Mds3 Ch19 Qualityassurance Mar2012

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Quality assurance for pharmaceuticals

Summary 19.219.1 Pharmaceutical quality 19.2

Pharmaceutical quality assurance framework Deningand assessing pharmaceutical quality Consequencesof poor pharmaceutical quality Determinants ofpharmaceutical quality Prevalence of poor-qualitypharmaceuticals Global quality-monitoring options

19.2 Practical approaches to quality assurance 19.8

19.3 Obtaining good-quality pharmaceuticals 19.10Careful product selection Careful supplier selection Product certication Product pedigrees Batchcerticates DRAs and the procurement markettoday Contract specications

19.4 Veriying the quality o shipped products 19.15Product identication technology Inspection of shipments Tiered pharmaceutical quality assessments Laboratorytesting

19.5 Maintaining pharmaceutical quality 19.17Appropriate storage and transport Appropriate dispensingand use Pharmaceutical product presentations: treatmentkits, co-packaging, and xed-dose combinations

19.6 Monitoring pharmaceutical quality 19.18Product problem reporting system Product recalls

19.7 Personnel and training in the supplysystem 19.20

Assessment guide 19.21

Reerences and urther readings 19.21

Figure 19-1 Quality assurance ramework 19.3Figure 19-2 Determinants o pharmaceutical quality 19.6Figure 19-3 Critical elements in quality assurance or

pharmaceutical procurement 19.10Figure 19-4 Sample medicine and supplier evaluation

orm 19.19

able 19-1 Medicines ound to have stability problems undertropical or high-temperature conditions 19.5

able 19-2 Percentage o tracer medicines that ailedquality testing in the public, private, and NGOsectors 19.8

able 19-3 Comparison o certificates used in pharmaceuticalprocurement 19.14

Box 19-1 Some substances exhibiting potential bioavailabilityproblems in conventional oral orms 19.5

Box 19-2 Countereits and diversion rom legalchannels 19.9

Box 19-3 WHOs prequalification o medicinesprogram 19.12

Box 19-4 Terapeutic window 19.16

CS 19-1 Building quality assessment inrastructure inanzania 19.11

Annex 19-1 Resource organizations 19.22

Part I: Policy and economic issues Part II: Pharmaceutical management Part III: Management support systems

Selection

Procurement

18 Managing procurement

19 Quality assurance for pharmaceuticals

20 Quantifying pharmaceutical requirements

21 Managing the tender process

Distribution

Use
http://www.msh.org/http://www.msh.org/http://www.msh.org/http://www.msh.org/


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19.2 P ROCUREMEN

19.1 Pharmaceutical quality

As in most manuacturing processes, the quality o afinal pharmaceutical product is determined by the start-ing materials, equipment, and technical know-how that gointo producing and packaging it. Unlike a steel bolt ora tailored suit, however, a medicine is a dynamic prod-uct whose color, consistency, weight, and even chemicalidentity can change between manuacture and ultimateconsumption. A medicine that passes all laboratory tests

upon receipt may be useless within a ew months i thepackaging, storage, and transportation conditions are notmaintained properly.

Te purpose o quality assurance in pharmaceutical sup-ply systems is to help ensure that each medicine reachinga patient is sae, effective, and o appropriate quality. Tequality o pharmaceutical products is ensured by the tech-nical and managerial activities o the quality system, whichincludes evaluating pharmaceutical product documenta-tion, perorming or reviewing quality-control laboratory

tests, and monitoring product perormance. Managerialactivities include selecting reliable suppliers, preparingcontract terms, monitoring supplier perormance, and per-orming inspection procedures throughout the distributionnetwork (Figure 19-1).

Note that quality assurance in pharmaceutical supply isnot the same as quality control in manuacturing.

Pharmaceutical quality assurance framework

Te ollowing five elements are critical to achieving theexpected treatment outcome. Using a pharmaceutical prod-uct to treat a patient presumes that the

1. Active pharmaceutical ingredient (API) has beenshown to be sae and effective or this treatment

2. Product is o suitable quality to provide an effectiveoutcome

3. Prescriber has accurately identified the need or thetreatment

Te purpose o quality assurance in pharmaceutical sup-ply systems is to help ensure that each medicine reachinga patient is sae, effective, and o acceptable quality. Acomprehensive quality assurance program includes bothtechnical and managerial activities, spanning the entiresupply process rom pharmaceutical selection to patientuse.

Established quality standards are published periodicallyin pharmacopoeias and in some government publica-tions. For the purposes o primary health care, the mostimportant characteristics o a pharmaceutical productare identity, purity, strength, potency, uniormity o dos-age orm, bioavailability, and stability.

Pharmaceutical quality is affected by starting materials,manuacturing process, packaging, transportation and

storage conditions, and other actors; these influencesmay be cumulative.

I a pharmaceutical does not meet established qual-ity standards, passes its expiration date, or has beendegraded by storage conditions, the possible conse-quences are

Lack o therapeutic effect, leading to prolonged ill-ness or death

oxic and adverse reactions Waste o limited financial resources Loss o credibility o the health care delivery system

A comprehensive quality assurance program must ensurethe ollowing

Pharmaceuticals selected have been shown to be sae

and efficacious or their intended use, are presentedin an appropriate dosage orm, and have the longestpossible shel lie.

Suppliers with acceptable quality standards areselected.

Pharmaceuticals received rom commercial suppli-ers and donors meet specified quality standards atthe time o delivery.

Packaging meets contract and usage requirements. Repackaging activities and dispensing practices

maintain quality. Storage and transportation conditions do not com-

promise product quality. Product quality concerns reported by prescribers,

dispensers, and consumers are properly catalogedand addressed.

Product recall procedures are implemented toremove deective products.

A quality assurance program should include training andsupervision o staff members at all levels o the supplyprocess and a suitable inormation system. Ofen, publicofficials must balance the costs o establishing and main-taining quality assurance systems against the benefits ohaving sae and effective medicines.

S U M M A R Y


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19 / Quality assurance for pharmaceuticals 19.3

4. Prescriber or dispenser has properly instructed thepatient on how to use the product

5. Patient complies with the prescribed regimen correctly

Te first two items are product-specific issues, whichare the most easily addressed technically, whereas itemsthree and our are practitioner-specific and depend on thepractitioners education, knowledge, and skill as well asthe rigorous enorcement o perormance standards. Itemfive is a patient-specific issue that depends on the patientsknowledge and commitment and the patients access toservices.

Te saety and effectiveness o an API may be establishedeither through a review o historical usage, such as in thecase o digoxins evolution rom the oxglove plant (digi-talis purpurea), or through complex procedures establishedor new chemical entities, such as those described by the

International Conerence on Harmonisation o echnicalRequirements or Registration o Pharmaceuticals orHuman Use (ICH).

Afer the saety and effectiveness o an API has beenapproved or marketing in an ICH market region, otherregions o the world ollow with little or no additionalassessment. Te ICH economic zones (European Union,Japan, United States) perorm almost 100 percent o thepharmaceutical research and consume over 85 percent (by

value) o the pharmaceutical products in the world. Teseregions allocate large amounts o resources to ensure thesaety and effectiveness o APIs granted market authoriza-

tion in their zones. Once the saety and efficacy have beenestablished through these procedures, other regions do nothave to expend the same level o resources to establish theseattributes. However, other product-quality issues, includ-ing bioavailability and bioequivalence, content uniormity,impurities and degradation, and medicine saety (pharma-covigilance), should be monitored on an ongoing basis in allmarket zones.

Te complexity o globalized pharmaceutical marketsand the difficulty in ensuring quality o imported products,

including API, have been illustrated in headlines aboutdeaths caused by adulterated products such as cough syrupin Peru and heparin in the United Statesboth tied toingredients rom China. As a result, the U.S. Food and Drug

Administration (FDA) seeks to increase its global presenceto make monitoring oreign manuacturers easier and tostrengthen its involvement with harmonization o pharma-ceutical standards (FDA 2010). In addition, the FDA wantsto help build regulatory capacity in oreign counterparts. Aspart o that international effort, the agency has opened per-manent offices in a number o cities around the world andhas entered into dozens o agreements with other drug regu-latory authorities (DRAs) to share inspection reports andother private inormation that can help improve the qualityo pharmaceutical products worldwide.

Te pharmaceutical regulatory and quality assurance pro-cesses that should be addressed by a countrys DRA include

(WHO 2004b)

Product registration: assessing and authorizing prod-ucts or market entry and monitoring their saety andeffectiveness afer entry

Regulation o manuacturing, importation, and distri-bution

Quality o manuacturing (good manuacturingpractices)

Procurement integrity (assuring the qualifications osuppliers)

Quality o medicines in the distribution system

(including product and premises inspection andproduct screening and testing) Regulation o medicine promotion and inormation:

including postmarketing pharmacovigilance and con-sumer education

O course, a countrys quality assurance system is only aseffective as its ability to monitor and enorce regulations.A country should address all issues at some level as parto a basic pharmaceutical quality assurance inrastructure;

Figure 19-1 Quality assurance framework

Decision makingand enforcement

Document review

Inspection of local/importedproduct samples, manufacturing

sites, and marketplace

Product testing

Reporting

Data analysisand evaluation

Source: CPM/MSH 2011.


