BCS-based biowaiver: Experimental assessment of

(quantitative) composition of the reference product

3rd Symposium on Harmonization of Bioequivalence Requirements

Amman, May, 2nd/3rd 2018

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1. HWI group

2. Analytical techniques: advantageous and limitations

3. Examples demonstrating challenges and solutions

Agenda

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HWI group

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› 1991 foundation of HWI pharma services GmbH, Ruelzheim by

Dr. Wissel and Prof. Häberlein

› 2006 foundation of i.DRAS GmbH, Planegg-Martinsried

› 2008 acquisition of the pharmaceutical development unit from

a CMO (HWI development, Appenweier)

› Today full service provider in the CMC field

› 160 employees (35% university graduates)

› GMP certificate, manufacturing licence (Ruelzheim and Appenweier site)

› Qualified Person (6), Qualified Person for Pharmacovigilance (6)

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Method development and validation

Purity testing of particular impurities – trace analysis

Structure elucidation

Trouble shooting (root cause analysis)

Extractables & Leachables testing

Batch release and stability testing

Reference standards for quality control

HWI group: Services for API, drug product & medical device

API characterisation and quality screening (up to OEB level 4)

Development of solid, semisolid and liquid dosage forms

Dry powder inhaler testing and development

Manufacturing of clinical batches

DoE approach

Laboratory services

Drug Development

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Compilation, review, assessment of IMPDs / IBs and dossiers

Management of MAA procedures

Technical documentations for medical devices

Drug-device combination products (EU/US)

Life-cycle management (dossier updates and variations)

HWI group: Services for API, drug product & medical device

GMP & GDP, GVP services

Compilation, revision and maintenance of package leaflets,

summaries of product characteristics (SmPCs) and labelling

Quality management services

Batch release, GMP-Audits

Regulatory affairs services

Vigilance & Quality Services

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1. HWI group

2. Analytical techniques: advantageous and limitations

3. Examples demonstrating challenges and solutions

Agenda

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Determination of the original drug product composition

(reverse engineering)

Reverse engineering is the decoding of an innovator product’s formulation

parameters.

Reverse engineering includes

› Qualitative and quantitative composition of the innovator product

› Solid-state characterization of the drug substance(s)

› Manufacturing process

The qualitative composition of the innovator product and the amount of the

API are known.

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Quantitation of excipients

1. Step: Separation of excipients from matrix (e.g. tablet)

› Differential solubility

› Filtration, centrifugation, chromatography

2. Step: Detection of separated excipients

› Gravimetric methods (major excipients of significant weight in the

dosage unit!)

› Spectroscopic methods (UV/VIS, Fluorescence, Light scattering, MS,

qNMR)

› Refractive index

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Quantification of excipients

Organic components

› HPLC

› GC (volatile components, residue solvents, flavours)

› HPTLC (components without chromophores, e.g. sugars)

› Size exclusion chromatography (for high molecular weight excipients)

› Hyphenated techniques using spectroscopic detection: LC-MS, GC-MS, LC-

NMR, LC-SPE/NMR

› Benefits:

› small amounts of organic excipients are best quantified using

sophisticated separation and quantification techniques

› Coupling experiments for separation of mixtures

› high selectivity and sensitivity

› Limitation: solubility of excipients!10

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Quantification of excipients

Inorganic Components, Counter-ions

› Titration (specific but not selective!)

› Atomic absorption spectroscopy (AAS)

› ICP-MS

› Scanning Electron Microscope/Energy Dispersive X-Ray (SEM-EDX)

Water

› Karl Fischer (small sample quantity -> coulometric detection)

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Solid-state characterization of API

Polymorphic form, anhydrous form, hydrate, solvate

Impact on

› Dissolution profile

› Bioavailability

› Stability (chemical and physical)

› Processability (hygroscopicity, flow, compressability)

Techniques

› DSC, Powder X-ray diffraction (XRD), Thermogravimetric analysis (TGA),

FTIR, RAMAN

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Molecular Properties

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Solid-state characterization of APIs

Crystallinity, particle size (micronization!), particle shape, porosity

Impact on

› Dissolution profile

› Disintegration time

› Processability (hygroscopicity, flow, compressability, hardness)

Techniques

› PSD: Laser light scattering (Malvern Master Sizer®, Helos®), Stroboscopic light

scattering (PartAn®)

› Microscopy, X-ray micro tomography (XMT), SEM-EDX

Benefits

› not destroying methods , no solubility needed

› XMT, SEM-EDX: particle size min. 50 nm diameter (high resolution!)

› fast and inexpensive13

Particle Properties

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Solid-state characterization of API

Bulk density, powder packaging, homogeneity

Impact on

› Flow properties

› Blending efficiency

› Capsule filling, Tablet size

› Compressibility

› Techniques

› Density testing, XMT, SEM-EDX

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3. Bulk Properties

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1. HWI group

2. Analytical techniques: advantageous and limitations

3. Examples demonstrating challenges and solutions

Agenda

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XMT applications: hard gelatine capsule

› submicron resolution

› elucidation of internal structures

› quantification of internal pores, cracks, densities

XMT capsule example (Skyscan

1172, 15 µm spatial resolution)

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XMT applications: tablet

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Polymer matrix in tablet: Examination of homogeneity