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Product Characteristics and Product Information – Links between Quality and Clinical

Product Characteristics and Product Information – Links between Quality and Clinical. Regine Lehnert. 6TH ANNUAL PREQUALIFICATION ASSESSMENT TRAINING (QUALITY) 18-21 May 2014. A “Good” Medicinal Product. Efficacy and Safety (Bioequivalence ). Pharmaceutical Quality. Product

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Product Characteristics and Product Information – Links between Quality and Clinical

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  1. Product Characteristics and Product Information – Links between Quality and Clinical Regine Lehnert 6TH ANNUAL PREQUALIFICATION ASSESSMENT TRAINING (QUALITY) 18-21 May 2014

  2. A “Good” Medicinal Product Efficacy and Safety (Bioequivalence) Pharmaceutical Quality Product information 6TH ANNUAL PREQUALIFICATION ASSESSMENT TRAINING (QUALITY) 18-21 May 2014

  3. Synopsis • Divisibility (scoring) • Crushing • Measuringdevices • ″Special“ excipients • Conclusions 6TH ANNUAL PREQUALIFICATION ASSESSMENT TRAINING (QUALITY) 18-21 May 2014

  4. Posology - Divisibility PQP guidance(GUIDELINES ON SUBMISSION OF DOCUMENTATION FOR A MULTISOURCE (GENERIC) FINISHED PHARMACEUTICAL PRODUCT FOR THE WHO PREQUALIFICATION OF MEDICINES PROGRAMME: QUALITY PART, S4 TRS 970 Annex 4 ) Scoring recommended / required, when indicated in WHO invitation for EOI specified for the comparator product (“innovator”) division into fractional doses is necessary according to posology 6TH ANNUAL PREQUALIFICATION ASSESSMENT TRAINING (QUALITY) 18-21 May 2014

  5. Posology - Divisibility Content/mass uniformity tests: methodology in accordance with recommendations of PQP Quality guideline Splitting of the tablets should be performed in a manner representative of that used by the consumer (e.g. manually split by hand). Presence of a score reflected in tablet description in FPP specification and QIS in product information (Summary of Product Characteristics, Labelling, Patient Information Leaflet) 6TH ANNUAL PREQUALIFICATION ASSESSMENT TRAINING (QUALITY) 18-21 May 2014

  6. Posology - Divisibility Standard wording on score lines <The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.> <The score line is not intended for breaking the tablet.> <The tablet can be divided into equal doses.> 6TH ANNUAL PREQUALIFICATION ASSESSMENT TRAINING (QUALITY) 18-21 May 2014

  7. Posology- Practical issue PQ evaluation: Some tablets are very difficult to split by hand Options: Improve scoring (when detected at an early stage) Provide a tablet cutter with each pack Indicate in the product information that a tablet cutteror knife is needed for division of tablets. Example (from WHOPAR MA047):“Forappropriatedosing in childrenfrom 2 to 11 monthsofage, thetabletshavetobedividedintoequalhalves.  Withthisproductthiscanonlybeachievedbyusing a knifeor a tabletcutter (whichis not included in the pack).“ 6TH ANNUAL PREQUALIFICATION ASSESSMENT TRAINING (QUALITY) 18-21 May 2014

  8. Divisibility - Special case Atazanavir 300 mg / Ritonavir 100mg FDC 1 cm 6TH ANNUAL PREQUALIFICATION ASSESSMENT TRAINING (QUALITY) 18-21 May 2014

  9. Divisibility- Special case Scoring not indicated in the EoI No innovator available Posology: One tablet once daily However: Clinicians in the team noted that patients may not be able to swallow the tablet whole. Question: Can the tablet be divided/crushed without changing the “performance” of the tablet? Scoring not required 6TH ANNUAL PREQUALIFICATION ASSESSMENT TRAINING (QUALITY) 18-21 May 2014

  10. Divisibility- Special case Bilayer tablet: Halving not regarded as problematic from Q point Divisibility: Impossible to divide without a knife, with knife okay Bioavailability: Unknown, if dividing/crushing leads to changes 6TH ANNUAL PREQUALIFICATION ASSESSMENT TRAINING (QUALITY) 18-21 May 2014

