Regulatory Requirements – Pediatric Formulation Development

Regulations in the US and EU both require and incentivize (via pediatric exclusivity) development of pediatric medicines. These regulations are designed to ensure that every new drug will be evaluated for use in pediatric patients and studied in this population when appropriate.

A key requirement is the submission of detailed plans that outline the studies to be conducted as part of the pharmaceutical and clinical development program:

  • EMA – Paediatric Investigation Plan (PIP)
  • FDA – Pediatric Study Plan (PSP)

The regulatory agencies require that companies demonstrate the “palatability” of drug products in pediatric patient populations as part of the pharmaceutical and clinical development program (unless a PIP or PSP waiver is granted).

Definition of Palatable

Many Active Pharmaceutical Ingredients (API) are extremely bitter or have other aversive sensory attributes such as a malodor, trigeminal irritation, or a gritty texture that can adversely affect doing compliance.

There are many definitions of “palatable” – dictionaries, expert opinions and regulatory perspectives. However, the shortcoming of all of them is that they are subjective.

Senopsys has advanced a definition of “palatable” that is based on the scientific principles of perception:

“Palatable drug products are those in which the aversive sensory attributes
are below the recognition threshold”

 

A key feature of Senopsys’ definition of palatable is that it has a measureable endpoint.

The Science of Perception

Psychophysics is the scientific study of the relation between stimulus and perception. Nearly all stimuli (taste, smell, sound, sight) follow a similar response profile idealized in on the right.

At low and high strengths, perceived changes in stimulus intensity become asymptotic to the changes in strength. Thus the linear portion of the stimulus response curve defines the human sensory world.

To this response curve, three important cognitive functions can be ascribed:

  • Detection threshold – strength at which subjects report a difference from baseline but that cannot be described.
  • Recognition threshold – strength at which stimuli elicit a qualitative response, e.g., bitter, sweet, cooling, cherry.
  • Saturation – point beyond which increases in strength produce no additional response.

The recognition threshold is the most important in developing palatable pediatric drug formulations – aversive sensory attributes below this intensity will not be perceptible to patients.

Illustrative Stimuli Response Curve
graph1

 

Sensory Analysis

Senopsys uses the seminal Flavor Profile Method to measure the sensory attributes of formulations – taste, aroma, mouthfeel and texture.  Flavor Profile is an internationally recognized, open-source method of sensory analysis. The Flavor Profile intensity measurement scale is established with chemical reference standards over the linear portion of the stimulus response curve. The output is analogous to a chromatogram, wherein each peak represents a separately identified sensory attribute and the peak height/area corresponds to its perceived intensity.

Flavor Profile is used to guide the development of taste-masked pediatric drug formulations, i.e. to measure the reduction in the aversive sensory attributes.

Understanding the psychophysics of perception, palatable pediatric drug formulations are those in which the aversive attributes have been reduced below their recognition thresholds. In other words, they are not overtly bitter, produce little trigeminal irritation, are smooth not gritty and have no perceptible malodors.

The Output of Flavor Profile Analysis is Analogous to a Chromatogram

graph2

 

 

A Tradition of Excellence in Pediatric Drug Formulation Development

Senopsys has conducted over 100 studies supporting the development of taste-masked pediatric drugs since our founding in 2006.

Developing palatable pediatric drug formulations can be a daunting undertaking filled with many clinical regulatory, market and technical challenges.

Our clients rely on our experience and expertise to guide development of palatable, taste-masked pediatric drug formulations throughout the pharmaceutical and clinical development process.

Taste Assessment (Following Successful First-in-Human Studies)

  • Identify the aversive sensory attributes of the drug active or prototype pediatric formulations – bitterness, malodor, irritation
  • Quantify the taste masking challenge
  • Establish recognition (palatability) threshold concentrations for the aversive attributes

Drug Product Design

  • Develop Pediatric Investigation Plan (PIP) / Pediatric Study Plan (PSP) strategy
    • Age-appropriate dosage form(s)
    • Requirements for taste masking, including need for an API modification technology (e.g., particle coating or adsorption)
    • Dosing vehicle selection (e.g. appropriate foods and beverages)
  • Define Critical Quality Attributes for taste, aroma, mouthfeel and texture

Pediatric Formulation Development

  • Develop palatable pediatric drug formulations that enable dose titration, applying Quality by Design (QBD) principles:
    • Liquids – solutions, suspensions
    • Solids – tablets (chewable, dispersible, orally disintegrating, mini-tabs), powders (sprinkles, sachets)
  • Identify pediatric-appropriate dosing vehicles to simultaneously optimize for:
    • Taste masking
    • Ease-of-preparation and administration
    • Ease-of-swallowing
    • In-use stability
  • Measure taste effects of solubility enhancement technologies:
    • API form – salts vs free base
    • Excipients – surfactants, lipids, emulsifiers
    • Particle size reduction
    • Hot melt extrusion
    • Spray dry dispersion

Taste Masking Technology Guidance

  • Determine maximum free (soluble) API concentration required for palatability
  • Measure effectiveness of taste masking technology – particle coating/encapsulation, adsorption, complexation, hot melt extrusion
  • Verify taste masking performance of pediatric drug formulations in dosing vehicles (e.g., bitter breakthrough)

Explore the Art and Science of Taste Masking

We invite you to explore the art and science of taste masking by viewing a recent case study or downloading our white paper.

Dedicated to Developing Palatable Drug Products

Senopsys is the taste-masking development partner of choice for 15 of the top 25 global pharma companies as well as dozens of emerging and mid-size pharma and biotech companies.

Ask us questions, inquire about our services or schedule a “lunch and learn” seminar about the art and science of taste masking.

CONTACT US