Post on 24-Dec-2019
Excipients in Pediatric Medicines: A Health Canada Perspective
CSPS Workshop: ExcipientsSeptember 20, 2019
Susan Lum, RPh, PhDTherapeutic Products Directorate
1
Better medicines for children
2
Medical Needs of the Pediatric
Population
Pediatric DrugDevelopment
ClinicalBarriers
Technical Formulation
Development Challenges
Public/Patient Market
Expectations
Pediatric Incentives – Access to Commercialized Pediatric Medicines
3
Global regulatory incentives (US FDA, EMA) and regulations have been drivers of growth of the pediatric pharmaceutical market.
Pediatric Research Equity Act (PREA)
FDA has the authority to require pediatric studies if meaningful therapeutic benefit exists - for all NDAs and BLAs unless the applicant has obtained a waiver or deferral. Limited to same
indication as in adults.
Mandatory Measures**
Best Pharmaceuticals for Children Act (BPCA)
Provides a six-month marketing exclusivity incentive to sponsors of marketed products
that conduct pediatric studies in response to a written request from FDA .
Voluntary Measures
* *Excludes generic development unless changes to the RLD (dosage form, route or API) would trigger conducting some form of pediatric investigation
European Medicines Agency
(EMA)
Paediatric investigation plans (PIPs) are required for all new products – submission is
incomplete without agreed PIP (specific or class-specific waiver or deferral)
Pediatric use Market Authorization (PUMA)
Provides 10 years of market protection for drugs with specific pediatric authorization reward on off patent medicines marketed
products to conduct pediatric studies
Canadian – Access to Commercialized Pediatric Medicines
4
• Review* of globally approved oral pediatric formulations shows about 1/3 of commercially available medications are approved and marketed in Canada
• Approx. 1/3* of the types of pediatric oral medications are marketed in Canada Tablets (to swallow, scored, orally disintegrating, chewable) Ready to use or powder for oral solution Ready to use or powder for oral suspensions Oral granules
• Improved access is needed for preservative free, taste masked medicines mini-tablets, granules, multiparticulates, powders in stick packets or sachets Soluble thin strips Specific dose administration calibrated devices eg. Pre-filled syringes for buccal Two piece capsules
• Since 2007, new pediatric formulations approved and marketed in Canada include: Tivicay (tablets) – antiviral Aptiom (tablets) – seizure therapy Orkambi (lumacaftor/ivacaftor, granules) – treatment of cystic fibrosis Zofran (ondansetron, oral solution) – prevention of nausea Isentress (raltigravir, chewable tablet) - antiviral Posanol (posaconazole, oral suspn) – antifungal Carbaglu (carglumic acid, dispersible tablet) – for chronic hyperammonemia Afinitor (everolimus, oral suspns) – seizure therapy Sabril (vigabatrin – pwd oral soln) – treatment of infantile spasms
*Refs: Strickley, R.G. et al. Pediatric Drugs – a Review of Commercially available Oral Formulations J. Pharm. Sci. 97(5) 2008 pp. 1731-1774Strickley R.G., Pediatric Oral Formulations: An updated review of Commercially Available Pediatric Oral Formulations since 2007, J. Pharm. Sci., 108 (2019) pp. 1335-1365
Use of Foreign Reviews – pediatric medications not otherwise broadly available
5
• International collaboration
• Use of Foreign Reviews would allow drug submissions, that might not otherwise be filed in Canada
• Foreign decisions pathway aims to facilitated access for Canadians to therapeutic products that meet a medical need
• Leverages the scientific reviews completed by trusted foreign regulators to reduce unnecessary duplication while maintaining the integrity of Health Canada’s regulatory review process (eg. relying on third party data)
• Significant international post-market experience
• Improved access
Better Medicines for Children – Challenges (Time, Cost, Risks)
• Includes 20-fold increase in patient size/weight between birth and adulthood
• Accompanying need to greatly increase dosages during growth
• Masking a drug's taste to improve patient compliance
• Identifying excipients to make the product palatable
Disease state can also impact taste/smell perception
• Oral liquids are challenging to develop in a stable form
Increased susceptibility to microbial contamination vs. solid dosage forms
• Formulations deemed acceptable by children have expiration periods too short for commercial viability
• Achieving global regulatory acceptability
• Rapid patient access
• Accelerated development timelines
6
Pediatric Considerations
7
“The joint goal for industry, regulators, practitioners and patients is to encourage paediatric drug development in order to create a situation where substantially more children have access to safe and effective medication”
•Age-appropriate formulations
Appropriate route of administration
Appropriate dosing volumes (oral and injectable)
Appropriate excipients and levels
For oral formulations – Palatable
