This document discusses pre-formulation studies in pharmaceutical development. It begins by welcoming the audience and introducing Christopher Lipinski and his influential "Rule of Five" for drug candidate screening. It then provides an overview of the scale of science involved in pre-formulation and early process development activities. Several key aspects of pre-formulation are examined in more detail, including Lipinski's Rule of Five analysis, challenges in dosage form development, influencing parameters, and characteristics of ideal drug candidates. The objectives and components of pre-formulation are outlined.

1. Scale of Science
Understanding of
Interactions and Controls in
Pharmaceutical Development
with reference to solid dosages
By
Satendra Kumar Vishwakarma, PhD
May 26, 2011 1

2. Welcome
This Presentation is dedicated to inventor of
Lipinski’s “Rule-of-Five” in Drug Candidate
Screening Methodology
Dr Christopher A. Lipinski
Exploratory Medicinal Sciences Department
Laboratories of Pfizer Global Research & Development, Connecticut,
USA.
May 26, 2011 2

3. Announcement
The views and graphics in this presentation are collected from
various sources and content(s) might have been modified on
the basis of scientific justification.
Narrator of this slide presentation believes that all the contents are Up-to-Date and is
ONLY for INFORMATION, NOT for direct APPLICATION without verifying, optimizing,
and validating the target.
Thank You
May 26, 2011 3

4. Understanding the Scale of Science
A
Fundamental Tools
in
Pharmaceutical Development
May 26, 2011 4

5. Early Process Development Activities
Expression Lab scale Pilot Develop Scale -up
System Process Plant GMP for Mfg
Selection Development Scale-up Process Commercial
GLP “Tox” Lots GMP Ph1 – 2 Ph 3 Clinical
Clinical Supplies Supplies
Cell Line Selection Pilot Plant Launch
Readiness
Process
Fermentation Dev Consistency Engineering Modification Process
Runs Trials for Tox MBR/SOP’s Validation
Process Lots Modification
Integration
GMP Process
Purification Tech Xfer from MBR/SOP’s Production for Develop Optimization
Process Dev Development to Finalization Ph1 Commercial
Pilot Plant Process Bridging Studies
Analytical Method Development Analytical SOP to QC
Preformulation Formulation TOX/ADME Transfer to
Manufacturing Site
Fill/Finish
Science based compatibility & Stability Studies Stability Studies
May 26, 2011 5
Phillip L. Gomez III, NIH, USA

6. Lipinski's Rule-of-Five Analysis
A significant empirical derivation from the analysis of World
Drug Index (32,000) facilitates to make the distinction
between Drug-Like and Non-Drug-Like molecule.
In order to be adsorbed through the gut and enter the blood
stream, orally administered drugs must have certain
molecular properties as proposed by Lipinski.
The Lipinski "Rule of Five Analysis" states that compounds
are likely to have good absorption and permeation in
biological systems (ADME) and are more likely to be
successful drug candidates if they meet the following criteria:
Christopher A. Lipinski Exploratory Medicinal Sciences Department, Connecticut, laboratories
of Pfizer Global Research & Development
May 26, 2011 6

7. Lipinski's Rule-of-Five Analysis
 Five or fewer hydrogen-bond donors (any OH+NH).
 Ten or fewer hydrogen-bond acceptors (any O+N).
 Molecular weight less than or equal to 500.
 Calculated log P less than or equal to 5.
 Fifth rule includes Number of rotatable bonds LT 15,
and other factors – number of aromatic rings, highly
reactive and chemically unstable groups.
Compound classes that are substrates for biological
transporters are exceptions to the rule.
 If two parameters are out of range, a "poor absorption or
permeability is possible" alert is a very visible educational
tool for the chemist and serves as a tracking tool for the
research organization.
May 26, 2011 7

8. Lipinski's Rule-of-Five Analysis
hydrogen-bond donors
May 26, 2011 8

9. Lipinski's Rule-of-Five Analysis
hydrogen-bond acceptors
May 26, 2011 9

10. Lipinski's Rule-of-Five Analysis
The compounds in Collection of Small Organic Molecules generally obey
Lipinski's "rule of five" making them ideal candidates for drug discovery.
Molecular weight
May 26, 2011 10

11. Lipinski's Rule-of-Five Analysis
Log P
May 26, 2011 11

12. Lipinski's Rule-of-Five Analysis
Number of rotatable bonds
May 26, 2011 12

13. Drug-Like vs Non Drug-Like
May 26, 2011 13

14. Drug-Like vs Non Drug-Like
May 26, 2011 14

15. Integrated Workflow Station
 Accelerate solubility, salt form, polymorphic form
and crystallization to minimize potential risk of new
polymorphic form
 Reduce time, resource and material by a factor of
10
 Large combinatorial experiment specifications i.e.
pre-formulation variables, experiment execution,
end-to-end software and database integration, high
quality productivity, fast submission
May 26, 2011 15