  11. Divisibility - Crushing Immediate releasetablet, not a dispersibletablet Target patientpopulation: adultstoinfants (> 6 months) Instructionsforuseinclude►swallowtabletswholeif not possible (e.g. in childrenlessthan 6 yearsofage) :►dispersion in a smallamountofwater (with/withoutpriorcrushing) or►crushingandmixingwith (certaintypesof) food 6TH ANNUAL PREQUALIFICATION ASSESSMENT TRAINING (QUALITY) 18-21 May 2014

  12. Divisibility - Crushing Potential issues Q: Disintegration? Q: Palatability (finenessofdispersion) / acceptability? BE: Study in mostcaseswithwholetablets– effectsofdispersing/crushing on bioavailability Q/BE: criticalexcipients? Ifinstructionsdifferfrominnovator: compatibilitywith(recommendedtypesof) food Interdisciplinaryapproach: check section 4.2 ( SmPC), consultwith WHOPAR- / clinical- and BE-assessors 6TH ANNUAL PREQUALIFICATION ASSESSMENT TRAINING (QUALITY) 18-21 May 2014

  13. Divisibility- How to proceed Check the disintegration time (> or < 3 minutes)Consult with BE: - very rapidly dissolving formulation (conservative dissolution tests [>85% in 15 min]) - special excipients (surfactant, disintegration enhancer) or -standard IR formulation "Alternatively, the tablets may be crushed and added toa small amount of semi-solid food or liquid, all of whichshould be consumed immediately.” 6TH ANNUAL PREQUALIFICATION ASSESSMENT TRAINING (QUALITY) 18-21 May 2014

  14. Posology - Measuring devices PQP requirements • As specified in the PhInt monograph “Liquid Preparations for Oral Use”: ‘Each dose from a multidose container is administered by means of a device suitable for measuring the prescribed volume. Usually - a spoon or a cup for volumes of 5 ml or multiples thereof, - or an oral syringe for other volumes - or, for oral drops, a suitable dropper.’ • [WHOPAR dosing aspects indicated here] 6TH ANNUAL PREQUALIFICATION ASSESSMENT TRAINING (QUALITY) 18-21 May 2014

  15. Posology - Measuring devices PQP requirements (cont.) • Inclusion of the device in the container closure system • Submission of data on this packaging component, including 1) specifications and 2) uniformity of mass of doses delivered by the device • The “Instructions on Use and Handling” should provide clear instructions. • A sample of the device should be provided. 6TH ANNUAL PREQUALIFICATION ASSESSMENT TRAINING (QUALITY) 18-21 May 2014

  16. Posology - Measuring devices “WHOPAR dosingaspects“ Uniformity of the mass at the lowest intended doseshould be demonstrated. HOW TO DETERMINE THE LOWEST INTENDED DOSE? • Consultation of • Company’s proposed Summary of Product Characteristics (SmPC) • SmPC of comparator product • Relevant guidelines (e.g. for PQP: WHO treatment guidelines) • Appropriateness of device may also depend on the pack size 6TH ANNUAL PREQUALIFICATION ASSESSMENT TRAINING (QUALITY) 18-21 May 2014

  17. Measuring devices - Practical case Example 1: Zidovudine oral solution 50 mg / 5 ml • Therapeutic indications • Treatment of HIV-infection in infants and children weighing ≥ 3 kg • Prevention of mother-to-child transmission (PMTCT) 6TH ANNUAL PREQUALIFICATION ASSESSMENT TRAINING (QUALITY) 18-21 May 2014

  18. Measuring devices - Practical case Example 1: Zidovudine oral solution 50 mg / 5 ml • Paediatric posology (according to WHO treatment guidelines) • 3 - 5.9 kg: 6 ml twice daily 6 - 9.9 kg: 9 ml twice daily10 - 13.9 kg: 12 ml twice daily • 4 mg/kg twice daily According to WHO Weight-for-Age Charts more than 97% of the newborns weigh at least 2 kg (3rd percentile) → lowest single dose 10 mg → 1 ml oral solution 6TH ANNUAL PREQUALIFICATION ASSESSMENT TRAINING (QUALITY) 18-21 May 2014

  19. Measuring devices - Practical case 6TH ANNUAL PREQUALIFICATION ASSESSMENT TRAINING (QUALITY) 18-21 May 2014

  20. Measuring devices - Practical case 6TH ANNUAL PREQUALIFICATION ASSESSMENT TRAINING (QUALITY) 18-21 May 2014

  21. Measuring devices - Practical case Zidovudine oral solution 50 mg / 5 ml • HOW CAN THE PACK SIZE DETERMINE THE SUITABILITY OF THE DOSING DEVICE? • Prequalified sizes: • Consider also in-use stability ! 6TH ANNUAL PREQUALIFICATION ASSESSMENT TRAINING (QUALITY) 18-21 May 2014

