WHO Drug Information · 101 WHO Drug Information Vol. 25, No. 2, 2011 WHO Prequalification of Medicines Programme Facts and figures for 2010 Evaluation of medicines by the WHO Prequalification

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WHO Prequalification ofMedicines ProgrammeFacts and figures for 2010 101

Safety and Efficacy IssuesSafety trials for long acting beta-agonists104Rotavirus vaccination: risk of intus-

susception 104Tumour necrosis factor blockers: hepato-

splenic T-cell lymphoma 106Dipeptidyl peptidase-4 inhibitors:

possible glycaemic complications 106Lenalidomide: risk of new malignancies 106Pneumovax 23®: injection site reactions 107Dabigatran etexilate mesylate capsules:

storage and handling 107Proton pump inhibitors: low magnesium

levels 108Seasonal influenza vaccines 108Ipilimumab: severe immune-mediated

reactions 108Fluticasone propionate: risk of

osteonecrosis 109Varenicline: hyperglycaemia in patients

with diabetes 109Quinine sulfate: serious adverse

reactions 110Risk of oral clefts in children born to

mothers taking topiramate 110WHO training course on pharmaco-

vigilance 111

Quality Assurance IssuesWHO Certification Scheme: questions

and answers 113

Regulatory Action and NewsBuflomedil: marketing authorization

suspended 122Dolasetron mesylate intravenous

injection: withdrawal 122

Abiraterone acetate approved forlate-stage prostate cancer 122

Rituximab approved for Wegenergranulomatosis and microscopicpolyangiitis 122

Human normal immuno-globulin: liftingof suspension 123

Everolimus approved for pancreaticcancer 123

Boceprevir approved for hepatitis C 124Linagliptin approved for type 2 diabetes 124Naproxcinod: withdrawal of marketing

authorization application 124Lumiracoxib: withdrawal of marketing

authorization application 125Erythropoietin: withdrawal of marketing

authorization application 125

ATC/DDD ClassificationATC/DDD Classification (temporary) 126ATC/DDD Classification (final) 128

Recent Publications,Information and EventsSelection and use of medicines 131Policy guidelines on controlled

substances 132List of medicines to save mothers and

children 133World medicines situation 133Artesunate instead of quinine saves lives134

Consultation DocumentsThe International PharmacopoeiaRevision of monograph on capsules 135Revision of monograph on tablets 139Paediatric retinol oral solution 147

Proposed InternationalNonproprietary Names List 105

WHO Drug Information

World Health Organization

Contents

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WHO Prequalification ofMedicines Programme

Facts and figures for 2010Evaluation of medicines by the WHOPrequalification of Medicines Programme(PQP) includes assessment of data andinformation on safety, efficacy and quality.Inspections are performed to assesscompliance with good manufacturingpractices (GMP) and include manufactur-ers of selected active pharmaceuticalingredients (API) and clinical sites.Clinical sites, including contract researchorganizations (CROs), are also inspectedto verify bio-equivalence with goodlaboratory practices and good clinicalpractices.

Thirty-six products were prequalified in2010, of which 30 were generics. At theend of 2010, the WHO list of prequalifiedmedicines totalled 252 products manufac-tured in 20 countries. WHO prequalifica-tion “firsts” included artesunate powderfor injection (which was the first prequali-fied sterile product made in China); thefirst combination tenofovir disoproxilfumarate/lamivudine and the first genericemtricitabine.

Six medicines quality control laboratories(QCLs) were also prequalified: one inBolivia, one in Canada, one in Peru, twoin Ukraine and one in Uruguay. At the endof 2010, a total of 17 QCLs had beenprequalified and a further 30 were work-ing towards becoming prequalified.

Invitations to manufacturers to submit anexpression of interest (EOI) for productevaluation were issued for anti-TB medi-cines, HIV/AIDS-related care and treat-ment products, and reproductive healthproducts. The new invitations incorporateadditional products and/or take intoaccount revisions made to WHO treat-

ment guidelines. Additionally, the firstinvitation to manufacturers of activepharmaceutical ingredients (APIs) wasissued in October 2010, marking thelaunch of WHO prequalification of APIs.(A second, expanded invitation to APImanufacturers to submit an EOI wasissued in March 2011.) It is expected thattime taken to reach prequalification will beshorter for finished pharmaceuticalproducts (FPPs) that are manufacturedusing WHO-prequalified APIs, than forFPPs that are manufactured using APIsthat have not previously been evaluatedby WHO PQP.

Assessment activitiesIn 2010, 51 dossiers were submitted and53 dossiers (two of which were receivedin late 2009) were accepted for evalua-tion. Nearly 1000 assessment reportswere produced. PQP also assessednearly 600 variations submitted bymanufacturers of prequalified products.

The assessment sessions held in Copen-hagen, Denmark, include a trainingcomponent which is enabling a growingnumber of developing country assessorsto acquire stringent regulatory expertise.The Copenhagen sessions also incorpo-rate technical consultations so thatapplicants can discuss technical issuesrelating to their dossiers with assessors.The consultations benefit from the pres-ence of a range of assessors with consid-erable assessment experience.

A new collaborative procedure for facilitat-ing registration of prequalified medicinesin the East African Community (EAC) waspiloted. The overall aim was to identify aframework, for WHO-EAC, for jointevaluation and approval of dossiers and

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inspections of medicine manufacturingsites, and to ensure that these assess-ments are integrated into national regula-tory decision-making. Two assessorseach from three EAC countries (Kenya,Tanzania and Uganda) and six WHOassessors jointly assessed two productdossiers submitted by a single manufac-turer. The dossiers were submitted inparallel, and with identical content, toeach participating EAC country and toPQP. The products were both prequali-fied: HA488 (abacavir, dispersible tablets60 mg) in August 2010 and TB217(amikacin, injection 500 mg/2 ml) inJanuary 2011. For the manufacturer, theprincipal benefit of this joint assessmentwas that once the products had beenjointly assessed and approved by WHO-EAC, they were granted immediateaccess to the markets of each of thecountries that had participated in the jointassessment. For the regulators involved,such joint assessment contributes toharmonization of regulatory requirementsat regional level. PQP is hoping to usethe same model for assessing selected,technically complex, high-priority prod-ucts. Several partners and stakeholderssee joint assessment as an effectivemeans of speeding up access to muchneeded products.

InspectionsPQP inspectors carried out 59 inspec-tions in 18 countries: 38 of finishedpharmaceutical product manufacturingsites; five of API manufacturing sites;seven of CROs and nine of pharmaceuti-cal QCLs. (Inspections were carried outmostly in India and in China, but also inAlgeria, Belgium, Bolivia, Egypt, France,Iran, Kenya, Morocco, the Netherlands,Peru, Russia, South Africa, Tanzania,Uganda, Uruguay, the United States andZimbabwe.)

A new collaborative procedure for jointinspections was initiated at the beginningof 2010. A secure web site has beenestablished for the sharing of inspection

plans, arranging of joint inspections, andsharing of information and inspectionreports, with recognition by participatingEAC parties and PQP. This will be furtherexplored and possibly expanded. Jointinspections are planned for 2011 in anattempt to prevent duplication of inspec-tions. Inspection reports will be shared bythe parties following the inspection. It ishoped that the outcome of the inspectionwill be accepted by all participatinginspectorates. PQP continues to invitelocal medicines regulatory authority staffor observers to participate in inspections.

The risk assessment procedure foridentifying which API manufacturing sitesshould be inspected has been completedfor substances used to manufactureproducts for the treatment of malaria andTB. It is planned to expand this riskassessment to APIs used in products forthe treatment of HIV/AIDS.

Advice and assistancePQP continues to respond to manufactur-ers’ request for assistance concerningissues relating to, for example, bioequiva-lence study protocols and choice ofcomparator products.

PQP continues to provide technicalassistance to manufacturers and nationalQCLs that aims at resolving specificpractical problems related to GMP, goodpractices for QCLs and/or meetingmedicines regulatory requirements.Assistance is given in the form of anaudit, advice on development of animprovement plan, and training in techni-cal or regulatory areas. Follow-up mis-sions are also organized to supportimplementation of improvement plans. In2010, PQP organized 22 technical assist-ance missions to pharmaceutical manu-facturers in four countries (Argentina,China, India and Indonesia) and 10technical assistance missions to nationalQCLs (in Argentina, Brazil, Burkina Faso,China, Egypt, Jamaica, Panama, Peruand Yemen).

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Training and hands-on practice remaincrucial to capacity building. PQP organ-ized, co-organized or supported 23training courses. Training on general orspecific technical issues was given tomanufacturers, and to MRA and QCLstaff, as well as an introduction and/orupdate on PQP requirements and serv-ices. Training included group sessions aswell as discussion sessions with mem-bers of assessment or inspection teamsworking with PQP. In 2010, these work-shops involved more than 1200 partici-pants representing regulatory authorities,pharmaceutical manufacturers and QCLstaff.

Testing of medicines qualityWhen implementing sampling and testingprojects PQP evaluates specifically thequality of WHO-prequalified products. Ina study of the quality of antimalarials,concluded in 2010, the quality of WHO-prequalified products far exceeded that ofnon-WHO-prequalified products. (Lessthan 4% of WHO-prequalified artemether-lumefantrine and artesunate-amodiaquinesamples failed to comply with interna-tional quality standards, whereas thefailure rate reached 60% for non-WHO-prequalified samples of the same compo-sition.) Similarly, a survey of the quality ofanti-TB medicines conducted in 2009/2010 in Armenia, Azerbaijan, Belarus,Kazakhstan, Ukraine and Uzbekistanshowed that all prequalified productssampled and containing isoniazid/ri-fampicin complied with internationalquality standards.

Norms and standards underpinning orrelevant to WHO prequalificationactivitiesThe Forty-fifth meeting of the WHOExpert Committee on Specifications forPharmaceutical Preparations adoptedfive monographs for HIV and relatedconditions, four monographs for antima-larial medicines, six monographs for

antituberculosis medicines, two mono-graphs for influenza-specific antiviralmedicines and one for a reproductivehealth product. The Committee alsoadopted a number of new or revisedguidelines and procedures of directrelevance to PQP’s activities.

Improving PQP servicesThe results of a survey of manufacturersprovided further information for develop-ing greater “client” focus. Based on thesurvey results, PQP staff worked onimprovements to the Programme, someof which have already been implemented.For example, raising awareness of theopportunity for manufacturers to meetand consult with PQP assessors, clarify-ing procedure for resolving disagree-ments surrounding questions raisedduring the assessment of product dossi-ers — and some of which (e.g., reducingthe time taken to review and reply toapplicants during the dossier assessmentprocess, providing the same assessorsthroughout the assessment process for aproduct dossier) depend upon completionof other activities (e.g., finalization ofPQP’s new information managementsystem). Others — for example, theperceived greater stringency of WHOGMP requirements — will require furtherdiscussion with manufacturers.

Benefits to manufacturersIn 2010, PQP initiated a study to help itdescribe and quantify the potentialbenefits to manufacturers of having aproduct or products prequalified by WHO.PQP will use the results to develop a“business case for participation in WHOmedicines prequalification” for presenta-tion to manufacturers.

Further information on the WHO Prequali-fication of Medicines Programme, includ-ing the full list of medicines prequalifiedby WHO can be found at: http://www.who.int/prequal.

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Safety and Efficacy Issues

Safety trials for long actingbeta-agonistsUnited States of America — To furtherevaluate the safety of long acting beta-agonists (LABAs) when used in combina-tion with inhaled corticosteroids for thetreatment of asthma, the Food and DrugAdministration (FDA) is requiring manu-facturers to conduct five randomized,double-blind, controlled clinical trialscomparing the addition of LABAs toinhaled corticosteroids versus inhaledcorticosteroids alone.

Four clinical trials will be conducted inadult and adolescent patients 12 yearsof age and older to evaluate:

• Budesonide and formoterol.

• Fluticasone and salmeterol.

• Mometasone and formoterol.

• Formoterol.

One clinical trial will be conducted inpaediatric patients aged 4 to 11 years andwill include 6200 patients. Patients in alltrials will be treated for six months, andthe primary endpoint will be a compositeof serious asthma outcomes: asthma-related death, intubation, or hospitaliza-tion. The paediatric trial will also assessother relevant quality of life endpointssuch as days of school missed andemergency room visits because ofasthma related illness.

The clinical trials will begin in 2011 andFDA expects to receive results in 2017.

Reference: FDA Drug Safety Communication,15 April 2011 at http://www.fda.gov/Drugs/DrugSafety

Rotavirus vaccination: riskof intussusceptionAustralia — The Therapeutic GoodsAdministration (TGA) has undertaken aninvestigation of a possible associationbetween the use of the rotavirus vaccinesRotarix® and RotaTeq® and the occur-rence of a rare form of bowel obstructionknown as intussusception (IS). This is acondition caused by the telescoping ofone segment of the bowel into another. Itis estimated to occur each year in around80 per 100 000 children under 12 monthsof age, which represents approximately200 cases per year in Australia. The peakincidence is in infants 5–10 months ofage, with 80% of cases occurring before24 months of age. It is much more com-mon in males than females.

IS was found to be a side effect of thefirst generation rotavirus vaccine,RotaShield®, that was available in theUnited States in 1998–1999 and wasestimated to cause IS in 10–20 of every100 000 doses given to infants. It wasvoluntarily withdrawn from the US marketin October 1999 (1, 2).

RotaShield® was not used outside theUSA, however, as the historical incidenceof IS is 2.5 to 3 times higher in infants inAustralia than in the US, this would havetranslated to 25–60 cases of IS for every100 000 doses of RotaShield®.

Subsequently, two new rotavirus vac-cines, Rotarix® and RotaTeq® weredeveloped and both were tested in largestudies designed to explore whether therewas a risk of IS (3, 4). In Australia, twopost-marketing studies have been con-ducted to investigate whether the new

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rotavirus vaccines are associated with anincreased risk of IS. The first study wasconducted using two surveillance sys-tems, the Paediatric Enhanced DiseaseSurveillance (PAEDS) and the AustralianPaediatric Surveillance Unit (APSU). Thisstudy found an apparent four-fold in-creased risk of IS in babies within oneweek of being given the first dose ofeither vaccine, compared with historicaldata on hospitalizations coded as IS, butno overall increase in overall rates of ISup to the age of nine months.

