Regulatory changes have resulted in the inclusion of clinical studies with pediatric patients as an integral part of pharmaceutical product development. In the US, the FDA guidance for pediatric drug development is provided by the BPCA [1] and PREA [2]. These regulations [3] apply to any NDA, new indication, new pharmaceutical form, or new route of administration. The product specific requirements are outlined in a written request which is issued by the FDA. The EU pediatric regulations [4,5] apply under similar product filing conditions but require the submission of a pediatric investigational plan (PIP) no later than upon completion of human pharmacokinetic studies in adults. This requirement shifts the planning for pediatric studies to earlier points in product development, sometimes in advance of selecting doses for adults. Milne et a.l [6] describe the pediatric patient population as a continuum of as many as six smaller populations with different requirements for optimum dosing and for product administration. The pediatric population includes preterm infants, neonates, infants and toddlers, preschool and school aged children and adolescents. The development of formulations, the clinical studies within the various populations and the supply of these products to the market are the key challenges which may require ‘out of the box’ thinking to provide for pediatric patient populations. Labeled pediatric formulations and industry verified (extemporaneous) preparations [7] are options to fulfill pediatric needs.
The European Medicines Agency has provided a reflection paper which considers the formulations of choice for pediatric populations [8]. This reflection paper is an acknowledgement of the challenges faced by pediatric formulation teams. The dosing regimen for adolescents, ages 12-17 years, may involve similar dosage form to the adult population and but may require lower potency dosage forms. School age children (6-11 years) may be able to be dosed with tablets or capsules but those patients that have issues with swallowing may prefer oral dispersible or chewable tablets. Preschool children ages (2-5 years) may utilize oral dispersible tablets according to the guidance but beginning with this age group, there is a shift in the dosing preferences to solution or suspension formulations. Hence the EMEA guidance would suggest that solutions or suspensions as the preferred oral dosage form for children ages five and under.
The varied presentations needed for pediatric products are further complicated with additional considerations. There are considerations of dosing volumes-- minimized so that the child can ingest the full dose and maximized so that care givers can accurately dose the patients. A product for an infant, for example, could be more concentrated than one for a child to minimize dosing volumes for the younger patients. The development of such formulations requires clear instruction to minimize dosing errors. The development of pediatric formulations includes consideration of the level and safety of excipients. This is complicated by concerns of the sensitivities of younger patients to preservatives, colorants and flavorants. Taste attributes of the formulations are critical for compliance in this patient population [9]. Further, it is known that taste preferences in adults and children differ [10]. Studies comparing liquid antibiotic suspensions suggest that appearance can also contribute to the acceptability of the formulations to pediatric patients [11,12]. Experiential considerations may also play an important role in taste acceptability [13]. The disease state of the target population may also impact taste preferences [6,14]. Solution and suspension formulation development include additional challenges beyond palatability including microbial considerations [15], tools for dosing and constitution, in some cases restrictive shelf life for constituted products (weeks instead of years) due to physical and chemical instabilities. Pediatric formulation development requires many tools.
In all cases, the objective of formulation development is providing formulations that have sufficient bioavailability, safe excipients, acceptable palatability, acceptable dose uniformity and stability. The defined formulation has guidance for easy and safe administration with precise and clear product information including clinical data to support use in the target patient population. The challenges of managing the varied oral formulation delivery requirements to serve pediatric populations suggest that ‘out of the box’ thinking may be needed to assure patient supply. Milne et al [6] describe a specialty pharmaceutical company in the UK which derives 50% of its business from pediatrics having 7000 formulations on file. The challenge is to achieve flexibility for patient needs with assurance of supply. The challenge is to achieve this flexibility with minimal dosing errors. As a consequence of these additional challenges, pediatric product commercialization frequently requires a new strategy for distribution and supply of these niche products [6].
