Excipients General Approach - Europa
Excipients general approachEMA workshop, London, 8 November 2011.Presented by: Caroline Le Barbier, PhD & Pedro Franco, Pharmacist andChemistScientific Administrators/Chemical Section /Quality of MedicinesAn agency of the European Union
AGENDA Objectives Reminder about excipients Background & References Excipients Case Studies Conclusion1Excipients and PIP, London, November 2011
OBJECTIVES To present the current knowledge and references for theexcipients To present challenges with excipients in PIP case studies.2Excipients and PIP, London, November 2011
BACKGROUND Medicines primarily developed for adults Children’s doses were unknown Small children were treated as small adults Excipients chosen were the same for adults and children Safety reports have shown that some excipients werenot safe for essentialmedicines/Promotion safe med childrens.pdf(benzyl alcohol safety in neonates)3Excipients and PIP, London, November 2011
REMINDER ExcipientsThe definition has evolved 11)“Inert substance that forms a vehicle”2)“Additives used to convert active substances into pharmaceutical forms”1-Excipients Toxicity and Safety by M.L Weiner and A. Kotkoskie, Drugs and the Pharmaceutical Sciences, volume 103and Handbook of pharmaceutical excipients4Excipients and PIP, London, November 2011
REMINDER Excipients 2Excipients can be used for: Aid processing during manufacture Improve physical and chemical attributes of the active substance Protect, enhance stability Enhance any other attribute of the Safety and Effectiveness(use or storage)5Excipients and PIP, London, November 2011
Excipients and functionsExamples for oral formulation:filler or diluent, preservative, binder, disintegrant, lubricants, antiadherents,glidants, wetting agents, colorants, sweeteners, antioxidants, adjuvants,flavours, taste masking Examples for parenteral forms:diluent, solubiliser, buffer, antioxidant, antimicrobial agent etc1–Paediatric drug handling by Costello, Long, Wong, Tuleu, Yeung, Pharmaceutical Press2-Toxic Additives in Medications for Preterm Infants Arch. Dis. Child. Fetal Neonatal Ed. published online 21 Jan 2009 by Whittaker, Mulla, Turner, Currie,Field and Pandya6Excipients and PIP, London, November 2011
SO WHERE TO START ?What are the main issues .?What guidance is out there concerning excipients ?7Excipients and PIP, London, November 2011
Critical points for paediatric formulations Route of administration. Appropriate dosage forms. Excipients - 50% of the PIPs – choice , safety, level, sideeffects Acceptability and palatability Delivery devices. Rate of infusion. Volume to be administered. Wastage.8Excipients and PIP, London, November 2011
REFERENCES 1Excipients in the Dossier for Application for MarketingAuthorization of a Medicinal Product(CHMP/QWP/396951/06, revised 2008).Excipients in the Label and Package leaflet of MedicinalProducts for Human Use (Eudralex 3BC7A)9Excipients and PIP, London, November 2011
REFERENCES 2Food Directives (i.e. Directive 2009/35/EC – colorants inmedicines).EFSA & CHMP OpinionsLiteratureExternal sources (WHO, FDA, Databases, external groupsEuPFI ).10Excipients and PIP, London, November 2011
REFERENCES 3Reflection paper (EMEA/CHMP/PEG/194810/2005) on “Formulation ofchoice for the paediatric population” (not a guideline!).Concept paper (EMEA/138931/2008) – future quality guideline.Guideline on pharmaceutical development of medicines forpaediatric use (EMEA/CHMP/QWP/180157/2011) – under consultation.Guideline on the investigation of Medicinal Product in the Termand Pre-term Neonate (EMEA/536810/2008)11Excipients and PIP, London, November 2011
REFERENCES 4Guideline on pharmaceutical development of medicines forpaediatric use (EMEA/CHMP/QWP/180157/2011) – underconsultation12Excipients and PIP, London, November 2011
Information sources on excipients ficarticlesRef. BooksEncyclopaediasEtc.CHMPScientific decisionsAssessmentExcipients forpaediatricsEFSA OpinionsFood LegislationExcipientsinMedicinesFor children13ICH & CHMPGuidelinesGuidancesReflection papersQ&AExcipients and PIP, London, November 2011ExpertCommittee on foodJECFA
Selection of excipients for paediatricformulations Pharmaceutical form; Well-known safety profile in paediatric population; The expected duration of treatment (short & Long term); Potential allergies and sensitization; Excipients used in paediatric formulations with no adverseevents; Novel excipients with lack of safety information in childrenshould be avoided;14Excipients and PIP, London, November 2011
Excipients for paediatrics- Safety concerns Justification on the safety profile of an excipient should beprovided; Toxicology data may be requested if no information is availablein children;15Excipients and PIP, London, November 2011
Excipients - Colouring agents Colouring agents allowed in foodstuffs might be used inmedicines; Colouring agents should be avoided as much as possible; Use of a colouring agent to be discussed and justified;16Excipients and PIP, London, November 2011
Excipients - Flavours agents Palatability extremely important; Use and selection of flavours should be justified; Qualitative and quantitative composition to be provided (MAA); Any safety concerns should be addressed;17Excipients and PIP, London, November 2011
Excipients - Preservatives The choice of the preservative system should be discussed The lowest concentration should be used The selection of the preservative system should take intoaccount the target age group18Excipients and PIP, London, November 2011
Excipients - Sugar versus sweetenersThe selection should take into account: Cariogenic effect of sugar Dosing frequency Duration of treatment High concentration of sugar additional preservatives Possible side effects Compatibility with other ingredients19Excipients and PIP, London, November 2011