Following this, a large self-controlled caseseries (SCCS) study using data on allhospitalized cases coded as IS wascommissioned by the TGA. This studyfound a statistically significant four-foldincrease in the occurrence of IS in thefirst 1–7 days following the first dose ofeither Rotarix® or RotaTeq® comparedwith other time periods after vaccinereceipt. This increase in risk translates toapproximately two additional cases of ISoccurring in every 100 000 first doses ofvaccine administered, or six additionalcases each year in children under 12months of age in Australia.

The World Health Organization (WHO)and the Australian Technical AdvisoryGroup on Immunization (ATAGI) haverecommended the continued use ofrotavirus vaccine for infants.

References

1. Withdrawal of Rotavirus Vaccine Recom-mendation. MMWR 1999;48(3):1107.

2. Murphy T, Gargiullo P, Massoudi M, NelsonD et al. Intussusception among infants givenan oral rotavirus vaccine. New EnglandJournal of Medicine 2001; 344(8):564–72

3. Ruiz-Palacios G, P rez-Schael I, VelazqueaF, H HA, Breuer T et al. Safety and efficacy ofan attenuated vaccine against severe rotavi-rus gastroenteritis. New England Journal ofMedicine 2006;354(1):11–22.

4. Vesikari T, Matson D, Dennehy P, DammePV et al. Safety and efficacy of a pentavalenthuman-bovine (WC3) reassortant rotavirusvaccine. New England Journal of Medicine2006;354(1):23–33.

5. Macartney KK, Porwal M, Dalton D, CrippsT et al. Decline in rotavirus hospitalisationsfollowing introduction of Australia’s nationalrotavirus immunisation programme. J PaediatrChild Health 2011; published online: 18 Jan2011 DOI: 10.1111/j.1440-1754.2010.01953.

6. Lambert SB, Faux CE, Hall L, Birrell FA etal. Early evidence for direct and indirect ef-fects of the infant rotavirus vaccine program inQueensland. Med J Aust 2009; 191: 157–160.

7. Haber P, Patel M, Izurieta H, Baggs J et al.Postlicensure monitoring of intussusceptionafter RotaTeq® vaccination in the UnitedStates, February 1, 2006, to September 25,2007. Pediatrics 2008;121(6):1206–12.

8. Velazquez FR, Colindres R, Grajales C,Hernandez MT, Mercadillo MG, Torres FJ,Yolanda M Apolinar C, DeAntonio-Suarez R,Ortega E, Blum M, Breuer T, Verstraeten T.Postmarketing surveillance of intussusceptionfollowing mass introduction of the humanrotavirus vaccine in Mexico: an interimanalysis. Excellence in Paediatrics, London,December 2–4, 2010

9. World Health Organization, Global AdvisoryCommittee on Vaccine Safety. Statement onRotarix® and Rotateq® vaccines and intus-susception. 22 September 2010.

10. Buttery JP, Danchin MH, Lee KJ, CarlinJB, McIntyre PB, Elliott EJ, Booy R, Bines JEfor the PAEDS/APSU Study Group. Intussus-ception following rotavirus vaccine administra-tion: post marketing surveillance in theNational Immunization Program in Australia.Vaccine, 2011. In Press.

11. Tapiainen T, Bonhoeffer J, Heininger U.Evaluation of the Brighton Collaboration casedefinition of acute intussusception during ac-tive surveillance. Vaccine 2006;24(9):1483–7.

12. Galati JC, Harsley S, Richmond P, CarlinJB. The burden of rotavirus-related illnessamong young children on the Australian healthcare system. ANZ Journal of Public Health2006;30:416-421.

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Tumour necrosis factorblockers: hepatosplenicT-cell lymphomaUnited States of America — The Foodand Drug Administration (FDA) continuesto receive reports of hepatosplenic T-Celllymphoma (HSTCL), primarily in adoles-cents and young adults being treated forCrohn disease and ulcerative colitis withmedicines known as tumour necrosisfactor (TNF) blockers, as well as withazathioprine, and/or mercaptopurine.Crohn disease and ulcerative colitiscause inflammation of the digestivesystem. Common symptoms are pain inthe abdomen, cramps, and diarrhoea.Bleeding from the rectum, weight loss,joint pain, skin problems and fever alsomay occur. Children with the disease mayhave growth problems, develop intestinalblockage and experience malnutrition.

FDA believes the risks and benefits ofusing TNF blockers, azathioprine, and/ormercaptopurine should be carefullyweighed when prescribing these drugs tochildren and young adults, especially forthe treatment of Crohn disease andulcerative colitis.

The product labels for infliximab(Remicade®) and adalimumab (Humira®)have been updated and the productlabels for azathioprine and mercaptopu-rine are being updated to include warn-ings about HSTCL that have been re-ported in patients treated with theseproducts.


Dipeptidyl peptidase-4inhibitors: possible glycaemiccomplicationsJapan — The Ministry of Health, Labourand Welfare (MHLW) has warned about

the risk of hypoglycaemia associatedwith concomitant use of dipeptidyl pepti-dase-4 (DPP-4) inhibitors and sulfony-lureas, and the risk of diabetic keto-acidosis and hyperglycaemia afterswitching from insulin to glucagon-likepeptide-1 (GLP-1) receptor agonists.

DPP-4 inhibitors and GLP-1 receptoragonists are antidiabetic drugs whichinactivate incretin. Incretin is a gastroin-testinal hormone which stimulatesinsulin secretion. DPP-4 inhibitors areused to treat type 2 diabetes mellitus byincreasing the endogenous active incretinlevel and thereby controlling bloodglucose. As of December 2010, sitagliptinphosphate hydrate, vildagliptin, andalogliptin benzoate have been approvedin Japan.

GLP-1 receptor agonists are used to treattype 2 diabetes mellitus by binding to theGLP-1 receptor to promote insulin secre-tion in response to the increase in bloodglucose. As of December 2010, liraglutide(genetic recombination) and exenatidehave been approved.

Reference: Pharmaceuticals and MedicalDevices Safety Information, No.275. Decem-ber 2010 at http://www.pmda.go.jp/english

Lenalidomide: risk ofnew malignanciesUnited States of America — The Foodand Drug Administration (FDA) hasprovided information on clinical trials thatfound that patients treated with lenalido-mide (Revlimid®) may be at increasedrisk of developing new types of cancercompared to patients who did not take thedrug.

FDA is currently reviewing all availableinformation on this potential risk andrecommends that patients continuelenalidomide treatment as prescribed bytheir physician. The benefits and the risks

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should be carefully weighed when pre-scribing this drug. Lenalidomide is usedto treat myelodysplastic syndrome and isused along with other drugs to treatpeople with multiple myeloma.

Preliminary data derived from evaluationof outcomes after longer-term exposureto lenalidomide and from controlledclinical trials conducted inside and out-side the Unites States shows an in-creased incidence of some secondprimary malignancies, particularly acutemyelogenous leukemia (AMaL) and B-celllymphoma malignancies when comparedto controls. Since lenalidomide is ananalogue of thalidomide, FDA is alsocurrently reviewing all available informa-tion on this potential risk for thalidomide.


Pneumovax 23®:injection site reactionsAustralia — The Therapeutic GoodsAdministration (TGA) is advising healthprofessionals not to administer a secondor subsequent dose of Pneumovax 23®vaccine pending the outcome of a reviewof an apparent increased rate of injectionsite reactions following administration ofthe second dose.

Pneumovax 23® vaccination is used toprevent life threatening bacterial infec-tions for anyone who is at high risk ofpneumococcal infections.

Pneumovax 23® vaccine is known to beassociated with a high rate of localinjection site reactions which can includesevere injection site reactions such ascellulitis and abscess. There is varyingevidence from published trials as towhether injection site reactions are morecommon following revaccination.

The Australian Technical Advisory Groupon Immunization (ATAGI) is currently

reviewing the place of Pneumovax 23®in the National Immunization Programme.This alert is not applicable to use of the7-valent pneumococcal conjugate vaccinePrevenar® or the 10-valent pneumococ-cal conjugate vaccine, Synflorix®, whichare given to babies.

Reference: Therapeutic Goods AdministrationSafety Alert. 18 April 2011. http://www.tga.gov.au/safety/alerts-medicine-pneumovax-110416.htm

Dabigatran etexilate mesylatecapsules: storage and handlingUnited States of America — The Foodand Drug Administration (FDA) is alertingthe public to important storage andhandling requirements for dabigatranetexilate mesylate (Pradaxa®) capsules.Due to the potential for product break-down from moisture and loss of potency,Pradaxa® capsules should only bedispensed and stored in the original bottleor blister package. However, manyconsumers use pill boxes or pill organiz-ers to aid them in remembering to taketheir medications.

Although the current Pradaxa® labelstates that the product should be dis-carded 30 days after the original bottle isopened, data currently under review bythe FDA indicate that the product main-tains its potency up to 60 days after bottleopening as long as it is stored in theoriginal bottle and the handling require-ments are met — including that the cap isclosed tightly after use and the bottle iskept away from excessive moisture, heatand cold. Pradaxa® capsules will hydro-lyse over time when exposed to humidity,causing a breakdown of active ingredientand rendering the medication less effec-tive.

Reference: FDA Drug Safety Communication,29 March 2011 at http://www.fda.gov/Drugs/DrugSafety

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Proton pump inhibitors:low magnesium levelsUnited States of America — The Foodand Drug Administration (FDA) is inform-ing the public that prescription protonpump inhibitor (PPI) drugs may causehypomagnesaemia if taken for prolongedperiods of time (in most cases, longerthan one year). In approximately one-quarter of the cases reviewed, magne-sium supplementation alone did notimprove low serum magnesium levelsand the PPI had to be discontinued.PPIs are used to treat gastroesophagealreflux disease (GERD), stomach andsmall intestine ulcers, and inflammation ofthe esophagus.

Prescription PPIs include esomeprazolemagnesium, dexlansoprazole, ome-prazole, lansoprazole, pantoprazolesodium, and abeprazole sodium.


Seasonal influenza vaccinesAustralia — During the 2010 influenzaseason, an excess number of cases offebrile reactions and febrile convulsionswere observed in paediatric populationsfollowing immunization with one of theregistered seasonal trivalent influenzavaccines. Consequently, the TherapeuticGoods Administration (TGA) has imposeda condition on the registration of all 2011seasonal influenza vaccines with apaediatric indication which were notsupplied in Australia in 2010. Sponsorsare required to undertake active surveil-lance of children from six months to nineyears of age to ensure effective monitor-ing of paediatric populations in Australiapreviously unexposed to these vaccines.Two sponsors were unable to meet thiscondition of registration. Although thesafety of Agrippal® and Fluarix ®hasbeen demonstrated in the northern

hemisphere 2010/2011 influenza season,the TGA does not have any safety dataon the use of these vaccines in Australianchildren. Hence, the TGA recommendsthat these vaccines are not used in anychild under the age of nine years.

For children under the age of nine years itis recommended that they be vaccinatedwith either Influvac® or Vaxigrip®. Thesetwo vaccines were not associated withincreased rates of fever or febrile reac-tions in 2010.

Reference: Therapeutic Goods AdministrationSafety Advisory, 11 March 2011. http://www.tga.gov.au/safety

Ipilimumab: severe immune-mediated reactionsUnited States of America — The Foodand Drug Administration (FDA) hasposted information from the manufacturerof Ipilimumab (Yervoy®) about the riskevaluation and mitigation strategy(REMS) developed to ensure that thebenefits of ipilimumab outweigh the risksof severe and fatal immune-mediatedadverse reactions.

Ipilimumab was approved in March 2011with a boxed warning stating that use ofthe product can result in severe and fatalimmune-mediated adverse reactions dueto T-cell activation and proliferation.These immune-mediated reactions mayinvolve any organ system. However, themost common severe immune-mediatedadverse reactions are enterocolitis,hepatitis, dermatitis (including toxicepidermal necrolysis), neuropathy, andendocrinopathy. The majority of theseimmune-mediated reactions initiallymanifested during treatment. However, aminority occurred weeks to months afterdiscontinuation.

Reference: FDA Medwatch Communication,Dear Healthcare Professional Letter, 6 April2011 at http://www.fda.gov/Drugs/DrugSafety

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Fluticasone propionate:risk of osteonecrosisCanada — Health Canada has receivedfive reports of osteonecrosis suspectedof being associated with fluticasonepropionate.

The potential for osteonecrosis with highdoses of inhaled corticosteroids has beensuggested in the literature. Becausecorticosteroid-induced osteonecrosistends to occur in younger patients andtreatment options for advanced diseaseare limited, early identification is impor-tant.

Fluticasone propionate is a highly potentglucocorticoid anti-inflammatory steroid.In Canada, it is available as an aqueousnasal spray, an inhalation aerosol, apowder for inhalation and a topical cream(1–3). Steroid-induced osteonecrosis, oravascular necrosis, is characterized bybone cell death resulting from compro-mized blood supply. Corticosteroids,administered orally or parenterally, havebeen associated with osteonecrosis (4).Osteonecrosis related to inhaled ortopical use of steroids has also beenreported but the oral or parenteral use ofsteroids was a confounding factor (4).The potential for osteonecrosis with highdoses of inhaled corticosteroids, such asin the treatment of severe persistentasthma or eosinophilic oesophagitis, hasbeen suggested (4).

Systemic adverse reactions may occurwith intranasal and inhaled use of corti-costeroids (1, 2). The long-term effects offluticasone propionate are still unknown.The relative determinants of systemicadverse reactions to inhaled and intrana-sal corticosteroids have been assessedand fluticasone propionate was deter-mined to have a high systemic potency(5). Because corticosteroid-inducedosteonecrosis tends to occur in youngerpatients (the average age at onset is 33)and treatment options for advanced

disease are limited, early identification isimportant (4).

Extracted from the Canadian AdverseReaction Newsletter, Volume 21(2), April2011 at http://www.healthcanada.gc.ca

References

1. Flovent HFA, Flovent Diskus® (fluticasonepropionate) [product monograph]. Mississauga(ON): GlaxoSmithKline Inc.; 2010.

2. Flonase® (fluticasone propionate) [productmonograph]. Mississauga (ON):GlaxoSmithKline Inc.; 2004.

3. Advair Diskus (salmeterol xinafoate/fluticasone propionate) [product monograph].Mississauga (ON): GlaxoSmithKline Inc.;2008.

