Wednesday, March 9, 2011

Pediatric Formulations: Technical and Regulatory Considerations

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. Liquid formulations
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.
Legislative activity. 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 unpalatable (5).
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.

Section references
1. J.T. Wilson et al., "Pediatric Labelling Requirements. Implications for Pharmacokinetic Studies," Clin. Pharmacokinet. 26 (4), 308–325 (1994).
2. N.Y. Rakhmanina and J.N. van den Anker, "Pharmacological Research in Pediatrics: From Neonates to Adolescents," Adv. Drug Deliv. Rev.58 (1), 4–14 (2006).
3. US Government Accountability Office (GAO), "Pediatric Drug Research: Studies Conducted under Best Pharmaceuticals for Children Act," GAO-07-557, March 2007.
4. R.L. Smyth and A.D. Edwards, "A Major New Initiative to Improve Treatment for Children," Arch. Dis. Child.91 (3), 212–213 (2006).
5. D.P. Lombardi, "Novel Organizational Strategies for Advancing Pediatric Products: Business Case Development," in Pediatric Drug Development: Concepts and Applications, A.E. Mulberg, S.A. Silber, and J.N. van der Anker, Eds. (Wiley–Blackwell, April 2009), p. 74.
6. B.W. McCrindle, "Screening and Management of Hyperlipidemia in Children," Pediatr. Ann.29 (8), 500–508 (2000).
Development of palatable formulations for children
By Jeff Worthington, president, and David Tisi, technical director, both with Senopsys, 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.

Figure 1: A typical development program for a pediatric formulation. GCP is good clinical practices; API is active pharmaceutical ingredient. (FIGURE 1 IS COURTESY OF PATHEON AND SENOPSYS)
Many existing medicinal formulations are not designed as suitable for children. Therefore, the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act were introduced in the United States, and legislation governing the development and authorization of medicines for use in children was also recently introduced in the European Union to stimulate pediatric formulation development through a combination of market incentives and regulatory requirements (1–3). The goals of these initiatives, however, are difficult to reach if the challenges in pediatric formulation and taste optimization are not well managed (4). A majority of formulations for children have complex compositions in a less desirable physical state, (e.g., liquid state) to provide dose flexibility and facilitate dose administration (e.g., ease-of-swallowing). These formulations are more susceptible to taste, physical, chemical, microbiology, and pharmacokinetics issues than those of conventional solid oral dosages for adults. Advanced knowledge in formulation (e.g., reaction kinetics, physical chemistry of drug solubility and forms, and special technologies for taste-masking), taste assessment/optimization, and biopharmaceutics are required. A hallmark of many successful pediatric formulation development programs is an integrated team of formulation and sensory scientists. As illustrated in Figure 1, a typical development program for pediatric formulations involves:
  • An exploratory and preparation stage for the development team consisting of formulation and sensory scientists to provide interdisciplinary input on formulation composition, and sensory characteristics (e.g., basic tastes, aroma, texture, mouthfeel, and aftertaste) to clearly define the development strategy
  • An experimental stage for the development team to establish viable options
  • An optimization stage to finalize the formulation and establish product, process, and design space; for example such as for preservative levels
  • A confirmatory stage to verify the flavor quality (i.e., palatability) of formulations (e.g., on aged products) and conduct stability/clinical/bioavailability programs in preparation for product registration.

