or investment centres canalso be considered at the level of vaccineproduction when different vaccines areproduced.

However, there are constraints whichmake the establishment of such centresmore complicated in the case of animalvaccine production in developingcountries.

One such constraint is the fact that the

Managers accountable for:

Cost centre

Expenses

IProfit centre

Expenses

Sales revenue

Investment centre

Expenses

Sales revenue

Capital investment

FIGURE 4

Cost control framework for single manufacturing enterprise

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208 Aspects of financial management of veterinary vaccine manufacturing operations in developing countries

production of vaccines is done in batchesand not continuously as for most industrialproducts. Nevertheless, the productionprocess is repetitive and thus open to unitcosting or cost accounting. The greaternumber of inputs and processing steps arevery strictly defined, which in a way makesthe process of unit costing easier.

Another potential constraint is that jointproduct costing (Drury, 1988) maycomplicate the financial control of themanufacturing process. Joint costs are costsof two or more kinds of outputs that areproduced simultaneously by a singleprocess and are not identifiable asindividual types of products until a split-off point is reached (Horngren, 1977). Thiskind of joint costing can be handled bydistinguishing one cost centre before andtwo (or more) cost centres after the split-off or, alternatively, by a cost allocationprocedure based on units or value relatedkeys.

Nevertheless, the financial managementof veterinary laboratories would clearly befacilitated by establishing cost or profitcentres around various core activities, oneof which would be vaccine production.Others might be serological services,applied research, quality control, etc.Overall management would be easier as anumber of tasks and functions could bedelegated to the appropriate centre. Thistype of business framework is quitecommon in the commercial world but,unfortunately, still rare in parastatal orgovernment institutes in developingcountries.

Overhead costsIn practical terms, developing unit costingsin a set-up with cost or profit centresrequires the allocation of overhead costs tothese centres. When, for the sake ofestimating unit production cost, aveterinary laboratory differentiatesexpenditure according to cost centre, there

are usually a number of overhead costswhich can fairly easily be allocated tospecific centres.

Time recording can be of help inassessing the labour inputs of employeesnot directly linked to a specific cost centre,for example the distribution of indirectmaterials such as stationery can berecorded for each cost centre. On the otherhand, expenditure on general maintenanceof the building, rent, heating, lighting, etc.cannot be allocated directly to specific costcentres. For this type of expense, theapportioning of cost must be based onother factors, such as the area occupiedand the number of staff.

As an example, assume that in aveterinary laboratory there are two typesof products vaccine A and serologicalservices and that these constitute the basisof differentiation of cost centres. The unitcosts of the vaccine and the serologicalservices need to be established in order toguide management decisions on pricing,stocks and distribution. The floor area ofthe laboratory is 10 000 m2, 3 500 m2 ofwhich is occupied by vaccine productionlaboratories, 2 500 m2 by serologicallaboratories, 2 000 m2 by shared productionfacilities and 2 000 m2 by offices and othergeneral facilities. If the total annual cost ofrent, lighting, heating, etc. is US$50 000then the apportioning could be done asfollows: for vaccine production 35 percentof its own area plus 10 percent of the sharedlaboratory (50 percent of the total) plus 10percent of the allocation for offices (50percent of the total) which comes to 55percent of total costs, or US$27 500. Theremaining 45 percent, or US$22 500, wouldbe the apportioned overhead cost forserological services.

Note that this method includes a secondlevel apportioning for the expenses thatare not directly linkable and thatexpenditure for offices could even beallocated on the basis of a specific

apportioning method, for example onebased on the total turnover of each costcentre.

It must be noted that there is no standardmethod for apportioning overhead costs;in each case a method should be foundthat has a causal ground for allocating coststo specific centres, such as the floor areaused in relation to building-relatedexpenses as shown above.

Similarly, labour inputs that cannot bedirectly allocated have to be apportionedon the basis of a key determinant,for example technicians who maintainand / or repair equipment in differentdepartments can easily record time ex-penditure on job sheets for the individualcost centres. Even management staff canto some extent record time expenditure bycost centre. It is clear, however, that thiscannot be done for the entire labour inputof service departments or management,since part of their input is of a generalnature and cannot be allocated to specificdepartments.

Other service departments that work forthe laboratory as a whole include libraries,the stores department, accountancy andsecurity guards. Their expenditure has tobe allocated on the basis of the perceivedbenefits that each cost centre receives, forexample the stores department'sexpenditure could be allocated on the basisof the number of material requisitions fromeach centre or on the more difficult toassess basis of the value of materialsdispatched to each centre.