•Appropriate stability and taste acceptance
Ease of dosing and patient compliance
•Dosage form child can take / caregiver can administer
•Dose flexibility while maintaining accuracy and safety
•Patient accessibility
European Federation of Pharmaceutical Industries and Associations (Efpi) 2009 position paper “Industry Perspectives on Pharmaceutical Development of Medicines for Paediatric Use”
Physiological concerns – once size does not fit all
8
Spectrum within the pediatric population
Source: Kearns, G.L. et al. Developmental Pharmacology- Drug Disposition, Action and Therapy in Infants and Children,, N.Eng. J. Med., 349 (2003) ; Tetelbaum, M, et. Al. Back to basics: Understanding drugs in children: Pharmacokinetic Maturation, Pediatrics in Review (2005) 26: 321-328 1160
Developmental Physiological Changes – impact on drug disposition
9
Source: Kearns, G.L. et al. Developmental Pharmacology- Drug Disposition, Action and Therapy in Infants and Children,, N.Eng. J. Med., 349 (2003) 1160
Evolution in Age Appropriate Dosage Forms
10
Source: European Medicines Agency: Reflection paper: formulations of choice for the pediatric population 28 July 2006Strickley, R.G. et al. Pediatric Drugs – a Review of Commercially available Oral Formulations J. Pharm. Sci. 97(5) 2008 pp. 1731-1774
Not applicable or applicable with problemsAcceptable/preferredDosage form of choice
Pediatric Dosage Form Suitability
Dosage form
Preterm newborninfants
Term newborn infants
(0d – 28d)
Infants andtoddlers(1m-2y)
Children(pre-school)
(2-5y)
Children(school)(6-11y)
Adolescents(12-16/18y)
Solution/drops
Emulsion/suspension
Effervescent dosage forms
Powders/multiparticulates/ mini-tablets
Orodispersable form
Chewable tablets
Tablets
Capsules
Assessment
11
Source: Case studies on pharmaceutical development of pediatric products for the global market, AAPS-PSWC Workshop 2010
Excipients – pediatric formulationsMajor difference for a pediatric formulation compared with an adult formulation
is an added layer of investigation when selecting excipients
Excipients chosen must be determined based on the specific drug under development as well as the pediatric product profile
• Effects of excipient in children of different ages, developmental stages
• Exposure, metabolism, elimination – safety of excipients (ICH S11 (draft))
• National databases for registered products• FDA IID – not updated – not stratified to pediatric indications
• UK Electronic Medicines Compendium
• Publically available excipient databases• Endorsed by regulatory agencies?
• eg. Safety and Toxicity of Excipients for Paediatrics (STEP) EuPFI
12
Refs: Buckley, L.A., et al. Challenges and strategies to facilitate formulation development of pediatric drug products: Safety qualification of excipients, Int. J. Pharm. 536(2) 2018 pp. 563-569Schmitt, G. Safety of Excipients in Pediatric Formulations – a call for toxicity studies in junvenile animals? Children (2) 2015 pp. 191-197
Excipient Safety
13
“All substance are poisons, there is none which is not a poison. The right dose differentiates a poison from remedy.” (Paracelsus 1493-1541)
If all excipients = active chemical components of pharmaceutical products
Requires the same ADME and pharmacodynamic evaluations as actives
Ignores prior history of use in patients
Adverse events linked to dosing excipients > recommended ADI (mg/kg)
(ref. Shehab, N., et al. Exposure to the pharmaceutical excipients benzyl alcohol and propylene glycol among critically ill neonates, Pediatric critical care medicine, 10(2) 2009 256-9. Cumulative dose in neonates median 4.5 mg/kg/day (0.6-319.5 mg/kg/day) for benzyl alcohol and 204.9 mg/kg/day (17.3-9472.7 mg/kg/day) for propylene glycol)
Nahata, MC., Safety of “inert” additives or excipients in pediatric medicines, Arch Dis Child Fetal Neonatal Ed 94 (2009) F392-393
Brown WJ, et al. Fatal benzyl alcohol poisoning in a neonatal intensive care unit Lancet 1982;1250 -benzyl alcohol preserved intravascular flush from 99-234 mg/kg/day >> 5mg/kg/day ADI
Excipients of concern in adults – particular concern in children
Ref. Annex to the European Commission guideline on ‘Excipients in the labelling and package leaflet of medicinal products for human use’ (SANTE-2017-11668) – Excipients and information for the package leaflet EMA/CHMP/302620/2017 corr. 1*
Excipient Evaluation
14
• Compilation of all nonclinical and human safety data • Assessment of an excipient based on exposure – context of use
• Context of the data with the risk and the anticipated health benefit of the formulation to the patient
• Leverage experience if excipients used in foods
• Risk management decisions informed by specific risk assessment methods and choices - scope• ADIs established by the WHO based on epidemiologic and toxicological data evaluated to determine ‘critical effect’
used in dose response evaluation --Joint FAO/WHO Committee on Food Additives (JECFA) and European Food Safety Authority (EFSA).