CASE STUDY 1Formulation issue: Capsules and oral solution Indicated for melanoma Long-term for patients above 12 years old Issue: sorbitol quantity, citric acid, and composition of oralsolution20Excipients and PIP, London, November 2011
CASE STUDY 1 - continuesDiscussion: Composition of the oral solution Impact of the citric acid (teeth erosion) may be considered Taking into account the quantities agreed- sorbitol not an issueConclusion: No major concerns regarding of the quality of oral solution Final composition of the oral solution should be provided21Excipients and PIP, London, November 2011
CASE STUDY 2Formulation issue: Oral solution Indication: Treatment of HIV Life long treatment from the age of 14 days (infants) Issue: Composition22Excipients and PIP, London, November 2011
CASE STUDY 2 - continuesDiscussion: This product already exists as tablets, soft capsules and oralsolution (patients who cannot swallow and below 6 years) Issue with concentration of propylene glycol and ethanolConclusion: The PDCO FWG requested: To provide data on exposure of propylene glycol and ethanol ininfants (SWP to review, especially chronic and risk accumulation)23Excipients and PIP, London, November 2011
CASE Study 3Formulation issue: Two formulations (IV form- for the neonate and oral suspension). Indication: Fungal infection. Short term use from neonates Issues: IV form contains Cyclodextrin derivative (CD Sulfobutylethyl β). Oral form contains benzyl alcohol, propylene glycol and liquidglucose- “sensitive” excipients24Excipients and PIP, London, November 2011
CASE Study 3- continuesDiscussion IV formulation: contains cyclodextrin derivative (CDSulfobutylethyl β). Applicant asked to provide safety studiesconducted on juvenile animals Oral suspension: agreed no concern since excipients present inthe flavouring (quantities below authorised limits)Conclusion 25PDCO FWG wanted more data from the applicant on safety ofCyclodextrin usedExcipients and PIP, London, November 2011
CASE STUDY 4Formulation issue: Solution for injection Treatment for hypotension Long term extremely low gestational age newborn and children to18 years Issue: sodium metabisulfite26Excipients and PIP, London, November 2011
CASE STUDY 4 - continuesDiscussion: High-content of sodium metabisulfite- potential toxicity (hypersensitivity)Conclusion: sodium metabisulfite: justify high content/replace by alternative antioxidantwith a better safety profile Further follow-up needed remove/minimise the amount of the antioxidantas key binding element27Excipients and PIP, London, November 2011
CONCLUSIONS Critical points for paediatric formulations Safety profile of excipient extremely important Excipients allowed in adult formulations might be different inpaediatric formulations Assessment of excipient - Information source Need for further research and collaboration (on-going ESNEE,EuPFI STEP database)STEP database http://www.eupfi.org/ and ESNEE project part of the EC Research Funding FP728Excipients and PIP, London, November 2011
THANK YOU FOR YOUR ATTENTION.ANY QUESTIONS?Thanks to the entire Quality & Paediatric Teams29Excipients and PIP, London, November 2011
REMINDER Excipients The definition has evolved 1 1) “Inert substance that forms a vehicle” 2) “Additives used to convert active substances into pharmaceutical forms” 1-Excipients Toxicity and Safety by M.L Weiner and A. Kotkoskie, Drugs and the Pharmaceutical Sciences, volume 103 a
002 europa league fc rostov maccabi haifa 1 - 2 v 2-3 - - - si 003 europa league djurgarden cfr 1907 cluj 0 - 1 v 0-1 - - - no 004 europa league ns mura psv 1 - 5 v 4 o - - - si 005 europa league rosenborg alanyaspor 1 - 0 l 0-1 - - - no 006 europa league willem ii rangers 0 - 4 v 4 o - - - no 010 europa league besiktas rio ave 1 - 1 e 2-3 .
International Pharmaceutical Excipients Council (IPEC) is an international industry association formed in 1991 by manufacturers, distributors and end-users of excipients. At the time of writing there are regional pharmaceutical excipient industry assoc
Table 5 Excipients Whose Inclusion in a Formulation will Require Special Labelling Requirements in Some Circumstances 21 Table 6 Examples of Ingredients Which Might be Excipients or Active Ingredients in Different Products 22 Table 7.1 Progress with Pharmaceutical Discussi
initiation of solubility studies Depending on route of administration determine: Solubility In suitable excipients Stability profile in those excipients Combinations of excipients for solubility screening Excipient compatibility Depending on final dosage form strategy, excipient compatibility must be performed
UEFA Europa League –21:00– CFR 1907 Cluj v Roma (Live on ) UEFA Europa League –18:55– Maccabi Tel-Aviv v Villarreal (Live on ) UEFA Europa League –21:00– AZ Alkmaar v Real Sociedad (Live on ) UEFA Europa League –18:55– Slovan liberec v Hoffenheim (Live on )
59 Source or Origin of the Substance: 60 Because excipients are manufactured for a wide variety of purposes, the source and origin is highly 61 variable. They range from whole food products such as wheat middlings and yeast to synthetic food 62 additives such as sodium benzoate and sodium
Apr 02, 2014 · 3DJH RI Noven Ex. 1003 _) '. Handbook of PHARMACEUTICAL EXCIPIENTS Second Edition Edited by Ainley Wade and Pau
ASTM C167 Standard test methods for thickness and density of blanket or batt thermal insulations ASTM C203 Standard test methods for breaking load and flexural properties of block-type thermal insulation ASTM C209 Standard test methods for cellulosic fiber insulating board (section 13) ASTM C209 Standard test methods for cellulosic fiber insulating board (section 14) ASTM C272/C272M Standard .