Figure 2: A decision tree for selecting the formulation and technology for a pediatric drug. (FIGURE II IS COURTESY OF PATHEON AND SENOPSYS)
It is important for the project team to define the strategies to address excipient compatibility, physical and chemical stability, taste, preservative, bioavailability, regulatory, and packaging issues as early as possible (5). A decision diagram for the selection of formulation and technology for pediatric formulations is provided in Figure 2. For excipient compatibility, it is unlikely that all combinations of excipients can be tested. To reduce technical risk and late-stage setbacks, an approach based on drug substance chemistry, drug/excipient sensory characteristics, excipient properties, and statistical design-of-experiments is recommended to generate data to set the direction for taste-masking and dosage-form selection and development. The excipients, including colorants, sweeteners, and flavors for consideration can be based on several acceptance criteria. These factors include regulatory acceptance; toxicity; function such as mouthfeel, viscosity and taste; disease state (acute versus chronic, and the disease itself); administration (dose strength, volume, and frequency); patient population; market potential; and dosage-form characteristics (6). For example, the use of sucrose may be more suitable for acute therapy than for long-term therapy such as in the treatment of HIV, provided patient compliance is not compromised. The decision in choosing excipients must be balanced and not overly constraining. Trade-offs should be identified and carefully considered by all stakeholders (e.g., clinical, regulatory, pharmaceutical development, and marketing (see Figure 2). For example, pediatric drug products often need more than one type of sweetener and taste modifier to effectively mask the bitterness of the active pharmaceutical ingredient (API) that is strong in intensity and long in duration. Nutritive sweeteners and sugar alcohols alone do not provide lingering sweetness. High-intensity sweeteners do not provide bulk, build viscosity, or provide beneficial mouthfeel effects and as such do not work in most systems by themselves. The development of palatable drug formulations requires human input for taste assessment and optimization. Sensory analysis methods are applied to create great tasting food products for decades and are increasingly being adopted in the pharmaceutical industry to develop palatable drug products. With qualified taste panels, analytical sensory tests are used to accurately identify and quantify perceived sensory characteristics of APIs, excipients, and products under controlled laboratory conditions to guide development programs (7, 8). To minimize exposure to drug substances, proper precautions, including good clinical practices for investigational new drugs, are taken to ensure the safety of the evaluators. For example, "sip and spit" tasting protocols and the use of surrogates of generally recognized as safe (GRAS) ingredient compositions are employed. Human taste panels require proper calibration, standardized sampling procedures, and reference standards to generate objective and reproducible data. Knowledge of flavor construction is required to properly translate the data to pediatric drug products. Instrumental taste measurement is finding application in quality control to detect lot-to-lot variations and reduce the sample testing burden on human taste panels. However, there are comparatively few applications of these instrumental techniques in formulation development owing to the general lack of API-specific data correlating human taste panel with instrumental output.

Table I: Sensory characteristics of common pharmaceutical excipients used in pediatric formulations. (TABLE I IS COURTESY OF PATHEON AND SENOPSYS)
Excipient selection. Developing a palatable drug product entails considerably more than adding flavors and sweeteners to overcome an unpleasant taste of an API. Excipients often contribute significantly to the palatability of the final product (see Table 1). For example, many excipients such as surfactants and solvents that are used in liquids for low-solubility drugs, are known to create taste-masking challenges. The development of patient-acceptable pediatric drug products need not be left to trial and error. Applying appropriate design-of-experiment techniques, a multidisciplinary team of formulation and sensory scientists with knowledge and understanding of the principles of flavor construction and the sensory characteristics as well as the pharmaceutical applications and properties of excipients can effectively and efficiently develop palatable pediatric drug products. Many oral liquid products are developed as an afterthought after a solid oral product is developed with the objectives of achieving bioequivalence and identical shelf life. Achieving bioequivalence can be challenging, especially when the drug substance has first-pass metabolism and/or a narrow absorption window. The product stability and impurity profile will likely be affected if the drug substance is sensitive to oxidation, hydrolysis, polymorphic changes, and formation of solvates. The formulation and taste optimization strategies often need to be adjusted to these product performance objectives. For example, a nonaqueous liquid, suspension, or powder for reconstitution may be required to meet the stability or bioavailability requirements. Certain excipients that can influence gastric emptying or gastrointestinal transit such as mannitol, may need to be avoided in taste optimization for drug substances with potential bioavailability issues (9).