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19.4 P ROCUREMEN

however, in a resource-constrained setting, the risks topatients or each process must be assessed so resources canbe allocated to ocus on the most significant health threats.

Defining and assessing pharmaceutical quality

Pharmaceutical quality can be defined and tested in manyways. Quality standards are published periodically in phar-macopoeias and in some government publications, whichprovide detailed descriptions o pharmaceutical character-istics and analytical techniques. Standards may vary slightlyrom one pharmacopoeia to another, so a particular phar-maceutical may meet the standards o one pharmacopoeiaand not those o another. When public standards have notbeen established, as is generally the case or newly marketedpharmaceuticals, analytical methods developed by the man-uacturer and submitted as a part o the tender or marketingauthorization requirements are usually applied.

Te major pharmaceutical manuacturing and export-

ing countries publish their own pharmacopoeias, andon a regional basis, the European Pharmacopoeia estab-lishes standards that are enorced by the governmentso the European Union and others that adopt them. TeInternational Pharmacopoeia, published by the World HealthOrganization (WHO), the U.S. Pharmacopeia, and theBritish Pharmacopoeiaare used requently by public-sectorpharmaceutical supply programs in developing countries.

One important limitation o the European Pharmacopoeiais that it provides ew specifications or individual dosageorms. Te WHO International Pharmacopoeia (WHO2008a) includes monographs on finished dosage orms,including antiretrovirals and newly developed antimalarial

medicines. Analytical procedures in the U.S. Pharmacopeiatend to use complex and expensive technology, which maybe beyond the reach o many developing countries. TeEuropean, Japanese, and U.S. pharmacopoeias are engagedin ongoing efforts to harmonize some o their standards,but progress is slow. Until common standards are finallyachieved, purchasers must speciy which dosage orm stan-dards are acceptable.

For pharmaceutical procurement organizations, pharma-ceutical quality is assessed as the products compliance withspecifications concerning identity, purity, strength, potency,and other characteristics. Uniormity o the dosage orm,

bioavailability, and stability are important characteristicsthat are also considered in the specifications.Identity. Te identity test should confirm the existence o

the active ingredient(s) indicated on the label. Tis charac-teristic is generally the easiest to check.

Purity. In addition to the API, most pharmaceuticals aremade with ingredients added or bulk, consistency, or colorthat should not contain potentially harmul contaminantsor microorganisms. Te product should not have significantquantities o other products rom cross-contamination.

Strength or potency. Te medicine should contain thedeclared amount o API. Harmul by-products o degrada-tion must be absent or should be below defined limits. Mostpharmacopoeias speciy an average content range, such as90 to 110 percent o the amount written on the label, ratherthan an exact amount. o ensure a long shel lie, manuac-

turers ofen produce pharmaceuticals with the maximumallowable amount (or example, 110 mg rather than 95mg), which provides a margin o saety or slight losses instrength or potency over time.

Uniformity of dosage form. he consistency, color,shape, and size o tablets, capsules, creams, and liquidsshould not vary rom one dose to the next. Any lack o uni-ormity may suggest problems with other quality parameterssuch as identity, purity, or strength or potency. Lack o dos-age uniormity may not influence the saety or effectivenesso a medicine, but it does reflect a lack o good manuactur-ing practices, which could influence the acceptability o aproduct to pharmacists, medical practitioners, and patients.

Bioavailability. Bioavailabilityreers to the speed andcompleteness with which a pharmaceutical administeredin a specific orm (tablet, capsule, intramuscular injection,subcutaneous injection) enters the bloodstream. Te bio-availability o a product may depend on the other ingre-dients used in the ormulation, such as solvents, binders,coloring agents, and coatings, or how ingredients are com-bined.

Te comparative bioavailability o two pharmaceuticals isparticularly important when a product that is usually pur-chased rom one manuacturer is replaced with a productcontaining the same drug substance in the same dosageorm, and in the same amount, but manuactured by a di-

erent firm. Even though the products both contain the cor-rect amount o the API, the preparations may not give theexpected therapeutic result i the API is released too quickly,too slowly, or incompletely when they are compared. wopharmaceuticals are said to be bioequivalentand may beused interchangeably i both are absorbed into the blood-stream at the same rate and to the same extent.

Human bioequivalence studies are required or a numbero medicines. Box 19-1 lists some medicines documentedto have problems in bioavailability that require studies todetermine the bioequivalence o products. Guidelines areavailable or the study o bioavailability, as well as specific

bioavailability protocols or a small number o medicines(WHO/EURO 1988; USP 2007).I purchasing is done through established and reliable sup-

pliers, the bioavailability o most brand-name and genericmedicines used in primary health care is sufficient to ensurethat the patient receives the intended effect. Deciding whichpharmaceuticals have a potential bioavailability problemis important, because manuacturers cannot supply clini-cal studies or all products, and government procurementprograms generally cannot perorm bioequivalence test-


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ing. Te Biopharmaceutical Classification System can helpidentiy potential bioavailability problem products (Kasimet al. 2004). Where pharmaceutical registration systemsexist, manuacturers or suppliers should be required to sup-ply data on clinical studies whenever needed. Procurementagencies should also work with country DRAs and use theirinormation in making decisions.

Stability. o be useul, a pharmaceutical must retain itsproperties within specified limits, such as particular storageconditions. Te manuacturer and, in some cases, a coun-trys DRA establish the time that a pharmaceuticals stabilityis under warranty, which ends with the expiration date. Aproducts stability depends on the active ingredient, which

can be affected by its ormulation and packaging. Improperstorage and distribution can lead to physical deteriorationand chemical decomposition, reduced potency, and occa-sionally, ormation o toxic by-products o degradation.Tese effects are more likely to occur under tropical condi-tions o high temperature and humidity.

WHO has published a list o pharmaceutical substancesthat are less stable and thereore require particular atten-tion (WHO 1990). However, ew data are available on thestability o medicines under true field conditions. Te ICH,

whose members comprise experts rom the major pharma-ceutical manuacturing countries, has established guide-lines on quality testing and storage in tropical regions (ICH2003). WHO has been updating its stability guidelines withinput rom member country DRAs and in cooperation withICH (WHO 2010d, 2009b). Several studies have exam-ined the stability o a small number o essential medicinesunder tropical conditions o excessive temperature (over40C), high humidity, and inappropriate storage condi-tions (Gammon et al. 2008; Hogerzeil et al. 1991; Hogerzeil,Walker, and de Goeje 1993). able 19-1 lists the medicinesthat have been ound to have problems under tropical andhigh-temperature conditions.

Consequences of poor pharmaceutical quality

A poor-quality medicine is one that does not meet specifi-cations. Te use o poor-quality products may have unde-sirable clinical and economic effects, as well as affect thecredibility o the health delivery system. Clinical effectscan include prolonged illness or death or adverse reactions.On the economic side, limited financial resources may bewasted on poor-quality medicines.

Table 19-1 Medicines found to have stability problems under tropical or high-temperature conditions

Oral solids (tablets) Oral liquids (syrups) Inhalation Injections/injectables

Acetylsalicylic acid

Amoxicilline

Ampicillin

Diltiazem

Lopinavir/ritonavir

Penicillin V

Retinol

Paracetamol Ipratropium Ergometrine

Lidocaine

Methylergometrine

Succinylcholine

Naloxone

Sources: Gammon et al. 2008; Hogerzeil et al. 1991; Hogerzeil et al. 1992; Hogerzeil, Walker, and de Goeje 1993; Pau et al. 2005.

API

Aminophylline

Ampicillin Carbamazepine Chloramphenicol Chloroquine Chlorpromazine Digitoxin Digoxin Dihydroergotamine Ergotamine Erythromycin

Estrogens, conjugated or esterified

Furosemide Glibenclamide Glyceryl trinitrate Griseoulvin Hydrochlorothiazide Iron sulate Isosorbide dinitrate Levodopa L-thyroxine Methotrexate

Methyldopa

Nitrourantoin Phenytoin Prednisolone Prednisone Quinidine Riampicin Spironolactone Teophylline Wararin

Source: WHO/EURO 1988.

Box 19-1

Some substances exhibiting potential bioavailability problems in conventional oral forms


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19.6 P ROCUREMEN

Figure 19-2 Determinants of pharmaceutical quality

Pharmaceutical production Plant environment

temperature

humidity cleanlines

Equipment andmaintenance

Manufacturingprocess

Pharmaceuticalformulation

Qualitycontrol

Immediatepackaging

Activeingredients

Port conditions

Shippingconditions

Repackaging: materials equipment procedures

Warehouseconditions

Transportationconditions

Storageconditions

Dispensing

conditions

Patient

handling

Externalpackaging

Inactiveingredients

diluent colors flavors emulsifiers coatings disintegrators bindings


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Lack of therapeutic effect may lead to prolonged illness

or death. Poor pharmaceutical quality can sometimes leadto serious health consequences and deathor example,the use o poor-quality cardiac medicines and medicinesor seizures and asthma. With others, such as cold remediesand minor painkillers, a reduction o up to 50 percent in the

content o the active ingredient may not have serious conse-quences apart rom ineffectiveness, although the best pro-curement policy requires all products to meet specifications.