16. Automated Workflow Station
Pharmaceutical Workflows Overview
Design Synthesis, processing, formulation Sample preparation
for screening Properties analysis Data analysis
May 26, 2011 16
http://www.symyx.com http://www.chemspeed.com

17. Automated Workflow Station
Solubility Workflows Overview
Process Development Optimization: Automated Solubility v pH
Measurements Discovery: Solubility Measurements Formulation, pH, and
Stability Testing
Accelerating Innovation for Broad Range of Applications
May 26, 2011 17
http://www.symyx.com

18. Molecular Pre-Formulation
Scale of Science
GENERIC HPLC METHODS
Benefits of Fast Generic Chromatographic Methods over
Traditional or Custom Chromatographic Methods
A knowledge of Molecule Structure and Retention
Time is relevant in Early- / Pre- Formulation
Development
May 26, 2011 18

19. HPLC in Pre-formulation Development
With a wide variety of analytical columns, detection systems, mobile phases, and
sample pre-treatment techniques, most physicochemical changes in formulation
components can be analyzed
HPLC Columns:
 Size-exclusion (or gel filtration), Reversed-phase, Ion-exchange, Hydrophobic
interaction, Affinity
HPLC Detectors:
 UV/VIS, Fluorescence, Reflective index, Mass spectrometers, Light scattering,
evaporative light scattering, Electrochemical, Chemiluminescence, Circular
Dichroism
HPLC Analysis:
 Quantitative analysis of physical degradation products
 Quantitative analysis of chemical degradation products
 Characterization of product impurities
 Rapid identification and concentration determination of products
May 26, 2011 19

20. Generic Gradient HPLC Methods
Rapid extraction of Physiochemical Parameters for quality drug
development and Generic Screening for Method Development
(MD)
Characteristics of rapid, generic gradient methods
 A combination of Methods – eliminate the need for
method development.
 Covers wide range of polarity range (Polar Ionic Mode,
Reverse Phase, Polar Organic Mode, Normal Phase for MD).
 Application of short columns with small particles (Column
coupling for multi-column screening for MD).
 Compromise resolution for speedy results (Quality is not
so important for screening of physical parameters and MD).
 Application of elevated column temp and high flow rate.
May 26, 2011 20

21. Generic Gradient HPLC Methods
Configuration of MDS with Isocratic System
DETECTOR
AUTOSAMPLER
PUMP
May 26, 2011 21
http://www.astecusa.com/publications/presentations/58.PPT#16

22. Molecular Pre-Formulation
Scale of Science
UNDERSTANDING OF FUNDAMENTAL
PHYSICOCHEMICAL
THEORY AND TECHNIQUES IN
PREFORMULATION
Knowledge of Molecule Structure & Interactions is vital to
understand manufacturing science through Pre-Formulation
/ Formulation Development
May 26, 2011 22

23. Introductory Pre-formulation Chapters
 Interface between formulation development and Early
formulation in drug innovation.
 Data on solubility determinations
 Physical chemical characterization of solids (thermal
methods, XRPD, particle size, moisture sorption).
 Polymorph screening studies & relative stability
determinations of detected solid phases.
 Characterize API in formulated product to support
pharmacology, toxicology, and PK.
May 26, 2011 23

24. Dosage Development Groups
Early and
Analytical Testing
Preformulation
Procedures
Stability
Specifications
Evaluation
In vitro
Vendor
Core Formulation Release
Testing
Qualification Functional
Method
Activities Validation
Reverse Transfer
Engineering
Reference Method
Standard Development
Characterization Optimization
May 26, 2011 24

25. Influencing Parameters
Disintegration
of
Formulation
Drug Drug
Characteristics Dissolution
PC and Stability
Bioequivalence
____________________________________
Bioavailability Drug
Drug
Absorption
Excretion
Drug Drug
Metabolism Distribution
May 26, 2011 25

26. Dosage Form Development Chart
Active Drug
Suspension
Solution
Suppositories Topicals Intrinsic
Dissolution
Dissociation Tonic
Constant pKa pH Effect Co-solvents Adjustment
Intrinsic pH?
Salts Saturated
Solubility Solubility IV Injection
PEG 400 + 5%
Other H2O + Glycerin
Delivery Capsule Solution Tonic
System Adjustment
Other Excipient Compatibility
Dosage Forms Stability
Tablets
May 26, 2011 26

27. Formulation Problem
May 26, 2011 27

28. Challenges in Development
Solid State Properties
Crystalline, Amorphous
Solvates / Hydrates
Excipient Degradation
Pathway Prediction &
Compatibility
Physical and
Chemical
? Characterization
Particle size, Shape
Solid State Stability
Surface Area
Physical and
Mechanical Characterization
Chemical
Properties Plastic,
Elastic, Brittle
May 26, 2011 28