Table II: Selection of excipients for oral pediatric formulations, contributions to osmolar laxative effects and carbohydrate content at nominal usage (Section references 10–22). (TABLE II IS COURTESY OF PATHEON AND SENOPSYS)
The choice of excipients for pediatric formulations should also be based upon toxicity concerns, regulatory acceptability, and flavor development. For example, sweeteners and their levels can be judiciously chosen with respect to contribution to osmotic diarrhea and energy intake (e.g., for children with Type I diabetes). Although low-molecular-weight polyols add to osmotic load, they are nonnutritive, noncariogenic, and low in carbohydrate content. The osmotic effects of disaccharide-type alcohols present generally fewer gastrointestinal effects than polyols of lower molecular weight, but they can still be used therapeutically as laxatives (e.g.. lactulose (9). Sucrose is digested by enzymes in the small intestine into fructose and glucose, which are then rapidly absorbed with minimum osmolar laxative effects. The usage level, osmotic contribution, and the energy impacts of a partial list of common excipients are provided in Table II (10-22). A good understanding of the technical, clinical, regulatory and market requirements using a multidisciplinary development approach, with solid scientific principles is critical for developing formulations that meet today's needs in pediatric medicine.
Section references
1. Public Law 107-109, "Best Pharmaceuticals for Children Act," (Washington, DC), 2002.
2. Public Law 108-155, "Pediatric Research Equity Act" (Washington DC), 2003.
3. Regulation No. EC 1901/2006, European Parliament and the Council, European Commission (Brussels), Dec. 12., 2006.
4. EMEA/CHMP/PEG/194810/2005, "Reflection Paper: Formulations of choice for the Pediatric Population," European Medicines Agency, July 28, 2006.
5. R.G. Strickley et al., "Pediatric Drugs: A Review of Commercially Available Oral Formulations," J. Pharm. Sci. 97 (5) 1731–1774 (2008).
6. M. Meilgaard, G. Civille, and B. T. Carr, Sensory Evaluation Techniques (CRC Press, Boca Raton, FL , 3rd edition, 1999).
7. A.J. Neilson, V.B. Ferguson, and D.A. Kendall, "Profile Methods: Flavor Profile and Profile Attribute Analysis," in: Applied Sensory Analysis of Foods, Vol. 1., Moskowitz, H., Ed. (CRC Press, Boca Raton, FL, 1988).
8. A. Cram et al., "Challenges of Developing Palatable Oral Pediatric Formulations," Int. J. Pharm. 365 (1–2), 1–2 (2009).
9. D.A. Adkin et al., "The Effects of Pharmaceutical Excipients on Small Intestinal Transit," Eu. J. Clin. Pharmac.39 (4) 381–387 (1995).
10. T.E. Edes and B.E. Walk, "Nosocomial Diarrhea: Beware the Medicinal Elixir," South. Med. J. 82 (12), 1497–1500 (1989).
11. M. Gracey and V. Burke, "Sugar Induced Diarrhea in Children," Arch. Dis. Child.48 (5), 331–336 (1973).
12. T.H. Grenby, Advances in Sweeteners, Blackie Academic & Professional (Chapman & Hall, London, 1996), pp. 288.
13. Handbook of Pharmaceutical Excipients, R.C. Rowe, P. J. Sheskey, S.C. Owen, Eds. (American Pharmacists Association and Pharmaceutical Press, Washington, DC), 2006, for online ed.,
14. FDA, Inactive Ingredients Guide, Rockville, MD,