In advanced cost accounting systems,overhead allocation does not stop at thelevel of cost or profit centre, but relates tothe specific tasks that pass these centres. Inthe context of vaccine production, thisleads to cost accounting being broughtdown to the level of individual batchesand not just to the vaccine production unit.Desirable as this may be, in government-controlled veterinary laboratories this kind

of breakdown is often far too ambitiousand cost allocation at the level of costcentres is usually quite adequate.

STOCK OR INVENTORY CONTROL

Inventories can be a major source of cashdrain for any kind of company. This isespecially so in firms that have littleworking capital. As vaccine producinglaboratories often depend on governmentsupport for establishing a capital basis, itis clear that they very often struggle withfinancial constraints because of a lack ofworking capital. Good stock control, ofboth inputs and outputs, is thus animportant element in the financialmanagement of such (semicommercial)manufacturers.

Inventories must be maintained so thatthe customer can be served on request(Horngren, 1977). In addition, in the caseof veterinary vaccines it may be necessaryto maintain a certain stock of specificvaccines in case an outbreak of a specificdisease requires immediate and medium-to large-scale intervention.

Inventories are cushions to absorbplanning errors and unforeseen fluc-tuations in supply or demand and tofacilitate smooth production and mar-keting operations. Inventories can alsominimize the interdependence of differentparts of the organization, so that each canwork effectively (Horngren, 1977). Anotherreason for companies to hold stocks is forspeculation whereby a firm buys in moreor fewer inputs than are required from astrict managerial point of view in order totake advantage of anticipated pricefluctuations. Unlike the other reasons forstockholding, this latter motive cannot begeneralized in guidelines for stock controlas the speculation motive is by definition amatter of uncertainty. Disregarding thespeculative aspect, the problem thatmanagement faces regarding stock controlis to find a good balance between the need

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210 Aspects of financial management qf veterinary vaccine manufacturing operations in developing countries

for inventories of inputs and outputs andthe desire not to tie up too much of thefirm's capital in idle stocks. As far as stockcontrol is concerned, manufacturingcompanies in developing countries findthat the shortage of raw materials is oftenmore of a problem than controlling excessinventories.

The question of stock valuation isimportant in the sense that managementmust decide on a policy for attachingspecific values (costs or prices) toindividual inputs or outputs that arereleased from storage for use in eithermanufacturing or sales. The inventoryvaluation methods used are usually one ofthe following three:

o First-in first-out (FIFO): the earliestacquired stock is assumed to be usedfirst, so that the impact of present priceeffects is delayed, as the prices usedreflect historical acquisition prices orunit costs.

o Last-in first-out (LIFO): the latestacquired or produced units aresupposed to be used or sold first. Withthis method, the value of stock itemsreleased is a reflection of present (or atleast recent) costings. LIFO usuallyleads to somewhat higher values asprice levels over time generally showrather a rising tendency than a fallingone.

e The obvious compromise is the useof some kind of average inventorymethod, which could be a movingaverage whereby each new addition tothe stocks is lumped with the previousones and average unit prices have to beadjusted with each change in stocks.

None of the above methods is entirelysatisfactory and each has it ownadvantages and drawbacks.

Security stocksThe financial burden of keeping stocks ofvaccines ready at hand for emergencies

should, in theory, not be borne by theproducing firm. In practice, however, thisis usually what happens. As a result, thecomplex administrative channels throughwhich reimbursemen.t has to be channelledin case of emergency delivery constitutean additional financial bottleneck forvaccine supplying companies.

The question is whether the cost ofholding such emergency stocks shouldand can be included in the firm'smanufacturing cost and consequently becovered by the sales price of the vaccine.The answer to this question is primarily apolicy issue which is related to the moregeneral problem of differentiating betweenthe health-related aspects of veterinaryservices, which are beyond the control ofindividual livestock owners, and thoseservices that primarily relate to theproductive activities of the livestock sectorand are under the control of individualfarmers.