Poor-quality pharmaceuticals may induce toxic or

adverse reactions. When some products expire or areexposed to adverse climatic conditions (or example, exces-sive heat and humidity), they may undergo physical orchemical changes that can result in the ormation o pos-sibly toxic degradation products. Although ear o toxicpharmaceutical degradation in tropical climates is preva-lent, tetracycline is the only common medicine in which it isknown to occur. Excessive active ingredients may also leadto toxic or adverse reactions.

A much more requent problem is contamination withmicroorganisms, usually bacteria or ungi. Te conse-quences o this lack o sterility can be quite severe, par-ticularly in the case o injectable medicines or in patientswho are immunocompromised. Contamination o creams,syrups, and other medicines in jars and tubes is especiallycommon in tropical environments, but the consequences

vary, depending on the type o organism and the phar-maceutical involved. Errors in ormulation and productcontamination are uncommon with manuacturers whostrictly comply with internationally accepted proceduresand good manuacturing practices (GMPs). In practice,however, adherence to GMPs may vary rom country to

country, rom manuacturer to manuacturer, or evenbetween production runs at the same manuacturer. Whencontaminants are highly toxic or when toxic substancesare inadvertently included in the product, the result canbe catastrophic.

Poor pharmaceutical quality wastes money. Ineffectivecare or the need to treat adverse drug reactions resultingrom poor product quality leads to more costly treatments.Poor pharmaceutical packaging casts doubts on prod-uct quality, leading to rejection by health personnel andpatients. Tese products will then expire on the medicalstores shelves, wasting limited financial resources.

Poor pharmaceutical quality may seriously affect healthsystem credibility. Patients and providers may suspect thequality o medicines when therapeutic ailure or adversedrug reactions occur. Changes in product appearance, suchas discoloration, crumbling o tablets, and hardening o oralsuspensions, or changes in taste and smell rightly influencepatients perceptions o product quality. Patients may be dis-couraged rom using health acilities, and worker moralemay be affected, particularly i medicine shortages are alsocommon.

Determinants of pharmaceutical quality

Te quality o a medicine product coming off the productionline is determined by the start-up materials, plant environ-ment, manuacturing equipment, and technical know-howinvested in developing and manuacturing the pharmaceuti-

cal. Te medicine that ultimately reaches the patient, how-ever, is urther affected by packaging and by transportationand storage conditions.

Tese influences, especially actors in the manuacturingprocess, can be cumulative. For example, the excipient sub-stances used to give tablets bulk and consistency may notaffect the color, texture, or chemical quality o a pharma-ceutical until the immediate container is opened in a hot,humid environment. Ten, depending on the ingredients,the tablet may remain firm and dry or become moist andcrumble within a matter o days. Factory humidity duringpackaging may also affect quality. I oral rehydration sachetsare not packaged in a very low-humidity environment,

moisture enters the sachet and may result in chemical orphysical changes in the mixture that make it difficult to use.Similarly, the amount o grinding, thoroughness o mixing,choice o packaging, maintenance o packaging equipment,and other actors can have an effect that may not appearuntil the medicine reaches the point o consumption. Figure19-2 summarizes these influences.

Te dynamic nature o pharmaceuticals and the cumu-lative effects o the production process, right through topackaging, handling, transport, and storage conditions,require quality assurance at all levels in the pharmaceuti-cal supply system (seeA Model Quality Assurance System

for Procurement Agencies[WHO/UNICEF/UNDP/UNFP/

World Bank 2007]).

Prevalence of poor-quality pharmaceuticals

Data summarized in able 19-2 indicate the extent o thepharmaceutical quality problem, as detected by pharmaceu-tical quality testing in the public, private, and nongovern-mental organization (NGO) sectors o six countries.

In recent years, national and international authoritieshave recognized the emergence o countereit medicinesas a serious problem. In most industrialized countries witheffective regulatory systems and market control, the inci-

dence o countereit medicines is an estimated 1 percent omarket value (WHO 2010b). Tereore, most countereit-ing cases occur in developing countriesespecially in Asia,where many o the countereit medicines are produced, andin Arica, where poverty and loose regulatory oversightmake marketing o countereit products easier (see Box19-2). However, countereiting is an increasing problem inall countries, including developed countries, where Internetpurchases are popular. Over hal o Internet medicine pur-chases rom illegal websites are countereit (WHO 2010b).


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19.8 P ROCUREMEN

Global quality-monitoring options

Currently, no global pharmaceutical quality standardsexist, even or the APIs used in worldwide pharmaceuti-cal product ormulation, which are produced by only a ew

countries. However, the ICH processes to establish GMPsor APIs were more inclusive than any o the previous pro-cesses; or example, besides the usual ICH parties, repre-sentatives rom the generics industry, the sel-medicationindustry, and the Pharmaceutical Inspection Conventionand Pharmaceutical Inspection Co-operation Scheme wereincluded in the deliberations (ICH 2000).

Tese GMP standards are the worlds first harmonizedstandards and have been adopted by the ICH regionsand the Pharmaceutical Inspection Convention andPharmaceutical Inspection Co-operation Scheme, in addi-tion to WHO and many other countries. Tis harmoniza-tion implies that any DRA could perorm an inspection

o an API manuacturer and expect it to conorm to theseconsensus GMPs. However, because almost all sovereignnations or market zones protect their local production opharmaceutical products through selective tariffs and othermechanisms, no incentive exists or the development o aworldwide quality standard or APIs (Chapter 7). Somepharmacopoeias, including the European Pharmacopoeiaand WHOs International Pharmacopoeia, have regionalquality standards or many APIs; however, these pharma-copoeial standards have not been harmonized, resulting in

varying specifications or APIs among regions (see Chapter6 or more inormation on pharmacopoeias).

Because o the lack o harmonized standards, no basisexists or a pharmaceutical product common market withuniversal recognition o quality standards. Te dearth ointernationally recognized specifications leaves each mar-ket zone to establish its own specifications. Among themajor pharmacopoeias, only the British Pharmacopoeiaand the U.S. Pharmacopeia have standards or a signifi-cant number o products, and even they have essentiallyno specifications or products under patent protection intheir markets.

19.2 Practical approaches to quality assurance

Te procedures to establish a comprehensive quality assur-ance program can be divided into three categories

1. Procedures to ensure that only medicine products thatmeet current standards or quality are bought. Teseinclude Careul product selection Careul supplier selection Certificate o analysis or each batch o product Certification o good manuacturing practices Batch certification (WHO-type certificate o a phar-

maceutical product) Inclusion o detailed product-quality specifications

in the contract2. Procedures to veriy that shipped goods meet the speci-

fications. Tese include Pre- and postshipment inspection Analytical pharmaceutical testing

3. Procedures to monitor and maintain the quality opharmaceuticals rom the moment they are receiveduntil the medicine is finally consumed by the patient.Tese involve Proper storage and distribution procedures Appropriate dispensing Instructions to the patient on proper use o medica-

tions Product deect and pharmacovigilance reporting

programs

Few pharmaceutical management programs can effec-tively manage all the possible quality assurance activitiesor all the medicines that are procured. Consequently,realistic goals must be set to identiy the combination omanagerial and technical quality assurance activities thatwill be most effective under existing conditions. Te criti-cal elements in quality assurance or pharmaceutical pro-curement are listed in Figure 19-3, and Country Study 19-1discusses how the anzania Food and Drugs Authority

Table 19-2 Percentage of tracer medicines that failed quality testing in the public, private, and NGO sectors

CountryNumber ofmedicines

Number ofsamples Public facilities Private facilities NGO facilities

Brazil (Minas Gerais) 8 64 13.6 9.1 10.0

Cambodia 14 132 13.0 9.6 7.7

El Salvador 10 87 50.0 28.6 27.3Tanzania 10 110 12.9 13.0 0

Ghana 7 103 6.3 2.9 0

India (Rajasthan) 9 125 6.0 12.7 0

Source: CPM 2003a, 2003b, 2003c, 2003d, 2003e, 2003f.


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Recent examples o dangerous countereit medicines inthe marketplace in countries worldwide include

Southeast Asia: O 391 samples o artesunate, 50 per-cent had little or no active ingredient and a wide rangeo wrong ingredients, including banned pharmaceuti-cals (Newton et al. 2008).Madagascar, Senegal, and Uganda:O 197 anti-malarial samples rom the public and private sectorsthat underwent ull laboratory quality-control test-ing, the ailure rates rom Senegal, Madagascar, andUganda were 44 percent, 30 percent, and 26 percent,respectively (USP and USAID 2009).United States: Te FDA warned consumers about 24websites selling countereit medicines (FDA 2007).Democratic Republic of Congo: Te antidepressant

fluvoxamine and the muscle relaxant cyclobenza-prine HCl had been labeled and sold as commonlyprescribed antiretrovirals or HIV/AIDS treatment(Ahmad 2004).Niger: Up to 2,500 people reportedly died afer beinggiven a ake meningitis vaccine (WHO 2003).