15. G.A. Koutsou et al., "Dose-Related Gastrointestinal Response to the Ingestion of Either Isomalt, Lactitol or Maltitol in Milk Chocolate," Eu. J. Clin. Nutr. 50 (1), 17–21 (1996).
16. G. Livesey, " Tolerance of Low-Digestible Carbohydrates: A General View," Br. J. Nutr.85 (Suppl. 1), S7–S16, 2001.
17. H. Mitchell, Sweeteners and Sugar Alternatives in Food Technology (Blackwell Publishing, Oxford, UK, 2006), pp. 413.
18. T. Oku and S. Nakamura, "Threshold for Transitory Diarrhea Induced by Ingestion of Xylitol and Lactitol in Young Male and Female Adults," J. Nutr. Sci. & Vitaminol.53 (1), 13–20 (2007).
19. T. Oku T. et al. "Maximum Permissive Dosage of Lactose and Lactitol for Transitory Diarrhea and Utilizable Capacity for Lactose in Japanese Female Adults," J. Nutr. Sci. & Vitaminol.51 (2), 51–57 (2005).
20. A. Ruskone-Fourmestraux et al., "A Digestive Tolerance Study of Maltitol after Occasional and Regular Consumption in Healthy Humans," Eu. J. Clin. Nutr.57 (1), 26–30 (2003).
21. D.M. Storey et al., "The Comparative Gastrointestinal Response of Young Children to the Ingestion of 25 g Sweets Containing Sucrose or Isomalt," Br. J. Nutr. 87 (4), 291–297 (2002).
22. Y.M. Wang and J. van Eys, "Nutritional Significance of Fructose and Sugar Alcohols," Ann. Rev. Nutr. 1, 437–475 (1981).
Thin-film technology
By Martha S. Sloboda, business manager with ARx LLC, a subsidiary of Adhesives Research.
The oral thin film (OTF) platform is a proven and accepted form of drug delivery for pediatric products. Its premeasured format provides an accurate and easily ingested dose without water that allows for portable and convenient "give and go" administration by a parent or caregiver. Patient compliance can be improved because of an OTF's ease of administration and subsequent difficulty in expectoration. The dosage format offers flexibility in base chemistry and base formulation development from raw material selection to final packaging configurations as well as an established and well-understood manufacturing path. Based on the continuous nature of production, formulators can also approach pediatric films as either unique, single-product formulations, or as a dosage modification of a preexisting product.
Tolerability and disintegration. Beyond efficacy, most OTF development for pediatric products focuses on two key attributes: tolerability and disintegration. Depending on the age range, region, and marketing needs, formulators can uses various flavors and compendial excipients to create a child-friendly formula. They can also choose to develop dye-free and alcohol-free products, add sensory components such as heating or cooling sensations, and/or modify texture. Different taste-masking approaches can be incorporated, and the dosage unit area can be modified to hit specific taste and disintegration profiles ranging from less than five seconds to multiple minutes. Additionally, dissolvable films may be formulated to demonstrate adhesion properties for use with other devices currently used by younger populations to deliver medications or vitamins. With a standard active pharmaceutical ingredient (API) loading level of 50% of the final unit mass and an adjustable final unit area, formulators have a lot of latitude in both how much API can be loaded and how other product attributes can be tailored for each product.

