1. Pediatric Formulation Development - A quality perspective
Julia C. Pinto, Ph.D.
Branch Chief, Office of New Drug Products
Office of Product Quality, CDER, FDA

2. Chemistry, Manufacturing and Controls (CMC) perspective
Extemporaneous preparations using approved adult drug product
for pediatric use
Compounding of approved adult drug product for pediatric use
Design and manufacture of drug product for Pediatric patients.

3. Limitations in Developing Extemporaneous Formulations
Lack of stability/sterility studies
Excipients used for the approved adult formulation
Dosing, Efficacy and safety concerns
Variations in practice

4. Limitations in compounding of a drug substance
for pediatric administration
Selection of Excipients
Stability of the compounded product
Sterility of the compounded product
Content and Blend uniformity
Viscosity (dosing limitations)
Dissolution

5. CMC Requirements for IND submissions using
Compounding or Extemporaneous Formulations
Quantitative Composition (Excipient safety) and method of preparation
Certificate of analysis comprising: Assay determination; Impurity profile (degradation); Content or blend uniformity; microbial or sterility data (if applicable)
Stability data

6. Challenges in New Formulation Development
Dose flexibility: accuracy of dosing low doses and small volumes across all the age groups (infants to tweens)
Route of administration and bioequivalence: Inability to swallow tablets/capsules
Patient Compliance: palatability, smell, texture
Choice of Excipients and Toxicity
Physical and Chemical Properties of the Drug Substance Solubility, pka, stability in liquids and foods

7. Dosage Form Variability Per Pediatric Age Groups
Common Dosage Forms
Neonates: 0-4 weeks
Indication dependent
Infants: 1 mth – 2 years
Liquids-small volumes (e.g., syrups, solutions)
Children: 2 – 5 years
Liquids; effervescent tablets dispersed in liquids; sprinkles on foods
Children: 6 – 11 years
Solids (chewable tablets, orally disintegrating tablets; oral films)
Adolescents: years
Solids (typical adult dosage forms - tablets, capsules)

8. Challenges with Oral Solid Dosage Forms
Manufacturing
Content uniformity with very low doses
Milling/Grinding – Particle Size
Tablet size and shape/capsule size
Scored tablets
Controls
Disintegration/dissolution
Impurities/degradation products

9. Challenges with Liquid Formulations
Palatability (taste, texture, smell)
Chemical Stability of Ready to Use Solutions or Suspension
Physical Stability of Suspensions
Proper Measuring Device(s)
Suitable Container/Closures (leachable/extractables)
Excipients (safety consideration)

10. Excipient Toxicity in Young Children
Administration
Adverse reaction
Benzyl alcohol
Oral, parenteral
Neurotoxicity, metabolic acidosis
Ethanol
Neurotoxicity
Polyethylene glycol
Parenteral
Metabolic acidosis
Polysorbate 20
Polysorbate 80
Liver & kidney failure
Propylene glycol
Seizures, neurotoxicity, hyperosmolarity

11. Powder for Oral Suspension
Stable Formulations
Formulation
Issue
Solution
Precipitation
Discoloration
Degradation
Loss of potency
Sterile Formulations
Microbial
Endotoxin testing/Sterility/ Particulate matter
Powder for Oral Suspension
caking - difficulty in dispersing the powder upon reconstitution
Tablet
loss of potency
chewable tablet hardening
friability

12. Example #1: Prilosec®
Modified/increased labeling to include 1 – 16 year olds
Delayed-Release Oral Suspension
Supplied as 2.5 or 10 mg unit dose packets
Directions: Empty contents of packet into 5 or 15 mL of water, let sit 2 minutes, drink
Contents of capsules may also be sprinkled on apple sauce

13. Example #2: Zenpep and Creon (pancrealipase)
New 3,000 USP units of lipase capsule
Indicated for infants ≤ 12 months
Contents of capsule may be sprinkled on soft acidic food such as apple sauce
Contents should not be mixed directly into formula or breast milk

14. Conclusions: Pediatric Product Design and Manufacture
Critical CMC Controls (compounding/extemporaneous preparations)
API stability (maintain potency)
Degradation (impurity profile)
Blend Uniformity
Dissolution (solid dosage forms)
Microbial/sterility testing
New Product Profile
Dose Flexibility (specific pediatric age group(s))
Palatable
Stable long term
Maintain Bioequivalence to Adult Formulation