WHO defines countereit medicines as those that aredeliberately and raudulently mislabeled with respect toidentity and/or source (WHO 2010c). Within this broaddefinition, it is useul to consider different categories ocountereiting activities

Proessional countereit organizations have modernproduction acilities capable o manuacturing prod-ucts and labeling strikingly similar to the authenticproducts. Tey operate in the most lucrative mar-ketsmostly developed countries.

Mediocre countereit organizations produce poorlymade look-alike products that in a side-by-sidecomparison can be discerned rom legitimateproducts.

Minor relabelers distribute to only a ew outlets inan attempt to preserve the value o their outdatedinventory by relabeling expired products with validexpiration dates and the same product name.

More advanced or major petty relabelers deal ina secondary pharmaceutical market or outdatedproducts primarily obtained rom legitimate sourcesin developing and developed countries but distrib-uted mostly in developing countries.

Substitution countereiters place lower-priced fin-ished dosage orms into more expensive packagingor marketing at higher prices. Tese relabeled out-dated products may be distributed in developing ordeveloped countries.

Formulating countereiters generally do not include

the active pharmaceutical ingredient in the ormula-tion. Substitution countereiters generally use thewrong medicine, whereas the relabelers generallyhave the right API present in about the right amount.Tereore, relabelers are the most difficult to detect, itheir labeling is well done. Generally, most counter-eits have flawed labels that can help identiy them assubstandard. I the pharmaceutical product is providedwithout its original label, however, this eature may notalways be helpul in identiying countereit products.Local or within-country countereit marketing dependson astute practitioners and consumers or detectionand a good internal communication system to supportprompt legal action.

Te different characteristics o countereiters can beroughly summarized as ollows in the table below.

In 2006, WHO launched the International MedicalProducts Anti-Countereiting askorce, which is WHOsprimary channel or anti-countereit activities.

Box 19-2

Counterfeits and diversion from legal channels

Category APIa Distribution scaleProductqualityb

Labelqualityc Detection

Professional No Large; frequently international Very good Excellent Testing, side-by-side comparisons

Hack No Generally within a country or alimited region of a country Poor Good Testing, physical examination

Minor petty Yes? Generally a few privately held stores Very good Good Label examination

Major petty Yes? Generally a limited market segmentin a given country

Excellent Good Label examination

Substitution No Generally a few privately held stores Good Good Testing, examination

a In general, only the relabelers may have the correct product.b Physical appearance, uniformity.cPrint quality, color.


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19.10 P ROCUREMEN

approached the design o its pharmaceutical quality assur-ance program.

Because resources are limited, countries should targetpriorities or quality assurance activities. Te VEN (vital,essential, nonessential) method (Chapter 40) helps iden-tiy a small group o medicines that have the greatest health

impact. Vital liesaving medicines (antibiotics, cardiac medi-cations, and intravenous solutions) warrant greater atten-tion than other important but not liesaving medications,such as analgesics. ABC analysis (Chapter 40) can be usedto identiy those medicines that have the greatest budgetaryeffect i their quality is unacceptable. Te choice o medi-cines to monitor closely is based on the ollowing criteria

Medicines with a narrow therapeutic window Medicines with inherent bioavailability problems Modified-release preparations Products rom new suppliers and suppliers with prob-

lems in the past

Medicines that require stable dosage orms andappearance

19.3 Obtaining good-quality pharmaceuticals

Obtaining medicines o good quality involves careul selec-tion o suppliers and products, compliance with GMPs,reliance on appropriate pharmaceutical product or batchcertificates, and detailed contract specifications.

Careful product selection

In many systems, therapeutic medicine ormulary commit-tees first assess the saety and efficacy o selected medicineson the basis o evidence rom clinical trials (Chapter 16).Specific product selection involves assessing the technicaldocumentation provided by the supplier on the pharmaceu-tical characteristics o the dosage orm. Dosage orms thatmay offer longer shel lie include

Powders or reconstitution instead o injectable liquids Powders or reconstitution instead o oral suspensions ablets instead o capsules

When appropriate, request and review product-specificstability studies rom the manuacturer. For a ew medicines,such as certain heart, asthma, and seizure medicines, studiesthat demonstrate bioequivalence among different manuac-turers products may also be necessary.

Select products with packaging that can withstand roughtransport and extreme climatic conditions. Plastic contain-ers may be better than glass bottles or intravenous solu-tions, oral liquids, and disinectants. Avoid metal tins thatwill rust. In some countries, unit-o-use packages (blister

Figure 19-3 Critical elements in quality assurance for

pharmaceutical procurement

1. Product selection products with longer shelf

life (for example, powders forreconstitution rather than oralsuspensions)

avoidance of products withbioavailability problems, whenpossible

2. Product certification supplier prequalification recent GMP inspection reports

from national drug authorities formal supplier-monitoring

system limitation of purchases from new

suppliers to noncritical products

3. Product certification GMP certificate from

drug regulatory authority(prequalification)

certificate of pharmaceuticalproducts (WHO-type) for all newproducts, new suppliers

batch certificate (WHO-type) forproblem drugs only

4. Contract specifications acceptable pharmacopeial

standards language, labeling requirements minimum shelf life packaging standards

5. Inspection of shipments physical inspection of all

shipments sampling for analysis of suspect

products

6. Targeted laboratory testing therapeutically critical drugs drugs with known bioavailability

problems new suppliers suppliers with quality difficulties

in the past

7. Product problem reportingsystem

system for reporting suspect orproblem products


11/23


packs) and containers with smaller quantities (or example,100 tablets rather than 1,000 tablets) may be cost-effective.Tese measures aim to avoid quality loss afer the containersare opened or as a result o requent handling. Te increasedcosts should be weighed against the wastage and contamina-tion that may occur with bulk containers, plus the costs o

any repackaging.

Careful supplier selection

Tis step may be the most critical in quality assurance (seeChapter 21). Suppliers can be selected competitively byrestricted tender with prequalification, through open ten-

der with postaward qualification, or in some cases, throughless ormal procedures (see Chapters 18 and 21). Standardprocedures should include requiring certifications, gather-ing inormation on supplier reliability and product quality,inspecting product samples, and i necessary, conductinglaboratory testing o pharmaceuticals with high potential or

bioavailability or stability problems. Country procurementoffices obtained a major resource or helping assure qualitypharmaceutical purchases when WHO launched its medi-cine prequalification program in 2001. Box 19-3 has moreinormation on the program.

Contacts with DRAs and purchasing groups (or example,the United Nations Childrens Fund and IDA Foundation)

Substandard pharmaceuticals circulating in the mar-

ket are a problem in many countries. As part o a 2001assessment, the Strategies or Enhancing Access toMedicines (SEAM) program took 110 samples o ten di-erent medicines and ound that 12.9 percent o the sam-ples rom public acilities and 13 percent rom privatepharmacies were substandard. A urther measure o thequality o medicines in the marketplace is the percentageregistered with the anzanian Food and Drugs Authority(FDA). Only 26 percent o the medicines surveyed inthe thirty-nine duka la dawa baridi,which are privatedrug shops, were registered, while a urther 24 percentwere notified. Te quality o notified and unregisteredmedicines cannot be assured, since they have not passedthrough the registration process, which would includealmost three-quarters o medicines sampled at the dukala dawa baridi.

SEAM collaborated with the FDA to establish a com-prehensive national quality assurance program that canensure that both imported and locally manuacturedpharmaceutical products meet approved quality stan-dards. Te main ocus o the intervention was on productexamination and testing at ports o entry and surveil-lance and testing o products circulating in the market.Market surveillance requires routine inspection o acili-ties and sampling o products in the marketplace, includ-

ing distributors and retail outlets. Tis strategy requiredenhancing inspection and pharmaceutical testing capac-ity within the FDA, which involved developing andincorporating a number o tools and activities, amongthem the ollowing

Flow charts and standard operating procedures orstructured inspection activities at ports o entry andacilities, such as warehouses, hospital dispensaries,

retail pharmacies, and over-the-counter drug shops.

Te flow charts and procedures have been compiledinto aLevel One Drug Inspectors Handbook.

A thin-layer-chromatography-based program toscreen pharmaceutical products (initially targeted atantimalarial medicines, then selected antibiotics andantiretrovirals).

Quality assurance protocols and training materialsbased on a combination o visual inspection andnon-laboratory-based testing (using thin-layer-chromatography Minilab). School o Pharmacy ac-ulty at the Muhimbili University College or HealthSciences collaborated on the development and over-sight o the inspectors training.

Support or FDA inspectors training, and moni-toring and evaluation.

Personal digital assistants to standardize the inspec-tion process and allow computer downloads oinspection results or management review.

Working closely with stakeholders and sensitizing themto quality requirements helped get the quality assur-ance program established in 2002. Since then, improvedefficiencies have resulted in a doubling o the number opharmaceutical products screened and a quadruplingo the number o premises inspectedall with relativelyew inspectors. Te new quality assurance program has

resulted in many product confiscations and importa-tion reusals, in addition to closures o premises andimprovements in standards. In summary, the qualityassurance activities were conducted with relatively mod-est resources yet increased the presence o the FDA inthe marketplace, providing a significant deterrent to themarketing o substandard and countereit products.