29. Challenges in Development
API Properties
NEW CHEMICAL
ENTITY
Chemical Form(s) Physical Form (s)
Crystallinity
Ionizable Group (s) Salt Forms
Neutral compound Polymorphs
Hydrates
Solvates
SOLUTION
CHARACTERISTICS SOLID STATE
PROPERTIES
Aqueous and pH Solubility
& Stability ABSORPTION Particle Morphology
CHARACTERISTICS Mechanical Properties
May 26, 2011 29

30. Excipient Selection in Dosages
Physicochemical Physicochemical Properties Manufacturing
Properties of Excipient of Drug Process Requirement
 Physically Stable  Polymorphic / Forms  Direct
(Polymorphic / Forms Hydrates compression
Hydrates)  Heat & moisture  Wet Granulation
 Hygroscopic  Fluid Bed
sensitive
 Chemically Stable Coating/
 Compatible with drug
 Poorly Soluble
Granulation
 Rheology Flow  Poorly absorbable  Spray Drying
 Poorly Stable in vivo  Other novel
processes
Excipients Choice
Route of Administration in Solid Dosage
 Oral Forms Desired Release
 Pulmonary Characteristics
 Transdermal  Immediate release
 Buccal  Sustained
Delivered Dose of
 Rectal/Vaginal Release
Drug
 Modified Release
 High Dose
e.g. enteric
 Low Dose
May 26, 2011 30
Vidya Joshi in WWW.DrugDeliveryTech.com

31. What are Characteristics of an Ideal
Drug Candidate?
 Molecular properties – MW, molecular surface area, size,
charge (pKa), H-binding potential
 Stable and Soluble* - formulatable
 Low toxicity (ideal > 10 - fold safety margin)
 Good bioavailability
 Similar metabolism in humans to a species under
investigation
 Stable or single polymorph for solid oral dosage form
* When the solubility of an API is less than 0.1 mg/ml, the optimization of
the particle size during preformulation may be critical to efficacy or
pharmaceutical equivalence. Other researchers believe that particle size
may be critical at a solubility of 1 mg/ml or less.
May 26, 2011 31

32. What is Pre-formulation?
Pre-formulation is an exploratory activity and interface
between Drug Substance (Solid / Liquid State Organic Chemistry)
and Drug Product (Solid / Liquid State Pharmaceutical Chemistry)
(i.e. it’s not only about stability and solubility)
According to PQRD / USFDA
The goal of pre-formulation is to “investigate critical
physicochemical factors which assure identity, purity of drug
substances, formulatability, product performance and
quality”
May 26, 2011 32
PQRD – Product Quality Research Division

33. What is Pre-formulation Objective?
“The objective of pre-formulation studies is to develop a
portfolio of information about the drug substance to serve
as a set of parameters against which detailed formulation
design can be carried out.
Pre-formulation investigations designed to identify those
physicochemical and biopharmaceutical properties of drug
substances and excipients that may influence the
formulation design, method of manufacture, pharmacology,
toxicology and PK - biopharmaceutical properties of
resulting product.”
May 26, 2011 33

34. What’s in Preformulation?
 Pre-formulation involves the application of (bio)
pharmaceutical principles to physicochemical
parameters of an active drug form. or
Pre-formulation (development) provides biophysical
characterization of drug – excipients matrix - an insight
into physical and chemical stability of Drug Product.
 The characterization of a drug molecule is a very
important part of the pre-formulation phase of product
development.
 Pre-formulation seeks to design an optimum drug
delivery system.
May 26, 2011 34
Daria Jouraleva, ACD Labs

35. Why Pre-formulation?
External : End-Use Properties of Drug Product
Generic Drug Product should be Pharmaceutical and
Therapeutic Equivalents with Same Clinical Effect and Safety
Profile.
1. Dose and Release – what amount of drug substance is
needed in what time?
2. Bioavailability and Toxicity – Drug performance level
compared with side effects.
3. Stability and Shelf-life – To ensure quality and
performance during storage.
VIA REGULATORY AGENCY
May 26, 2011 35

36. Why & How Pre-formulation?
Internal: End-Use Properties of Drug Product
 Reducing set-backs (risks) during development and
maximizing chances of clinical success.
 The set of process - analytical activities to determine the
desired (native) form to an undesirable form (upon storage)
of the drug (It is a significant for formulation development).
 The complete characterization, i.e. Solubility, permeability,
stability, and compatibility testing at pre-formulation stage.
These are driving force for successful drug development –
stable formulation, analytical development & registration
application.
May 26, 2011 36

37. Overall Pre-formulation
Compartments (Prelim)
 Patent Literature / literature searches.
 Physical properties/chemical properties of API.
 Powder characterization.
 Chemical reactivity & forced degradation.
 Excipient compatibility studies.
 Vehicle selection (factorial techniques - QbD).
 Package compatibility.
May 26, 2011 37