4. Powell C, Chang C, Naguwa S, et al.Steroid induced osteonecrosis: an analysis ofsteroid dosing risk. Autoimmun Rev2010;9(11):721–43.

5. Lipworth BJ, Jackson CM. Safety ofinhaled and intranasal corticosteroids. DrugSaf 2000;23(1):11–33.

Varenicline: hyperglycaemiain patients with diabetesCanada — Health Canada has received18 reports of hyperglycaemia suspectedof being associated with varenicline(Champix®) in patients with type 1 andtype 2 diabetes.

Varenicline is indicated for smoking-cessation treatment in adults in conjunc-tion with smoking-cessation counselling.The current Canadian product mono-graph lists diabetes mellitus and hypogly-caemia under “less common clinical trialadverse drug reactions” and describesthese adverse reactions (ARs) as infre-quent and rare, respectively.

Diabetes mellitus is a chronic metabolicdisorder characterized by the presence ofhyperglycaemia and consequently is a

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confounder. Other confounders identifiedin some of the reports included infection,medications (e.g., insulin, oral antidiabeticagents, diuretics), alcohol consumptionand smoking cessation. In some in-stances, the patient was still smokingwhile taking varenicline.


References

1. Champix® (varenicline) [product mono-graph]. Kirkland (QC): Pfizer Canada Inc;2010.

2. Kristensen PL, Pedersen-Bjergaard U,Thorsteinsson B. Varenicline may triggersevere hypoglycaemia in type 1 diabetes.Diabet Med 2008;25(5):625-6.

Quinine sulfate: seriousadverse reactionsCanada — Quinine sulfate, in combina-tion with a second antimalarial drug, isrecommended for the treatment of un-complicated Plasmodium falciparummalaria. Quinine sulfate is not indicated inCanada for the prevention or treatment ofnocturnal leg cramps. However, quininesulfate is used for the prevention andtreatment of leg cramps, at a dose of 200to 300 mg at bedtime. The use of quininesulfate to prevent leg cramps has been asubject of recent concern. Several inter-national regulators have taken action toeither withdraw this indication for use orhave added conditions for its use for legcramps.

Adverse reactions to quinine sulfateinclude life-threatening blood-relatedreactions, such as sudden, severethrombocytopenia.


References

1. CATMAT. Canadian recommendations forthe prevention and treatment of malariaamong international travellers 2009. CanCommun Dis Rep 2009;35(Suppl 1):1–82.

2. Quinine sulfate [Canadian PharmacistsAssociation monograph]. In: e-CPS. Ottawa(ON): Canadian Pharmacists Association;2010.

3. Adverse Drug Reactions Advisory Commit-tee (ADRAC) Quinine indications – crampsdeleted. Aust Adv Drug Reactions Bull2004;23(5):20.

4. Medsafe. Quinine – not for leg crampsanymore. Prescriber Update 2007;28(1):2–3.

5. US Food and Drug Administration. Quininesulfate (marketed as Qualaquin®): off-label(not approved by FDA) use of quinine. FDADrug Safety Newsletter 2009;2(2):11–3.

6. Medicines and Healthcare products Regula-tory Agency. Quinine: not to be used routinelyfor nocturnal leg cramps. Drug Safety Update2010;3(11):3–4.

7. US Food and Drug Administration. FDADrug Safety Communication: New riskmanagement plan and patient MedicationGuide for Qualaquin® (quinine sulfate). 7August 2010.

8. Aster RH, Bougie DW. Drug-inducedimmune thrombocytopenia. N Engl J Med2007;357(6):580–7.

9. Brinker AD, Beitz J. Spontaneous reports ofthrombocytopenia in association with quinine:clinical attributes and timing related to regula-tory action. Am J Hematol 2002;70(4):313–7.

Risk of oral clefts in childrenborn to mothers takingtopiramateUnited States of America — The Foodand Drug Administration (FDA) is inform-ing the public of new data that show thatthere is an increased risk for the develop-

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ment of oral clefts in infants of womentreated with topiramate (Topamax® andgeneric products) during pregnancy.

Topiramate is an anticonvulsant used totreat epilepsy. It is approved for use toprevent migraine headaches. Topiramateis being placed in Pregnancy Category Dindicating positive evidence of humanfetal risk but with potential benefits thatmay be acceptable in certain situationsdespite its risks.


WHO training course onpharmacovigilanceA recent survey by the WHO Programmefor International Drug Monitoring identi-fied serious gaps in technical capacity forpharmacovigilance (PV) in resourcelimited settings. The Inter-regionalPharmacovigilance Training Course, heldin February 2011 in New Delhi, India, waspart of the WHO strategy to help establishminimum standards for PV as identifiedby WHO and the Global Fund during aconsensus meeting in 2010.

The course identified leveraging oppor-tunities offered by liaison and sharingresources with lymphatic filariasis publichealth programmes. By introducing PVwithin mass preventive treatment cam-paigns, the quality of care and patientsafety within such programmes could besignificantly improved.

The specific objectives of the trainingcourse were to:

• Raise awareness about public healthissues and patient safety in relation tothe use of medicines.

• Demonstrate the importance of PVactivities in improving patient safety andtreatment outcomes.

• Provide training on the latest tools inbasic adverse drug reaction (ADR)reporting, to enhance reporting withincountries and to the WHO Programmefor International Drug Monitoring.

• Build or reinforce capacity of nationalPV centres.

• Share experiences and challengesfaced in establishing or strengtheningPV programmes.

• Establish networking among regulatoryagencies, PV centres, national ne-glected tropical diseases (NTD) controlprogrammes and WHO for informationsharing and providing assistance indetecting signals and making judgmentsbased on sound science.

Two participants per country attendedfrom Cambodia, Lao PDR, Maldives,Nepal and Viet Nam, with six participantsfrom India. Others represented thenational PV centre or the NTD controlprogramme.

The five-day course covered the followingtopics:

• WHO Programme for International DrugMonitoring.

• Establishing a PV centre; how to pro-mote reporting.

• Vigibase (a WHO global database ofindividual case reports), VigiFlow (aweb-based case report managementsystem), WHO Adverse ReactionTerminology and WHO Drug Dictionary.

• Causality assessment.

• Collaboration with public health pro-grammes and NTD control programmesin particular.

• Risk management and the prevention ofADRs.

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Spontaneous monitoring systems are useful in detecting signals of relatively rare, serious orunexpected adverse drug reactions. A signal is defined as “reported information on a possiblecausal relationship between an adverse event and a drug, the relationship being unknown orincompletely documented previously. Usually, more than a single report is required to gener-ate a signal, depending upon the seriousness of the event and the quality of the information”.All signals must be validated before any regulatory decision can be made.

• Rational use of medicines.

• Communication in pharmacovigilance.

• Development of country-specific actionplans for next year.

At the end of the course participantspresented draft plans of priority activitiesfor the next ten months for PV in theirsettings, with key deliverables, timelinesand expected outcomes.

Countries that are not yet members of theWHO Programme (Lao PDR, Maldives)described their plans to establish a PVcentre and join the Programme in thefuture. Participants from Cambodia, anassociate member of the WHO Pro-

gramme, expressed their intention tobecome a full member by sending arequired number of ADR reports to theWHO Programme. Three countries thatare members of the WHO Programme —India, Nepal, and Viet Nam — presentedplans to strengthen or expand theircurrent PV work by holding workshops onPV for stakeholders, improving collabora-tion between PV and public health pro-grammes and other actions. Participantsfrom Nepal and Viet Nam confirmed thatthe course was useful in establishingcollaboration for the first time between thenational PV and the NTD control pro-grammes.

Reference: World Health Organization.Pharmaceutical Newsletter, April 2011 athttp://www.who.int/medicines

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WHO Certification Scheme:questions and answersQ1 What is the WHO CertificationScheme on the Quality of PharmaceuticalProducts Moving in International Com-merce?

A1 It is a Scheme developed by theWorld Health Organization (WHO) inresponse to the request of WHO MemberStates to facilitate international trade inpharmaceutical products between Mem-ber States.

Q2 When was the Scheme developed?

A2 It was first developed in 1975. Sincethen it has been revised in 1988, 1992and in 1997.

Q3 How can it facilitate trade in pharma-ceutical products?

A3 The Scheme is an administrativeinstrument that requires a participatingMember State (a certifying country), uponapplication by a commercially interestedparty (the applicant company), to certify/attest to the competent authority ofanother participating Member State (therecipient country) that:

• A specific pharmaceutical product isauthorized for marketing in the certifyingcountry, or if not, the reason why au-thorization has not been accorded.

• The manufacturing facilities and opera-tions conform to good manufacturingpractices (GMP) as recommended byWHO.

The WHO Certification Scheme on the Quality of Pharmaceutical Products Movingin International Commerce is an international voluntary agreement mechanism whichprovides information to participating countries on the quality status of finished phar-maceutical products moving in international commerce. The primary focus of theScheme is the Certificate of a Pharmaceutical Product (CPP).

The WHO Expert Committee on Specifications for Pharmaceutical Preparations(ECSPP) recommended that the WHO Certification Scheme on the Quality of Phar-maceutical Products Moving in International Commerce should be reviewed in linewith changing practices and rapid globalization of the pharmaceutical manufacturingsector, regulatory environment and procurement systems. However, the Schemecan only be opened for revision by decision of the World Health Assembly (1). As aninterim measure, the ECSPP requested that a question and answer document onthe functions of the Scheme should be prepared (2). Version one of the documenthas been developed with the aim of improving understanding of the objectives of theScheme and its implications for quality improvement and provision of effective, safemedicines by participating countries. Comments and suggestions on this documentmay be sent to Dr Samvel Azatyan, Medicines Regulatory Support Programme, WorldHealth Organization, 1211 Geneva 27, Switzerland, or e-mail: [email protected].

Quality Assurance Issues

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Q4 Why is it called the WHO CertificationScheme?

A4 It is called the WHO CertificationScheme because it was developed byWHO in response to the request ofMember States.

Q5 How does the Scheme operate?

A5 The Scheme operates as follows:The certificate recipient authority has inits national medicine legislation or guide-lines a requirement for the submission ofa Certificate for a Pharmaceutical Product(CPP) for products being imported intothe country as a support to ensure thequality of the product being imported. (Insome countries the CPP forms part of thedossiers to be submitted to the medicinesregulatory authority (MRA) to have aproduct registered by the authority).

The applicant/importing company re-quests a CPP from the certifying authoritythrough the exporting company.

The certifying authority issues a CPP tothe importing/applicant company via theexporting company. At the time of thedevelopment of the Scheme the under-standing was that a CPP would be sentdirectly to the recipient authority by theissuing authority.

Q6 Is the Scheme mandatory?

A6 No. The Scheme is not mandatory. Itis a voluntary agreement devised toenable countries with limited regulatorycapacity to obtain partial assurance fromexporting countries concerning thequality, safety and efficacy of the pharma-ceutical product they plan to import.

Q7 Can anyone issue a CPP?

A7 No. Only countries and regionalorganizations such as the EuropeanMedicines Agency (EMA) that are party tothe Scheme can issue a CPP.

Q8 How can a WHO Member State orregional organization be eligible forparticipation in the Scheme?

A8 Any WHO Member State or regionalorganization intending to participate in theScheme may do so by notifying theDirector-General of WHO in writing:

• Of its willingness to participate in theScheme.

• Of any significant reservations it intendsto observe relating to its participation.

• By providing the names and address ofits MRA or other competent authority.

Q9 Where can one find the list of organi-zations and countries party to theScheme?

A9 WHO publishes the names andaddresses of Member States party to theScheme. The list is available at http://www.who.int/medicines/areas/quality_safety/regulation_legislation/certification/en/index.html. A hard copy ofthe list is also published and distributed toMember States. The list is regularlyupdated.

Q10 Does the list of Member States andorganizations party to the Schemeprovide the names and addresses ofthose government organizations author-ized to sign and issue a CPP?

A10 Yes. The list provides the namesand full addresses of those governmentorganizations authorized to sign andissue a CPP. MRAs receiving a CPP canuse this list to check and verify if thecertificate they are receiving has beenissued by the authorized organization.

Q11 Is there any written document thatprovides detailed information on the WHOCertification Scheme?


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A11 Yes. Guidelines for implementationof the WHO Certification Scheme on theQuality of Pharmaceutical ProductsMoving in International Commerce areavailable at http://www.who.int/medicines/areas/quality_safety/regulation_legislation/certification/guidelines/en/index.html”http://www.who.int/medicines/areas/quality_safety/regulation_legislation/certification/guidelines/en/index.html.

Q12 What should Member States andregional organizations possess in order toissue a CPP to support the export phar-maceutical products?

A12 In order to issue a CPP, MemberStates and regional organizations shouldhave the following infrastructure andsystems in place:

• An effective national licensing systemfor pharmaceutical products, manufac-turers and distributors.

• GMP requirements consonant withthose recommended by WHO to whichall manufacturers of finished pharma-ceutical products (FPPs) are required toconform.

• Effective controls to monitor the qualityof pharmaceutical products registeredor manufactured within the country,including access to an independentquality control laboratory.

• A national pharmaceutical inspectoratehaving the technical competence,experience and resources to assesswhether GMP and other controls areeffectively implemented and the legalpower to conduct appropriate investiga-tions.

• The administrative capacity to issue therequired certificates, to institute inquiriesin the case of a complaint associatedwith a potentially serious quality defector other hazard and to notify WHO andother concerned parties.

Q13 Does WHO issue CPPs?

A13 No. WHO does not issue CPPs orany of the certificates described under theScheme.

Q14 Should a CPP issued by MemberStates bear the WHO emblem or refer tothe WHO acronym?

A14 No. Certificates should not bear theWHO emblem or the acronym. Use of theemblem or acronym creates the impres-sion that the certificate is issued or en-dorsed by WHO. This is an illegal act andcountries receiving such CPPs shouldreject them and report such practices toWHO.

Q15 What products are covered underthe WHO Certification Scheme?

A15 Pharmaceutical products are cov-ered under the Scheme and include:

• FPPs intended for administration tohuman beings.

• Pharmaceutical products intended foradministration to food-producing ani-mals.

• Active pharmaceutical ingredients(APIs). There is now a separate schemecalled the WHO pharmaceutical startingmaterials certification scheme (SMACS)which has guidelines on importation ofAPIs.