  22. Measuring devices - Practical case Example 2: Abacavir oral solution 20 mg / ml • First evaluation of product sample “ A dosing device is not included in the pack.(... .)You are requested to include a device in your container closure system which allows suitable dosing for children. It is of utmost importance that the device allows for accurate dosing also at the low end of the dose range. The paediatric dosing recommendations of WHO should be considered.” 6TH ANNUAL PREQUALIFICATION ASSESSMENT TRAINING (QUALITY) 18-21 May 2014

  23. Measuring devices - Practical case Abacavir oral solution 20 mg / ml Paediatric posology (according to WHO treatment guidelines) 3 - 5.9 kg: 3 ml twice daily 6 - 9.9 kg: 4 ml twice daily 10 - 13.9 kg: 6 ml twice daily In Adults (according to innovator) 30 ml/day (= 600 mg) PQP pack sizes: 100 ml 240 ml 6TH ANNUAL PREQUALIFICATION ASSESSMENT TRAINING (QUALITY) 18-21 May 2014

  24. Measuring devices - Practical case Abacavir oral solution 20 mg / ml • Company‘s reply (a dosing cup with various markings at 2.5, 3, 5, 6, 7.5, 9, 10, 11, 13, 15 and 20 ml) Markings not horizontal 6TH ANNUAL PREQUALIFICATION ASSESSMENT TRAINING (QUALITY) 18-21 May 2014

  25. Measuring devices - Practical case Abacavir oral solution 20 mg / ml • Second evaluationofproduct sample “The devicesreceivedwereconsideredunacceptable. The 3 ml demarcationlinesoftwoofthethreedevicesarenotedtobeskewed. In addition, thedeviceisconsideredimpractically large forconsistentlyprovidingtherecommendeddoses ranging from3 to 6 ml andcouldthereforeleadtooverdosing. Westronglyencourageyoutoprovide a moresuitabledevice. Regardlessofwhether a newortheexistingdeviceisused, uniformityofthevolume at thelowestintended dose shouldbedemonstrated. In addition, ifyouretainthecurrentdevice, youarerequestedtoprovideassurancethatthedevicecanbeconsistentlymanufacturedwiththeappropriate, correctlyorienteddemarcations.” 6TH ANNUAL PREQUALIFICATION ASSESSMENT TRAINING (QUALITY) 18-21 May 2014

  26. Measuring devices - Practical case Abacavir oral solution 20 mg / ml • Company‘s reply ► (According to WHO guidance patients with a BW ≥ 14 kg are recommended to use tablets. Therefore, the oral solution is considered primarily a paediatric formulation and the measuring device is acceptable.) 6TH ANNUAL PREQUALIFICATION ASSESSMENT TRAINING (QUALITY) 18-21 May 2014

  27. Measuring devices - Practical case Example 3: Granules for Second line TB Therapy • Dosing recommendations: 345 mg/kg/day, divided into two equal daily doses. A 4.6 g measuring spoon with markings at 1, 2, 3, 4 and 4.6 g is provided with the product. • Issue 1: Dosing accuracy for the weight of the child 6 kg body weight (1035 mg/dose), 12 kg (2070 mg/dose), 18 kg (3105 mg/dose), 24 kg (4140 mg/dose), 27 kg (full spoon, 4657 mg/dose)… . • Issue 2: Accuracy of the measured dose 6TH ANNUAL PREQUALIFICATION ASSESSMENT TRAINING (QUALITY) 18-21 May 2014

  28. Measuring devices - Practical case • 2 g • 4.6 g Request company to submit new device with smaller diameter/surface and 0.5 ml markings 6TH ANNUAL PREQUALIFICATION ASSESSMENT TRAINING (QUALITY) 18-21 May 2014

  29. Another common deficiency… Taste/Palatabilityof formulation:e.g. liquid formulations, dispersible tablets - Poor palatability andbad taste mayleadto non-compliance,especially in childrenandwhenused in long-term therapy. - Companies shouldbeencouragedtoimprovetheseproductcharacteristics. ► Difficulty: Whatis a generallyacceptable taste? → potential interculturaldifferences PQP: Presently, palatabilitystudiesareonlyrequiredforzinctablets 6TH ANNUAL PREQUALIFICATION ASSESSMENT TRAINING (QUALITY) 18-21 May 2014