Some parenteral, sterile products have relied on compounding practices [16] to support commercialization. Compounded sterile products can be provided as lyophilized powders or concentrates in the market place. The product that is manufactured and distributed to pharmacies has superior stability and shelf life as compared to the final product that is administered to the patient. Preparation of the sterile product that is administered to the patient is through the execution of explicit steps for compounding the final delivered material and includes instructions for labeling and storage of the constituted product to assure safe patient administration. Once prepared at the desired concentration for administration, the compounded formulation may have a considerably restricted, but, well defined, shelf life and storage condition. This approach provides the market with a product with a manageable shelf life specifically from a supply and distribution perspective. Instructions for preparation and use are clearly outlined to seek to minimize dosing errors. Understanding the value of such products, the FDA has issued a guidance document to industry the set expectations for information needed to support the use of reconstituted products [16].
Using the manipulations found to be acceptable for products which are less stable in their administered state as described above, consider the case for the development of industry verified (extemporaneous) recipes. The objective of these preparations is to provide a product developed for patient use (which may have a restricted shelf life). The preparation is derived from a formulation that is able to support manufacture, distribution, and supply logistics. The industry verified recipe provides similar explicit instructions for preparation, information about concentration and stability data supporting the shelf life of the constituted product. Suspensions and solutions requiring multiple dosing also need to include considerations of microbial stability of such formulations. Sterile compounded formulations provide a template for the development of industry verified formulations for oral use.
A lisinopril industry verified preparation [17,18] was developed to support pediatric clinical studies and the recipe was filed to provide instruction for the preparation of a lisinopril formulation for pediatric dosing. The lisinopril industry verified preparation regulatory filing includes adult and pediatric PK information as well as clinical efficacy data in pediatric patients [19,20]. The Chemistry and Manufacturing Control (CMC) section of the regulatory filing references supportive data from the compounding vehicle manufacturer (as one would for any proprietary excipient). The compounding vehicle is used to prepare the suspension formulation that is required for dosing children. The CMC data supporting the shelf life of the constituted product include stability and dissolution assessment using validated, analytical methods. Microbiological assessments were conducted to assure adequate preservation of the product during patient use. The constituted suspension has a considerably, more restrictive shelf life as compared to the adult tablet formulation. Hence, like the compounded parenteral product, explicit instructions for preparation and storage are used to support safe and effective dosing in pediatric patients. The filing further includes packaging information and extractable testing for containers. An additional level of rigor includes ‘in use’ stability studies to simulate daily patient sampling from the container over the course of the 4 weeks shelf life. Finally, the ease and reproducibility of the recipe preparation is confirmed by assessing the label claim using multiple preparers and using multiple lots of raw materials (including tablets and compounding vehicles). Modeled after the validation batches, this approach serves as a means to validate the recipe in terms of ingredients and preparers.
The recipe prepared formulations are used in the clinical studies examining adult and pediatric pharmacokinetics and pediatric efficacy trials [19,20]. Following completion of development, clinical and regulatory activities, and submission and acceptance of the pediatric information, the product label [21] was modified to include a recipe for suspension preparation. Dosing information was also provided with a starting dose of 0.07 mg/kg once daily (up to 5 mL total). Finally, the label is updated with ages for dosing patients > 6 years of age.
The approach of using industry verified recipes seeks to provide timely pediatric formulations utilizing more streamlined supply strategies. The recipe developed above for lisinopril does not require grinding or other manipulation of the tablet dosage form but there are timed steps for shaking and there are multiple steps for water and vehicle addition. Another challenge with this option is seeking to assure supply of vehicles and bottles in all pharmacy situations. A pediatric kit could be considered for such an application. The extent of manipulation during compounding may vary and it may be advantageous to seek to apply standards to seek to minimize errors in this step. This preparation only provides for a single concentration hence patient dosing is varied by changing dosing volume.
Another example of an industry verified recipe is the filed losartan pediatric preparation. Studies were conducted using losartan potassium tablets which were constituted in a compounding vehicle to produce a suspension for pediatric use. The constituted suspension was then characterized for physical and chemical stability, microbial stability and package compatibility. This particular preparation is different from the lisinopril preparation in that taste masking of the bitter active was achieved by pH adjustment with the compounding vehicles. The resulting suspension contains precipitated active to minimize its bitter taste. The development program evaluated the ability of the suspension to provide uniformity of dosing following shaking both immediately after preparation and during the course of the in-use stability testing. This formulation was evaluated in adult and pediatric PK studies and used in clinical trials to support the addition of pediatric information to the label [22]. The preparation instructions to prepare a losartan potassium suspension [23] were provided in the updated product label.