Q16 What are the different types ofCertificate that can be requested withinthe scope of the Scheme?

A16 Three types of certificate can berequested within the scope of theScheme:

• A Certificate for a PharmaceuticalProduct (CPP) or Product Certificate(PC);


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• A Statement of Licensing Status ofPharmaceutical Product(s) (SLSPP);

• Batch Certificate of a PharmaceuticalProduct (BCPP).

Q17 By whom and when is a Certificatefor a Pharmaceutical Product (CPP)issued?

A17 A CPP is issued by the competentauthority of the exporting country and isintended for use by the competent author-ity of the importing country:

• When a pharmaceutical product isunder consideration for a productlicence/marketing authorization forimportation and sale in the importingcountry.

• When administrative action is requiredto renew, extend, vary or review suchlicence.

Q18 When and by whom is a Statementof Licensing Status of PharmaceuticalProduct(s) (SLSPP) issued?

A18 An SLSPP is issued by the compe-tent authority of the exporting country andis intended for use by importing agentswhen considering bids in an internationaltender. It is requested by the importingagent as a condition for bidding.

Q19 What is a Batch Certificate?

A19 A Batch Certificate accompanies andattests to the quality and expiry date of aspecific batch or consignment that hasalready been licensed/approved formarketing in the importing country.

A batch certificate is usually issued by themanufacturer.

In case of biological products, a lotcertificate is issued by the competentauthority of the exporting country.

Q20 Is there a standard format forCPPs?

A20 Yes, there is a standard format. TheWHO standard format was last agreed bythe World Health Assembly in 1997 (1).

The standard WHO format for CPPsfacilitates understanding and review bythe recipient authority. It obliges certifyingauthorities to disclose important informa-tion to the importing country.

Recipient authorities should refrain fromobtaining data other than in the WHOstandard format or in addition to thestandard CPP format.

Certifying authorities should not issue afree-sale certificate. This has beenreplaced by the WHO format CPP.

Q21 Is the CPP evidence of quality,safety, efficacy review and approval?

A21 Yes, the CPP is based on theassumption that the authorities issuing aCPP have the capacity to assess thequality, safety, and efficacy (QSE) of theproduct they have approved for market-ing.

Based on the intention of the Schemeand when evidence of approval in an-other country is required, a recipientauthority may request a CPP if it isunable to undertake a full review of QSEdata.

Q22 Does the CPP provide evidence ofgood manufacturing practices (GMP)status?

A22 Yes. The GMP declaration in theCPP refers to assurance of GMP for theproduct approved in the certifying countryat the stated manufacturing site.

In addition, certificates from medicinesregulatory authorities (MRAs) party to thePharmaceutical Inspection Cooperation


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Scheme (PIC/S) and International Confer-ence on Harmonisation (ICH) (USA,Japan, and EU) provide evidence of GMPstatus.

Q23 What is the difference betweenapproval of the quality data in the submis-sion and evidence of GMP?

A23 Approval of the quality information ina submission is a determination of howthe applicant proposes to manufactureand control the quality of the product atthe time of manufacture and throughoutthe life of the product.

Evidence of GMP compliance confirmsthat the applicant company has been ableto demonstrate that the manufacturingfacilities and operations conform to goodmanufacturing practices (GMP) asrecommended by WHO.

Q24 When would a CPP be required?

A24 When the CPP replaces either a fullor partial quality, safety and efficacy(QSE) review. The CPP would be acondition of approval but it would not berequired at the time of submission.

If local legislation stipulates provision of aCPP at the time of submission, theauthority review should comprise averification procedure with published,communicated timelines that should beshort and avoid delaying patient access.

Q25 Are there any alternatives to a CPPas evidence of approval by an MRA?

A25 In addition to the WHO CertificationScheme other forms of evidence include:

• Product approval letters (or copies oflicences) from well-established MRAs,e.g., Australia, Canada, China, Den-mark, Finland, Germany, India, Japan,Norway, Republic of Korea, Spain,United Kingdom, United States ofAmerica.

• Positive scientific opinion from theEuropean Medicines Agency (EMA).

• Decisions of the European Commission.

• Licensing/approval information onregulatory authority web sites.

• Evidence of approval on the UnitedStates Food and Drug Administrationweb site.

Q26 Is it necessary for a pharmaceuticalproduct to be exported from the samecountry as the certifying authority?

A26 No. It is not necessary for theproduct to be exported from the certifyingcountry as long as a declaration of GMPassurance appears on the CPP.

The Scheme was established on thebasis that the certifying country was alsothe country where finished productmanufacture took place and was, there-fore, the exporting country. Subsequentrevisions to the Scheme allow scope forCPPs to be issued by other referenceauthorities. Most certifying authoritiescurrently provide CPPs when the finishedproduct is not manufactured in the certify-ing country on the basis of GMP assur-ance.

Many authorities assume that certifyingauthorities issue CPPs even whenfinished product manufacture does notoccur in the certifying country. Strictadherence to the above assumptionpotentially limits licensing and registrationoptions and can delay the introduction oraffect the continued supply of neededmedicines.

Q27 Is it possible to obtain a CPP from acertifying authority that is not of thecountry where the manufacture of thefinished product takes place?

A27 Yes. The GMP declaration on theCPP will refer to assurance of GMP for


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the product approved in the certifyingcountry at the stated site, even if themanufacturing site is in a different countrythan the issuing authority.

The Scheme has a provision that whenmanufacture takes place in a countryother than that where the product certifi-cate is issued, an attestation that suchmanufacture complies with GMP may stillbe provided as an attachment to theproduct certificate on the basis of inspec-tions undertaken for registration pur-poses.

Q28 Is it necessary for the CPP to comefrom the country where finished productmanufacture takes place?

A28 No. Although the Scheme was setup assuming that the certifying countrywas also the country where finishedproduct manufacture takes place, there isscope within the Scheme for CPPs to beissued by other authorities that canprovide independent assurance of theGMP compliance status.

There needs to be an appreciation of thecomplexity of manufacturing and sourcingroutes currently employed by companiesoperating internationally. WHO MemberStates may define the source differently:

• Country of finished product manufac-ture.

• Country of final packing.

• Country of final release.

• Country of headquarters of the pharma-ceutical company, etc.

A critical element is confirmation that allproduction/manufacturing/quality opera-tions are carried out according to GMP.

Due to complex modern sourcing routes,together with varying local regulatory

processes, approval in the country wherefinished product manufacture takes placemay be subsequent to that in othercountries. In this case it is a matter ofjudgment whether it is necessary for theCPP to be issued from the country wherefinished product manufacture takes place.Preferred action, in order to speed uppatient access, would be to accept theCPP from the earlier approving country.In order to approve the product thecertifying authority must be assured ofGMP.

GMP implementation and complianceensures product quality. Any requirementfor an additional CPP for the release site,if it is different from the product manufac-ture site, will delay patient access be-cause multiple CPPs provide no addi-tional value.

Q29 What is the significance of thedeclaration of marketing status (i.e.,whether the product is actually on themarket in the exporting country)?

A29 A declaration of marketing authoriza-tion approval is the aim of the CPP. It istrue that the WHO format CPP includesinformation on marketing status (if theproduct is actually on the market of theexporting country) but the Scheme alsohas a provision whereby the issuingauthority can indicate why the productmay not be marketed. In circumstanceswhere the product is not actually on themarket, the issuing authority can indicatethis on the certificate.

The actual presence on the market of theproduct depends on many other factors.The recipient authority should not requirethat a product be marketed in the certify-ing country.

Q30 Should recipient authorities requirea CPP from more than one certifyingauthority?


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A30 No. They should not require a CPPfrom more than one certifying authority. AWHO-format CPP from a single certifyingauthority should provide appropriateevidence of approval and GMP status.

Q31 Is it necessary for recipient authori-ties to require GMP certificates in additionto a CPP?

A31 No. Since the CPP includes a GMPdeclaration, additional GMP certificatesare not necessary.

Following introduction of the WHO CPPsome authorities no longer issue GMPcertificates (e.g., US FDA).

In the presence of a CPP, separate GMPcertificates are redundant and are there-fore discouraged. CPPs should beaccepted (in particular from PIC/S andICH countries) as evidence of GMPstatus.

However, outside of the Scheme, thereare occasions when it is appropriate torequire a GMP certificate.

Q32 When a CPP forms part of a regula-tory review, is it necessary to conduct asite inspection as well?

A32 An inspection should not be neces-sary when the GMP declaration on theCPP covers the product to be approved inthe recipient country.

Inspections outside of this condition are adecision which should be made by therecipient country. Mechanisms andsystems for recognizing inspectionscarried out by other authorities is encour-aged to reduce duplication of inspections.

CPPs should be accepted (in particularfrom PIC/S and ICH countries) as evi-dence of GMP status. The decision toinspect should be made after a risk-basedassessment of the facility, taking intoaccount GMP and inspection statusprovided by other authorities.

Q33 Imagine a situation in which com-pany A in one European country called Mproduces a pharmaceutical product calledX and the product is authorized formarketing in that country. Company Aalso produces X under contract manufac-turing in country Z in Asia and wants toexport it to country Y in Africa. Theauthority in the importing country Yrequires a CPP to approve importation.(See figure 1 overleaf.)

The questions are:

Q33a Is contract manufacturing ac-cepted?

A33a Yes. Contract manufacturing isaccepted under GMP.

Q33b In the case of a contract-manufac-tured product, from which country shouldthe authority in the importing country(receiving authority) accept the CPP?

A33b Country Z can issue a CPP if theproduct is registered by the authority ofcountry Z. If the product is not registeredin Z then the authority in Z cannot issuethe CPP.

If the contract-manufactured product isalso authorized for marketing in theEuropean country, then the Europeancountry can issue the certificate.

If the product is not registered in bothcountries, then the only country that canissue a certificate will be the Europeancountry, M. The authority of the Europeancountry will issue the CPP after it hassatisfied itself that the product undercontract manufacture is the same in allaspects as the one produced in its owncountry and that the product is producedin compliance with GMP.

Q34 Can a CPP also be used to provideevidence of an administrative review andapproval, e.g., as certification of accept-ability of a company name change?


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A34 Yes. The CPP can also provideevidence of an administrative review andapproval (e.g., as certification of accept-ability of a company name change, or fora name change of the owner of a manu-facturing or production site) which oftenhappens in the context of companymergers and acquisitions.

For administrative approvals that nowinvolve a QSE review, recipient authori-ties should use alternatives to a CPP as apreferred and quicker option (see Ques-tion 9).

Issues related to manufacturing companyname change (administrative review) mayindeed create various practical difficultiesfor exporters–importers but are notassociated directly with safety/qualityconcerns and should be given lessprominence.

Q35 Imagine a situation in which aproduct is authorized for marketing in thecountry of manufacture but is not actuallyavailable on the market. Can the compe-

tent authority of the exporting countryissue a CPP to support export?

A35 Yes, it can issue a CPP. What itshould do is explain why it is not on themarket. One reason for not being on themarket could be that the disease/healthproblem for which the product is indicatedmay not be prevalent in the country.

Q36 Sometimes a country may wish toimport a special dosage form, strength orformulation of a certain known productand this particular product may not beregistered in the manufacturing country.Under such circumstances can theauthority of the exporting country issue aCPP?

A36 Yes. It can issue a CPP but it shouldexplain on the certificate that the particu-lar product is not authorized for marketingin the exporting country, that it has beenproduced based on the request of theimporting country and that manufacturingis in compliance with GMP.


Figure 1. Question 33: contract manufacturing

CPP PRODUCT

Country Y in Africa

Importing

Company Aproduces X in a

European country M

Product X isregistered in that

country

Company A also con-tract manufactures X in

country Z in Asia

▼

▼

▼▼

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Q37 Is it necessary to legalize the CPP?

A37 No. Legalization is not part of theWHO Scheme and it is not considered toprovide additional assurance of authentic-ity. Approval status in key referencecountries is currently available as publicinformation.

Legalization should not be necessarysince an official governmental authority ofthe certifying country signs the CPP.Legalization delays availability of the CPPand thereby delays access to medicinesfor patients. If a recipient authority hasany doubts about the validity of a CPP itshould contact the certifying authoritydirectly.

Q38 What should receiving countries doin case of any doubt about a CPP?

A38 In case of any doubt, the competentauthorities of receiving countries shouldcommunicate directly with the authorizedbody that has issued the certificate orcontact WHO to clarify the matter.

Q39 Are certifying authorities penalized ifthey issue CPPs, but do not meet WHOrequirements for self-certification andsubsequent issue of CPPs?

A39 No. There is no penal system. WHOdoes not have the power to certify,inspect or penalize certifying authorities.

Q40 What are the main problems en-countered in the application of theScheme?

A40 A number of problems have beenreported during use of the Scheme, whichinclude:

• Countries not party to the Scheme issuecertificates.

• Authorities that do not meet the require-ments stated in the guidelines for theScheme issue certificates.

• Some issuing authorities put the WHOemblem, logo or acronym on the certifi-cate, thereby creating the impressionthat the certificate is authenticated byWHO.

References

1. WHO Certification Scheme on the Quality ofPharmaceutical Products Moving in Interna-tional Commerce. World Health Assemblyresolution WHA22.50 (1969), World HealthAssembly resolution WHA28.65 (1975), WorldHealth Assembly resolution WHA41.18 (1988),World Health Assembly resolution WHA45.29(1992), and World Health Assembly resolutionWHA50.3 (1997) available at: http://www.who.int/governance

2. World Health Organization. Expert Commit-tee on Specifications for PharmaceuticalPreparations. Technical Report Series,2009;953:47-48 at http://www.who.int/medi-cines/publications.


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Regulatory Action and News

Buflomedil: marketingauthorization suspendedFrance — On 11 February 2011, theHealth Products Safety Agency(AFSSPS) suspended the marketingauthorization for buflomedil-containingproducts. This action was taken followingnotification of serious nervous and car-diac events especially during accidentalor voluntary overdose.

Reference: Spécialités à base de Buflomédil– Retrait de produits. 17 February 2011 athttp://www.afssaps.fr

Dolasetron mesylateintravenous injection:withdrawalCanada — The manufacturer of dolase-tron mesylate (Anzemet®) has an-nounced withdrawal of the injectableform. New data show that intravenousadministration of the injectable form ofdolasetron mesylate is associated withQTc prolongation to an extent which maypotentially result in serious arrhythmias atthe doses recommended for the preven-tion of nausea and vomiting associatedwith chemotherapy. Dolasetron mesylateinjectable is no longer indicated to pre-vent nausea and vomiting in adultsundergoing chemotherapy.

