FORMULATION CONSIDERATIONS AND STRATEGIES FOR PEDIATRICS 23 July 2018 CRS Pediatric Roundtable Karen C Thompson Merck Research Labs West Point, PA
Why “ There is a moral imperative to formally study drugs in children so that they can enjoy equal access to existing as well as new therapeutic agents” Committee on Drugs , Pediatrics 1995. 95 (2) 286-294. Acknowledgements: Varsha Biyyala, Andrew Farrington, Chris Granelli, Fran Flanagan, Mary Ann Johnson, Alanna Cleary, Merck Pediatric Development teams 2
CONSIDERATIONS IN PEDIATRIC FORMULATIONS: THE PATIENTS 3
Pediatric Patients Age Definitions • Preterm Newborn Infants • Term Newborn Infants (0-27 days) • Infants and toddlers (1 month-23 months) • Children (2-11 Years) • Adolescents (12-18 years) – EMEA CHMP 2005 4
Critical Acceptability Attributes in Oral Pharmaceutical Formulations , as identified by Kozarewicz* Dosage Form Critical Acceptability Attributes Monolith solid dosage forms to be swallowed Size and shape, taste and after taste for uncoated. Multiparticulate solid dosage forms to be swallowed Particle size, shape, texture (surface agents), hardness (grittiness), taste and after taste, dose volume, need for measuring counting device and ease of administration Solid dosage form to be chewed Taste and aftertaste, mouth feel, smell, time needed to chew, effort required to chew. Solid dosage form to be dispensed in mouth Taste and aftertaste, mouth feel, smell, time needed to dissolve/disperse, Liquid dosage forms – solution , suspensions Taste and after taste, smell , volume , viscosity, mouth feel, need for measuring device, ease of preparation/administration, appearance. * Kozarewicz, P. Regulatory Perspectives on Acceptability of Dosage Forms in Children, Int J. Pharm. 469 ( 2014) 245-248. 5
Pediatric Formulations – Design Considerations 6
CURRENT LANDSCAPE OF PEDIATRIC FORMULATIONS 7
Recent Review of Acceptable Oral Pediatric Medicines* Age Group Liquids Mini monolithic Multiparticulate Orodispersible Chewable Tablet tablet tablet neonate <0.5 ml volume 2 mm acceptable N/A N/A N/A Neutral taste infants <2.5 ml volume < 3 mm tablets, up Neutral taste <6.5mm tablet N/A Neutral taste to 3 tablets per neutral taste dose Age 2-5 years <2.5 ml volume Up to 10 mini Neutral taste <9.5 mm tablets <9.5mm tablets Neutral taste tablets acceptable Neutral taste Neutral taste <4mm up to 3 tablets per dose 6-12 years <10 ml volume <7mm tablets up Neutral taste <9.5mm tablet <14.7 mm tablet neutral taste to 3 tablets per neutral taste Neutral taste dose * P. Mistry and H. Batchelor Journal of Pharmacy and Pharmacology 69 (2017) 361-376. 8
FDA Requirements Safety Considerations for Product Design to Minimize Medication Errors In 2000 the Institute of Medicine* (. published a report that 44,000 to 89,000 deaths occur each year due to medical errors. 7000 deaths annually were attributed to medication errors. The report urged the agency to incorporate principles of cognitive and human factors engineering in its review process. Considerations of the end user and the environment of use. Risk assessments to include failure mode and effects analysis and simulated use testing. This is to be considered for all products with additional guidance for combination products required devices for administration defined in 21 CFR 4.2. *Kohn LT, Corrigan JM, Donaldson MS eds. To Err is Human: Building a Safer Health System . Institute of Medicine, National Academies Press: Washington DC 2000 Human Factor Considerations: Europe: Read and Understand the Information for Use USA: Since 2014, “Demonstrate Ability to Perform” 9
Dosing Flexibility Why Minitablets? • Liquid-like flexibility (in single mini tab increments if needed) • Shelf life and storage of a solid • Ease of swallowing in younger patients Conventional Manufacture Operations • Similar granulation techniques 2mm diameter “oral granule” • Tablet compression with multi-tip tooling • Ability to taste mask with coating process Presentation and Administration Options • Sprinkle onto soft food , disperse in liquids, or swallow directly • Capsule, stick pack presentations Sprinkle onto soft food for administration 10
What are Minitablets • Very small tablets – 2-mm tablets and tooling are shown • Multi-tip tooling utilized – Importance of Powder Flow – Uniformity impacts dissolution, hardness, friability, etc. 11
MINITABLET DEVELOPMENT CONSIDERATIONS 12
How are Minitablets Manufactured? DC powder dispensing Granulation (fluid bed, HSWG, roller compaction) Milled hot melt Spray extrudate Multi-tip tooling drying Similar equipment as in regular tableting for upstream processing Specialized multi-tip tooling – Multi-tip tooling Requires excellent flow and appropriate particle size Flow and uniform die fill critical to weight control 10
Impact of Granulation Direct Compression Roller Compaction 110% 110% Minitab % Label Claim Minitab % Label Claim 100% 100% 90% 90% 80% 80% 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 Sample Pull # Sample Pull # Use of a granulated process improves uniformity of the minitablets • Significant improvement on weight and content uniformity • A well-designed granulation has superior flow as compared to a non-granulated blend of powder. 14
Uniformity Across a Longer Run Development – 1 minitablet per result Release– 5 minitablets per result 140 140 120 120 % Label Claim % Label Claim 100 100 80 80 60 60 RSD= 9.0% 40 40 0 10 20 30 40 0 10 20 30 40 Location Number Location Number • Uniformity is utilized to interrogate the manufacturing process – Single minitablets tested to maximize discrimination – Patient-relevant number of minitablets are tested for release 15
Development Batch CU Data RC Scale Up Batch Single minitab per prep All run on automation For the QC methods and release specifications, the number of minitabs per test was increased to ensure appropriate risk level. CU and Disso: 5 minitabs per unit Composite Assay: 40 minitabs per sample Clinical Release CU Data Average 99.6%, Range 98.0-101.8 %, AV = 3.0 (≤ 15.0 is specification)
Coating of Minitablets Minitablets are robust to coat Due to more uniform surface to volume ratio and more uniform surface morphology Suitable hardness and friability should be used for successful coating application Key is to strike a balance between coating weight gain and release profile Non- functional and functional coatings (taste-masking, modified-release etc.,) Typical ways to coat these minitablets include Wurster and pan coating processes 17 Pan Coating Wurster Coating
More Micro CT Images 5% 15% 10% Coating is listed as % weight gained during coating These images are the view from the side of the minitab, perpendicular to the axis of compression Defects are more obvious from this angle, in corners Micro CT images and data courtesy of Jerry Klinzing
Packaging Options for Minitablets Capsules Counting Devices Counting spoon Sprinkle Capsules Dispensers Sachets/Stick Packs 19
Enabling Personalized medicine for the future? • Geriatric Patients • Patients with Impaired Swallowing Mini tablets • Personalized Medicine • Dose Flexibility 20
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