As a general rule, cash generated fromsales or the collection of receivables is anidle asset unless it is put to use internally(reinvested) or externally (invested inshort-term securities). If, however, theeconomic situation in a country ischaracterized by high inflation rates,investment in short-term securities canonly make sense if the real interest rate ispositive, i.e. higher than inflation. If not,investments are a waste of resources. Theproblem in many developing countries,however, is the lack of efficientlyfunctioning and fully developed moneyand capital markets (Sun, Gao and Soenen,1993). This may mean that capital marketsare not tuned to the characteristics of theeconomy but are centrally controlled bygovernment.

On the other hand, manufacturingcompanies that are controlled and / orowned by governments may also benefitfrom this situation. The firm's equity isoften provided by government authorities

without having an explicit cost attachedto it, for example enterprises have beenfinanced in the past by state equity capitalthat was free of charge (Sun, Goa andSoenen, 1993). This situation came aboutbecause veterinary vaccine productionwas thought to belong to the government'sessential tasks and was therefore mono-polized under government control. Thelack of competition gave companies noincentive to aim at efficiency gains andgovernments considered it appropriate tosupport these firms through the provisionof equity capital, independent of theconditions in the capital markets. In recentyears discussions have increasinglycentred around the question of whatexactly is included in the government'sessential tasks. There is a tendency amongdonor agencies and international bankinginstitutes to consider the support of vac-cine production as non-essential for agovernment. Vaccinations, on the otherhand, will in many cases continue to beconsidered as an essential task of thegovernment and explicit governmentinterference may therefore be deemedfeasible and acceptable.

CONCL._ .LEMARKS

On the basis of historical costs and with aproper accounting system it should bepossible for veterinary vaccine producersto keep track of both direct and indirectcosts and overheads. The principalproblems that remain will be the properallocation of overheads and theclarification of the goal of manufactur-ing versus other social or commercialfunctions. In the context of this manual itis impossible to cover the details of costcontrol in the different cost centres of amanufacturing firm. Nor is it possible todeal with the accounting principles behindsuch a cost control system in any detail.Apart from indicating some fields ofspecial interest, reference will have to be

made to the professional literature in thisfield.

The main purpose of this chapter hasbeen to point out a number of problemsthat may arise, especially in animal vaccinemanufacturing institutes or enterprises indeveloping countries. The role of thegovernment, often as owner and / orcontroller of veterinary laboratories, iscrucial in this respect. Mostly because ofexternal pressures, this role is changingrapidly and the process of manufacturingis increasingly being left to the privateand semi-private market. Whenever thisis happening, businesslike approaches tothe management of such manufacturingprocesses become increasingly important.Donor agencies may play an importantrole in this respect in supporting and / ororganizing management training forscientific staff of such veterinaryinstitutes.

Such actions would encourage a realincentive for improved economic per-formance and this in turn would lead to abetter and more efficient use of scarceresources for the benefit of the community.This is the major goal of economics.

BIBILIOGRAPHY

Drury, C. 1988. Management and costaccounting. London, Chapman Sz Hall.857 pp.

Fama, E.F. & Miller, M.H. 1972. The theoryof finance. Hinsdale, Ill., USA, Dryden.344 pp.

FAO. 1992. A coordinated multi-donorprogramme for tick and tick-borne diseasecontrol in Eastern, Central and SouthernAfrica. Report of the FormulationMission, Rome.

Gittinger, J.P. 1982. Economic analysis ofagricultural projects. Baltimore, USA andLondon, Johns Hopkins University Press.505 pp.

Horngren, C.H. 1977. Cost accounting - a

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212 Aspects of nancial management of veterinary vaccine manufacturing operations in developing countries

managerial emphasis. London, Prentice-Hall International. 934 pp.

Naylor, T.H. & Vernon, J.M. 1969.Microeconomics and decision models of thefirm. New York, Harcourt, Brace andWorld. 482 pp.

Sun, B., Gao, G. & Soenen, L. 1993. Financialmanagement practices in Chinese state

enterprises. RVB Research Papers,p. 1-5.

Thompson Jr., A.A. 1977. Economics of thefirm theory and practice. N.J., USA,Prentice-Hall. 638 pp.

van Hemert, P. 1972. Vaccine production as aunit process. Delft, the Netherlands,Technische Hogeschool. 175 pp.

The istics of accinE nufacture ineveo g countries

Producers of veterinary vaccines in devel-oping countries are faced with constraintsnot encountered by manufacturers inindustrialized countries; many vaccineproduction centres are government-fundedwith limited resources, often with facilitiesnot specifically designed for the purpose.The implementation of good manufactur-ing practices (GMPs) (Sharp, 1983) isdifficult under these conditions. Financialconstraints limit flexibility in the modi-fication of existing plants and producersusually obtain little support from fiscalauthorities owing to a general lack ofinsight into the requirements of vaccinemanufacture.

