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Progress made in the Medicines Quality Assurance
Programme For "Better Medicines for Children"
Xiaoqiong ZHENG, Technical OfficerQuality Assurance and Safety: Medicines
Essential Medicines and Pharmaceutical Policies
The Third Partners Meeting on Better Medicines for Children, 21‐22 November 2011, Geneva
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Contribute to WHA60.20
Developing norms, standards and guidelines to promote better medicines for children through the WHO Expert Committee on Specifications for Pharmaceutical Preparations
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Progress Made: 2007‐2011
Development of paediatric medicines: points to consider in formulation
Monograph developmentMonographs for paediatric medicinesPaediatric approached work plan
Training: 2007, South Africa, Estonia 2008,India; 2010,Beijing; 2012,Singapore
Regulatory advice: First meeting of the Paediatric Medicines Regulators' Network, 2010Paediatric medicines in the WHO Prequalification of Medicines Programme
Guideline development Other activities
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Scope of the documentTo inform regulatory authorities and manufacturers on issues that require special attention in pharmaceutical development of paediatric medicines.
Not to detail instructions, rather to make reference to relevant literatureFormulation and dosage forms
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History of the document
First draft
New draft
Adopted
Coordination with other ongoing activities both within and outside WHODiscussion at informal consultations in 2008 (2), 2010, 2011Circulation for comments, inputs and feedbackPresentation to Expert Committee meetings: 43rd , 45th , 46th
46thExpert Committeemeeting
42ndExpert Committee meeting
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Contents
1. Introduction
2. Paediatric dosage forms
3. Dosage forms to be considered in particular
4. Formulation design
5. Oral administration
6. Rectal administration
7. Parenteral administration
8. Dermal and transdermaladministration
9. Inhalations
10. Packaging and labelling
11. Glossary
12. References
Development of paediatric medicines: points to consider in formulation
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Dosage forms selection principle
The guiding principle for selecting paediatric dosage forms should be – as for adults – the balance of risk/benefit, taking into account the specific needs of this vulnerable population.
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Dosage forms selection principle
Acceptability & palatability
Minimum dosing frequency
Acceptability in dosage form, dosing device, dose volume/size, packaging, and clear and accurate labelling, etc. Palatability in itself without any need for further modifications
Facilitate compliance to dosing scheme for both caregivers and older children
Convenient, reliable administration
End‐user needsConvenient to produce and affordableRestrictions on the applicable dose volume/size – minimum to be attemptedSupply chain considerations, e.g. ease of transportation, storage requirements Access to clean waterAdequate product information
Dose volume or size appropriate for the target age group/accurate dosing requirementsDose manipulation should be kept to a minimum level
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Dosage forms to be considered in particular
Technology, including formulation and related processes, that can be used to obtain different dosage forms, different strengths and/or accommodate different APIs.- produce multiparticulate
solids, e.g. pellets, minitablets
Flexible solid dosage form is the most suitable dosage form
Consider platform technology if precise dose measurement or titration is needed
A dosage form that can be administered to patients in more than one manner, e.g. taken orally as a whole or to be dispersed or dissolved prior to administration.
- e.g. orodispersible tablets, dispersible tablets, soluble tablets
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Dosage forms to be considered in particular
Dosage forms Key advantage Key considerationFlexible solid dosage forms
Suitable for both developed and developing countriesCan be used for preparation of oral liquids suitable for very young children: <6 monthsMay be used for various APIs
Not suitable for medicines requiring a precise dose titration
Compatibility of API and breast milk needs study
Requiring precise dose measurement -oral medicines
Suitable for precise dose measurement or titration
Platform technology
Parenteral formulations
For severe disease conditions Requiring a trained caregiver to use
Rectal preparations Severely ill children or children unable to swallow
Cultural barriers to use
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Formulation design
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Excipients
Use of excipients is driven by functional requirements and should be justified through a risk‐based assessment, taking into account the paediatric age group, frequency of dosing, duration of treatment, etc.
Should be minimum required number and their level in a formulation.
Excipients may lead to adverse reactions not experienced, or not seen to the same extent, in adults. Adverse reactions are mostly associated with excipients used for liquid dosage forms.
Well‐known excipients with a well‐defined safety profile to be preferred.
Only use novel excipients when safety, quality and appropriateness of use in children have been established.
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Route of administration
Oral administration
Rectal administration
Parenteral administration
Dermal and transdermal administration
Inhalations
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Packaging and Labelling
Container‐closure systems are designed and constructed of materials meeting relevant regulatory requirements and taking into accountthe stability of the medicine during transport, storage and use.
In cases where the paediatric medicine is significantly different from a similar adult medicine, the product packaging should be noticeably different between the two products.
Facilitate safe self‐administration of medicine in school children and adolescents.
Adequate information about the medicine and its use; specific instructions about how to measure and administer a precise dose.
Strongly recommend drawings or pictograms showing time, method and route of administration.
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Coordination
The preparatory work has involved coordination with other ongoing activities, both within and outside WHO, especially with the European Medicines Agency, the United Nations Children's Fund, the WHO Model List of Essential Medicines and the Essential Medicines project.