• No-observed-adverse-effect-level (NOAEL) adjusted by safety factors to establish an acceptable dose of exposure usually >100 x below dose causing no effects in animals (NOEL)
• Based on long-term studies and observations of humans – safe intake level for an adult that may be ingested over a lifetime without an appreciable health risk
“Biological pathways involved in the response to the drugs in infants and children is often available from studies in adults – basic information about the actions of already-approved and investigational medications.*
• Internal datamining (use and levels /exposure in other approved therapeutic products)
• Uncertainty in extrapolation of exposure and effect between adults and children
• Extrapolation between non-clinical species and humans
• Toxicology studies in juvenile animals may be needed (novel excipients in pediatric medicines)
• Characterize effects on growth and development
• Neonates – vulnerability to adverse effects
* Ref: Pediatric pharmacology expert J. Steven Leeder of Children's Mercy Hospitals and Clinics in St. Louis, Missouri, Pediatric subcommittee of the Oncologic Drugs Advisory Committee, 15 Dec 2009
Risk based assessments
15
• Identify the pediatric population and recommended dose based on weight or body surface area (BSA)
• The excipient exposure should be calculated based on maximum recommended dose (mg/kg/day) for each pediatric category (eg. based on age, weight)
• Permitted Daily Exposure (PDE) for the excipient should be estimated – based on available NOAEL from public literature (mg/kg/day) using the most conservative data eg weight – with several fold safety margins
PDE = NOAEL (mg/kg/day) x Weight Adjustment (kg) / F1 x F2 x F3 x F4 x F5 x F6
F1= 5, to account for extrapolation from eg. rat to humans
F2= 10, to account for differences between individual humans
F3= 1, for a eg. 4 month study in rodents;
F4= 5, for pre-cancerous lesion observed;
F5= 1, given that a NOAEL was established
F6 = 10 or 100 include also safety factor of a minimum of 10 for neonates and infants
* Ref: Pediatric pharmacology expert J. Steven Leeder of Children's Mercy Hospitals and Clinics in St. Louis, Missouri, Pediatric subcommittee of the Oncologic Drugs Advisory Committee, 15 Dec 2009
Notable Excipients
16
• Sweeteners (eg. aspartame, fructose, glucose, maltitol, mannitol, sorbitol, sucrose, xylitol)
• Preservatives (eg. benzoates, benzyl alcohol, sulphites)
• Enhancers (eg. cyclodextrins, ethanol, propylene glycol)
*Refs: Annex to the European Commission guidline on ‘Excipients in the labelling and package leaflet of medicinal products for human use’ (SANTE-2017-11668) –Excipients and information for the package leaflet EMA/CHMP/302620/2017 corr. 1*Strickley, R.G. et al. Pediatric Drugs – a Review of Commercially available Oral Formulations J. Pharm. Sci. 97(5) 2008 pp. 1731-1774Strickley R.G., Pediatric Oral Formulations: An updated review of Commercially Available Pediatric Oral Formulations since 2007, J. Pharm. Sci., 108 (2019) pp. 1335-1365
Sweeteners:
acesulfameK
aspartame
dextrose, fructose, glucose
eErythritol
monoammmoniumglycyrrhizinate
maltodextrin, maltol
mannitol, sorbitol, xylitol
saccharin (Na)
sucralose
sucrose
For taste masking:
carbomers
celulloseacetate
ethylcellulose
glyceryl behenate
povidone/crospovidone
methacrylate copolymers
sodium polystyrene sulfonate (ion exchange resins)
xanthan gum
Enhancers/surfactants:
(polyoxyl) castor oil, lecithin
docusate sodium
glycerol / macrogolstearate
medium chain triglycerides
PEG, propylene glycol
Poloxamers
polysorbates
TPGS
Sodium lauryl sulfate
17
18
19
*carbomers, celullose acetate, ethylcellulose, glyceryl behenate, povidone/crospovidone, methacrylate copolymers, sodium polystyrene sulfonate (ion exchange resins), xanthan gum
