Pediatric drug products require specialized consideration in formulation development. Recent changes to US and European regulatory
requirements for pediatric drugs have transformed what once was only a niche area to an important field in drug development.
To gain a perspective on the regulatory and technical considerations of pediatric formulations, Pharmaceutical Technology conducted a roundtable of leading experts. Lynn Gold, vice-president of CMC services, and Kenneth V. Phelps, president and
CEO, both of Camargo Pharmaceutical Services (Cincinnati, OH), and Peter R. Joiner, CEO of Madeira Therapeutics (Leawood,
KS), address liquid formulations. Jeff Worthington, president, and David Tisi, technical director, both of Senopsys (Woburn,
MA), and Susan Lum, principal scientist of pharmaceutical development services (PDS) and pharmaceutics, and Kwok Chow, PhD,
senior director of global PDS technology and alliances, both with Patheon (Toronto), examine the development of palatable
formulations for children. Martha S. Sloboda, business manager for ARx LLC, a subsidiary of Adhesives Research (Glen Rock,
PA), discusses oral thin-film technology. Theodore Clemente, Jr. vice-president of business development at MonoSol Rx (Warren,
NJ), details a specific application of oral thin film delivery using a pacifier or porous nipple member.
LAUREN NICOLE/GETTY IMAGES
By Lynn Gold, PhD, vice-president of CMC services and Kenneth V. Phelps, president and CEO, both with Camargo Pharmaceutical
Services, and Peter R. Joiner, CEO of Madeira Therapeutics.
Overview of pediatric drugs.
There is a profound need for pharmaceutical products that have been tested and approved safe and effective for use by children.
From 1973–1997, the percentage of approved drugs that contained no labeling information for children remained fairly stable
at 71–81% (1). Of the 33 new molecular entities approved in 1997, 27 had potential for pediatric use, but only nine contained
any pediatric labeling information (2). Two-thirds of the drugs that currently are prescribed to children have not been studied
and labeled for pediatric use (3).
With so few medicines containing adequate labeling information to guide their use, off-label use of medicines has become,
unfortunately, a necessary and accepted part of pediatric medical practice (4). Off-label prescribing includes the use of
drugs for unapproved indications, in a different age group, or with a different dosage, frequency, or route of administration.
Off-label prescribing also includes the administration of extemporaneous formulations (e.g., oral suspensions made from adult
tablets) with untested bioavailability and stability.
Recognizing the need to have a determination of pediatric applicability and adequate labeling instructions for children,
Congress included incentives for conducting needed studies in the Food and Drug Administration Modernization Act of 1997 (FDAMA).
Due to slow progress, Congress added additional incentives in the Best Pharmaceuticals for Children Act (BPCA) in January
2002. In essence, this act provided the innovator a six-month extension of exclusivity if adequate pediatric studies were
performed and allowed FDA to formally request that such studies be performed. In 2003, Congress passed the Pediatric Research
Equity Act (PREA), which provided FDA with the authority to use bridging data from adult studies in approving pediatric medicines.
These three acts, together with continuing enabling legislation through the Prescription Drug User Fee Act (PDUFA) renewals,
encourage the development of pediatric drugs. The Food and Drug Administration Amendments Act (FDAAA) of 2007 extended and
amended BPCA and PREA.
Until these acts (BPCA, PREA, and FDAAA) were passed, the approach in pediatric drugs was first to develop a drug for adults
and then adjust the dose to suit children. The thinking was if a drug were safe enough for adults, it would be safe enough
for children. The three acts (BPCA, PREA, and FDAAA) make the development of an "age-appropriate formulation" a legal requirement
if the drug under development is appropriate for children.
Penicillamine is a good example of a less-than-optimum formulation for pediatric use. Penicillamine tablets are too large
for children and have to be crushed to administer them to children, leading to uncertainty of the actual dose delivered. Dosing
of penicillamine is also required for extended time periods. The crushed tablet is foul smelling, and the taste and odor are
Pediatric drug development
. The goal for any new drug product is a safe, effective dosage form that facilitates maximum compliance through the course
of treatment. Formulations for pediatrics usually must cover a broad age range. Drugs that must be dosed based on body weight
or endocrine status (e.g., puberty) require either solid doses that are scored or different doses. Children under 12 years
of age often have difficulty swallowing capsules and/or chewing tablets. A liquid formulation, therefore, is often chosen
for pediatric administration. Liquid formulations facilitate dose titration and are easily administered. Liquid formulations,
however, have certain constraints. Taste is an important issue for pediatric formulations, and the more frequent the dosing,
the more critical this issue can be. Stability of the liquid in multiple-dose bottles must be maintained, often by using preservatives.
Taste-masking agents, preservatives, and solubilizing excipients must have an acceptable safety profile in pediatrics.
Special considerations must be taken to reformulate currently approved adult drugs to be a pediatric friendly product. As
an example, Madeira Therapeutics is developing a pediatric formulation of a marketed statin for a population with an inherited
cholesterol gene that often leads to early heart disease (6). This product requires flexibility in dosing as the amount of
drug required can be variable. To meet the requirements of a flexible dose level and integrate the characteristics of the
active pharmaceutical ingredient (API), an oral syrup formulation was identified as the target formulation. As expected, many
of the formulation steps are the same as with any drug-development program. The physical and chemical properties, such as
solubility, salt form, stability, and the taste of the API must be known or established.
The major difference for a pediatric formulation compared with an adult formulation is an added layer of investigation when
choosing excipients. The traditional sources, the generally regarded as safe (GRAS) list (i.e., 21 CFR Parts 182, 184, and 186) and FDA's Inactive Ingredients Guide are based on the safety obtained primarily in adult subjects. Investigation into the safety data in the pediatric population
available for the potential excipients to be used should be performed. The specific excipients chosen must be determined based
on the drug under development as well as the pediatric product profile under consideration.