Figure 3: Examples of thin films for pediatric use. (FIGURE 3 IS COURTESY OF ADHESIVES RESEARCH)
Other approaches in OTFs . Another approach to development is to leverage higher-dose, preexisting formulations for pediatric populations. Dissolvable films are currently manufactured as a continuous roll stock that is unitized during final packaging. With this approach, the packager cuts the film strip to an alternative size to achieve a different dose. For example, a 10-mg dose could become a 5-mg dose by halving the unit size. This approach is attractive because only one formulation is developed, but two or more products and dosage forms can be marketed (see Figure 3). Examples of this approach have been launched in the pediatric market, including cough/cold and gastrointestinal products. Precision-coating techniques derived from transdermal and filled-pad production translate base chemistries into final dosage units with unit tolerances as tight as ± 2.5% around the potency target. Specialized coat weight monitoring systems and liquid deposition techniques enable any OTF product to hold and maintain consistent cross and downstream uniformity during manufacture. These manufacturing approaches are well understood and controlled, enabling robust, efficient development from bench to commercial scale.

Table III: Examples of commercially available over-the-counter thin-film pediatric products. (TABLE III IS COURTESY OF ADHESIVES RESEARCH)
The flexibility in base chemistry combined with an established production process enables formulators to present a new platform to the patient. From a materials-selection standpoint, the OTF format provides formulators with the flexibility to add or omit ingredients that are more or less desirable for pediatric populations while still producing a scalable product. Table III provides examples of commercially available thin-film over-the-counter pediatric products. The dose accuracy, ease-of-use, convenience, and potential for improved compliance of dissolvable films continue to drive new formulations and applications for pediatric populations. New programs are emerging for topical, transdermal, and oral modified release pediatric products. In addition, OTFs have the potential to extend product life cycles for approved oral APIs via a simplified filing path such as a 505 (b)(2). OFT's flexibility in base formulations make them a viable strategy in pediatric formulations.
Oral thin-film delivery via a pacifier
By Theodore Clemente, Jr., vice-president of business development with MonoSol Rx.
The pediatric population represents one of the most challenging patient groups for administering drugs as compliance, proper dosing, and safety are difficult to manage with most standard modes of drug delivery. Thin-film dosage-form technology has become more prominent in pediatrics because it provides an accurate, convenient, and effective way to deliver medications to infants and young children. Thin films are easy to administer and fast-acting and does not require the patient to actively swallow or chew the dosage unit as is required with a liquid or chewable tablet. Thin film is a highly flexible drug-delivery technology. The strips can be manufactured to different sizes and tastes, can carry various drugs, and be applied to a host of surfaces within the oral cavity to enable the desired drug delivery outcomes.
An infant's natural propensity to suckle makes pacifiers and bottle nipples useful devices for administering medication and vitamins. MonoSol Rx has developed a patented technology for administering film dosage units to infants and young children using this approach.
The system relates to the delivery of drugs and/or vitamins contained in a thin film that is attached or placed inside of a pacifier or porous nipple member such as the tip of a baby bottle. Affixing a quick dissolving thin film into the porous nipple of a bottle or pacifier ensures that the active ingredient is immediately released into the oral cavity upon contact with saliva or liquid from the bottle. Delivery of a complete and accurate dose is confirmed as the thin film dissolves and disappears from the inside surface of the pacifier or porous nipple.

Figure 4: Example of thin film placed inside a pacifier or porous nipple member. (FIGURE 4 IS COURTESY OF MONOSOL RX)
The dissolvable thin film is attached to the inner surface of the nipple and held in place with retaining fingers (see Figure 4). The porous nipple member can possess holes or slits, which allow saliva to enter the inside of the nipple member and drug from the dissolved thin film to be suckled into the oral cavity. The pacifier or nipple member can be developed as a single-use application or as a reusable system. Flavoring agents and/or coated drug particles can easily be added to the thin film for the purpose of taste-masking. This property enhances the likelihood that the infant or young child will continue to suckle the nipple member, further ensuring that the entire dose is consumed. In addition, a translucent material can be used for the nipple member, so the parent or caregiver can visually determine that the thin film has been completely dissolved and that the entire dose has been administered.
Distinct attributes of the thin-film dosage also make it advantageous for pediatric use without the pacifier or nipple member delivery method. Since the polymeric films are very thin (i.e., typically 50 to 150 microns), the technology ensures rapid disintegration due to a larger surface area for wetting and subsequent dissolution. It is virtually impossible for a film strip to be swallowed intact when placed on the tongue because the rapid wetting of the film generally causes adhesion to the tongue or other oral mucosal surface immediately. The film quickly dissolves and is ingested along with the saliva into the gastrointestinal tract.
Thin-film drug-delivery also offers the potential for reduction of dosing errors in a healthcare-provider setting because the dosage forms are usually supplied in printed individual pouches. The thin quick-dissolving film and low-dosage mass also allow for a shorter residence time in the oral cavity, which eliminates the possibility of the child spitting out the medication.
Thin film is likely to play a larger role in pediatric drug delivery in the future. Likely applications will include the delivery of prescription drugs, oral vaccines, nutritional supplements, and over-the-counter medications .

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