38. Overall Formulation Compartments
(Final)
 Formulation development for early safety studies.
 Physical testing of prototype.
 Preliminary process identification.
 Preliminary analytical development.
 Prototype formulations for in-vitro studies (clinical trials).
 Commercial formulation development.
The question based review (QbR) or data on drug development
and analytical development may required for scrutiny during or
after registration of application
May 26, 2011 38

39. Pre-formulation Characterization
Characterizations Techniques and Technical Tests
Heat, Freezing, pH, Light, Agitation,
Accelerated SS
Oxidation, Dehydration, Stress, Shear
Aggregation, Oxidation, Deamidation,
Key Degradation
Stability Studies Cleavage, Surface adsorption, Surface
Products
Stress Denaturation
Stability-indicating HPLC, Electrophoresis, Spectrometry,
assays Particle Count, Turbidity
Primary, secondary, tertiary, and quaternary structures, Thermal
Physical Denaturation Temperature, Solubility, Viscosity, MW, Extinction
Chemical Coefficient, pKa, Solid State Spectroscopy & Analyzers, Salt
Selection, Polymorphs, etc.
Biological Substrate or Receptor Affinity, in vitro Bioassay
Color indicates For Biopharmaceutical Pre-formulation
May 26, 2011 39

40. Why Physicochemical Parameters?
 Physicochemical data used to understand biological data eg
intestinal absorption of drug.
 Drug solubility for absorption and ability of molecule to
permeate barriers for bioavailability are two key properties
must meet BCS and ADMET.
 Parallel attention, not only to Potency, should be given to
Biological (selectivity), Toxicological and Pharmacokinetics
(Activity) towards target.
 Attrition during drug development process is often due to
inappropriate physicochemical characteristics and related
poor pharmacokinetics and poor absorption.
May 26, 2011 40
ADMET – Absorption, Distribution, Metabolism, Excretion and Toxicity

41. Pre-formulation Parameters
Bulk Properties of Excipients & Drug Substances
Fundamental Properties
Crystallinity and Polymorphism
Particle Size, Shape and Surface Area
Secondary Properties
Bulk or Tapped Density
Powder Flowability
Adhesion
Compressibility or Compactability
Visio / Organoleptic
Water Adsorption
Lubricity
May 26, 2011 41

42. Pre-formulation Characterizes
 Solubility
 pKa
 Partition coefficient – Log P
 pH – dependent Log D
 Chemical stability profile
 Crystal properties and polymorphism
 Particle size, shape, surface area
 Specification for New Drug Substances and Products
 Dosage Form Development Chart
May 26, 2011 Daria Jouraleva, ACD Labs 42
http://www.raell.demon.co.uk/chem/logp/logppka.html#Contents

43. Pre-formulation Parameters
Physiochemical Properties of Drug Substances
 Salt selection (salt forms screening, dissociation
constant pKa / ionization state determination).
 Solubility profiles (polar / non - polar i.e. aqueous
/ buffers / organic solvents) and pH dependence
of solubility profile i.e. pH-rate profile.
 Partition Coefficient (pH partition coefficient i.e.
log p or log D), hydrophilicity and lipophilicity.
May 26, 2011 43

44. Pre-formulation Parameters
Physiochemical Properties of Drug Substances
 Crystallization studies (impact on amorphous, particle
shape, size analysis and brittleness).
 Polymorph determination studies (identification,
screening, relative stability – enantiotropy / monotropy,
process design, and scale up to ensure that robustness
of the polymorphic form, dosage method of mixture).
 Drug pKa and stability information.
 Solution and solid state stability.
May 26, 2011 44

45. Preformulation Parameters
Chemical Stability Data Studies
 Chemical stability, accelerated and stress studies (heat /
light / acid / base / oxidizer)
 Stability profile in aq solutions (pH, buffer, solvent,
temperature).
 Hygroscopicity (RH – moisture sorption isotherm
(formation of hydrates / deliquescence) or upon storage
conditions).
 Accelerated stability studies - degradation / degradation
kinetics.
 Thermal properties with and without excipients
 Solid state stability alone and in combination with
excipients.
May 26, 2011 45

46. Pre-formulation Parameters
Combinational Data Studies
 Drug (small molecules) / excipient compatibility studies
(depending on dosage route).
 Aqueous Solubility – solubility / dose ratio?
 Order of addition and identification spectrometrically for
critical process related variables.
 Osmolarity measurements / aggregation phenomena.
 Dissolution methodology (design composition and form
according to acceptance criteria / specifications, dose
and bioavailability).
 Packaging compatibility studies.
 Customer’s risk analysis.
May 26, 2011 46

