presentation - excipients – general approach
TRANSCRIPT
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An agency of the European Union
Excipients general approach EMA workshop, London, 8 November 2011.
Presented by: Caroline Le Barbier, PhD & Pedro Franco, Pharmacist and Chemist Scientific Administrators/Chemical Section /Quality of Medicines
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AGENDA
• Objectives
• Reminder about excipients
• Background & References
• Excipients
• Case Studies
• Conclusion
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OBJECTIVES
•To present the current knowledge and references for the excipients
• To present challenges with excipients in PIP case studies.
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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 were not safe for children
http://www.who.int/medicines/publications/essentialmedicines/Promotion_safe_med_childrens.pdf (benzyl alcohol safety in neonates)
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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
and Handbook of pharmaceutical excipients
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REMINDER Excipients 2
Excipients 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)
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Excipients and functions
Examples 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…etc
1–Paediatric drug handling by Costello, Long, Wong, Tuleu, Yeung, Pharmaceutical Press
2-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 Pandya
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SO WHERE TO START ?
What are the main issues….?
What guidance is out there concerning excipients…… ?
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Critical points for paediatric formulations • Route of administration.
• Appropriate dosage forms.
• Excipients - 50% of the PIPs – choice , safety, level, side effects……
• Acceptability and palatability
• Delivery devices.
• Rate of infusion.
• Volume to be administered.
• Wastage.
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REFERENCES 1
Excipients in the Dossier for Application for Marketing Authorization of a Medicinal Product (CHMP/QWP/396951/06, revised 2008).
Excipients in the Label and Package leaflet of Medicinal Products for Human Use (Eudralex 3BC7A)
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REFERENCES 2 Food Directives (i.e. Directive 2009/35/EC – colorants in medicines).
EFSA & CHMP Opinions
Literature
External sources (WHO, FDA, Databases, external groups EuPFI…).
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REFERENCES 3 Reflection paper (EMEA/CHMP/PEG/194810/2005) on “Formulation of
choice for the paediatric population” (not a guideline!). Concept paper (EMEA/138931/2008) – future quality guideline.
Guideline on pharmaceutical development of medicines for paediatric use (EMEA/CHMP/QWP/180157/2011) – under consultation.
Guideline on the investigation of Medicinal Product in the Term and Pre-term Neonate (EMEA/536810/2008)
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REFERENCES 4
Guideline on pharmaceutical development of medicines for paediatric use (EMEA/CHMP/QWP/180157/2011) – under consultation
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Information sources on excipients for paediatrics
ICH & CHMP Guidelines
Guidances Reflection papers
Q&A
CHMP Scientific decisions
Literature Scientific articles
Ref. Books Encyclopaedias
Etc.
Excipients in
Medicines For children
In-house information
Food Legislation EFSA Opinions
Expert Committee on food
JECFA
Assessment Excipients for paediatrics
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Selection of excipients for paediatric formulations •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 adverse events;
•Novel excipients with lack of safety information in children should be avoided;
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Excipients for paediatrics - Safety concerns • Justification on the safety profile of an excipient should be provided;
• Toxicology data may be requested if no information is available in children;
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Excipients - Colouring agents
• Colouring agents allowed in foodstuffs might be used in medicines;
• Colouring agents should be avoided as much as possible;
• Use of a colouring agent to be discussed and justified;
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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;
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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 into account the target age group
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Excipients - Sugar versus sweeteners
The 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 ingredients
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CASE STUDY 1
Formulation issue:
Capsules and oral solution Indicated for melanoma Long-term for patients above 12 years old Issue: sorbitol quantity, citric acid, and composition of oral
solution
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CASE STUDY 1 - continues
Discussion:
Composition of the oral solution
Impact of the citric acid (teeth erosion) may be considered
Taking into account the quantities agreed- sorbitol not an issue
Conclusion:
No major concerns regarding of the quality of oral solution
Final composition of the oral solution should be provided
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CASE STUDY 2
Formulation issue:
Oral solution Indication: Treatment of HIV Life long treatment from the age of 14 days (infants) Issue: Composition
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CASE STUDY 2 - continues
Discussion:
This product already exists as tablets, soft capsules and oral solution (patients who cannot swallow and below 6 years)
Issue with concentration of propylene glycol and ethanol
Conclusion: The PDCO FWG requested:
To provide data on exposure of propylene glycol and ethanol in infants (SWP to review, especially chronic and risk accumulation)
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CASE Study 3
Formulation 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 liquid
glucose- “sensitive” excipients
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CASE Study 3- continues Discussion
IV formulation: contains cyclodextrin derivative (CD Sulfobutylethyl β). Applicant asked to provide safety studies conducted on juvenile animals
Oral suspension: agreed no concern since excipients present in the flavouring (quantities below authorised limits)
Conclusion PDCO FWG wanted more data from the applicant on safety of
Cyclodextrin used
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CASE STUDY 4
Formulation issue:
Solution for injection Treatment for hypotension Long term extremely low gestational age newborn and children to
18 years Issue: sodium metabisulfite
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CASE STUDY 4 - continues
Discussion:
High-content of sodium metabisulfite- potential toxicity (hypersensitivity)
Conclusion:
sodium metabisulfite: justify high content/replace by alternative antioxidant with a better safety profile
Further follow-up needed = remove/minimise the amount of the antioxidant as key binding element
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CONCLUSIONS • Critical points for paediatric formulations
• Safety profile of excipient extremely important
• Excipients allowed in adult formulations might be different in paediatric 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 FP7
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THANK YOU FOR YOUR ATTENTION. ANY QUESTIONS?
Thanks to the entire Quality & Paediatric Teams