A producer may be forced to make aparticular biological product as a result ofpolitical or administrative policy, despitea lack of appropriate technology orfunding. Faced with the responsibility ofproducing a safe and effective productunder suboptimal conditions, the decisionas to whether to produce or import anequivalent product must be assessed. Therelatively high price of imported productsneeds to be weighed against the capitaloutlay needed to manufacture products ofequivalent quality and safety. Since therole of vaccine producers is ultimately thebenefit of agriculture, no advantage canbe gained from insisting on producingsubstandard or excessively expensivevaccines locally.

While vaccine manufacturing plantsshould comply with certain minimalstandards, the structural shortcomings ofbuildings should not be used as an excuse

P. Hunter

for failing to implement operationalGMPs such as correct work flow pro-cedures, hygiene and documentation. Withingenuity and dedication a safeand effective product can usually beobtained.

FORWARD PLANNING

In many developing countries animalimmunization is conducted on a campaignbasis and planning of vaccine productionmust make provision for producing largequantities of vaccines in a short period oftime.

Vaccines for important diseases suchas rinderpest and foot-and-mouth diseasecan be stored as strategic reserves; thePlowright rinderpest vaccine is stable forapproximately four years in the freeze-dried state at 4°C (Doel, 1993) whilefoot-and-mouth disease vaccine can bestored as a frozen concentrate in liquidnitrogen indefinitely and formulated ondemand. Freeze-dried lumpy skin diseasevaccine stored at 4°C or -20°C will retainits original titres for two to four years (Doel,1993).

In countries where important arthropod-transmitted diseases are endemic, there isusually a seasonal demand for vaccine inspring and early summer. Failure on thepart of farmers to immunize their livestockon a sustained basis can result in massivelogistical problems for producers; forexample the vaccination of sheep againstRift Valley fever in southern Africa shouldbe carried out to provide animals withadequate herd immunity during the long

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214 The logistics of vaccine manufacture in developing countries

intra-epidemic periods which characterizethe disease. Live Rift Valley fever vaccineis easily produced in large quantities andconfers lifelong immunity, but at the onsetof an epizootic of Rift Valley fever, farmerscannot make use of the live vaccine inpregnant animals. There is therefore amassive demand for the inactivatedvaccine which requires a larger antigenicmass per dose and a longer lead time forproduction.

The clostridial toxoid vaccines aregenerally very stable and lend themselvesto storage as concentrates at 4°C.

A campaign approach to production,whereby only one product is produced fora short period of time, allows the manu-facture of a large amount of vaccine tosupply seasonal or other dem.and ifproduction capacity is restricted andprevents cross-contamination if con-tainment facilities are suboptimal. This isalso a practical approach with a vaccinesuch as anthrax which has a disastrouspotential for the contamination of pro-duction and bottling plants.

The production of vaccines which havea very short shelf-life, such as the bloodvaccines for rickettsial and protozoaldiseases in Africa, need special attentionwith regard to planning. The procurementof susceptible animals, infection, bleeding,collection and bottling of vaccines must becarefully planned to avoid the wastage ofresources. Producers may have to supplyclients according to a schedule, for exampleweekly in the summer months but onlymonthly in winter.

Ordering materialsAs in any production plant, orderingmaterials for vaccine production must bedone in a timely manner, so that there issufficient time for checking and qualitycontrol (QC). In developing countries,there is the additional problem of rawmaterials frequently being imported and

time must be allowed for importation andrelease from customs. Further problemssuch as receiving the wrong product in aconsignment of raw materials can delayproduction. Stockpiling crucial raw ma-terials is advisable if sufficient storagespace is available and as long as theproduct is stable on storage (Lambert andBirch, 1985). However, stockpiling ties upcapital and adds to the unit cost of theproduct compared with those produced indeveloped countries where manufacturerscan rely on a just-in-time approach.

Since many raw materials for vaccineproduction are analytical grade chemicals,most conform with the specifications ofthe manufacturer. Using cheap culturesubstrates which are available locally toreduce costs (e.g. using meat broth or cornsteep for clostridial vaccines) causescomplications because these substancesmay vary in composition from batch tobatch. Additional QC tests such as proteinor nitrogen content (on meat broth) andtotal solids (on corn steep) are necessary toeliminate poor substrates. In addition,careful growth tests must be done to ensuretheir suitability for use.