Source: SEAM 2007.

Country Study 19-1

Building quality assessment infrastructure in Tanzania


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19.12 P ROCUREMEN

and product-quality testing laboratories can help with reer-ence checks and exchanges o inormation on problem prod-ucts. Publications by medicine inormation services andproessional organizations, such as the U.S. Pharmacopeia,the FDA, and the American Society o Health-SystemPharmacists, provide inormation on the bioequivalence opharmaceuticals as well as on pharmaceutical recalls (seeAnnex 19-1).

A procurement office or agency needs to analyze inor-mation on suppliers perormance and develop and applyoperational definitions and criteria to assess the reliabilityo suppliers and avoid subjectivity. Lack o explicit defi-nitions and criteria provides rejected suppliers with theopportunity to question the integrity o the procurementprocess.

For products rom new suppliers, visual inspection osamples o the product, packaging, and labeling is impor-tant. Some programs send samples or laboratory testingon a routine basis; others do so only when concerns ariseabout specific products. Although prepurchase testing may

detect deective products, bear in mind that the samplesare provided by the supplier, which will make every effortto ensure that the samples meet the standards. Te sam-ples may not, however, be representative o what is actuallydelivered.

Chapter 21 discusses the need or an inormation systemthat provides the procurement office and tender commit-tee with eedback on suppliers compliance with contracts.Keeping a record o condition o received goods, compliancewith contract terms, and timeliness o delivery is essential.

Tis inormation, and that rom the adverse drug reactionand product-quality reporting system, should be consideredwhen assessing offers and awarding supply contracts.

Product certification

WHO has established GMPs or pharmaceutical products,similar to those enorced by the national pharmaceutical

control agencies in industrialized countries. Tey includecriteria or personnel, acilities, equipment, materials, man-uacturing operations, labeling, packaging, quality control,and in most cases, stability testing.

In countries with effective pharmaceutical control agen-cies, adherence to GMPs is enorced by a system o inspec-tions and regulatory controls, ofen specific to individualmedicine dosage orms. A manuacturer may have accept-able standards or solid dosage orms but not or sterileinjectable preparations. Recent reports o GMP inspectionsand pharmaceutical recall histories can be obtained by writ-ing to national pharmaceutical control agencies. Ofen, a

supplier must approve or at least expedite requests or per-ormance reports rom national pharmaceutical controlagencies, and ailure to obtain such reports or the buyermakes past perormance suspect.

Buyers with pharmaceutical staff trained in GMP inspec-tion may perorm their own inspections o local manuac-turers that are potential suppliers, i unds are available todo so.

Countries that participate in the scheme agree to certiythat pharmaceuticals are registered in the exporting country

In 2001, WHO, in partnership with the United NationsJoint Programme on HIV/AIDS, the United NationsChildrens Fund, and the United Nations PopulationFund, and with support rom the World Bank, launchedits prequalification o medicines program to assess andapprove manuacturers o medicines to treat HIV/AIDS,malaria, and tuberculosis. Since then, the program hasadded medicines and commodities related to reproductivehealth, and it also prequalifies quality-control laboratories.Te program evaluates data on medicine saety, efficacy,and quality and inspects acilities or compliance withGMPs. Inspection activities have expanded to includemanuacturers o selected APIs as well as clinical sites andcontract research organizations. In addition, the programoffers training workshops on how to meet prequalifica-

tion requirements, assess multisource interchangeablemedicines, and conduct and assess stability studies.

In 2009, the program prequalified 44 products, or atotal o 237 products manuactured in sixteen countries(WHO 2010c). Te program also prequalified threenew quality-control laboratories to bring the total toeleven.

Originally intended or United Nations procurementagencies, the program has become a valuable resource orany purchaser, including countries themselves.

More inormation on the prequalification program ison WHOs website at http://apps.who.int/prequal/ . Tewebsite lists all product and manuacturing site require-ments, standards used in evaluating the product, and theprofile o the inspection teams. It also includes the list oprequalified medicines and their manuacturers.

Source: WHO 2010c.

Box 19-3

WHOs prequalification of medicines program
http://apps.who.int/prequal/http://apps.who.int/prequal/


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and that manuacturers acilities have been inspected andcomply with GMPs. However, a WHO study (1995) showedthat very ew importing countries actually request pharma-ceutical product certificates or registration or procurementpurposes.

Tis certification scheme provides some assurance, based

on inspection o the manuacturing acilities or GMPs bythe competent authority o the exporting country. For theprocurement office, it is an inexpensive means to help ensurethe quality o purchased products. Trough the certificationscheme, the procurement office should be able to obtain theollowing inormation

Whether a product is legally marketed in the exportingcountry, and i not, the reasons why

Whether the supplier manuactures the dosage orms,packages, and/or labels a finished dosage orm manu-actured by an independent company, or is involved innone o these activities

Whether the manuacturer o the product has beeninspected and the periodicity o inspection

Whether the certificate is provisional, pending techni-cal review

Whether the inormation submitted by the suppliersatisfies the certiying authority on all aspects o manu-acture o the product undertaken by another party

Te reliability o the pharmaceutical product certificatesissued under the WHO scheme and access to them dependlargely on the

Reliability and responsiveness o the exporting coun-

trys authority Capability o the exporting countrys authority to make

adequate GMP inspections Capability o the importing countrys authority to

assess the authenticity or validity o the certificate o apharmaceutical product submitted, especially when itis submitted through the manuacturer or importingagent

Tereore, product certification under the WHO schemeis only as reliable as the agency perorming it, and WHOestimates that only about 20 percent o member countries

have a national drug regulatory system that can ensurethe quality o medicines circulating in their national mar-kets (WHO 2008b). For this reason, certificates should beaccepted with caution unless the national DRAs compe-tence to ulfill the scheme is known. In addition, althoughnational pharmaceutical-control agencies in the majorpharmaceutical-exporting countries are generally conscien-tious in their assessments, receiving reports may take sometime. Agencies in some countries have been ound to be lessreliable and responsive.

WHO recognizes that todays pharmaceutical manuac-turing sector looks much different rom when the schemewas ormulated decades ago under the assumption that apharmaceutical product would be sold directly rom thecountry o manuacture to the country o final destination.Pharmaceutical manuacturing and trade have become

ar more globalized in that different stages o manuac-turing take place in different countries beore the productreaches the final destination. Because o this evolution andother identified problems, WHO has proposed revising thescheme (WHO 2008b).

Product pedigrees

Te purpose o a pharmaceutical pedigree is to establish achain o custody rom the manuacturer to the dispenserby documenting all parties that have handled a particularunit o a pharmaceutical as it travels through each step inthe supply chain. Pharmaceutical wholesalers who provide

raudulent or no product pedigrees may help divert counter-eits into legitimate distribution systems. Failure to complywith the pedigree requirements is against the law in theUnited States.

Implementing a pharmaceutical pedigree process can bedone with paper or electronic records. For example, affix-ing radio requency identification (RFID) or bar codes topackaging would help maintain supply chain integrity andimprove inventory control (see Section 19.4). Althoughelectronic tracking is likely more efficient and secure, itrequires expensive technology and training. Paper-basedsystems may be executed quickly but in the long run maybe more time-consuming and more susceptible to orgery.

Batch certificates

Reliable pharmaceutical manuacturers may comply withGMPs by routinely conducting batch analyses. Local manu-acturers that do not have their own quality-control labo-ratories may contract quality-control testing services romother manuacturers, private testing acilities, or nationalreerence laboratories.

Some pharmaceutical procurement offices request othercertificates, such as the certificate o ree sale, the certifi-cate o origin, or the certificate o licensing status (see able

19-3). Tese certificates do not provide important inorma-tion regarding compliance with GMPs, or results o labo-ratory testing o samples rom individual batches. For thisreason, the WHO-type certificate o a pharmaceutical prod-uct and batch certificate are preerred.

DRAs and the procurement market today

In many countries, DRAs and procurement offices do notwork together effectively, nor are integrated inormation


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19.14 P ROCUREMEN

systems in place. Ideally, when a DRA exists and the medi-cine registration system is operational, procurement by gov-ernment agencies should be limited to medicines registeredby the DRA. Procurement offices should seek inormationrom the DRA and strive or closer cooperation with theauthority. o acilitate registration o generic medicines, theevaluation and approval process should not be complicated.Clinical trial data, except or bioequivalence data, are notnormally required, allowing the submission o an abbrevi-ated application by the manuacturer or distributor. WHOrecommends that all medicines on the public or private

market in a country, whether they are imported or locallymanuactured, be subject to the same standard o control,including medicine registration.

Te standard o control varies rom country to country.In some exporting countries, medicines are registered andreely sold but not rigorously evaluated or efficacy. In othercountries, which do evaluate efficacy, certain medicinesmay have been registered beore evidence o efficacy waslegally required. Moreover, in some countries, manuactur-ers may produce exclusively or export; the exporting coun-

trys DRA may not closely scrutinize these manuacturingplants. Procurement offices still need to request certificatesrom the DRA o the exporting country, as recommendedby WHO.