47. Pre-formulation Instrumentation
Solid State Characterization in Drug Development
 Powder Analyzers – Optical and Laser light (flow /
compaction / density / particle size / surface area).
 BET (Moisture Adsorption / desorption phenomena).
 Microscopy – Light and Polarized (particle morphology).
 Freeze-Drying and Hot-Stage Microscopy (Melting Point)
 Isothermal Heat Conduction Micro-calorimetry.
 Thermal Analysis (DSC, DTGA, TMA).
 Molecular Spectroscopy (FTIR / NIR / Raman / NMR,
LC/MS).
 X-ray Powder Diffraction (XRPD / EDAX).
 Single crystal structure determination.
May 26, 2011 47

48. Why Control Water Activity?
Water interactions with Pharmaceutical Solids
 Water activity (aw) influences solid-state analysis, pre-
formulation, formulation, chemical stability, manufacturing
process (flow, compaction, hardness, coating), dissolution,
product shelf-life properties.
 Materials that have a high capacity for binding water
equilibrate more slowly to higher levels of mobile water and
consequently show greater chemical compatibility with a
moisture-sensitive drug than materials with lower binding
capacities for water.
 Free water has properties of bulk water and hence critical to
chemical and physical stability of DS / DP.
 Bound water (immobile) is not readily available for chemical
interaction with other species.
May 26, 2011 48

49. Why Measure Water Activity?
What is Water Activity in Pharmaceutical Dosage Form?
 Water activity (aw) or Equilibrium relative humidity (ERH) is
a measure of free water (or residual or mobile or unbound
water).
 Water activity (aw) is derived thermodynamically as
a w = f / fo ≡ p / po = ERH (%) / 100
f = fugacity or escaping tendency of a substance,
fo = escaping tendency of pure material
p = vapor pressure of water in material
po = vapor pressure of pure water
 Water activity is a better index for microbial growth than
water content.
May 26, 2011 49

50. Water Activity Limits: Microbial Growth
Water Activity Microorganism
<0.60 No microbial proliferation
0.61 Xeromyces bisporus (xerophilic fungi)
0.62 Zygosachharomyces rouxii (osmophilic yeast)
0.78-0.75 Aspergillus niger/flavus, Halobacterium halobium
Penicillium chrysogenum/glabrum, Paecilomyces variotti,
0.84-0.81
Aspergillus fumigatus
0.86 Staphylococcus aureus
0.90 Bacillus subtilis, Saccharomyces cerevisiae
0.92 Mucor plumbeus, Rhodotorula mucilaginosa
0.93 Micrococcus lysodekticus, Rhyzopus nigricans
0.94 Enterobacter aerogenes
Bacillus cereus, Clostridium botulinum/ perfringens, Escherichia
0.95
coli, Lactobacillus viridescens, Salmonella spp.
0.97 Pseudomonas aeruginosa
May 26, 2011 50
http://www.pharmaquality.com

51. Molecular Pre-Formulation
Scale of Science
POLYMORPHISM
‘When a substance can exist in more than one
physical crystalline state it is said to exhibit
polymorphism’
A Variability Issue in Manufacturing and Stability
May 26, 2011 51

52. What is Active Drug Substance?
■ “Same” active
ingredient = same
active moiety and
same salt or ester
as the brand
product
■ Typically may
differ in
Polymorphic or
other physical
properties
May 26, 2011 52

53. What are Polymorphs?
Chemical Compound ICH Definition
on Polymorphism
Habit Internal Structure
Ordered Disordered
Crystalline Amorphous
arrangement arrangement
Single Entity
Molecular Adducts
Polymorphs
Non - stoichiometric Stoichiometric
Inclusion Compounds Solvates (Hydrates)
Channel Layer Cage (Clathrate)
May 26, 2011 53
Haleblian JK. J. Pharm. Sci. 64:1269-88 (1975)

54. Definition of Polymorphs
“When a solid crystalline substance can exist in more than one
physical state, it is said to exhibit polymorphism” or
“Polymorphs are drug substances that are the same active
ingredient but in different physical forms e.g.
A drug substance with different crystalline forms and a drug
substance with different waters of hydration”
How Different is Different?
Melting point Color
Sublimation point Morphology
Heat capacity Hygroscopicity
Conductivity Solubility
Volume Dissolution rate
Density Chemical stability
May 26, 2011 54

55. Allotropism vs Polymorphism
Property Particles involved Particles combine to form
Allotropism Atoms Molecules or crystals
Polymorphism Molecules Crystals
Example of Carbon “Allotropism”
Diamond Graphite Carbon Nanotube Fullerene 60
May 26, 2011 55

56. Analytical Methodology
Method Data Measured Features
DSC, MDSC Heat flow vs Temperature Phase change during cooling + heating
Change of Mass vs thermodynamics difference during
TGA / DTGA
Temperature dehydration or desolvation
Molecular chemical information,
FTIR Vibrational IR Spectrum intermolecular interactions about solvent,
solvates and quantitation
Complementary information to IR, No /
Raman Raman Spectrum
negligible sample preparation, quantitation
Solid State NMR Magnetic Resonance Chemical interactions, quantitation
X-RPD Diffractogram Quant/ Qualitative analysis of polymorph
Microscopy under light or
Microscopy Morphology, Textural information
electron
May 26, 2011 56
Source: Giron, D Monitoring of Polymorphism Proceedings ISIC, 13-28, 2002