Since few laboratories can affordto import complete cell culture media,powdered media or individual com-ponents are usually purchased. Althoughbuying from reputable companies maycost more it does reduce the risks ofunscrupulous companies dumping poor-quality products in developing countries.

THE PRODUCTION PROCESS

Media preparationCell culture medium. Cell culture mediummust be formulated with double-distilledwater or water produced by reverseosmosis and filtered sterilely into stainlesssteel tanks or into bottles. If sterile roomfacilities are unavailable for sterile filling,small laminar flow units can be used.Careful sterility checks at 37°C and room

temperature are essential if conditions arenot optimal.

Bacterial culture media. Bacterial culturemedia are usually sterilized by heat intanks or glass flasks a process which isgenerally associated with fewer problemsthan sterile filling. However, the functionof autoclaves and the qu.ality of the steamused for sterilization may affect the heat-sterilization process and sterility tests mustbe carried out.

The preparation of agar plates or slopesshould be done in laminar flow cabinets orunder laminar flow units if no sterile roomsare available.

Virus vaccines

Cell lines. Cells for virus production canbe obtained from culture collections orreputable laboratories, where the identity,chromosomal characteristics and freedomfrom extraneous agents have been es-tablished. If in-house testing is not possibleintermittent checks can be done by otherlocal laboratories that are able to check cellidentity and freedom from mycoplasmaland viral contamination.

It is essential to check cell lines forextraneous viruses. As in-house facilitiesare seldom available for this, help shouldbe enlisted from universities or otherlaboratories with experience in detectingthe viruses that may affect the cells usedfor production. With this in mind, it ismore convenient if viral vaccines producedfrom cell lines are manufactured on acampaign basis to eliminate the need forcontinual testing for extraneous viruses.

Media. The importation of completeformulated media for vaccine productionis impractical owing to freight costs,despite the advantages of QC and growthchecks thereby becoming unnecessary. Itis more econom.ical to buy powderedmedia, but cell growth checks must be

done, as the quality of water used forformulation can affect the product.

Storing cell and virus seed. Erratic powersupplies make it essential that cell andvirus stocks should be duplicated andstored at various institutes as back-upsupplies.

Viral master seed stocks. The identity,purity, passage history and titres must becarefully noted. Recording the passagelevel of live attenuated virus vaccine strainsis of major importance and failure tocontrol this can lead to serious problemsin the field.

Production

The production of live vaccines on cellculture requires less antigen and cantherefore be performed in roller bottles orin Roux flasks. Inactivated virus vaccinesrequire a large amount of antigen, whichmay necessitate the production of vaccinevirus in suspension culture. This has beendone successfully with BHK cells for rabiesand foot-and-mouth disease vaccineproduction.

However, in developing countries it maybe more practical to use a labour-intensive,scale-up rnonolayer system as has beenused for foot-and-mouth disease vaccineproduction (Ubertini et al., 1963) and for

Aujesky's disease and PI3 vaccines(Panina, 1985).

Bacterial vaccines. The productionmethods of many bacterial vaccines areuncomplicated and appropriate for use inmost developing countries. However, theproduction of vaccines for Brucella abortusand B. melitensis should not be attemptedwithout adequate containment andbiosafety facilities.

Undemanding anaerobes such as theclostridia can be produced withoutdifficulty but strict anaerobes such as

Vaccine manual 215

Bacteroides nodosus require totally oxygen-free gases which are not readily availablein developing countries.

Although most modern bacterialvaccines are produced in fermentationvessels, labour-intensive methods ofproducing vaccines on agar layers in Rouxflasks are suited to the conditions in somedeveloping countries. Clostridial toxoidvaccines such as those against botulismand tetanus are easily produced by thedialysis bag method (Sterne and Wentzel,1950) if fermentation technology isunavailable.

Protozoal vaccines. Since the productionof redwater (Babesia spp.) andanaplasmosis (Ana plasma centrale) vaccinesfor cattle may require the use ofsplenectomized cattle, the appropriatefacilities must be available or the servicesof universities or private clinics must beelicited. Animals need to be maintainedunder tick-free conditions, by means ofwater-trenches around stables and theprovision of sterilized feed.