Contract specifications

Detailed specifications to help ensure that high-qualityproducts are bought and received include the ollowing

Analytical methods and source o reerence materials

or documented evidence o suitability or the materialused to assess product-quality attributes and certificateo analysis.

Portions o manuacturers reerence materials to beused in product-quality assessments. For these reer-ence materials, the manuacturers will supply eitherthe API used in the manuacture o the product ora purified portion o the API. Because the reerencematerial is used to assign qualitative and quantita-tive properties, its identity must be assured and its

Table 19-3 Comparison of certificates used in pharmaceutical procurement

Type of certificate Uses Limitations

WHO-type certificates

Certificate of pharmaceutical product

Issued by DRA in exporting country

Provides licensure status of product Provides inspection status of manufacturer

Essential for product licensure

Ideally required for all new products Prequalification of suppliers Screening of new suppliers

Is only as reliable as issuing DRA

Does not provide batch-specific information

Statement of licensing status

Issued by DRA in exporting country States that product is licensed

Prequalification of suppliers Screening of new suppliers

Does not provide batch-specific information

Batch certificate

Issued by manufacturer or DRA in exportingcountry

Confirms that individual batches conform tospecifications

Linked to certificate of pharmaceuticalproduct

Usually requested for antibiotics May be required for problem medicines

Issued by few DRAs Easily falsified Many require additional expense

Non-WHO-type certificates

Free-sale certificate

Issued by DRA in exporting country Confirms product is sold in the country of

origin

Commonly used for licensure No indication that product has beenevaluated for safety and efficacy

No indication that product is registered foruse in country of origin

GMP certificate

Issued by DRA in exporting country Prequalification of suppliers Only as reliable as issuing DRA

Analytic batch certificate

Issued by manufacturer Contains results of analytical tests Not linked to certificate of pharmaceutical

product

Postqualification of suppliers Manufacturers certificates may be falsified Does not necessarily conform to

specifications approved at time of productlicensure


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purity must be suitable to perorm the assessmentsat an appropriate confidence level or the intendeduse o the material. Te identity o a reerence mate-rial is generally assessed by inrared spectral com-parisons and quantitative assessments perormed byultraviolet-visible spectral measures, either directly

or in conjunction with chromatographic procedures.However, or most pharmaceutical measurements, theidentity and quality o solid materials can be assessedby melting point/mixed melting point measurements,while liquids can be assessed by reractive index mea-surements.

Language or the product label and package insert,which should be the language or languages common tothe country.

Minimum inormation required on the label (genericor International Nonproprietary Name, dosage orm,strength, quantity, expiration date, manuacturer,batch number).

Additional inormation, such as the product registra-tion number and date o manuacture.

Standards or packaging that will withstand the spe-cific storage and transport conditions (or example,corrugated boxes with specifications or dividers,maximum size, and maximum weight).

o reduce thef and resale, some programs may requirelabeling and logos to indicate that the product is solely ordistribution within a particular health care program (orexample, ministry o health, social security und).

Contract specifications are discussed in detail in Chapter39.

19.4 Verifying the quality of shipped products

Te quality o products received should be verified as soonas possible by physically inspecting each shipment andtesting selected products in the laboratory as required byregulation. In addition, more advanced product-trackingtechnologies have been introduced to help ensure the integ-rity o the pharmaceutical supply chain.

Product identification technology

he traditional approach to assuring product integ-rity is labeling with batch number and expiration date.Unortunately, this labeling is easily duplicated. o makeraud more difficult, several approaches are available thatuse overt or covert systems. Overt technologiesare visibleto the eye, and covert technologiesrequire devices or detec-tion. Because each step up in identification technology costsmore, the most advanced technologies are used on high-

value products or in large-quantity inventory control.

Bar coding:Te simplest and least expensive technol-ogy or product tracking is the bar code, which hasbeen adopted widely in many industries. Its uses rangerom tracking shipping containers to individual dosageunits. Te airline industry makes extensive use o thistechnology to track and direct baggage, and the retail

industry has made bar coding the standard to trackinventory and sales. Because o their widespread useand simplicity, bar-code detecting devices are relativelyinexpensive.

Radiofrequency identication:Te RFID tag is a radio-requency transponder chip with a permanent uniqueidentification code and the ability to be programmedwith product inormation, such as batch number andexpiration date. Te combination o product inorma-tion and identification code provides a high level osecurity against countereiting. RFID can be used overtlyor covertlyeither visible on the product or hidden inthe packaging. Another advantage o the RFID technol-

ogy is the ability to detect several different items at thesame time, unlike visual bar-code readers, which musthave each tag visible and separate or reading. However,until this RFID technology matures and becomes morewidespread, it will remain much more expensive than thetraditional bar-code technology.

Holograms:Hologram technology provides visual authenti-cation that can be very difficult to countereit or remove(although instances o ake holograms have been oundon countereit antimalarial products in Southeast Asia).However, the technology is not easily automated andoptimally requires an authentic label or accurate imageor visual comparison.

Other technologies that have been developed or productauthentication include color-shifing inks, ultraviolet print-ing, and embedded chemical markers and inrared tags. Asthe technologies mature, several will likely be used to assuredifferent aspects o the supply chain. Te continuing adop-tion o these authentication technologies will make productcountereiting more difficult and expensive, but unortu-nately will not likely eliminate it.

Inspection of shipments

Regardless o other quality assurance procedures in use, eachpharmaceutical shipment should be physically inspected.Tis means veriying adherence to contract specificationsand order completeness as well as inspecting samples oall items to spot any major problems. raining competentreceiving staff can be an economical means o ensuringpharmaceutical quality and reducing losses rom suppliernegligence or raud.

Inspection in the exporting country beore shipmentcan be arranged through an independent agency (or


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19.16 P ROCUREMEN

example, the Socit Gnrale de Surveillance), or earlydetection o noncompliance with contract terms or deec-tive products.

Tiered pharmaceutical quality assessments

As mentioned earlier in the chapter, the saety and efficacyo an API is the most critical attribute o a pharmaceuticalproduct. Te saety and efficacy o new APIs in the EuropeanUnion, Japan, and the United States are determined inaccordance with exhaustive ICH consensus guidelines thathave been incorporated into the laws and regulations othose sovereign areas.

When the saety and efficacy o an API have been estab-lished, the dosage regimen is set so the minimum thera-peutic level is attained without exceeding the maximumtolerated dose. Tat level o efficacy is called the therapeu-tic window (see Box 19-4). Pharmaceutical quality assess-ments may include bioavailability testing to ensure that the

API alls within the therapeutic window.Tree tiers o product-quality assessment differ by cost

and levels o precision, accuracy, and sensitivity

1. Minilab screening assessments: Te Global PharmaHealth Fund developed the Minilab to rapidly assesswhether products are grossly substandard and to

detect countereit products with no API or the wrongingredients (see http://www.gph.org/web/en/minilab or more inormation). Te Minilab uses a thin-layer-chromatography method that does not require stan-dard laboratory resources, so it can be used in the field,such as at ports o entry, while providing a good level

o quality assurance. Te Minilab has methods avail-able or more than fify pharmaceutical products and isregularly incorporating more.

2. Validated laboratory assessments or legal referencemethod assessments:Tese methods are used toassess assays, content uniormity, known impurities,and API dosage release. For medicines with a nar-row therapeutic index, such as wararin sodium, oror pharmaceuticals that ail the first-tier screeningassessment, more accurate laboratory assessmenttechnologies are required to support litigation con-cerning quality standards violations. Legal reerencemethods are methods o analysis that have been

adopted into law and are suitable or use in litigation;however, Minilab screening and validated assess-ments are generally quicker, less labor intensive, andless expensive than legal reerence methods, whichare the gold standard.

3. Specialized instruments: Methods such as high-perormance liquid chromatography coupled with

Fortunately, the overwhelming majority o pharmaceuti-cal products have a large therapeutic window, which isa great advantage or manuacturers and consumers. Awide therapeutic window allows the production o ewerdosage levels, which reduces production, supply, andinventory costs and allows consumers to more easily takea dose o a medicine that is efficacious and well toler-ated. Products with a narrow therapeutic window requirestrict monitoring o the patients therapeutic response;or example, patients taking the anticoagulant wararinsodium must have their individual coagulation timesstrictly monitored to determine the ideal dose. A urtherindicator o the critical dosing requirement or this prod-

uct is the large number o tablets available containing 1,2, 2.5, 3, 4, 5, 6, 7.5, or 10 mg. Tese dosing levels contrastmarkedly with those o acetaminophen (paracetamol),which has a wide therapeutic window. In the UnitedStates, acetaminophen is ofen marketed as a 325-mgdosage unit, whereas in Europe the dosage unit gener-ally is 500 mg. Te dosing instructions or both productsinstruct the user to take one or two units up to our timesper day.