57. Polymorph by Raman Spectroscopy
The Principle of Molecular Vibrational Finger Print Raman
Spectroscopy
Absorbed …Infra Red
Laser Light Transmitted
What will happen?
Scattered …Raman Effect
May 26, 2011 57

58. Raman Scattering
The Principle of Molecular Vibrational Finger Print
Raman Spectroscopy
Scattered
l0 l 1 > l0 l 2 < l0
Excited state
(Virtual)
Light
l0
Dh1
Energy
Dh2 Absorption
Initial state
Rayleigh Scattering Anti-Stokes Raman Scattering
May 26, 2011 Stokes Raman Scattering 58

59. Raman Spectrum of L-Glutamic Acid
1 [cm] 1 [cm]
= -
l0 [nm] l [nm]
Intensity
l0
l2 l1 Some Specific Peaks for α, β form can be seen!
In Dry Powder
Raman Shift [cm-1]
0
May 26, 2011 59

60. Raman & X- RPD in Quantification
Mixed Glutamic Sample
(Pure a-form & Pure b-form)

X-Ray Powder Diffraction
&
Raman Instrumentation
Raman can be used for quantitative analysis (dry powder) directly!
May 26, 2011 60

61. Why Polymorphs so Important?
Effects of Polymorphs on Product’s Quality
POLYMORPHS
Melting Point
 Hygroscopicity
Melting Point
Chemical
Hygroscopicity
Stability
Physical & Chemical Properties Chemical Stability
Physical Stability
Physical Stability
Apparent
Shape of Crystals Stability Solubility Apparent Solubility
Solubility
Dissolution
Dissolution
 
Manufacturability
Quality of Products Manufacturability
Bioequivalence
Bioequivalence
Bioavailability
Fluidity of Dyestuff: Bioequivalence Bioavailability
Powders Colors Bioavailability
May 26, 2011 61

62. Polymorph Screening Approach
Tier1: Isolate crystals from single solvents. Identify binary
systems that offer control of API solubility.
Tier2: Performed controlled crystallizations in miscible /
immiscible binary systems.
Tier3: Perform non-conventional crystallizations (seeding,
vapor diffusion, varied temperatures.
Tier4: Prepare new polymorphs for solution and solid-state
characterization: solubility, stability, hygroscopicity.
May 26, 2011 62

63. What Factors are Important in
Polymorphism?
 Hydrogen bonding ability
 Presence of solvents
 Degree of rigidity or floppiness of a molecule
 Stabilities of low energy forms
In general, in a series of polymorphs of a compound, the
polymorph with the lowest melting point is the most
thermodynamically stable.
May 26, 2011 63

64. Polymorphic Form Conversion
During Manufacturing
Interconversion among polymorphs
 Wet Granulation
Inter-conversions between anhydrates and hydrates,
or between different hydrates
 Spray – Drying
Amorphous form
 Milling / Micronization / Tabletting
Q. Polymorph Appearing and Disappearing?
Q. DS polymorph changes throughout a Stability Testing
Period?
May 26, 2011 64

65. Decision Tree Development on
Polymorphism
 Process for evaluating when and how polymorphs
of drug substances in ANDAs should be monitored
and controlled are:
■ Based on the ICH Guidance Q6A decision
trees on polymorphism
■ Biopharmaceutics Classification System (BCS)
May 26, 2011 65

66. Must Investigate Polymorphism
Application of Decision Trees on Polymorphs
ICH Q6A: Decision Tree Criteria for Polymorphism in DS & DP
 Decision Tree #1. Investigating the need to set acceptance
criteria of polymorphs
 Decision Tree #2. Investigating the need to set acceptance
criteria of polymorphs for drug substance
 Decision Tree #3. Investigating the need to set acceptance
criteria of polymorphs for drug product
 Decision Tree #4.
Part 1- Do multiple polymorphic forms exist?
Part 2 - Is routine polymorph testing of DS valuable?
Part 3 - Is routine polymorph testing of DP valuable?
May 26, 2011 66
http:www.fda.gov

67. Screening Decision Tree # 1
Acceptance Criteria of Polymorphs for DS
No further test or
Are there polymorphic acceptance
known polymorphs NO criteria for drug
START with different apparent substance and drug
solubility? product
Initial Elucidation
of Structure and
other Scientific YES END
Characterization
of the Form (s): Are
all known YES
X-RPD, DSC, TA,
polymorphs highly
Microscopy, and soluble?
Spectroscopy Adequate knowledge of drug
NO substance polymorphs is available by
the time an ANDA is filed
Decision Tree # 2
May 26, 2011 67
http:www.fda.gov