  30. Excipients • In PQP WHOPAR Guideline - referenceto EC Guideline: Excipients in thelabelandpackageleafletofmedicinalproductsfor human use(NOTICE TO APPLICANTS, VOLUME 3B, 2003) • Whilstitisdesirablethatexcipientsshouldhavelittleornopharmacologicalactionoftheirown, some do indeedhave a recognisedactionoreffect in certaincircumstances. • Warningstatementsrelatingtothepresenceofcertainexcipients in medicinalproducts. • The Annex provides a listoftheexcipientswhichshouldbestated on thelabellingandoutlinestheinformationwhichshouldappear in thepatientinformationleaflet. 6TH ANNUAL PREQUALIFICATION ASSESSMENT TRAINING (QUALITY) 18-21 May 2014

  31. Excipients Excipientsdefinedastheconstituentsofthepharmaceutical form thatistakenbyoradministeredtothepatient, otherthantheactivesubstance. Forexample: • colouring matter, preservatives, adjuvants, stabilisers, thickeners, emulsifiers, flavouringaromaticsubstancesandliquid diluents • Also theconstituentsoftheoutercoveringofthemedicinalproducts – capsules, gelatinecapsules, rectalcapsulesorconstituentsoftheprintingink. 6TH ANNUAL PREQUALIFICATION ASSESSMENT TRAINING (QUALITY) 18-21 May 2014

  32. Excipients • Clinical condition to be treated has to be borne in mind for assessing the appropriateness of including warning statements (benefit/risk assessment; e.g. for treatment of XDR TB the warning on lactose content to be phrased more cautiously). • For non-functional excipients (e.g. colouring agents), less harmful excipients should be used in the manufacture (e.g. inorganic colourants (e.g. iron oxide black/red/yellow or titanium dioxide) instead of azo organic colouring agents with a high sensitizing potential. • Of note: Different thresholds may apply for medicines for paediatric use (‘Excipients guideline‘ currently under revision) 6TH ANNUAL PREQUALIFICATION ASSESSMENT TRAINING (QUALITY) 18-21 May 2014

  33. Excipients - „lactose warning“ • SmPC • EU Guideline: Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine. • WHOPAR TB210Moxicip-400 Tablets contains a small amount of lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption may experience symptoms of intolerance. 6TH ANNUAL PREQUALIFICATION ASSESSMENT TRAINING (QUALITY) 18-21 May 2014

  34. Excipients - „lactose warning“ • PIL • EU Guideline:If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product • WHOPAR TB210(moxifloxacin for second-line treatment of TB)As per guideline 6TH ANNUAL PREQUALIFICATION ASSESSMENT TRAINING (QUALITY) 18-21 May 2014

  35. Conclusions • The assessmentofthepharmaceuticalqualityof a productincludestheevaluationoftheappropriatenessof • - theformulation • - thedosingdevice • - theproductinformation (e.g. descriptionofthevisualappearanceoftheproduct, instructionsforuse, warnings on specificexcipientsandinstructionsforhandling. • - and, ifpossible, also thepalatability/taste. • →whenpossible, discusswithmedicalstaff/clinician (especially ‘tricky‘, non-standard situations) 6TH ANNUAL PREQUALIFICATION ASSESSMENT TRAINING (QUALITY) 18-21 May 2014

  36. 6TH ANNUAL PREQUALIFICATION ASSESSMENT TRAINING (QUALITY) 18-21 May 2014

  37. Backup slides 6TH ANNUAL PREQUALIFICATION ASSESSMENT TRAINING (QUALITY) 18-21 May 2014

  38. Why is the product information relevant? Safe use of the product (for physicians and patients) detection of counterfeit productsby clear description of product specifics- visual appearance of formulation- detailed information on primary pack Product information 6TH ANNUAL PREQUALIFICATION ASSESSMENT TRAINING (QUALITY) 18-21 May 2014

  39. Product Information - Selected Aspects Transfer/Supply • Use of recommended texts/structure/format - Submission of mock-ups of SmPC and PIL to PQP to reassure compliance • Supply with the packs (SmPC and PIL)- deficient in contents - deficient in numbers e.g. Pack size of product 24 x 28 tablets only 2 pack inserts! 6TH ANNUAL PREQUALIFICATION ASSESSMENT TRAINING (QUALITY) 18-21 May 2014

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