However, tablets for oral use may still beused as the risk of developing an abnor-mal heart rhythm with the oral form of thisdrug is considered less than that seenwith the injectable form.

Reference: Health Canada, Medeffect. 26April 2011. http://www.healthcanada.gc.ca/medeffect and http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/new-neuf-advisories-avis-eng.php

Abiraterone acetate approvedfor late-stage prostate cancerUnited States of America — The Foodand Drug Administration (FDA) hasapproved abiraterone acetate (Zytiga®) incombination with prednisone to treatpatients with metastatic castration-resistant prostate cancer who havereceived prior docetaxel.

Patients who received the Zytiga® andprednisone combination had a medianoverall survival of 14.8 months comparedto 10.9 months for patients receiving theplacebo and prednisone combination.

The most commonly reported side effectsincluded joint swelling or discomfort, lowlevels of potassium in the blood, fluidretention (usually of the legs and feet),muscle discomfort, hot flashes, diarrhoea,urinary tract infection, cough, high bloodpressure, heartbeat disorders, urinaryfrequency, increased night-time urination,upset stomach or indigestion and upperrespiratory tract infection.

Reference: FDA News Release, 28 April 2011at http://www.fda.gov

Rituximab approved forWegener granulomatosis andmicroscopic polyangiitisUnited States of America — The Foodand Drug Administration (FDA) hasapproved rituximab (Rituxan®) in combi-nation with glucocorticoids to treat pa-tients with Wegener granulomatosis (WG)and microscopic polyangiitis (MPA), tworare disorders that cause vasculitis.

Rituximab is an antibody that is manufac-tured through biotechnology methods.

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WHO Drug Information Vol. 25, No. 2, 2011 Regulatory Action and News

Safety and effectiveness was demon-strated in a single controlled trial in which197 patients with WG or MPA wereassigned at random to receive eitherRituxan® plus glucocorticoids once aweek for four weeks or oral cyclophos-phamide plus glucocorticoids daily toinduce remission. After six months, 64%of patients treated with Rituxan® hadcomplete remission compared to 53% ofpatients treated with cyclosphosphamide.

Rituximab carries a boxed warning forinfusion reactions. Other boxed warningsinclude severe mucocutaneous reactionsand progressive multifocal leukoence-phalopathy. Rituximab is not recom-mended for use in patients with severe,active infections.

The most common side effects in studyparticipants with WG and MPA includedinfection, nausea, diarrhoea, headache,muscle spasms, and anaemia.

Rituximab, which has been marketedsince 1997, is also indicated for thetreatment of patients with non-Hodgkinlymphoma, chronic lymphocytic leukae-mia, and rheumatoid arthritis.

Reference: FDA News Release, 19 April 2011at http://www.fda.gov

Human normal immuno-globulin: lifting of suspensionEuropean Union — The EuropeanMedicines Agency Committee for Medici-nal Products for Human Use (CHMP) hasrecommended the lifting of the suspen-sion of the marketing authorizations forhuman normal immunoglobulin 5% and10% (Octagam®) and associated names,and the re-introduction of the medicineonto the market in the European Union.

The lifting of the suspension is subject toa change in the manufacturing process.Human normal immunoglobulin is an

intravenous solution used to strengthenthe body’s immune system.

The CHMP recommended the suspen-sion of the marketing authorizationsfollowing an unexpected increase inreports of thromboembolic reactions,including stroke, myocardial infarctionand pulmonary embolism in patientsreceiving the medicine.

An in-depth review of all available data onthe safety and quality issues identifiedpreviously has now been finalized. TheCHMP has concluded that the unex-pected presence of a pro-coagulant,factor XIa, was the main cause of thethromboembolic events and that anumber of critical steps in the manufac-turing process could explain the presenceof substances that triggered the throm-boembolic events.

The Committee’s opinion has now beenforwarded to the European Commissionfor the adoption of a legally bindingdecision. It is expected that supply ofOctagam® will resume shortly after theadoption of the Commission decision.

Reference: EMA Press Release, EMA/297816/2011, 14 April 2011 at http://www.ema.eu

Everolimus approved forpancreatic cancerUnited States of America — The Foodand Drug Administration (FDA) hasapproved everolimus (Afinitor®) to treatpatients with progressive neuro-endocrinetumours located in the pancreas (PNET)that cannot be removed by surgery orhave become metastatic.

Neuro-endocrine tumours found in thepancreas are slow-growing and rare. It isestimated that there are fewer than 1000new cases in the United States eachyear.

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The most commonly reported side effectsincluded stomatitis, rash, diarrhoea,fatigue, edema, abdominal pain, nausea,fever and headache.

Afinitor® is also approved to treat pa-tients with advanced renal cell carcinomaafter they fail treatment with sunitinib orsorafenib, and patients with subependy-mal giant cell astrocytoma associatedwith tuberous sclerosis who cannot betreated with surgery.

Reference: FDA News Release, 6 May 2011at http://www.fda.gov

Boceprevir approvedfor hepatitis CUnited States of America — The Foodand Drug Administration (FDA) hasapproved boceprevir (Victrelis®) to treatcertain adults with chronic hepatitis C.Boceprevir is used for patients who stillhave some liver function and who eitherhave not been previously treated withdrug therapy for hepatitis C or who havefailed such treatment. Boceprevir isapproved for use in combination withpeginterferon alfa and ribavirin.

Safety and effectiveness of boceprevirwas evaluated in two phase III clinicaltrials with 1500 adult patients. In bothtrials, two-thirds of patients receivingboceprevir in combination with pegylatedinterferon and ribavirin experienced asignificantly increased sustained virologicresponse.

According to the US Centers for DiseaseControl and Prevention, about 3.2 millionpeople in the United States have chronichepatitis C. Most liver transplants per-formed in the United States are due toprogressive liver disease caused byhepatitis C virus infection.


Linagliptin approvedfor type 2 diabetesUnited States of America — The Foodand Drug Administration (FDA) hasapproved linagliptin (Tradjenta®) tabletsfor use with diet and exercise, to improveblood glucose control in adults with Type2 diabetes which is the most commonform of the disease, affecting between 90and 95% of the 24 million diabetics in theUnited States.

Linagliptin was demonstrated to be safeand effective in eight double-blind, pla-cebo-controlled clinical studies involvingabout 3800 patients with Type 2 diabetes.

Linagliptin has been studied as a stand-alone therapy and in combination withother type 2 diabetes therapies includingmetformin, glimepiride, and pioglitazone.Linagliptin has not been studied in combi-nation with insulin, and should not beused to treat people with type 1 diabetesor in those who have diabetic ketoacido-sis.


Naproxcinod: withdrawal ofmarketing authorizationapplicationEuropean Union — The EuropeanMedicines Agency (EMA) has beennotified by the manufacturer of its deci-sion to withdraw its application for acentralized marketing authorization forthe medicine naproxcinod (Beprana®),375 mg hard capsules.

Naproxcinod was intended to be used forthe relief of the signs and symptoms ofosteoarthritis of the knee and hip inadults.

In its official letter, the company statedthat their decision to withdraw the appli-

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cation was based on the fact that theCommittee for Medicinal Products forHuman Use (CHMP) considers that thedata provided do not allow it to concludeon a positive benefit-risk balance.


Lumiracoxib: withdrawal ofmarketing authorizationapplicationEuropean Union — The EuropeanMedicines Agency (EMA) has beennotified by the manufacturer of its deci-sion to withdraw its application for acentralized marketing authorization forthe medicine lumiracoxib (Joicela®) 100mg film-coated tablets. Lumiracoxib wasintended to be used for symptomatic reliefin the treatment of osteoarthritis of theknee and hip in patients who are non-carriers of the DQA1*0102 allele.

In its official letter, the company statedthat its decision to withdraw the applica-tion was based on its inability to addressthe CHMP request to provide additionaldata within the timeframe allowed in thecentralized procedure.


Erythropoietin: withdrawal ofmarketing authorizationapplicationEuropean Union — The EuropeanMedicines Agency (EMA) has beennotified by the manufacturer of its deci-

sion to withdraw its application for acentralized marketing authorization forthe medicine erythropoietin (Epostim®),2000 IU/ 0.5 ml, 4000 IU/0.4 ml, and10 000IU/ml solution for injection in pre-filled syringes.

This medicine was intended to be usedfor the following indications:

• Treatment of anaemia associated withchronic renal failure in paediatric andadult patients on haemodialysis andadult patients on peritoneal dialysis.

• Treatment of severe anaemia of renalorigin accompanied by clinical symp-toms in adult patients with renal insuffi-ciency not yet undergoing dialysis.

• Treatment of anaemia and reduction oftransfusion requirements in adultpatients receiving chemotherapy forsolid tumours, malignant lymphoma ormultiple myeloma.

• To increase the yield of autologousblood from patients in a predonationprogramme.

• To reduce exposure to allogenic bloodtransfusions in adult non-iron deficientpatients prior to major elective ortho-paedic surgery.

In its official letter, the company statedthat its decision to withdraw the applica-tion was based on its inability to addressthe CHMP’s request to provide additionaldata within the timeframe allowed in thecentralized procedure.


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ATC/DDD Classification

The following anatomical therapeutic chemical (ATC) classifications and defined dailydoses (DDDs) were agreed by the WHO International Working Group for Drug Sta-tistics Methodology March 2011. Comments or objections to the decisions should beforwarded to the WHO Collaborating Centre for Drug Statistics Methodology [email protected]. The new ATC codes and DDDs will be considered final and be in-cluded in the January 2012 issue of the ATC index. The inclusion of a substance inthe lists does not imply any recommendation of use in medicine or pharmacy. TheWHO Collaborating Centre for Drug Statistics Methodology can be contacted throughe-mail at: [email protected].

ATC/DDD Classification (temporary)

ATC level INN/Common name ATC code

New ATC 5th level codes:abiraterone L02BX03aflibercept S01LA05axitinib L01XE17bosutinib L01XE14brentuximab vedotin L01XC12catridecacog B02BD11crizotinib L01XE16dapagliflozin A10BX09dexlansoprazole A02BC06levomethadone N07BC05losartan and amlodipine C09DB06meloxicam, combinations M01AC56mipomersen C10AX11naproxen and misoprostol M01AE56pasireotide H01CB05perampanel N03AX22ruxolitinib L01XE18sipuleucel-T L03AX17tafamidis N07XX08telaprevir J05AE11tesamorelin H01AC06vemurafenib L01XE15

ATC name changes

Previous New ATC code

Antigrowth hormones Somatostatin and analogues H01CBCalcium, combinations with Calcium, combinations with other drugs vitamin D and/or other drugs A12AXEnzyme inhibitors Aromatase inhibitors L02BG

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New DDDs:

INN/common name DDD Unit Adm.R ATC code

aspoxicillin 4 g P J01CA19aztreonam 0.225 g Inhal. solution J01DF01bekanamycin 0.6 g P J01GB13carumonam 2 g P J01DF02cefbuperazone 2 g P J01DC13cefminox 4 g P J01DC12conestat alfa 3.5 TU P B06AC04desvenlafaxine 50 mg O N06AX23fingolimod 0.5 mg O L04AA27flomoxef 2 g P J01DC14histrelin 0.137 mg1 implant H01CA03isepamicin 0.4 g P J01GB11ribostamycin 1 g P J01GB10tapentadol 0.4 g O N02AX06ticagrelor 0.18 g O B01AC24vernakalant 0.2 g P C01BG11

1. DDD assigned according to the total content of the implant.

Herbal medicinal products*

New ATC 5th level codes::

Name ATC code

St. John’s Wort N06AX25

2. Assessed and approved by regulatory authorities based on dossiers including efficacy, safety,and quality data (e.g., well-established use procedure in EU).


.../...

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The following anatomical therapeutic chemical (ATC) classifications and defined dailydoses (DDDs) were agreed by the WHO International Working Group for Drug Sta-tistics Methodology in October 2010. They will be included in the January 2012 issueof the ATC index. The inclusion of a substance in the lists does not imply any recom-mendation of use in medicine or pharmacy. The WHO Collaborating Centre for DrugStatistics Methodology can be contacted at [email protected].

ATC/DDD Classification (final)


New ATC level codes (other than 5th level):Drugs used in hereditary angioedema B06AC

New ATC 5th level codes:aspoxicillin J01CA19azilsartan medoxomil C09CA09bekanamycin J01GB13cabazitaxel L01CD04carumonam J01DF02cefbuperazone J01DC13cefminox J01DC12cinchocaine S02DA04conestat alfa B06AC04dienogest G03DB08dimeticone P03AX05donepezil and memantine N06DA52doxylamine,combinations R06AA59ecallantide B06AC03emtricitabine, tenofovir disoproxil and rilpivirine J05AR08flomoxef J01DC14fluindione B01AA12iloperidone N05AX14ipilimumab L01XC11meningococcus B, multi-component vaccine J07AH09metformin and linagliptin A10BD11metformin and saxagliptin A10BD10motavizumab J06BB17panobinostat L01XX42pentosan polysulfate sodium G04BX15


.../...

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pirfenidone L04AX05ramipril and amlodipine C09BB07rilpivirine J05AG05secukinumab L04AC10sinecatechins D06BB12teduglutide A16AX08tetrachlorodecaoxide D03AX11vilazodone N06AX24von Willebrand factor B02BD10

ATC code changes:

INN/common name Previous ATC New ATC

alitretinoin D11AX19 D11AH04C1-inhibitor, plasma derived B02AB03 B06AC01icatibant C01EB19 B06AC02

ATC name changes

Previous New ATC code

Agents for atopic dermatitis, excluding Agents for dermatitis, corticosteroids excluding corticosteroids D11AHOther cold combination preparations Other cold preparations R05X

New DDDs:

INN/common name DDD Unit Adm.R ATC code

asenapine 20 mg O N05AH05corifollitropin alfa 0.15 mg P G03GA09dienogest 2 mg O G03DB08eltrombopag 50 mg O B02BX05fampridine 20 mg O N07XX07flupirtine 0.4 g O N02BG07indacaterol 0.15 mg Inhal. powder R03AC18indometacin, combinations 0.1 g1 O,R M01AB51mifamurtide 0.7 mg P L03AX15prucalopride 2 mg O A03AE04roflumilast 0.5 mg O R03DX07velaglucerase alfa 300 U P A16AB10

1. refers to indometacin



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Herbal medicinal products*

New ATC 5th level codes::

Name ATC code

Horse chestnut, seeds C05CX03

* Assessed and approved by regulatory authorities based on dossiers includingefficacy, safety, and quality data (e.g., well-established use procedure in EU).

