FORMULATION CONSIDERATIONS AND STRATEGIES FOR PEDIATRICS 23 July - - PowerPoint PPT Presentation

FORMULATION CONSIDERATIONS AND STRATEGIES FOR PEDIATRICS

Karen C Thompson Merck Research Labs West Point, PA

23 July 2018 CRS Pediatric Roundtable

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.

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Acknowledgements: Varsha Biyyala, Andrew Farrington, Chris Granelli, Fran Flanagan, Mary Ann Johnson, Alanna Cleary, Merck Pediatric Development teams

CONSIDERATIONS IN PEDIATRIC FORMULATIONS: THE PATIENTS

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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

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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.

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* Kozarewicz, P. Regulatory Perspectives on Acceptability of Dosage Forms in Children, Int J. Pharm. 469( 2014) 245-248.

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Pediatric Formulations – Design Considerations

CURRENT LANDSCAPE OF PEDIATRIC FORMULATIONS

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Recent Review of Acceptable Oral Pediatric Medicines*

Age Group Liquids Mini monolithic tablet Multiparticulate Orodispersible tablet Chewable Tablet neonate <0.5 ml volume Neutral taste 2 mm acceptable N/A N/A N/A infants <2.5 ml volume Neutral taste < 3 mm tablets, up to 3 tablets per dose Neutral taste <6.5mm tablet neutral taste N/A Age 2-5 years <2.5 ml volume Neutral taste Up to 10 mini tablets acceptable <4mm up to 3 tablets per dose Neutral taste <9.5 mm tablets Neutral taste <9.5mm tablets Neutral taste 6-12 years <10 ml volume neutral taste <7mm tablets up to 3 tablets per dose Neutral taste <9.5mm tablet neutral taste <14.7 mm tablet Neutral taste

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* P. Mistry and H. Batchelor Journal of Pharmacy and Pharmacology 69 (2017) 361-376.

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.

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*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”

Why Minitablets?

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Dosing Flexibility

• 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
• 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

2mm diameter “oral granule” Sprinkle onto soft food for administration

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.

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MINITABLET DEVELOPMENT CONSIDERATIONS

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Granulation (fluid bed, HSWG, roller compaction) DC powder dispensing Spray drying Milled hot melt extrudate

Multi-tip tooling

How are Minitablets Manufactured?

 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

Impact of Granulation

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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.

Direct Compression Roller Compaction

80% 90% 100% 110% 0.5 1 1.5 2 2.5 3 3.5 4 4.5

Minitab % Label Claim

Sample Pull # 80% 90% 100% 110% 0.5 1 1.5 2 2.5 3 3.5 4 4.5

Minitab % Label Claim

Sample Pull #

40 60 80 100 120 140 10 20 30 40 % Label Claim

Location Number

Uniformity Across a Longer Run

• Uniformity is utilized to interrogate the manufacturing process

– Single minitablets tested to maximize discrimination – Patient-relevant number of minitablets are tested for release

Development – 1 minitablet per result RSD= 9.0%

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40 60 80 100 120 140 10 20 30 40 % Label Claim

Location Number Release– 5 minitablets per result

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

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• 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

Pan Coating Wurster Coating

5% 15% 10%

Micro CT images and data courtesy of Jerry Klinzing

 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

More Micro CT Images

Packaging Options for Minitablets

Capsules Counting Devices Dispensers

Sprinkle Capsules

Sachets/Stick Packs

Counting spoon

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Enabling Personalized medicine for the future?

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• Geriatric Patients
• Patients with

Impaired Swallowing

• Personalized

Medicine

• Dose Flexibility

Mini tablets

THANK YOU