*Refs: Strickley, R.G. et al. Pediatric Drugs – a Review of Commercially available Oral Formulations J. Pharm. Sci. 97(5) 2008 pp. 1731-1774Strickley R.G., Pediatric Oral Formulations: An updated review of Commercially Available Pediatric Oral Formulations since 2007, J. Pharm. Sci., 108 (2019) pp. 1335-1365
Sweeteners – approved in medications with pediatric indications
20
Regulatory acceptance
Toxicity
Contribution to osmotic load
Physical chemical stability
Manufacturability
Flavor developmentRelative sweetness
Onset
Duration
Bitterness suppression
Liquid development
• Aspartame shows hydrolysis in solution and high temperature storage
Gastrointestinal tolerance
• Disaccharide type alcohols
• Sucrose has no effect on small intestinal transit rate
Low melting points, adhesion and poor flow
• Managed with processing and particle size controls
*Acesulfame K, aspartame, dextrose, erythritol, fructose, glycerol, high fructose corn syrup, monoammmonium glycyrrhizinate, maltodextrinmaltol, mannitol, saccharin (Na), sorbitol, sucralose, sucrose
*Refs: Strickley, R.G. et al. Pediatric Drugs – a Review of Commercially available Oral Formulations J. Pharm. Sci. 97(5) 2008 pp. 1731-1774Strickley R.G., Pediatric Oral Formulations: An updated review of Commercially Available Pediatric Oral Formulations since 2007, J. Pharm. Sci., 108 (2019) pp. 1335-1365
Contribution to osmolar effects – initial estimates
21
3Source: Case studies on pharmaceutical development of pediatric products for the global market, AAPS-PSWC Workshop 2010
3
Flavour and Sweeteners – stability in aged product
22
• Flavors or sweeteners may be solid or liquid
Development studies eg. e-tongue
• Evaluate chemical and organoleptic stability
Degrade with light, temperature, headspace oxygen, water etc.
Some are not stable in liquids or form insoluble complexes
• Organoleptic / sensory evaluation
Or quantitative analytical assessment eg. HPLC/ GC chromatogram
• Oil soluble carriers soybean, other oils
• Water soluble carriers water, ethanol, propylene glycol,
glycerin and emulsifiers
• Dry carriers
maltodextrin, corn syrup solids, modified starches, gum arabic, sugars, whey protein
Parabens
23
In adultsFDA has approved parabens in foods [methylparaben (21 CFR 184.1490) and propylparaben (21 CFR
184.1670)] are (GRAS) when used as chemical preservatives in foods, with use limits of 0.1% each.
European Food Safety Authority (EFSA) Scientific Panel on Food Additives, Flavorings, Processing Aids and Materials in Contact with Food adopted the ADI of 0 to 10 mg/kg/day as an opinion on the safety of paraben usage in food (EFSA 2004, (Directive 2006/52/EC))
EMA reflection papers propose ADIs of 10 mg/kg/day for methylparabens and 2mg/kg/day propylparabens for pediatric and adult populations
Form Methyl- Na methyl - Na ethyl- Propyl Na propyl Butyl Oral / Soln 2mg/ dose 2.6 mg/mL 50 mg/mL 0.2 mg/mL 16.88 mg/75 mL 0.08 mg/mL
Oral / Suspn 1000 mg/ 5 mL 3.43 mg/mL 2 mg/ 5 mL -- -- 8 mg/ 5 mL Oral/Liquid suspn 1 mg/ mL -- -- 200 mg/ 5mL 1mg/5mL 6 mg/ 120 mL
Syrup 50 mg/mL -- -- -- 28.4 mg/mL
Parabens concentrations in approved products (listed in IID 2019) FDA database
*Refs: EMA guideline on pharmaceutical development of medicines for paediatric use EMA/CHMP/QWP/805880/2012 rev 2EMA Reflection paper formulations of choice for the paediatric population (2006) EMA/CHMP/PEG/194810/2005EMA reflection paper on the use of methyl- and propylparaben as excipients in human medicinal products for oral use (2015) EMA/CHMP/SWP/272921/2012
Methylparaben PropylparabensRange % 0.015 – 0.2 0.02 – 0.06
Max/day (50kg adult) 2.8 mg/kg/day 1 mg/kg/dayPDE 10 mg/kg 2 mg/kg
