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