preformulation & clustering analysis · 2014-06-20 · michael boruta subject: european...
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Preformulation & Clustering Analysis
Michael BorutaIndustrial Solutions Manager
Optical Spectroscopy Product Manager
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Outline
• Background
• Challenges
• Managing Data
• Clustering
• Review & Decision Making
• Summary
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Preformulation Background• Preformulation involves the application of biopharmaceutical
principles to the physicochemical parameters of a drug with the goal of designing an optimum drug delivery system.
• Different Stages of Preformulation– Selection of appropriate salt and polymorph form
– Characterization the solid-state properties of the drug substance
– Determination of solution properties
– Determination of compatibility with excipients
• At the start of preformulation a target has been identified and the patent process has started – therefore the clock starts ticking
PROCESS
DEVELOPMENTDISCOVERY
PRE-
FORMULATIONCLINICAL MFG
PRODUCT
LAUNCH
Interface Between Drug Substance and Drug Product
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What Is Salt Selection?
• Simply put—it is creating various salt forms for a target API.
• Creating salts is not an exact science. It uses a trial and error approach with some guidance from past experiences.
• There are many possible combinations of solvent ratios, acids, bases, that could be used to produce salts along with various conditions such as application of heat, anti-solvents, or seed crystals.
• HTS allows many possible combinations to be attempted with low sample requirements
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What Are Polymorphs?• Simply put – polymorphs are different crystal forms of the same compound.
– A different packing order in the crystal, means different molecular associations between adjacent molecules.
– These different associations can change energy levels of the atoms and the crystal lattice.
– Changes in the energy levels lead to changes in the properties of the materials; stability, bio-availability, etc.
• It is rare for a compound to have a single crystal form. One of the fears of the pharma people is did I miss a crystal form – this could lead to patent infringement.
• The conditions that are used to create crystals (the salt selection process) can effect the form of the crystal.
• HTS allows many possible combinations to be attempted with low sample requirements
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Challenges
• Labs are now running more experiments to find possible salt forms and polymorphs
• Laboratory instrumentation is heterogeneous with many disparate data types and experiments that need to be coordinated sometimes from different sites, countries or continents
• Groups involved are having difficulties accessing all relevant data in a timely manner and then analyzing it.
• Report creation is cumbersome and time consuming
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Unified Laboratory IntelligenceManaging the Data
CrystallizationConditions Casual users
FilesImagesStructures Metadata
XRPD
DSC, HPLC, …
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View Experimental Data
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Clustering
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Clustering
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Analysis/Review
Compare each spectrum to the average for its group
Compare different clustering methods
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Data Review
XRPD Overlays
Graph
Overlay Legend
Nearest Neighbors Table
DSC curve
TGA curve
Image
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Supervision & Decision Making
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Reporting
Avg_HQI (ListA) where Supervised="0" (82 pts)Avg_HQI (ListA) where Supervised="1" (14 pts)
XrpdID15105
0.35
0.40
0.45
0.50
0.55
0.60
0.65
0.70
0.75
0.80
...
#List # #ID Spec# XrpdID Avg_HQI Supervised
1 48001 1 (XRAY Spectrum) 2 (CURVE Spectrum) 3 (CURVE Spectrum)
10 0.4840 0
2 4800217 2 (XRAY Spectrum)
10 0.4823 0
3 480039 3 (XRAY Spectrum)
16 0.4864 0
Database: PostgreSQL DB on localhost <test96>, Record ID: 48027
3530252015105
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
1.1
1.2
5.48
27
Avg_XRay_2
Avg_HQI (ListA) where Supervised="0" (82 pts)Avg_HQI (ListA) where Supervised="1" (14 pts)
XrpdID15105
0.35
0.40
0.45
0.50
0.55
0.60
0.65
0.70
0.75
0.80
...
#List # #ID Spec# XrpdID Avg_HQI Supervised
1 48001 1 (XRAY Spectrum) 2 (CURVE Spectrum) 3 (CURVE Spectrum)
10 0.4840 0
2 4800217 2 (XRAY Spectrum)
10 0.4823 0
3 480039 3 (XRAY Spectrum)
16 0.4864 0
Database: PostgreSQL DB on localhost <test96>, Record ID: 48026
3530252015105
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
1.1
1.2
3.23
26
Avg_XRay_2
Avg_HQI (ListA) where Supervised="0" (82 pts)Avg_HQI (ListA) where Supervised="1" (14 pts)
XrpdID15105
0.35
0.40
0.45
0.50
0.55
0.60
0.65
0.70
0.75
0.80
...
#List # #ID Spec# XrpdID Avg_HQI Supervised
1 48001 1 (XRAY Spectrum) 2 (CURVE Spectrum) 3 (CURVE Spectrum)
10 0.4840 0
2 4800217 2 (XRAY Spectrum)
10 0.4823 0
3 480039 3 (XRAY Spectrum)
16 0.4864 0
Database: PostgreSQL DB on localhost <test96>, Record ID: 48025
3530252015105
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
1.1
1.2
2.97
25
Avg_XRay_2
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Summary
• One unified environment for multiple sources of data and multiple techniques Consolidation of data, IP protection if data are provided by third parties
• Data are minable by structure, substructure, meta data, spectrum,…. Then report is only a couple of clicks fast reporting to regulatory department
• Commercial off the shelf application to support the scientists’ decisions and for managing the workflow better throughput, wiser decisions,
• The solution is a part of a Unified Laboratory Intelligence strategy within the organization contributing to corporate knowledge management while also taking advantage of it
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