Tick stabilate vaccines such as thoseprepared for Theileria sp. and heartwater,where the vaccine consists primarily ofinfected ticks ground into a suspension,must be prepared with caution because ofthe prevalence of tick-borne diseases whichcan affect humans such as tick-bite fever(Rickettsia conori) and the viruses whichcause haemorrhagic fevers.

Serum for culture media. Foetal calf serumis rarely available in developing countriesand has to be imported. Althoughexpensive, the advantage of this is that asterile product which has passed appro-priate growth tests is received.

Normal bovine or other sera are usuallymore easy to obtain from abattoirs butthe quality can be a problem. Collectionis rarely from animals bled by trocharand inevitably the blood collected at

exsanguination has high microbial conta-mination and resultant high endotoxinlevels. However, the serum collected inthis manner is cheap and, providing thelaboratory has a separator for defibrinationand facilities for sterile filtration, a usableproduct is usually obtained although thesuitability of each batch for cell cultureneeds to be checked and stringent sterilitychecks are essential. Because of the risk ofadventitious viruses which may be presentin serum, for example BVD virus (Kriazeff,Wopschall and Hopps, 1975), bovine serafor use in live vaccines should be irradiatedor heated.

The problem of the presence ofantibodies in serum, which may react withthe virus to be cultured, can be overcomeby precipitation with polyethylene glycol(Abaracon and Giacometti, 1976; Barteling,1974).

Downstream processingWhether it be the removal of bacterial cellsfor the processing of toxoids or theconcentration of virus harvests, the majorconcern for a vaccine producer in devel-oping countries is the selection of methodswhich combine low capital outlay withlow-cost maintenance. Of the variety ofprocesses available, only ultrafiltration issuitable for large-scale processing; theequipment is simple and of relatively lowcost but it has the disadvantage thatpurification cannot be achieved to anygreat extent.

AdjuvantsAdjuvants. Alum (potassium aluminiumsulphate) and aluminium phosphate arerelatively cheap and easy adjuvants toformulate. They are commonly used foradjuvanting toxoid vaccines. The in-houseproduction of aluminium hydroxide gel(alhydrogel), which is the most widelyused adjuvant for veterinary vaccines, ismore demanding. The aluminium content,

216 The logistics of vaccine manttfacture in developing countries

pH and conductivity need monitoring andthe poor heat conduction of the gel requirescareful control of sterilization. With this inmind, the cost-effectiveness of buying acommercial product which conforms tosafety and efficacy requirements must beweighed against that of in-house pro-duction of the product.

Oil adjuvants. Mineral oils used for singleor multiple oil formulations in veterinaryvaccines are usually imported intodeveloping countries and, because of thepropensity of oil formulations for causinglocal reactions, attention must be paid tothe quality and purity of the oils. Vaccineproducers must insist on certificates ofanalysis and must check the containers inwhich the oils are delivered to ensure theabsence of contamination with otherproducts. The oils should be stored undernitrogen to prevent oxidation duringstorage.

Saponin. This adjuvant usually has to beimported and the producer should beaware that the quality varies with supplier.While some brands which are not highlypurified have good adjuvant activities andcan be used with success, for example inthe anthrax spore vaccine, they can affectcertain antigens such as foot-and-mouthdisease virus on storage. Some initialresearch should therefore be undertakento determine an appropriate supplier.Purified saponins are less likely to destroythe antigen, but are extremely expensiveand some have poor adjuvant activity.

Filling and freeze-dryingThe vaccine filling and freeze-drying plantis the bottleneck area in most productionfacilities. In developing countries theadditional problem exists that equipmentis imported and service back-up from thesupplier becomes very important.Ampoules used for freeze-drying can be

manufactured locally to keep the unit pricelow, but these are often not produced tospecification, leading to breakages bycapping machines. This is a seriousproblem not only because of wastage, butbecause it becomes a safety problem whenbottling freeze-dried products such asBrucella sp. and live attenuated mouse-brain adapted strains of African horsesickness virus (Erasmus, personal com-munication).

Producers are often forced to use a fillingline for both live and killed products; ifthis is unavoidable, live products must bebottled at the end of a week, afterkilled products, and the facility mustthen be disinfected with an appropriatedisinfectant, or fumigated with for-maldehyde, and allowed to stand over aweekend.

The malfunctioning of freeze-dryingmachines can cause a high moisturecontent in the product which results inpoor stability of the vaccine, which isimportant in tropical and subtropicalcountries.