Calculate the maximum intake per day based on the maximum recommended dose and compare to the permitted daily exposure (PDE) of the excipient
Ethanol and Propylene Glycol as an Excipient in Pediatric Medicines
24
In children ↑ risk of severe hypoglycemia due to acute ethanol intoxication
< 5% and/or the medicinal product should not produce blood ethanol concentration > 0.125 g/L following the administration of only one dose*
FDA limits OTC liquids to NMT 5% ethanol. WHO NMT 0.5% for children < 6yrs
Calculated limit example – should consider the dose volume
For a 6-year old 20 kg child this is equivalent to the ingestion of 1.5 g ethanol = 1.9 mL ethanol = ingestion of 38 mL of solution containing 5% v/v ethanol = 75 mg/kg
EMA (2014) limits to blood alcohol concentration
Dose (g)/ [Vol. Distrib (L/kg) x Wt (kg) ]
As noted by the JECFA (reported by Joint FAO/WHO Expert Committee on Food Additives) ethanol poses no safety concern at its current level of intake when used in flavoring agents
1 month infant Infant Child Adolescent/Adultweight ca. 4.5 kg < 7 kg conservative 10kg ~ 50 kg
*Refs: EMA guideline on pharmaceutical development of medicines for paediatric use EMA/CHMP/QWP/805880/2012 rev 2EMA Reflection paper formulations of choice for the paediatric population (2006) EMA/CHMP/PEG/194810/2005EMA Questions and Answers on Ethanol in the context of the revision of the guideline on ‘Excipients in the label and 6 package leaflet of medicinal products for human use’ (CPMP/463/00) EMA/CHMP/507988/2013 (2014)
Ethanol 2 – 6 yrs > 6 yrs AdultBAC 0.01 g/L 0.125 g/L 0.5 g/L – 3 g/L
Ethanol and Propylene Glycol as an Excipient in Pediatric Medicines
25
In neonates ↓ ability to eliminate propylene glycol
may = adverse events including serious heart, kidney, breathing problems
concomitant administration with ethanol inhibits metabolism
accumulation risk*
JECFA (reported by Joint FAO/WHO Expert Committee on Food Additives)
ADI < 25 mg/kg
EMA limits
1 month infant Infant Child Adolescent/Adultweight ca. 4.5 kg < 7 kg conservative 10kg ~ 50 kg
*Refs: EMA guideline on pharmaceutical development of medicines for paediatric use EMA/CHMP/QWP/805880/2012 rev 2EMA Reflection paper formulations of choice for the paediatric population (2006) EMA/CHMP/PEG/194810/2005EMA Questions and answers on propylene glycol used as an excipient in medicinal products for human use (2017) EMA/CHMP/704195/2013
Propylene glycol neonates 1 month - 5 yrs > 5 yrs- Adult1 mg/kg/day 50 mg/kg/day 500 mg/kg/day
References
26
• Buckley, L.A., et al. Challenges and strategies to facilitate formulation development of pediatric drug products: Safety qualification of excipients, Int. J. Pharm. 536(2) 2018 pp. 563-569
• EMA guideline on pharmaceutical development of medicines for paediatric use EMA/CHMP/QWP/805880/2012 rev 2
• EMA Reflection paper formulations of choice for the paediatric population (2006) EMA/CHMP/PEG/194810/2005
• EMA reflection paper on the use of methyl- and propylparaben as excipients in human medicinal products for oral use (2015) EMA/CHMP/SWP/272921/2012
• Schmitt, G. Safety of Excipients in Pediatric Formulations – a call for toxicity studies in juvenile animals? Children (2) 2015 pp. 191-197
• Strickley, R.G. et al. Pediatric Drugs – a Review of Commercially available Oral Formulations Ju. Pharm. Sci. 97(5) 2008 pp. 1731-1774
• Strickley R.G., Pediatric Oral Formulations: An updated review of Commercially Available Pediatric Oral Formulations since 2007, J. Pharm. Sci., 108 (2019) pp. 1335-1365
• Valeur, K.S., et al, Excipients in neonatal medicinal products: never prescribed, commonly administered, Pharmaceutical Medicine, 32 (2018) pp 251-258
27