Bloodlevel

Maximum tolerated dose

50

45

Therapeuticwindow

40

35

30

25

20

15

10

Minimum therapeutic effect5

0

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38

Time in hours

Box 19-4

Therapeutic window
http://www.gphf.org/web/en/minilabhttp://www.gphf.org/web/en/minilab


17/23


mass spectrometry may be used to determineunknown impurities and metabolites. Generally, thesetechnologies are expensive and require highly trainedindividuals to operate them and interpret the data.

In summary, wide-therapeutic-index products may be

screened rapidly to assess their quality clearance with mini-mal risk o compromising their saety and efficacy. Narrow-therapeutic-index products and those that ail the rapidscreening technologies should be assessed by validatedtechnologies that are ast and efficient. Products that ail the

validated technologies may require urther assessments bythe legal reerence methods o the sovereign state to sup-port litigation or with specialized instrumentation to litigateuntoward or unexpected contamination.

Laboratory testing

Upon arrival afer shipment, batch samples may be labora-

tory tested routinely or by exception. Most programs testselected samples rom only some o the batches. esting byexception means that analyses are done only when a supplieror a particular product is suspect.

Laboratory testing is costly in terms o technical humanresources, equipment, and reagents. Guidelines shouldtarget sampling to products that (a) have the greatestpotential or bioavailability and stability problems, (b) arerom new or questionable suppliers, and (c) have been thesource o complaints. With new suppliers, a probationarytesting periodor example, testing the first three ship-ments, then shifing to intermittent samplingis useul.Suppliers whose ailure rates are unacceptable are dropped

rom uture tenders. Sampling rom well-established sup-pliers is done much less requently, ofen only or at-riskproducts.

Programs that require routine testing o samples or allproducts prior to distribution to health acilities ofen pro-duce significant delays in product availability at the health-acility level. Te need or laboratory testing o productsreported to have problems should be careully assessed;many problems with quality are detectable on visual inspec-tion and do not require laboratory testing. For example,

verified observations o tablets that crumble beore theirexpiry date, oral suspensions that harden, or injectable solu-

tions that contain particles are enough to justiy recallingthe product without testing.Te tests that should be perormed depend on the phar-

maceutical and the reason or testing. Basic chemical anal-yses are done to veriy the identity o the medicine andunder extenuating circumstances to look or degradation,chemical contamination, or adulteration. WHO advocatesa system o economical, less technically demanding basictests or commonly used medicines (WHO 1998) that canbe done in simple laboratories. A complete analysis o tab-

let and capsule orms includes tests or identity, strengthor potency, uniormity, impurities, disintegration, and dis-solution.

Biological testing is more specialized and can be per-ormed only in established acilities with staff trainedto use microbiological and pharmacological methods.

Microbiological tests include sterility tests or injectablemedicines and eye preparations and microbiological assayso antibiotics and vitamins. Pharmacological tests includethe pyrogen test; toxicity tests; hormone assays, such as orinsulin and pituitary derivatives; and tests to determine thebioavailability o selected pharmaceuticals.

Construction o a quality-control laboratory where onedoes not already exist should be considered with caution.It may not be cost-effective or some countries to establisha sophisticated national pharmaceutical control laboratoryor a number o reasons, including

Low projected volume o work

Insufficient financial resources or land purchase, acil-ity construction, testing equipment, urniture, sup-plies, equipment maintenance, salaries, training, andother operating costs

Lack o trained personnel, such as microbiologists,pharmacologists, laboratory technicians, and animalcaretakers

Lack o local capacity or maintenance and repair oequipment, difficulty in obtaining spare parts, irregularand unstable power supply

In some countries, a college o pharmacy or an inde-pendent laboratory may have some o the required test-

ing acilities. Also, many international quality-controllaboratories provide pharmaceutical analyses at a relativelyreasonable price. I analyses are perormed by oreignlaboratories, oreign exchange and billing problems maybe reduced by requiring the suppliers to pay the labora-tory directly, with the arrangement clearly described inthe purchase contract. In addition, chain-o-custody andlegal standing o the testing laboratory in the importingcountry may be at issue.

19.5 Maintaining pharmaceutical quality

Maintaining medicine quality requires careul attention tostorage conditions and transport, as well as to dispensingpractices and use.

Appropriate storage and transport

Procedures to help maintain pharmaceutical quality beginwith proper storage conditions at the port and promptrelease. Storage activities are discussed in Chapters 42, 44,


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19.18 P ROCUREMEN

and 46, and proper transport conditions are addressed inChapter 25.

Appropriate dispensing and use

Inappropriate dispensing procedures contribute to pharma-

ceutical product deterioration and contamination or medi-cation errors. Te ollowing procedures help maintain thequality o pharmaceutical products

Use only proper dispensing containers (or example,airtight containers, light-resistant bags or vials); thepaper envelopes ofen used or end-user dispensing donot protect tablets and capsules.

Require clear labeling o dispensed medicines,and enorce procedures to label products with thepatients name, the medicines name, its strength, itsexpiration date, and instructions or its use andstorage.

Write inormation and instructions in the local lan-guage, avoiding the use o abbreviations, or use sym-bolic instructions.

Te prescriber and the dispenser should counsel thepatient on the proper use o medications, explaining whatthe medicine is, why the patient needs it, how to take it, andwhere and how to store it until treatment is completed, inaddition to possible contraindications and adverse reactions(see Chapter 30).

Pharmaceutical product presentations: treatmentkits, co-packaging, and fixed-dose combinations

Medicines can be packaged according to therapeuticregimens or or delivery to dispensing sites or individ-ual patients to acilitate and reduce the costs o inven-tory management and distribution systems. For example,a tuberculosis treatment kit could include enough anti-microbial products or a particular number o patients.Broader-based treatment kits or poorly served areas mayinclude a selection o essential medicines that supplementsthe national supply system (see Chapter 26 or more inor-mation).

Co-packaging or co-blistering is a method commonly

used to deliver multiple medicines or a specific treatmentregimen such as tuberculosis. Tese packages are preparedrom individual pharmaceutical products, so their qualityassessments should be based on each products individualstandards, including stability testing.

Fixed-dose combination (FDC) products have morethan one active ingredient ormulated into one prod-uctor example, the anti-tuberculosis medicines isonia-zid and riampin are available as single products or asan FDC in one pill. FDCs simpliy the prescription o

medicines and the management o pharmaceutical supply,improve patient adherence, and may also limit the risko treatment-resistant inections caused by inappropriatemedicine selection and monotherapy, as is the case withartemisinin-based combination therapies. WHO recom-mends FDCs be developed or antiretroviral pharmaceuti-

cal products to simpliy HIV/AIDS treatment regimensand to improve patient adherence. From a regulatorystandpoint, FDCs are treated as new pharmaceutical enti-ties in which the individual APIs must be shown to bestable and bioavailable in this composite product (WHO2003).

19.6 Monitoring pharmaceutical quality

Despite every effort, deective products occasionally slipthrough, and the quality o even the best-manuacturedproduct may deteriorate. Furthermore, health care person-

nel and patients alike may have erroneous perceptions thatonly brand-name products rom innovator firms are o goodproduct quality, especially when generic products are notwell known and accepted.

Product problem reporting system

Establishing a national product problem reporting systemis important so that health workers can report suspectedor confirmed problems with specific pharmaceutical prod-ucts. Product problem reporting should be part o an overallpharmacovigilance system, which also includes monitoringand reporting adverse drug events and medication errors.

Chapter 35 covers those areas o pharmacovigilance indetail.

Figure 19-4 is a sample medicine and supplier evaluationorm that pharmacy staff and health care providers at all lev-els can use to report suspected lapses in pharmaceutical orpackaging quality. Standard procedures or product prob-lem reporting should speciy

Who should report the perceived product qualityproblem

How to fill in the reporting orm Where and to whom the reporting orm should be sent

What additional measures need to be taken, such assending samples or inormation concerning the quan-tities involved

What ollow-up inormation should be provided to theperson or acility that reported the problem

Quality assurance program staff should careully ana-lyze all reports, using laboratory testing as required, andtake appropriate actions. Te reporter should be inormedabout the results and the actions taken, even i products are


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Figure19-4

Samplemedicineandsupplierevaluationform

OrganizationofEasternCaribbeanStates

EasternCaribbeanDrugService

Submittedby:

Country:

Date:

SampleLocation:

C

MS

Other

(specify)

MEDICINEANDSUPPLIEREVALUATIONFORM

Addresscommunicationsto:

ECDS

POBox3093

LaClery

Castries

St.Lucia

Telephone:(809-45)25058/25895

MedicineDescription:

GenericName,

Strength,Form,

BrandName

Medicin

eorSupplier

LotNumberorBatch

Number

ExpirationDate

C

omments

Suggestedcriteriaformedic

ineevaluation:

1.

Physicalcharacteristics

e.g.,

hardness,color,mixingease

forreconstitution

2.

Packaging

expirydate,

lotorbatchnumber,packageinsert

3.

Labeling

language(Englishvs.French),legibility(especiallyampoules)

4.

Patientacceptability

taste,color,sizeoftablet,etc.