This recipe seeks to address several product attributes. The compounding preparation begins with a hold time in water which is to allow for the disintegration of the film coated tablets. It is important to note that the losartan potassium is very water soluble so the first wetting and disintegration steps dissolve the drug. Once the compounding syrup is added, the pH shift minimizes the bitter taste of the active. The compounding vehicle has a pH which results in precipitation of the active into a fine suspension. Studies were conducted to assure the chemical stability and dose uniformity of the resulting suspension and storage conditions were selected minimize physical changes in the resulting suspension. Compendia tests were conducted assure adequate microbial protection of the formulation. Studies were conducted to assure the packaging material was compatible with the suspension. The formulation is able to maintain dose uniformity and to support patient dosing up to 4 weeks as shown by stability and in use testing. Moreover, the restrictive 5°C storage is supported by dissolution studies which confirm that the particle size is maintained over the constituted formulation shelf life.
A losartan potassium suspension formulation was recently launched in Europe [24]. This suspension starts with the powder blend of the tablet formulation and fills that material directly into a sachet instead of being provided via compression and film coating. The sachet contents are poured into a PET bottle and the materials are directly diluted with the supplied vehicle. The suspension preparation is streamlined as the addition of water and the 1 hour hold time steps are not required, one simply adds the vehicle and shakes to disperse the suspension. The resulting suspension that the patient receives has similar stability as the industry verified recipe. The suspension product is provided as a kit with instructions for pharmacy preparation.
A final example is the found by reviewing the product information [25] for oseltamivir phosphate. In this case the manufacturer has provided for capsule and oral suspension formulations. They provide guidance for dosing adult, geriatric and pediatric patient populations. The oseltamivir phosphate oral suspension provides a 12 mg/mL suspension which is diluted with water and has a ten day expiration date. The label also includes industry verified recipes prepared from the capsule formulation and compounded in either one of two listed diluents. The recipes designate storage conditions, shelf life and containers. The label includes dosing instructions relative to patient body weight for treatment and prophylaxis. Supply challenges with labeled suspension formulation requires the utilization of the industry verified option to fulfill patient needs [26].
The required dosing for the continuum of pediatric patients requires multiple formulation options. Industry verified recipes like actual labeled, pediatric formulations provide stability, compatibility, microbial and clinical data to support the safe and effective used of these products. It is proposed that industry verified recipes and other strategies may be considered to fulfill commercial supply challenges. The development of industry verified recipes seeks to provide similar information as required in the regulatory guidance for compounded parenteral formulations. These regulatory tools provide a framework for the development of industry verified (extemporaneous) recipes and help to assure that pediatric populations can benefit from new medicines.
References
1. USA Public Law 107-109, Best Pharmaceuticals for Children Act January (2002).
2. Pediatric Research Equity Act of 2003, S650, 108th Congress
3. Food and Drug Administration. Pediatric Exclusivity Labeling Changes (as of 14 July 2006)
4. Regulation (EC) No 1901/2006 of the European Parliament and of the Council of December 12, 2006 on medicinal products for pediatric use.
5. J. Breitkreutz, “European Perspectives on Pediatric Formulations” Clinical Therapeutics 30(1) (2008) 2146-2154.
6. C-P Milne JB Bruss, “The Economics of Pediatric Formulation Development for Off Patent Drugs” Clinical Therapeutics 30(11) (2008) 2133-2145.
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8. Committee for Medicinal Products for Human Use (CHMP), European Medicines Agency (EMEA), 2005. “Reflection Paper: Formulations of Choice for the Paediatric Population”.
9. J. Breitkreutz and J. Boos, “Paediatric and Geriatric Drug Delivery” Exp. Opinion Drug Del. 4(1) (2007) 37-45.
10. J.A. Minella, G.K. Beauchamp. “Optimizing Oral Medications for Children.” Clinical Therapeutics 30(11) (2008) 2120-2132.