68. Screening Decision Tree # 2
Acceptance Criteria of Polymorphs For DS
Is there a
polymorphic specification NO 1) Different
in the USP? (e.g., polymorphic form
melting point) 2) Allow to establish
tight specification
Decision Tree # 1 YES
Is the USP NO Set new polymorphic
polymorphic specification acceptance criteria for
adequate? drug substance
YES
Set the same polymorphic
acceptance criteria for Decision Tree # 3
drug substance as the USP
May 26, 2011 68
http:www.fda.gov

69. Screening Decision Tree # 3
Acceptance Criteria of Polymorphs For DP
Is
there sufficient No need to set polymorphic
concern that polymorphic NO acceptance criteria for
acceptance criteria for drug drug product
product should be
established?
Decision Tree # 2
END
YES
Next Slide In general, there should not be a concern if
1) The most stable polymorphic form is used or
Continue… 2) The form is used in a previously commercialized
product
May 26, 2011 69
http:www.fda.gov

70. Screening Decision Tree # 3 (contd)
Acceptance Criteria of Polymorphs For DP
FDA BA/BE Guidance: “It is recommended that the
Previous Slide sponsor select the agitation speed and medium that
provide adequate discriminating ability, taking into
account all the available in vitro and in vivo data.”
Does
drug product
YES Set acceptance criteria for the
dissolution testing
drug product dissolution testing
provide adequate controls if
polymorphic ratio
as a surrogate for polymorph
changes? control in the drug product
NO
Set acceptance criteria for the END
drug product using other
approaches, such as solid Dissolution testing can frequently detect
characterization method potential conversion of polymorphs. In rare
cases, solid characterization methods have to
END be used.
May 26, 2011 70
http:www.fda.gov

71. What is it? and How BCS Works?
Allows waiver of requirement for in-vivo
bioequivalence studies for IR products
 The BCS (Biopharmaceutics Classification System) is a
scientific framework for classifying drugs based on their
aqueous solubility and intestinal permeability.
Biopharmaceutics Class Solubility Permeability
Compounds Compounds
I High* High
II ** Low High
III High* Low
IV Low Low
* Highly-soluble substance in a rapidly-dissolving formulation
** If Do Low ~ Highest probability of In vitro / in vivo correlation
May 26, 2011 71

72. Biopharmaceutics Classification System
BCS Examples B
May 26, 2011 72

73. Regulatory Issues : Polymorphism
1. Pre-clinical Drug Development
 Identification
 Early awareness of possible variations in crystalline
form
2. Early Investigational Phases (IND Phase 1 & 2)
 Identification
 Monitoring for possible variations in crystalline form
and solvation
 Increased efforts to find polymorphs and solvates:
"polymorph screen"
May 26, 2011 73
http://www.fda.gov

74. Regulatory Issues : Polymorphism
3. Late Phase Drug Development (IND Phase 3 / NDA
Pre- submission)
 Monitoring the manufacturing process for variations in
crystalline form, including solvates
 Bulk scale-up issues: solvents, temperature, drying,
milling
 Product manufacturing issues: material handling,
granulation, compaction
 Control issues: dissolution, hardness
May 26, 2011 74
http://www.fda.gov

75. Regulatory Issues : Polymorphism
4. Pre-Marketing (NDA Submission and Review)
 Justification of in-process controls on manufacturing
 Consistent crystalline form in clinical and
bioavailability studies
 Stability studies: monitoring for possible changes in
crystalline form
5. Post-Approval
 Influence of manufacturing changes on the product
 New bulk drug suppliers: do they manufacture the
same crystalline form?
May 26, 2011 75
http://www.fda.gov

76. Salt Screening in Preformulation
Why Salt Screening
 Converting poorly absorbable free acid/base (API) form
to a salt form in order to improve solubility and
bioavailability.
 Saltification improves physical and chemical stability
and handleability.
of 21 New Molecular Entities approved by FDA in 2003,
ten were salt forms. Exceptions are out there.
May 26, 2011 76
http://www.cardinal.com

77. Salt Screening in Preformulation
What to be done
 Selection of right counterion functionalities with
optimum physico-chemical characteristics is crucial
during drug development – Physical chemical
properties (solubility, crystallinity, solid state stability,
hygroscopicity) of New Salt Form, Processability
under various manufacturing conditions, and
bioavailability is crucial and significant.
 Analyze by High–Throughput Screening XRPD
Instrument.
May 26, 2011 Follow Decision Tree 77

78. Salt Screening Decision Tree
Green border
indicate
processes
that may
occur in
parallel
Red border
indicate
critical
selection
criteria
May 26, 2011 78
http://www.cardinal.com

