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

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. www.fda.gov

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 www.fda.gov

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 www.fda.gov

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 www.fda.gov

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 www.fda.gov

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: 12 - 18 years Solids (typical adult dosage forms - tablets, capsules) www.fda.gov

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 www.fda.gov

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) www.fda.gov

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 www.fda.gov

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 www.fda.gov

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

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

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