QUALITY CONTROL

As the number of QC tests performedincreases, so does the cost of the finalproduct, and often only essential tests areselected.

Physical and chemical testsThe manufacturer should not underesti-mate the value of visual inspection of theproduct. Numerous problems can be de-tected merely by looking at a formulation:the colour, consistency, presence of foreignbodies, proportion of alhydrogel andappearance of freeze-dried pellet canindicate a problem in the final product.Basic tests such as pH determination aresimple to perform and give valuableinformation about the reagents used andin monitoring each stage of the vaccineproduction process. QC tests must be

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218 The logistics of vaccine manufacture in developing countries

validated by including standards and, ifnecessary, by requesting other laboratoriesto duplicate tests.

Raw materials. The extensive QC testsperformed on raw materials in developedcountries are seldom performed in devel-oping countries because of the cost. Lessaffluent producers must neverthelessensure that analytical grade chemicals areused and growth tests are performed onformulated media.

In-process tests. The monitoring ofinactivation is essential in order to obviateusing vaccines containing non-inactivatedorganisms. When aziridines are used asinactivants, the inactivation process can becontrolled by monitoring the pH changesduring the process of cyclization of thereagent and by sampling and titration ofthe antigen (Bahnemann, 1990).

Moisture content of freeze dried vaccines.Since a high moisture content will affectthe stability of vaccines Karl Fischermoisture determination should be per-formed, if possible, by the producer or ananalytical laboratory. An acceleratedstability test can pre-empt the issuing ofvaccine with high moisture content ifmoisture determination tests cannot beperformed.

Innocuity/salei:y testil1,5 Abnormal toxicitytesting is done on two guinea pigs (2 mlintraperitoneally or subcutaneously) andon five mice (0.5 ml). This test is importantif the analysis of raw materials and in-process controls cannot be done.

Specific safety tests, as for the abnormaltoxicity test, are essential and become allthe more important if the quality of raw.materials and other reagents cannot becontrolled. These tests are essential for liveattenuated vaccines. Susceptible target

animal species are inoculated with at leastone dose of the specific vaccine.

Potency testing. As with potency testingin developed countries, titrations of liveorganisms or serology are performed inplace of challenge tests on large or smallanimals, where this is possible. Performingserological tests may be difficult in somecountries, owing to the problem of findingseronegative animals to ensure immuno-logical responsiveness to specific antigens.In South Africa, sheep have to bepurchased from an area in the countrywhere bluetongue does not occur and haveto be maintained in insect-free stables whilethey are tested for their serologicalresponse to the bluetongue vaccine.

The lack of containment facilities mayprevent developing countries fromperforming challenge tests for vaccinessuch as rinderpest and contagious bovinepleuropneumonia and only serology willbe carried out.

DTOZOAL AND RICKETTSIAL VACCINES

The cattle used for the production of bloodvaccines, such as those for babesiosis andanaplasmosis, should be tested forinfectious agents which could contaminatethe blood vaccine (OIE, 1992) and sheepused for heartwater vaccine productionshould be free of Ana plasma ovis, Erlichiaovis and Trypanosorna ovis (Oberem andBezuidenhout, 1987).

STORAGE

Sufficient storage capacity in cold rooms,freezers or liquid nitrogen tanks is essentialfor storing vaccine or antigen. A minimumrequirement is a recordin.g system forvalidating constant temperature control,since a loss of refrigeration or freezing incold rooms can affect the antigen or thefinished product. If temperature monitor-ing cannot be done electronically, manualhourly checking can be done by production

staff and after hours by security staff.Ideally, alarm systems should be utilizedto alert production managers to sucheventualities.

DISPATCH AND DISTRIBUTION

Dispatch and distribution should pre-ferably be undertaken by distributors withfacilities for handling and dispatching thefinished product. Consigning vaccines tothe mercies of rail or road transport indeveloping countries can lead to seriouslosses. Vaccines are often offloaded at smallrailway sidings or bus depots over week-ends and the recipient is only informed ofthe arrival of the consignment the follow-ing Monday.

Maintaining a cold chain during thedispatch of biological products is com-monly believed to be an obstacle to usingvaccines in developing countries. Yilma(1989) mentions a particular problem inEthiopia with regard to hot arid conditions.Other authors (Belsham et al., 1989) havestated that cold chains are often availablefor medical supplies and human vaccinesand these can be utilized for veterinarybiologicals. Effective cold packages can bedevised using polystyrene containers intowhich frozen cool-bricks can be packed tokeep vaccine within the optimum tem-perature range for 24 hours, provided thepackage is well sealed.