Reflection Paper: Formulations of Choice for the Paediatric population(2006),European Medicines Agency (EMA)First draft
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Perspective
Paediatric medicines development is limited in some areas (e.g. acceptability of dosage forms, safety of excipients), but it is also a rapidly developing field. An update of the document might be needed in the not too distant future.
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References: guideline
1. Clinical Investigation of Medicinal Products in the Paediatric Population, ICH Topic E11.
2. WHO guideline on quality risk management (working document QAS/10.376).
3. Guidelines for registration of fixed‐dose combination medicinal products (2005). In: thirty‐ninth report of the WHO Expert Committee on Specifications for Pharmaceutical Preparations. Geneva, World Health Organization. WHO Technical Report Series, No. 929, Annex 5.
4. Pharmaceutical development for multisource (generic) pharmaceutical products (working document QAS/08.251/Rev.1).
5. Impurities in New Drug Substances, ICH Topic Q3A(R2).
6. Impurities in New Drug Products, ICH Topic Q3B.
7. Impurities: Guideline for Residual Solvents, ICH Topic Q3C.
8. Guideline on the Limits of Genotoxic Impurities (CPMP/SWP/5199/02).
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References: guideline (continued)9. Q&A on the CHMP Guideline on the Limits of Genotoxic Impurities
(EMEA/CHMP/SWP/431994/2007).
10. Specification Limits of Residues of Metal Catalysts (CPMP/SWP/QWP/4446/00).
11. Proposal to waive in vivo bioequivalence requirements for WHO Model List of Essential Medicines immediate‐release, solid dosage forms (2006). In: fortieth report of the WHO Expert Committee on Specifications for Pharmaceutical Preparations. Geneva, World Health Organization. WHO Technical Report Series, No. 937, Annex 8.
12. Public Statement on antimicrobial preservatives in ophthalmic preparations for human use (EMEA/622721/2009).
13. Guideline on the Investigation of Medicinal Products in the Term and Preterm Neonate (EMEA/566810/2008).
14. Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability (2006). In: fortieth report of the WHO Expert Committee on Specifications for Pharmaceutical Preparations. Geneva, World Health Organization. WHO Technical Report Series, No. 937, Annex7.
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References: literature
1. Kearns GL et al (2003). Developmental Pharmacology – Drug Disposition, Action and Therapy in Infants and Children. N.Eng.J.Med. 349(12):1157‐1167.
2. EMEA Reflection Pater: Formulations of Choice for the PaediatricPopulation. (EMEA/CHMP/PEG/196810/2005).
3. Ernest TB et al (2007). Developing Paediatric Medicines: Identifying the Needs and Recognizing the Challenges. J. Pharm. Pharmacol., 59:1043‐1055.
4. Krause J, Breitkreutz J (2008). Improving Drug Delivery in Paediatric Medicine. Pharmaceutical Medicine 22:41‐50
5. Allen LV (2008). Dosage Form Design and Development. Clin.Ther. 30(11):2102‐2111.
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References: literature (continued)6. Siewert M et al (2003). FIP/AAPS Guidelines for Dissolution/In vitro
Release Testing of Novel/Special Dosage Forms. Dissolution Technologies, February Issue, page 15.
7. Breitkreutz J, Boos J (2007). Paediatric and Geriatric Drug Delivery. Expert Opin.Drug.Deliv. 4(1):37‐45.
8. Shehab N et al (2009). Exposure to the Pharmaceutical ExcipientsBenzyl Alcohol and Propylene Glycol among Critical Ill Neonates.Pediatric Critical Care Medicine,10(2):256‐259.
9. “Inactive” Ingredients in Pharmaceutical Products: Update: http:/www.pediatrics.org/cgi/content/full/99/2/268.
10. WHO Technical Report Series on evaluation of certain food additives. List of publications: http://www.who.int/ipcs/publications/jecfa/reports/en/index.html.
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References: literature (continued)11. Pollock I, Young E, Stoneham M (1989). Survey of Colorings and Preservatives in Drugs.
Brit. Med. J., 299:649‐651.
12. Pefferi G, Restani P (2003). The safety of Pharmaceutical Excipients. Il Farmaco, 58:541‐550.
13. Mennella JA, Beauchamp GK (2008). Optimizing Oral Medications for Children. Clin.Ther., 30(11):2120‐2132.
14. Strickly RG et al (2007). Paediatric Drugs – A Review of Commercially Available Oral Formulations. J. Pharm. Sci., 97(5):1731‐1774.
15. Thomson SA et al (2009). Mini‐tablets: New Modality to Deliver Medicines to Preschool‐aged Children. Paediatrics, 123(2):e235‐e238.
16. Seager H (1998). Drug‐Delivery Products and the Zydis Fast‐Dissolving Dosage Form. J. Pharm. Pharmacol., 50:375‐382.
17. Dolovich M (2000). Influence of Inspiratory Flow Rate, Particle Size and Airway Caliber in Aerosolized drug Delivery to the Lung. Respiratory Care,45:597‐608.
18. Schüepp K, Jauernig J, Janssens H (2005). In Vitro Determination of the Optimal Particle Size for Nebulised Aerosol Delivery to Infants. J. Aerosol. Med.,18(2):225‐235.
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