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Recent Publications,Information and EventsSelection and use of medicinesWorld Health Organization — The 18thmeeting of the WHO Expert Committeeon the Selection and Use of EssentialMedicines took place in Accra, Ghana on21–25 March 2011. The purpose of themeeting was to review and update theWHO Model List of Essential Medicines(EML) as well as the WHO Model List ofEssential Medicines for Children (EMLc).

In accordance with its approved proce-dures, the Committee evaluated thescientific evidence on the comparativeeffectiveness, safety and cost effective-ness of medicines and updated the WHOModel List of Essential Medicines and theModel List of Essential Medicines forChildren. The Committee:

• Approved the addition of 16 new medi-cines to the EML.

• Approved the deletion of 13 medicinesfrom the EML.

• Approved new indications for 4 medi-cines already listed on the EML.

• Approved the addition of a new dosageform or strength for 4 medicines alreadyon the EML.

• Rejected 9 applications for the additionof a medicine to EML.

• Approved the addition of 16 new medi-cines to the EMLc.

• Approved the deletion of 15 medicinesfrom the EMLc,

• Rejected 3 applications for the additionof a new medicine to the EMLc.

Some of the main recommendationsmade, in order of their appearance on theEML, were:

• Section 6: addition of artesunate +amodiaquine combination tablet for thetreatment of malaria in adults andchildren, in line with current WHOtreatment guidelines. In making itsdecision, the 2011 Committee reviewedthe latest clinical evidence and theinformation about licensing in severalcountries of the fixed dose combinationtablet. The Committee noted thatappropriate doses of both medicinescan also be achieved using combina-tions of the mono-component products,including as co-blistered presentations.

• Section 10: addition of tranexamic acidinjection for the treatment of adultpatients with trauma and significant riskof ongoing haemorrhage. On the basisof the results of a very large trial of theuse of tranexamic acid specifically fortrauma patients — including those whohave been in road traffic accidents, theCommittee concluded that there issufficient evidence to support theproposal that listing tranexamic acidmay contribute to a reduction in thiscause of death.

• Section 18.5 : addition of glucagoninjection, 1 mg/ml to treat acute severehypoglycaemia in patients with diabe-tes, to support efforts in many countriesto ensure appropriate treatment of theincreasing number of patients withdiabetes. The Committee also recom-mended that careful attention be paid tothe cost of procuring glucagon andnoted that based on experience withother high cost medicines, such as

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antiretrovirals, inclusion in the EML mayhelp to contribute to a reduction inprices.

• Section 22.1: addition of misoprostoltablet, 200 micrograms for the preven-tion of post-partum haemorrhage, whereoxytocin is not available or cannot besafely used. WHO guidelines currentlyrecommend that in situations wereoxytocin is not available, misoprostolcan be used to prevent and treat postpartum haemorrhage due to uterineatony.

Based on the evidence provided, theCommittee considered that misoprostolcan be safely administered to women toprevent post-partum haemorrhage byhealth workers trained in its use in thethird stage of labour. The addition ofmisoprostol for the treatment of post-partum haemorrhage was not approved.The clinical trials that compare miso-prostol to oxytocin in women who needtreatment for post-partum haemorrhageshow that misoprostol is not as effectiveas oxytocin. In addition, there is noevidence to support the safety andefficacy of the 800-microgram dose fortreatment of post partum haemorrhagewhen given to women who have alreadyreceived prophylactic misoprostol 600micrograms orally. Countries need towork to make oxytocin available fortreatment of women who are bleedingafter delivery and misoprostol shouldonly be used if there is no other option.

Other medicines that were added to theEML are: isoflurane, propofol, midazolam,clarithromycin, miltefosine, paclitaxel anddocetaxel, bisoprolol, terbinafine cream/ointment, mupirocin cream/ointment, andatracurium.

A summary of reasons for all changes tothe EML is in Section 1 of the report. Allapplications and documents consideredby the Committee will remain available

on the web site for the meeting at http://www.who.int/selection_medicines/com-mittees/expert/18/en/index.html.

The next update of the WHO Model Listof Essential Medicines will take place in2013.

Reference: Unedited report of the 18thmeeting of the WHO Expert Committee on theSelection and Use of Essential Medicines athttp://www.who.int/medicines/publications/unedited_trs/en/index.html

Policy guidelines oncontrolled substancesWorld Health Organization — The WHOAccess to Controlled Medicines Team haspublished “Ensuring balance in nationalpolicies on controlled substances: guid-ance for availability and accessibility forcontrolled medicines”. This book providesguidance on policies and legislation withregards to availability, accessibility,affordability and regulation of controlledmedicines.

It includes 21 guidelines on varioustopics: content of drug control legislationand policy; authorities and their role in thesystem; policy planning for availabilityand accessibility; healthcare profession-als; estimates and statistics; procure-ment, and nationally listed drugs. Eachguideline is followed by an explanationand a description of the legal context. TheCountry Assessment Checklist enablesthe user to determine which guidelinesstill need to be worked on. A CD-ROMprovides additional information.

The guidelines are currently available inEnglish. Other on-line language versionswill follow, some of them very soon(Armenian, Bulgarian, French, Georgian,Greek, Hungarian, Khmer, Polish, Rus-sian, Serbian, Slovakian, Slovenian andTurkish). The publication will also becomeavailable in print in English and French.

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Reference: Ensuring Balance in NationalPolicies on Controlled Substances, Guidancefor Availability and Accessibility of ControlledMedicines at: http://www.who.int/medicines/areas/quality_safety/guide_nocp_sanend/en/index.

List of medicines to savemothers and childrenWorld Health Organization — The newdocument, “Priority medicines for mothersand children” contains a list of 30 medi-cines developed to advocate for bettersupply and use of the most importantessential medicines. The vast majority ofmaternal and child deaths can be pre-vented when these 30 medicines areavailable in the right formulations andprescribed and used correctly.

Medicines on this new priority list wereselected based on burden of diseasedata and their potential for impact onmaternal and child mortality and morbid-ity. All medicines on the list are already inthe WHO Model List of Essential Medi-cines and the latest WHO treatmentguidelines. The list was developed by theDepartment of Essential Medicines andPharmaceutical Policies (EMP) in collabo-ration with the Departments of Child andAdolescent Health and Development(CAH) and Making Pregnancy Safer(MPS), UNICEF and UNFPA.

Reference: Priority medicines for mothers andchildren, WHO/EMP/MAR/2011.1 at http://www.who.int/mediacentre/news/notes/2011/mother_child_ medicine_20110321. The listcan be downloaded at http://www.who.int/medicines/publications/emp_mar2011.1/en/index.html

World medicines situationWorld Health Organization — The thirdedition of the “World Medicines SituationReport 2011” brings together new data on24 key topics relating to pharmaceutical

production and consumption, innovation,regulation and safety.

Topics include selection, procurement,supply management, rational use,financing and pricing. Cross-cuttingchapters cover household medicines use,access and human rights, good govern-ance, human resources and nationalmedicines policies.

The chapters released in April 2011 are:

• Background on past and present effortsto document and improve sharing ofinformation.

• Medicines prices, availability andaffordability featuring data and informa-tion from surveys using WHO standardmethodology.

• Rational use of medicines describes theproblem of bad practices in medicinesprescribing and the harmful conse-quences in terms of morbidity, mortalityand impact to health cost. This chapterlooks at global data, and draws atten-tion to trends in developing and transi-tional countries, in both public andprivate sectors.

• Traditional medicines: global situationissues and challenges describes use oftraditional and herbal medicines aroundthe world.

• Access to controlled medicines. Interna-tional drug treaties stress that psycho-tropic and narcotic substances must beavailable for medical and scientific use,even if they are classified as controlledmedicines.

• Good governance reviews the findingsof country studies, highlighting weak-nesses and strengths in pharmaceuticalsystems that can help policy-makersbetter understand problems and identifysolutions.

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Reference: The World Medicines SituationReport 2011, available at http://www.who.int/medicines/areas/policy/world_medicines_situation/en/index.html

Artesunate instead of quininesaves livesMédecins sans Frontières (MSF) havereleased a report calling for a change insevere malaria treatment protocols fromcenturies old quinine use to the newer,more effective drug artesunate (1).

In its report “Making the Switch”, MSFcalls on African governments to followWorld Health Organization (WHO)guidelines, and switch from the far lesseffective quinine to artesunate whichcould avert nearly 200 000 deaths eachyear.

For decades, quinine has been used insevere malaria but it can be both difficultto administer and dangerous. Artesunateis safer, easier and more effective thanquinine. Quinine has to be given threetimes a day in a slow intravenous dripthat takes four hours: a treatment that isburdensome for both patients and

health staff. Artesunate, in contrast, canbe given in just four minutes as anintravenous or intramuscular injection.

A landmark clinical trial in late 2010concluded that the use of artesunateto treat children with severe malariareduces the risk of death by nearly aquarter. The study, carried out in nineAfrican countries, found that for every 41children given artesunate over quinine,one extra life was saved. Because of thecomplexities of administering quinine,children in the trial who were assigned toreceive quinine were almost four timesmore likely to die before even receivingtreatment.

MSF participated in the trial through itsresearch affiliate Epicentre, with a re-search site in Uganda. MSF has sincechanged its own treatment protocols andnow plans to work with national healthauthorities to roll out artesunate in itsprojects over the coming months.

Reference: Médecins sans Frontières.Making the Switch at http://www.msf.org/msf/articles/2011/04/malaria-making-the-switch.cfm

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Revision of monograph on capsules

This monograph was adopted by the Forty-fourth WHO Expert Committee on Specifi-cations for Pharmaceutical Preparations in October 2009 for addition to The Interna-tional Pharmacopoeia.

Capsules

The requirements of this monograph do not necessarily apply to preparations that areintended for use other than by oral administration, such as vaginal or rectal capsulesetc. Such preparations may require a special formulation, method of manufacture, orform of presentation appropriate to their particular use. Starch capsules (often knownas cachets) are not included in this monograph.

DefinitionCapsules are solid dosage forms with hard or soft shells. They are of various shapesand sizes and contain a single dose of one or more active ingredients. They areintended for oral administration.

Capsule surfaces may bear symbols or other markings.

Capsule shells are made of gelatin or other substances, the consistency of which maybe modified by the addition of substances such as glycerol or sorbitol. The shellshould disintegrate in the presence of digestive fluids so that the contents are re-leased. The contents of capsules may be solid, liquid, or of a paste-like consistency.Capsule shells and contents may contain excipients such as diluents, solvents, sur-face-active substances, opaque fillers, antimicrobial agents, sweeteners, colouringmatter authorized by the appropriate national or regional authority, flavouring sub-stances, disintegrating agents, glidants, lubricants, and substances capable of modify-ing the behaviour of the active ingredient(s) in the gastrointestinal tract. The contentsshould not cause deterioration of the shell.

When excipients are used, it is necessary to ensure that they do not adversely affectthe stability, dissolution rate, bioavailability, safety, or efficacy of the active ingre-dient(s); there must be no incompatibility between any of the components of thedosage form.

The different categories of capsule include hard capsules, soft capsules, and modified-release capsules [including delayed-release capsules (gastro-resistant/enteric cap-sules) and sustained-release capsules (extended-/prolonged-release capsules)].

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Consultation Documents

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ManufactureThe manufacturing and filling processes for capsules should meet the requirements ofgood manufacturing practices (GMP).

Very broad guidelines concerning the main critical steps to be followed during produc-tion of capsules, indicating those that are the most important, are provided below.Additional guidelines specific for hard or soft capsules are provided in the respectivesubsections below.

In the manufacture of capsules, measures are taken to:

• ensure that the active ingredient(s) when present in solid state form have appro-priate solid-state properties such as particle-size distribution and polymorphic form;

• ensure that mixing with excipients is carried out in a manner that ensures homo-geneity;

• minimize the degradation of the active ingredient(s);

• minimize the risk of microbial contamination, and

• minimize the risk of cross contamination.

The particle size of the active ingredient(s) may be of primary significance in determin-ing the rate and extent of dissolution and the bioavailability of the drug product, espe-cially for substances of low solubility in aqueous media. The uniformity of the final drugproduct is affected by the particle size of the active ingredient(s) as well as the excipi-ents.

Throughout manufacturing, certain procedures should be validated and monitored bycarrying out appropriate in-process controls. These should be designed to guaranteethe effectiveness of each stage of production.

Packaging is required to be adequate to protect capsules from light when required,and from moisture and damage during transportation.

Visual inspectionUnpack and inspect at least 20 capsules. They should be smooth and undamaged.Evidence of physical instability is demonstrated by gross changes in physical appear-ance, including hardening or softening, cracking, swelling, mottling, or discoloration ofthe shell.

Uniformity of massCapsules comply with the test for 5.2 Uniformity of mass for single-dose preparations,unless otherwise specified in the individual monograph.

Uniformity of contentWhere a requirement for compliance with the test for 5.1 Uniformity of content forsingle-dose preparations is specified in an individual capsule monograph, the test for5.2 Uniformity of mass for single-dose preparations is not required.


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Dissolution/disintegrationWhere a choice of test is given (either test A or test B may be applied), follow theinstructions in the monograph. Where a requirement for compliance with a dissolutiontest is specified in the individual monograph, the requirement for disintegration statedin the sections below do not apply.

LabellingEvery pharmaceutical preparation must comply with the labelling requirements estab-lished under GMP.

The label should include:

1. The name of the pharmaceutical product.2. The name(s) of the active ingredient(s); International Nonproprietary Names (INNs) should be used wherever possible.3. The amount of the active ingredient(s) in each capsule and the number of capsules in the container.4. The batch (lot) number assigned by the manufacturer.5. The expiry date and, when required, the date of manufacture.6. Any special storage conditions or handling precautions that may be necessary.7. Directions for use, warnings, and precautions that may be necessary.8. The name and address of the manufacturer or the person responsible for placing the product on the market.