Cold chain monitors are availablecommercially. These indicate by a colourchange on an indicator card whetherthe product has been exposed to hightemperatures for any length of time. Maxi-mum / minimum thermometers can beincluded in packages to monitor theirability to maintain the required tem-perature. In some countries, such asLesotho, where temperatures drop belowfreezing in winter and vaccine is sometimescarried on horseback, inactivated vaccinessuch as rabies must be transported ininsulated packages to prevent freezing.

POULTRY VACCINES FOR DEVELOPING

COUNTRIES

Producing vaccines for intensive poultryraising systems in developing countries isuneconomic owing to the very low unitcost at which these vaccines can besupplied by large international companies.The latter also produce a wide variety ofvaccines and can therefore provide thepoultry producer with a complete range ofproducts. In addition, intensive poultryfarming calls for vaccines with a high safetyand efficacy index. Any reactions causedby virulence of an attenuated strain,adjuvant reactions or infection withadventitious agents causing death, failureto protect, failure to gain weight or a dropin egg production will occur on a scalewhich affects the profit margins of theproducer. De novo development of poultryvaccines, therefore, requires extensiveefficacy and safety testing which fewdeveloping countries are able to undertake.The production of vaccines in embryonatedeggs requires a source of specific pathogen-free (SPF) eggs and SPF birds are requiredfor many of the QC tests performed forpoultry vaccines.

COMPANION ANIMAL VACCINES

Developing countries vary in their demandfor companion animal vaccines, other thanrabies which is usually the concern ofgovernment authorities. In general, thegreater the affluence of the country themore the attention given to the vaccinationof pet animals. As in the case of the poultryindustry, the demand for safety andefficacy of vaccines is high and, unless aproducer can do sufficient research anddevelopment and safety testing, producingthese vaccines is not economically viable.Producing a single component vaccinesuch as live attenuated distemper may befeasible, but more sophisticated consumerswill demand combination vaccines whichcontain multiple antigens.

Vaccine manual 219

220 The logistics of vaccine manufacture in developing countries

LICENSING OF BIOLOGICAL PRODUCTS

The situation with regard to the licensingof biologicals in developing countriesvaries considerably; in some SouthAmerican countries government au-thorities have the facilities for testingvaccines and have personnel who are wellinformed on vaccine production facilitiesand processes. Other countries may haveonly a small government department witha few officials encumbered with thelicensing of local and imported biologicals.These officials may not be well informedabout vaccines and vaccine production;often minimal data on safety and efficacyis required to license a product. In thesouthern African region, for example, eachcountry has its own small group oftechnical advisers. It may be advantageousfor countries in this situation to poolresources and devise a harmonized re-gistration and regulatory system, whichwill prevent duplication of registrationoffices and costs.

BIBLIOGRAPHY

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Bahnemann, H.G. 1990. Inactivation of viralantigens for vaccine preparation withparticular reference to the applicationof binary ethylenimine. Vaccine, 8:299-303.

Barteling, S.J. 1974. Use of polyethyleneglycol treated serum for the productionof foot-and-mouth disease virus ingrowing BHK suspended cell cultures.Bull. Off. int. Epiz., 81(11-12): 1243-1254.

Belsham, G.J., Anderson, E.C., Murray, P.K.,Anderson J. & Barrett, T. 1989. Immuneresponse and protection generated bya vaccinia virus recombinant expressing

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Doel, T.R. 1993. In A.R. Peters, ed. Vaccinesfor veterinary application. London,Butterworth-Heinemann.

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OIE. 1992. Manual of Standards for DiagnosticTests and Vaccines for List A and B Diseasesof Mammals, Birds and Bees, 2nd edition.Paris, Office International des Epizooties.

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Sterne, M. & Wentzel, L.M. 1950. A newmethod for the large-scale productionof high-titre botulinum formol-toxoidtypes C and D. J. Immunol., 65: 175-183.

Ubertini, B., Nardelli, L., Dal Prato, A.,Panina, G.F. & Santero, G. 1963. Large-scale cultivation of foot-and-mouthdisease virus on calf-kidney cellmonolayers in rolling bottles. Zentralbl.Veteriner. Med., (B), 10: 93-101.

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