11. T.E. Kairuz and I. Jordaan, “Children’s Preference for Medicines-A Pilot Study in the Eastern Province Region of South Africa” J. Applied Therapeutic Research 5(1) (2004) 38-42.
12. R.H. Schwartz, “Enhancing Children’s Satisfaction with Antibiotic Therapy: A Taste Study of Several Antibiotic Suspensions.” =Current Therapeutic Research 61(8) (2000) 570-581.
13. F.M. Clydesdale, “Color as a Factor in Food Choice” Critical Reviews in Food Science and Nutrition 33(1) (1993) 83-101.
14. S.S. Schiffman “Taste and Smell in Disease” in Mechanism of Disease F.H. Epstein, Editor, New England Journal of Medicine 308 (21) (1983) 1275-1279.
15. A. Ghulan, K. Keen, C. Tuleu, I.C-K. Wong, P.F. Long, “Poor Preservative Efficacy Versus Quality and Safety of Pediatric Extemporaneous Liquids.” The Annuals of Pharmacotherapy 41(2007) 857-860.
16. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER), “Guidance for Industry Dosage and Administration Section of Labeling for Human Prescription Drug and Biological Product-Content and Format” April 2007.
17. K.C. Thompson, Z. Zhao, J.M. Mazakas, C.A. Beasley, R.A. Reed, C.L. Moser, “Characterization of an Extemporaneous Liquid Formulation of Lisinopril” American J. Health Syst. Pharm. 60 (2003) 69074.
18. C.A. Beasley, J. Shaw, Z. Zhao, R.A. Reed, “Development and Validation of a Stability Indicating HPLC Method for Determination of Lisinopril, Lisinopril Degradation Product and Parabens in the Lisinopril Extemporaneous Formulation” J. Pharm and Biomed. Anal. 37(3) (2005) 559-567.
19. R.J. Hogg, A. Delucchi, G. Sakihara, T.G. Wells, F. Tenney, D.L. Batisky, J.L. Blumer, B.A. Vogt, M.-W. Lo, E. Hand, D. Panebianco, R. Rippley, W. Shaw, S. Shahinfar, “A Multicenter Study of the Pharmacokinetics of Lisinopril in Pediatric Patients with Hypertension” Pediatric Nephrol. 22 (2007) 695-701.
20. B. Soffer, Z. Zhang, K. Miller, B.A. Vogt, S. Shahinfar, “A Double-Blind, Placebo Controlled Dose Response Study of the Effectiveness and Safety of Lisinopril in Children with Hypertension” Am. J. Hypertens. 16(2003) 795-800.
21. “Lisinopril Tablets” Physician’s Desk Reference 62(2008) 2065-2069.
22. S. Shahinfar, F. Cano, B.A. Soffer, T. Ahmed, E.M. Santoro, Z. Zhang, G. Gleim, K. Miller, B. Vogt, J. Blumer, I. Brizgounov, “ A Double-Blind, Dose-Response Study of Losartan in Hypertensive Children” Amer. J. Hypertens. 18 (2005) 183-190.
23. “Losartan Potassium Tablets” Physicians’ Desk Reference 62 (2008) 1946-1951.
24. National Health Service, “Cozaar (Losartan) 2.5 mg/ml Powder and Solvent for Oral Suspension.” 07 July 2009.
25. “Oseltamivir Phosphate Capsules and for Oral Suspension” Physician’s Desk Reference 62(2008)2753-2757.
26. “Guideline for Compounding Oseltamivir Oral Suspension Issued by FDA.” American Pharmacists Association 02 Nov 2009.
Karen Cassidy Thompson is a distinguished senior investigator in Pharmaceutical Research and Development in West Point PA. She received a BA in Chemistry from Dartmouth College and a PhD in Physical Chemistry from Duke University. Following a post doctoral appointment at Columbia University, she joined Merck where she has been involved in preformulation and formulation for over 21 years. Recent research interests include pediatric and adult formulation development and strategies. In past years, she has been an invited speaker to DIA meetings both in the US and in Helsinki, Finland and at the AAPS meeting. She enjoys the excitement of formulation design and development—it is a great ride and one is always learning. So much to do and see…so little time.