StorageCapsules should be kept in well-closed containers. They should be protected fromlight when required, and from excessive moisture, or dryness, and should not besubjected to temperatures above 30 °C. Additional special packaging, storage, andtransportation recommendations are provided, where necessary, in the individualmonograph.

Requirements for specific types of capsules

Hard capsules

DefinitionHard capsules have shells consisting of two prefabricated cylindrical sections that fittogether. One end of each section is rounded and closed, and the other is open. Thecontents of hard capsules are usually in solid form (powder or granules).

ManufactureSometimes, the physical characteristics of the mixture of the active ingredient(s) andexcipients allow it to be directly filled into the shell, but it may occasionally be neces-sary to granulate before filling. Normally the granulate needs to be mixed with lubri-cants and/or disintegrating agents. The use of excessive amounts of lubricants shouldbe avoided since these may deleteriously affect the capsules.

In-process controls during hard capsule production should include the moisture con-tent of the mixture and/or granulate (as well as of the shells), the size of granules, theflow of the final mixture, and the uniformity of mass, capsule size, integrity of the seals,and disintegration or dissolution rate (e.g., for modified-release capsules) of thefinished dosage form.


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Disintegration testHard capsules comply with 5.3 Disintegration test for tablets and capsules.

Use water as the immersion fluid unless hydrochloric acid (0.1 mol/l) VS or othermedium is specified in the individual monograph. Operate the apparatus for 30 min-utes, unless otherwise justified and authorized and examine the state of the capsules.If capsules float, use a disc as described under 5.3 Disintegration test for supposito-ries.

Soft capsules

DefinitionSoft capsules have thicker shells than hard capsules, and antimicrobial preservativesare usually added. The shells are of one piece and various shapes. The contents ofsoft capsules are usually solutions or suspensions of the active ingredient(s) in non-aqueous liquids. Partial migration of the contents into the shell may occur (and viceversa) depending on the nature of the materials used and the product in question.

ManufactureSoft capsules are usually formed, filled, and sealed in one operation. However, shellsfor extemporaneous use are sometimes prefabricated. Liquids may be incorporateddirectly. Solids are usually dissolved or dispersed in a suitable excipient(s) to give asolution, suspension or dispersion of paste-like consistency.

In-process controls during soft capsule production should include the viscosity of thecontents, and the uniformity of mass, capsule size, integrity of the seals, and disinte-gration or dissolution rate (e.g., for modified-release capsules) of the finished dosageform.

Disintegration testSoft capsules comply with 5.3 Disintegration test for tablets and capsules, using wateras the immersion fluid unless hydrochloric acid (0.1 mol/l) VS or other medium isspecified in the individual monograph. Add a disc to each tube. Liquid active sub-stances dispensed in soft capsules may attack the disc; in such circumstances andwhere authorized, the disc may be omitted. Operate the apparatus for 30 minutes andexamine the state of the capsules. If the capsules fail to comply because of adherenceto the discs, the results are invalid. Repeat the test on a further 6 capsules omittingthe discs.

Modified-release capsules

DefinitionModified-release capsules are hard or soft capsules in which the contents or the shellor both contain excipients or are prepared by special procedures such as micro-encapsulation which, separately or together, are designed to modify the rate, place ortime of release of the active ingredient(s) in the gastrointestinal tract.

Sustained-release capsules (extended- or prolonged-release capsules)

DefinitionSustained-release capsules are designed to slow the rate of release of the activeingredient(s) in the gastrointestinal tract.


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All requirements for these specialized dosage forms are given in the individual mono-graphs.

Delayed-release capsules (gastro-resistant/enteric capsules)

DefinitionDelayed-release capsules are hard or soft capsules prepared in such a manner thateither the shell or the contents resist the action of gastric fluid but release the activeingredient(s) in the presence of intestinal fluid.

ManufactureThe additional statements given under either hard or soft capsules apply, as appropri-ate to delayed-release capsules.

Disintegration testDelayed-release capsules with a gastro-resistant shell comply with 5.3 Disintegrationtest for tablets and capsules, using hydrochloric acid (0.1 mol/l) VS as the immersionfluid. Operate the apparatus without the discs for 2 hours, unless otherwise specified inthe individual monograph (but in any case for not less than 1 hour), and examine thestate of the capsules. No capsule should show signs of disintegration or rupturepermitting the contents to escape. Replace the acid by phosphate buffer solution, pH6.8, TS with added pancreatin R where specified in the individual monograph. Add adisc to each tube. Operate the apparatus for 60 minutes and examine the state of thecapsules. If the capsules fail to comply because of adherence to the discs, the resultsare invalid. Repeat the test on a further 6 capsules omitting the discs.

For capsules in which the contents, rather than the shell, resist the action of gastricfluid, carry out a suitable dissolution test to demonstrate the appropriate release of theactive substance(s).

Revision of monograph on tablets

This monograph was adopted by the Forty-fourth WHO Expert Committee on Specifi-cations for Pharmaceutical Preparations in October 2009 for addition to The Interna-tional Pharmacopoeia.

Tablets

The requirements of this monograph do not necessarily apply to preparations that areintended for use other than by oral administration, such as implants, solution-tabletsfor injections and irrigations, tablets for external use, vaginal tablets, etc. Such prepa-rations may require a special formulation, method of manufacture, or form of presenta-tion, appropriate to their particular use.

DefinitionTablets are solid dosage forms usually obtained by single or multiple compression ofpowders or granules. In certain cases tablets may be obtained by moulding or extru-sion techniques. They are uncoated or coated.


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Tablets are normally right circular solid cylinders, the end surfaces of which are flat orconvex and the edges of which may be bevelled. They may have lines or break-marks(scoring), symbols, or other markings.

If the break-mark(s) is/are intended to facilitate breaking the tablet for ease of swallow-ing a dose consisting of one or more whole tablets, the scoring is not critical. However,if the break-mark(s) is/are intended to permit accurate subdivision of the tablet in orderto provide doses of less than one tablet, the scoring is critical. Tablets containingactive ingredients having a narrow therapeutic window should generally not be pre-sented with break-marks for subdivision. Non-functional break-marks should beavoided.

Tablets contain one or more active ingredients. They may contain excipients such asdiluents, binders, disintegrating agents, glidants, lubricants, substances capable ofmodifying the behaviour of the dosage forms and the active ingredient(s) in the gas-trointestinal tract, colouring matter authorised by the appropriate national or regionalauthority, and flavouring substances. When such excipients are used, it is necessaryto ensure that they do not adversely affect the stability, dissolution rate, bioavailability,safety, or efficacy of the active ingredient(s); there must be no incompatibility betweenany of the components of the dosage form.

Tablets are single-dose preparations intended for oral administration. Some areintended to be swallowed whole, some after being chewed and some after beingcrushed, some are intended to be dissolved or dispersed in water before being takenand some are intended to be retained in the mouth where the active ingredient(s) is/are liberated.

The different categories of tablet include:

• uncoated tablets

• coated tablets (including film-coated and sugar-coated tablets)

• soluble tablets

• dispersible tablets

• effervescent tablets

• chewable tablets

• tablets for use in the mouth (including sublingual and buccal tablets)

• modified-release tablets (including delayed-release tablets (gastro-resistant/enteric-coated tablets) and sustained-release tablets (extended-/prolonged-release tablets)).

ManufactureThe manufacturing processes for tablets should meet the requirements of goodmanufacturing practices (GMP).

The following information is intended to provide broad guidelines concerning thecritical steps to be followed during production of tablets.


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In the manufacture of tablets, measures are taken to:

• Ensure that the active ingredient(s) have appropriate solid-state properties such asparticle size distribution and polymorphic form.

• Ensure that mixing with excipients is carried out in a manner that ensures homogene-ity.

• Ensure that the tablets possess a suitable mechanical strength to avoid crumbling orbreaking on subsequent processing, e.g. coating, storage and distribution.

• Minimize the degradation of the active ingredient(s).

• Minimize the risk of microbial contamination.

• Minimize the risk of cross-contamination.

In addition, in the manufacture of those scored tablets (tablets bearing a break-mark ormarks) for which subdivision is intended in order to provide doses of less than onetablet measures are taken to:

• Ensure the effectiveness of break-marks with respect to the uniformity of mass of thesubdivided parts so that the patient receives the intended dose.

A suitable test to assess this aspect of product quality during development is asfollows:

Take 30 tablets at random. Break each tablet by hand and take one part for the testand reject the other part(s). Weigh each of the 30 parts thus obtained and calculate theaverage mass. No individual mass is outside the limits of 75% to 125% and not morethan one individual mass is outside the limits of 85% to 115% of the average mass.

The particle size of the active ingredient(s) may be of primary significance in determin-ing the rate and extent of dissolution, the bioavailability, and the uniformity of a drugproduct, especially for substances of low solubility in aqueous media.

Sometimes, the physical characteristics of the mixture allow it to be directly com-pressed. In this case, the particle size distribution and flowability of the ingredientsbecomes particularly important because of the risk for segregation during handling ofthe mix. However, it is usually necessary to granulate before compression, preferablyby wet-granulation but in certain cases dry-granulation or slugging may be preferred.Generally, wet-granulation of the mix before compression reduces the risk for segrega-tion. When a wet-granulation technique is employed, control of the residual moistureafter the drying step is important for smooth tablet compression. Too low or too highmoisture contents may influence the chemical and physical stability of the final tablet.The granulate and powders normally need to be mixed with glidants and lubricantsbefore the compression stage to improve the powder flow and to reduce sticking andadhesion to die walls and punches during compression. The use of excessive amountsof glidants and lubricants should be avoided since these will deleteriously affect thetablets. Some lubricants like magnesium stearate may in excessive amounts or bylong mixing times reduce the mechanical resistance of tablets and prolong disintegra-tion and dissolution time.


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Throughout manufacturing, certain procedures should be validated and monitored bycarrying out appropriate in-process controls. These should be designed to guaranteethe effectiveness of each stage of production. In-process controls during tablet pro-duction should include the moisture content of the mixture and/or granulate, the sizeof granules, the flow of the final mixture and, where relevant, the uniformity of mass oftablet cores before coating. In-process controls during tablet production should alsoinclude the dimensions (thickness, diameter), uniformity of mass, hardness and/orcrushing force, friability, disintegration, or dissolution rate (for example, for modified-release tablets) of the finished dosage form.

In the manufacture, packaging, storage and distribution of tablets, suitable measuresare taken to ensure their microbiological quality.

Packaging is required to be adequate to protect the tablets from light, moisture, anddamage during transportation.

The validation of the manufacturing process and the in-process controls are docu-mented.

Visual inspection

Unpack and inspect at least 20 tablets. They should be undamaged, smooth, andusually of uniform colour.

Evidence of physical instability is demonstrated by:

• Presence of excessive powder and/or pieces of tablets at the bottom of the container(from abraded, crushed, or broken tablets).

• Cracks or capping, chipping in the tablet surfaces or coating, swelling, mottling,discoloration, fusion between tablets.

• The appearance of crystals on the container walls or on the tablets.

Uniformity of mass

Tablets comply with the test for 5.2 Uniformity of mass for single-dose preparations,unless otherwise specified below or in the individual monograph.

Uniformity of content

Where a requirement for compliance with the test for 5.1 Uniformity of content forsingle-dose preparations is specified in an individual tablet monograph the test for 5.2Uniformity of mass for single-dose preparations is not required.

Dissolution/disintegration

Where a choice of test is given (either test A or test B may be applied), follow theinstructions in the monograph. Where a requirement for compliance with a dissolutiontest is specified in the individual monograph, the requirements for disintegration statedin the sections below do not apply.


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LabellingEvery pharmaceutical preparation must comply with the labelling requirements estab-lished under GMP.

The label should include:

1. The name of the pharmaceutical product.

2. The name(s) of the active ingredient(s); International Nonproprietary Names (INN) should be used wherever possible.

3. The amount of the active ingredient(s) in each tablet and the number of tablets in the container.

4. The batch (lot) number assigned by the manufacturer.

5. The expiry date and, when required, the date of manufacture.

6. Any special storage conditions or handling precautions that may be necessary.

7. Directions for use, warnings, and precautions that may be necessary.

8. The name and address of the manufacturer or the person responsible for placing the product on the market.

For scored tablets where the directions for use include subdivision to provide doses ofless than one tablet, the label should also include:

9. The storage conditions for and period of use of those subdivided part(s) not immedi ately taken or administered.

StorageTablets should be kept in well-closed containers and protected from light, moisture,crushing, and mechanical shock. Tablets should be able to withstand handling, includ-ing packaging and transportation, without losing their integrity. Moisture-sensitiveforms, such as effervescent tablets, should be stored in tightly closed containers ormoisture-proof packs and may require the use of separate packages containing water-adsorbent agents, such as silica gel. Moisture-sensitive forms, such as effervescenttablets, should be stored in tightly closed containers or moisture-proof packs and mayrequire the use of separate packages containing water-adsorbent agents, such assilica gel, or in unit dose packaging (blister cards).

Additional special packaging, storage, and transportation recommendations areprovided, where necessary, in the individual monograph.

Requirements for specific types of tablets

Uncoated tablets

DefinitionThe majority of uncoated tablets are made in such a way that the release of activeingredients is unmodified. A broken section, when examined under a lens, showseither a relatively uniform texture (single-layer tablets) or a stratified texture (multilayertablets), but no signs of coating.


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Disintegration testUncoated tablets, except soluble tablets, dispersible tablets, effervescent tablets andtablets for use in the mouth comply with 5.3 Disintegration test for tablets and cap-sules. Operate the apparatus for 15 minutes, unless otherwise specified in the indi-vidual monograph, and examine the state of the tablets.

Soluble tablets

DefinitionSoluble tablets are uncoated or film-coated tablets that are intended to be dissolved inwater giving a clear or slightly opalescent solution.

Disintegration testSoluble tablets disintegrate within 3 minutes when examined by 5.3 Disintegration testfor tablets and capsules, but using water R at 15–25 °C.

Dispersible tablets

DefinitionDispersible tablets are uncoated tablets or film-coated tablets intended to be dis-persed in water before administration giving a homogeneous dispersion.

Disintegration testDispersible tablets disintegrate within 3 minutes when examined by 5.3 Disintegrationtest for tablets and capsules, but using water R at 15–25 °C.Fineness of dispersion

Place 2 tablets in 100 ml of water R and stir until completely dispersed. A smoothdispersion is produced, which passes through a sieve screen with a nominal meshaperture of 710 µm.