5.

Healthcareprovideracceptability

e.g.,

istheampouleeasytobreak?

Guidelinesformedicinesam

pling:

1.Takesamplesfrompreviouslyunopenedcontainers.

2.Minimumsamplesize:table

ts/capsules200;injections40ampoules;liquids40mL.

3.Tablets/capsulesmustbetightlypackedinplastic/glassvial(DONOTUSEPAPERORPLASTICENVELOPES).

4.EncloseCOMPLETELABEL(genericname,strength,quantity,manufacturerandsuppliernames,lot/batchnumber,expiry

date,dateofmanufacture).

5.Printlabellegibly,anddoub

lechecklotnumberforaccuracy.


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19.20 P ROCUREMEN

not deective, to encourage continued participation in theprogram. Product problem reports and results should berecorded to provide inormation or uture procurement.

Product recalls

Pharmaceutical products ound to be deective should berecalled quickly. Te quality assurance unit in the countrysDRA should develop standard procedures or carrying outthe recall. Rapid action helps avoid unnecessary exposureonce the problem has been detected. Te central distributorsinventory control system should include inormation on allbatches that have been received. Because tracking individualbatches to the health acility is ofen either impractical orraught with uncertainty, recall notices have to be sent to allhealth acilities that received any o the products in questionto check their shelves and return the products to the centraldistribution point.

Recalls may be classified according to the degree o risk

to the consumer: (a) serious illness or death, (b) temporaryor mild illness, or (c) no adverse clinical effect. Te level orecall is determined by both the degree o risk and the extento distribution o the product and may be directed at thepatient, the health acility, or the medical stores level.

Afer issuing a recall, the quality assurance programshould monitor its progress to ensure complete compli-ance. Te supplier should be notified and required to replacedeective products. Te procurement office should pursueother remedies specified in the contract, such as withhold-ing payment or obtaining reimbursement or or replace-ment o the deective products.

19.7 Personnel and training in the supplysystem

Central to the operation o most well-run pharmaceuti-cal supply systems is at least one qualified pharmacistwith some training or experience in industrial pharmacyand procurement. Such an individual can be invaluablein establishing and overseeing quality-control practicessuited to local requirements. Tis person should partici-pate in

Selecting medicines Setting technical specifications or pharmaceutical

contracts Reviewing supply offers and selecting suppliers Reviewing storage and transportation acilities Coordinating any pharmaceutical quality testing and

helping to train the inspectors who check pharmaceu-tical shipments

In some government systems, qualified pharmacists areemployed at all levels, including the district hospitals, andthey are expected to oversee local storage and transportationconditions. In addition, they report problems or questionsconcerning individual medicines to the main office. In othercountries, locally trained dispensers are responsible or

much o the day-to-day work and must be trained to detectand report quality problems. Some countries must rely onstaff that has not received any technical training in pharma-ceutical management.

In addition to pharmacists and pharmaceutical assis-tants, other staff members involved in quality assuranceneed training and supervision as a part o quality assuranceefforts.

Physicians, health administrators, and health systemofficials must know about the actors that influencepharmaceutical quality to make inormed decisionsabout supply sources and to monitor and promote

quality assurance in their acilities. Port-clearing personnel should be trained to identiy

the categories o pharmaceuticals requiring specialstorage and transport conditions.

Clerks responsible or inspecting pharmaceutical ship-ments should receive ormal training in inspectionprocedures.

Pharmaceutical inspectors must be amiliar enoughwith pharmaceutical labeling and packaging materialsto determine whether contract conditions regardingpharmaceutical dosage, packaging, and labeling havebeen met.

Staff involved with local repackaging should be trained

to ensure pharmaceutical quality and to ollow goodpractices, especially regarding label control.

Physicians, nurses, and paramedical personnel han-dling pharmaceuticals throughout the health systemneed to know about the actors that influence phar-maceutical quality and what they can do to ensurethat the medicines dispensed to patients are sae andeffective.

Quality assurance is a widely shared responsibility. With-in a supply system, the organizational structure needs toestablish the responsibilities or the review and preserva-

tion o pharmaceutical quality at all levels. I a pharmaceuti-cal becomes ineffective or unsae by the time it reaches thepatient, then all the other activities o the supply system havebeen in vain. n


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References and further readings

H= Key readings.

Ahmad, K. 2004. Antidepressants Are Sold as Antiretrovirals in DRCongo. Lancet363:713.

Bogdanich, W. 2007. Chinese Chemicals Flow Unchecked onto WorldDrug Market. New York Times,October 31.

CPM (Center or Pharmaceutical Management). 2003a. Access toEssential Medicines: Cambodia, 2001. Prepared or the Strategiesor Enhancing Access to Medicines Program. Arlington, Va.:Management Sciences or Health.

. 2003b. Access to Essential Medicines: El Salvador, 2001.Prepared or the Strategies or Enhancing Access to MedicinesProgram. Arlington, Va.: Management Sciences or Health.

. 2003c.Access to Essential Medicines: Ghana, 2001. Prepared

or the Strategies or Enhancing Access to Medicines Program.Arlington, Va.: Management Sciences or Health.

. 2003d.Access to Essential Medicines: Minas Gerais, Brazil,2001. Prepared or the Strategies or Enhancing Access to MedicinesProgram. Arlington, Va.: Management Sciences or Health.

. 2003e.Access to Essential Medicines: Rajasthan, India, 2001.Prepared or the Strategies or Enhancing Access to MedicinesProgram. Arlington, Va.: Management Sciences or Health.

. 2003.Access to Essential Medicines: Tanzania, 2001.Preparedor the Strategies or Enhancing Access to Medicines Program.Arlington, Va.: Management Sciences or Health.

CPM/MSH (Center or Pharmaceutical Management/ManagementSciences or Health). 2011. Center for Pharmaceutical Management:

Technical Frameworks, Approaches, and Results. Arlington, Va.: CPM.FDA (U.S. Food and Drug Administration). 2010. Oice o

International Programs website.

. 2007. FDA Warns Consumers about Countereit Drugs romMultiple Internet Sellers. FDA news release P07-76, May 1.

Gammon, D. L., S. Su, J. Jordan, R. Patterson, P. J. Finley, C. Lowe, andR. Huckeldt. 2008. Alteration in Prehospital Drug Concentrationafer Termal Exposure.American Journal of Emergency Medicine26(5):56673.

Hogerzeil, H. V., G. J. A. Walker, and M. J. de Goeje. 1993. Stabilityof Injectable Oxytocics in Tropical Climates: Results of Field Surveysand Simulation Studies on Ergometrine, Methylergometrine and

Oxytocin. Geneva: World Health Organization.Hogerzeil, H. V., A. Battersby, V. Srdanovic, and N. E. Stjernstrom.

1992. Stability o Essential Drugs during Shipment to the ropics.British Medical Journal304:2102.

Hogerzeil, H. V., A. Battersby, V. Srdanovic, L. V. Hansen, O. Boye, B.Lindren, G. Everitt, and N. E. Stjernstrom. 1991. WHO/UNICEFStudy on the Stability of Drugs during International Transport.Geneva: WHO/UNICEF.

Hussain, K., P. Ibrahim, Z. Ismail, M. . Majeed, and A. Sadikun. 2009.raditional and Complementary Medicines: Quality Assessment

Quality assurance structures

Are there stated policies and practices aimed atensuring pharmaceutical quality?

Who is responsible or monitoring pharmaceuticalquality?

In what laboratories is quality-control testing done? Does a ormal system exist or reporting product

quality complaints?

Quality assurance procedures

Is the WHO Certification Scheme on the Quality oPharmaceutical Products Moving in InternationalCommerce used systematically?

Are avorable GMP inspections required or all sup-pliers, including local manuacturers?

Is a physical inspection made o all pharmaceuticalsreceived?

Are all pertinent documents and labeling, includingpatient inserts, reviewed or accuracy and compli-ance with standards?

How many laboratory analyses were perormed dur-ing the past year o the total number o products orbatches procured?

o whom are results o analyses o suspected or con-firmed deective products communicated?

Are the test results o substandard medicinesrecorded or use in uture procurement assess-ments?

Is inormation on pharmaceutical stability and prob-

lem pharmaceuticals used in evaluating suppliersand pharmaceutical products?

Are storage conditions periodically evaluated at theports o entry? At the central warehouse? At districtand regional stores? In hospital pharmacies? Athealth centers and rural health posts?

Are transport conditions maintained to ensureproduct quality?

Are good dispensing practices ollowed in the healthacilities or pharmacies?

Are the various levels o health workers adequatelytrained to carry out their respective roles in qualityassurance?

Outcome of quality assurance

In the previous year, how many reports were submit-ted on pharmaceutical product problems?

What number o pharmaceuticals or batches ailedquality-control testing o the total number o phar-maceuticals or batches tested in the previous year?

A S S E S S M E N T G U I D E


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19.22 P ROCUREMEN

Strategies and Sae Usage. Southern Med Review 2(1):1923.

ICH (International Conerence on Harmonisation o ec

Documents

Mds3 Ch19 Qualityassurance Mar2012