Effervescent tablets

DefinitionEffervescent tablets are uncoated tablets generally containing acid substances andcarbonates or hydrogen carbonates that react rapidly in the presence of water torelease carbon dioxide. They are intended to be dissolved or dispersed in waterbefore administration.

ManufactureThe manufacture of effervescent tablets is carried out in low-humidity conditions sothat the reaction between acidic and basic components of the formulation does nottake place.

LabellingThe label should state: “Not to be swallowed directly”.

Disintegration testPlace one tablet in a 250 ml beaker containing 200 ml of water R at 15–25 °C. Numer-ous bubbles of gas are evolved. When the evolution of gas around the tablet or itsfragments ceases, the tablet should have disintegrated, being either dissolved ordispersed in the water so that no agglomerates remain. Repeat the operation on five


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additional tablets. The tablets comply with the test if each of the six tablets used in thetest disintegrates within 5 minutes, unless otherwise specified in the individual mono-graph.

Chewable tablets

DefinitionChewable tablets are usually uncoated. They are intended to be chewed before beingswallowed.

In the manufacture of chewable tablets, measures are taken to:

• Ensure that the tablets are easily crushed by chewing.

• Ensure that the tablets are palatable.

Tablets for use in the mouth (sublingual, buccal)

DefinitionTablets for use in the mouth are usually uncoated. They are usually formulated toeffect a slow release and local action of the active ingredient(s) (for example, com-pressed lozenges) or the release and absorption of the active ingredient(s) under thetongue (sublingual tablets) or in other parts of the mouth (buccal) for systemic action.

ManufactureIn the manufacture of tablets for use in the mouth, measures are taken to:

• Ensure the release characteristics are appropriate to the intended use

Coated tablets

DefinitionCoated tablets are tablets covered with one or more layers of mixtures of substancessuch as natural or synthetic resins, polymers, gums, fillers, sugars, plasticizers,polyols, waxes, colouring matters authorized by the appropriate national or regionalauthority, flavouring substances, and sometimes also active ingredients. A brokensection, when examined under a lens, shows a core which is surrounded by a continu-ous layer of a different texture.

The tablets may be coated for a variety of reasons such as protection of the activeingredients from air, moisture, or light, masking of unpleasant tastes and odours, orimprovement of appearance. The substance used for coating is usually applied as asolution or suspension.

Three main categories of coated tablet may be distinguished: sugar-coated, film-coated, and certain modified-release tablets.

Sugar-coated tablets

Uniformity of massThe test for 5.2 Uniformity of mass for single-dose preparations, does not apply tosugar-coated tablets (see in-process controls under “Manufacture”).


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Disintegration testSugar-coated tablets comply with 5.3 Disintegration test for tablets and capsules.Operate the apparatus for 60 minutes, unless otherwise specified in the individualmonograph, using water, and examine the state of the tablets. If any of the tabletshas not disintegrated, repeat the test on an additional six tablets, using hydrochloricacid (0.1 mol/l) VS.

All six tablets must disintegrate.

Film-coated tablets

DefinitionA film-coated tablet is covered with a thin layer of resins, polymers, and/or plasticiz-ers capable of forming a film.

Disintegration testFilm-coated tablets comply with 5.3 Disintegration test for tablets and capsules.Operate the apparatus for 30 minutes, and examine the state of the tablets.

Modified-release tablets

DefinitionModified-release tablets are coated, uncoated, or matrix tablets containing excipi-ents or prepared by procedures which, separately or together, are designed tomodify the rate, the place or the time of release of the active ingredient(s) in thegastrointestinal tract.

Sustained-release tablets (Extended-/prolonged-release tablets)

DefinitionSustained-release tablets are designed to slow the rate of release of the activeingredient(s) in the gastrointestinal tract.

All requirements for these specialized dosage forms are given in the individual mono-graphs.

Delayed-release tablets (gastro-resistant/enteric-coated tablets)

DefinitionDelayed-release tablets are intended to resist gastric fluid but disintegrate in intestinalfluid. This is achieved by using coating substances such as cellacefate (celluloseacetate phthalate) and anionic copolymers of methacrylic acid and its esters. It issometimes necessary to apply more than one layer.

Uniformity of massThe test for 5.2 Uniformity of mass for single-dose preparations does not apply todelayed-release tablets.

Disintegration testDelayed-release tablets comply with 5.3 Disintegration test for tablets and capsules,using hydrochloric acid (0.1 mol/l) VS as the immersion fluid. Operate the apparatusfor 2 hours, unless otherwise specified in the individual monograph (but in any case


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for not less than 1 hour), and examine the state of the tablets. No tablet should showsigns of either disintegration (apart from fragments of coating) or cracks that wouldallow the contents to escape. Replace the acid by phosphate buffer solution, pH 6.8,TS. Operate the apparatus for 60 minutes and examine the state of the tablets.

Paediatric retinol oral solution

Draft proposal for The International Pharmacopoeia (February2011). Please address any comments to Quality Assurance andSafety: Medicines, World Health Organization, 1211 Geneva 27,Switzerland. Fax +41227914730 or e-mail to [email protected]. Asubscriber mailing list is now available to speed up consultation.For more information please contact [email protected].

[Note from the secretariat: Paediatric retinol soft gel capsules in doses of 100 000 IUand 200 000 IU have a unique mode of delivery for use in public health programmesworldwide: unlike other capsules, these preparations are equipped with a nipple to besnipped before use. The dosage form is then squeezed and its content is delivereddirectly into the patient’s mouth.

WHO has developed a public standard which could be applicable to oral oily solutionsin multidose dispensers as well as to single doses, each encapsulated in a soft gelatinshell.

Feedback is sought in particular about the proposed determination of the retinolcontent per delivered dose for single-dose containers. An alternative would be todetermine the retinol content per single-dose container (capsule). The different ap-proaches will influence the assay results as investigations have shown that about 10%of the material filled into soft capsules remain inside and is not actually deliveredunder the typical condition of use.]

Other name. Paediatric vitamin A oral solution.

Category. Vitamin.

Storage. Paediatric retinol oral solution should be kept in a tight, light-resistant,container.

Labelling. The labelling should state the name of the retinol ester or esters present,the proportion of vitamin A expressed in International Units (IU), and the names andproportions of any stabilizing agents added.

Additional information. Strength in the current WHO Model List of Essential Medi-cines for Children:

Oral oily solution in multidose dispenser: 100 000 IU/ml.

Oral oily solution as single-doses (capsules): 100 000 IU; 200 000 IU.


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REQUIREMENTS

Complies with the monograph for “Liquid preparations for oral use”.

Definition. Paediatric retinol oral solution contains Retinol concentrate, oily formdiluted in a suitable vegetable oil. It may contain suitable antimicrobial agents andstabilizing agents such as antioxidants. The oral solution contains not less than 90%and not more than 120% of the amount of vitamin A stated on the label.

Paediatric retinol oral solution may be presented either in a multidose container with asuitable administration device or as single doses, each encapsulated in a soft gelatinshell. The capsule shell is designed so that it may be broached (for example, with anipple which may be cut) and so that the oral solution may be administered easily bymouth when the broached shell is squeezed gently.

Manufacture. For an oral solution presented as single doses, each encapsulated in asoft gelatin shell, the composition and method of manufacture of the soft gelatin shelland the packaging of the final product is chosen and/or validated to ensure that thecontents can be adequately expressed with use of only gentle pressure.

Carry out the analytical procedures as rapidly as possible, avoiding exposure to actiniclight and oxidizing agents, and maintaining whenever possible an atmosphere ofnitrogen above the solutions.

Identity tests

Either tests A and B, or tests A and C, or tests A and D may be applied.

A. Carry out test A.1 or, where UV detection is not available, test A.2.

A.1 Carry out the test as described under 1.14.1 Thin-layer chromatography, usingsilica gel R6 as the coating substance and a mixture of 12 volumes of cyclohexane Rand 1 volumes of ether R as the mobile phase. Apply separately to the plate 2 µl ofeach of the following 4 solutions in cyclohexane R. For solution (A) dissolve a quantityof the oral solution containing the equivalent of 50 000 IU of vitamin A in 10 ml. Forsolution (B) prepare a solution of retinol acetate RS equivalent to 5000 IU of vitamin Aper ml. For solution (C) prepare a solution of retinol propionate RS equivalent to 5000IU of vitamin A per ml. For solution (D) prepare a solution of retinol palmitate RSequivalent to 5000 IU of vitamin A per ml. After removing the plate from the chromato-graphic chamber, allow it to dry in air, and examine the chromatogram in ultravioletlight (254 nm).

The principal spot obtained with solution (A) corresponds in position and appearanceto one or more of the spots obtained with solutions (B), (C) and (D).

A.2 Carry out the test as described under 1.14.1 Thin-layer chromatography, using theconditions described above under test A.1 but using silica gel R5 as the coatingsubstance. After removing the plate from the chromatographic chamber, allow it to dryin air and spray with antimony trichloride TS. Examine the chromatogram in daylight.The principal spot obtained with solution (A) corresponds in position and appearanceto one or more of the spots obtained with solutions (B), (C), and (D).


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B. Dissolve a drop of the oral solution in about 1 ml of dichloromethane R and add 5 mlof antimony trichloride TS; a blue colour is immediately produced which turns graduallyto violet-red.

C. See the test described below under Assay method B. The retention time of theprincipal peak in the chromatogram obtained with solution (1) corresponds to that ofthe principal peak in the chromatogram obtained with solution (2).

D. To a quantity of the oral solution containing the equivalent of 50 000 IU of vitamin A,add 100 ml of ethanol (~750 g/l) TS. Dilute 1 ml of the resulting solution to 50 ml with amixture of 100 volumes of ethanol (~750 g/l) TS and 1 volume of hydrochloric acid(~420 g/l) TS. Immediately after preparation measure the absorbance (1.6) in therange 300 to 400 nm. The solution exhibits a single maximum at 326 nm. Heat thesolution in a water bath for 30 seconds and cool rapidly. The absorption spectrum ofthe resulting solution, when observed between 300 and 400 nm, exhibits a shoulder at332 nm and maxima at 348, 367 and 389 nm

Uniformity of deliverable dose (single-dose containers). For an oral solutionpresented in single-dose containers the individual mass of the expressed contents ofat least 18 of the single-dose containers as weighed under Assay is within ± 10% ofthe average mass and no individual mass is outside ± 20%.

[Note from the secretariat: feedback is sought on the proposed determination of theretinol content per delivered dose for singe-dose containers. An alternative would be todetermine the retinol content per capsule.]

Assay. For an oral solution presented in single-dose containers express the contentsof 20 single-dose containers, following the directions for use as stated on the label.Weigh directly the individual contents delivered from each single-dose container andcalculate the average mass. [Do not weigh the contents delivered by difference be-tween full and empty containers.] Carry out the assay using the mixed oral solutionfrom the 20 containers.

Either method A, where valid, or method B may be applied.

A. Immediately dissolve a quantity of the oral solution containing the equivalent ofabout 200 000 IU of vitamin A, accurately weighed, in 5 ml of n-pentane R and dilutewith 2-propanol R to a presumed concentration of 10-15 IU per ml. Verify that theabsorption maximum of the solution to be examined, against 2-propanol as blank, liesbetween 325 nm and 327 nm. Measure the absorbances at 300 nm, 326 nm, 350 nmand 370 nm. Calculate the ratio Α

λ/Α

326 for each wavelength. If the ratios do not exceed

0.60 at 300 nm, 0.54 at 350 nm and 0.14 at 370 nm, calculate the content of vitamin Ain IU.

For an oral solution presented in a multidose container calculate the content of vitaminA in IU per ml from the expression: Α

326 x V x d x 1900/ (100 x m), where A

326 is the

absorbance at 326 nm, V is the total volume used for the dilution to give 10–15 IU perml, m is the mass of sample used in g, d is the weight per ml (1.3.1) of the oral solu-tion and 1900 is the factor to convert the specific absorbances of esters of retinol intoIU per g.


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For an oral solution presented as single doses calculate the deliverable content ofvitamin A in IU per capsule from the expression: Α

326 x V x d x 1900/ (100 x m), where

A326 is the absorbance at 326 nm, V is the total volume used for the dilution to give 10-15 IU per ml, m is the mass of sample used in g, AM is the average mass of theexpressed contents in g per capsule and 1900 is the factor to convert the specificabsorbances of esters of retinol into IU per g.

If one or more of the ratios Αλ/Α

326 exceeds the values given, or if the wavelength of

the absorption maximum does not lie between 325 nm and 327 nm, use Method B.

B. Carry out the test as described under 1.14.4 High-performance liquid chromatogra-phy, using a stainless steel column (15 cm x 4.6 mm) packed with particles of silicagel, the surface of which has been modified with octadecysilyl groups (5 µm). As themobile phase, use a mixture of 95 volumes of methanol R and 5 volumes of water R.Prepare the following solutions. For solution (1) transfer a quantity of the oral solutioncontaining the equivalent of about 100 000 IU of vitamin A, accurately weighed, into a100 ml volumetric flask. Dissolve immediately in 5 ml of n-pentane R. Add 40 ml of 0.1M tetrabutylammonium hydroxide TS in 2-propanol R. Swirl gently and allow themixture to stand for 10 minutes at a temperature between 60 ° and 65 °C, swirlingoccasionally. Allow to cool to room temperature, dilute to volume with 2-propanol Rcontaining 1 g/l butylated hydroxytoluene R, and homogenise carefully to avoid airbubbles. Dilute 5 ml of the resulting solution to 50 ml with 2-propanol R. For solution(2) transfer an amount of retinol acetate RS or retinol palmitate RS containing about100 000 IU of vitamin A, accurately weighed, into a 100 ml volumetric flask. Proceedas described for solution (1).

Operate with a flow rate of 1 ml per minute. As a detector use an ultraviolet spectro-photometer set at a wavelength of about 325 nm.

Inject alternately 10 µl each of solutions (1) and (2) and record the chromatograms for1.5 times the retention time of retinol.

Measure the areas of the peak responses obtained in the chromatograms fromsolutions (1) and (2). Determine the weight per ml (1.3.1) and calculate the content ofvitamin A in IU per ml of the oral solution or, where appropriate, in IU delivered percapsule.