79. Salt Screening Decision Tree
CRYSTALLINITY
NO Continue crystallization attempts
Can crystalline salt be
prepared?
YES
HYGROSCOPICITY
YES Unacceptable
Does the salt
deliquesce at high
humidity? ON
Solubility
SOLUBILITY enhancement
NO If necessary
Does the salt Have
aqueous solubility? YES
May 26, 2011 79
Next Slide

80. Next Slide Here
Salt Screening Decision Tree
STABILITY Stability enhancement
NO If necessary
Is the salt physically
stable under
accelerated
YES
conditions?
Lead Candidate
POLYMORPHISM FINAL SALT
Are there multiple NO
polymorphs of the salt
?
YES
SECONDARY
CONTROL
CANDIDATE
NO
Can the process be
controlled to produce Lead Candidate
the desired form? YES FINAL SALT
May 26, 2011 80

81. Potential of Physicochemical Property
Process of Drug Dissolution in a Dosage Form
Formulated Drug Solubilized Drug Absorbed Drug
Kdd Kprecip Kdd = Rate of Disintegration
Drug Particles Kid Kprecip = Rate of Precipitation
Kid = Rate of Intrinsic Dissolution
When Kdd > Kid, dissolution is Intrinsic Dissolution Controlled and physical
attributes of the active pharmaceutical ingredients are Important. When
Kdd < Kid, dissolution is disintegration Controlled and the cohesive properties
of the formulation are important. When Kdd ≈ Kid, dissolution is
Intrinsic Dissolution and disintegration Controlled and both cohesive and
physical properties may be important.
May 26, 2011 81
Source: Cynthia Brown et al Pharma Technology 2004

82. Potential of Physical Property
is the acid-base ionization constant indicating a
pKa molecule or ion is likely to keep a proton at its
ionization centre
is the water – octanol / liposome partition
Log P coefficient indicating a molecule will prefer an
aqueous or organic phase. Log P is a means to
understand relationship between solubility and
permeability with respect to pH
is used for ionizable drugs. It is the ratio of
Log D concentration of all forms (ionized + unionized)
dissolved in the two phases. It is a combination
of pKa and Log P. It produces an apparent
partition coefficient for any pH value
May 26, 2011 82

83. Why is pKa Important?
 Information on pKa reflects molecular state of stability over
the pH range (e.g. stomach and blood pH ).
 Neutral molecules are easily absorbed while ionized
molecule can affect drug-receptor binding pathway.
 Ionized molecules remain in plasma and are cleared by
renal excretion (Ampholytes have special properties).
 Most drug molecules (60-70%) contain Ionizable groups that
ionize in solution. This group belongs to Lipophilicity,
permeability & solubility class are pH dependent – a factor
in drug transport & absorption.
 pKa is required in drug formulation for the choice of counter-
ion and excipients.
 pKa must be recorded for regulatory compliance (either by
Gradient Titrator or Spectroscopic Techniques).
May 26, 2011 83

84. Why is pKa Important?
Distribution of Ionizable compounds (32,437) in World Drug
Index (51,596 compounds) 1999
Combination of ionizable % from above number
groups in the molecule
1 Base, no Acid 42
2 Base, no Acid 25
1 Acid, no Base 12
1 Acid, 1 Base 8
2+ Acid, no Base 3
1 Acid, 2+ Base 4
2+ Acid, 1 Base 3
Others 3
Commercial available drugs are 2/3 ionizable molecules with bases only
May 26, 2011 84

85. Why Log P (Partition) is Important?
Biological membranes are lipoidal in nature, rate of drug transfer for
passively absorbed drugs is directly related to lipophilicity of
molecule. Partition coefficient (water/ octanol or chloroform or
liposome) is a measure of a drug's lipophilicity and an indication of
its ability to cross cell membranes.
The partition coefficient is the ratios between concentrations of
substances in two immiscible phases i.e. organic and aqueous
phases at equilibrium.
Po/w = (C oil / C water) equilibrium
The lipophilic/hydrophilic balance - a contributing factor for the rate
and extent of drug absorption. It is the best predictor of absorption
rate, the effect of dissolution rate, pKa, and solubility on absorption
must not be neglected.
Drugs with Po/w greater than 1 are classified as lipophilic otherwise
are indicative of a hydrophilic drug
May 26, 2011 85

86. Polarity and Partition Relation
 The partition coefficient of a drug depends upon both
polarity and size.
 Drugs with high dipole moment, even though un-ionized,
have low lipid solubility and, hence penetrate poorly.
 Ionization reduces lipid solubility as well as slows down the
movement through charged membranes. (Tip: ionized
molecules do not penetrate membranes. In such cases,
membrane transport carriers that neutralize the charge or
shield the molecule are required for absorption).
 Log P is used in QSAR studies and rational drug design as
a measure of molecular hydrophobicity.
May 26, 2011 86

87. Why is Lipophilicity Important?
The lipophilicity of a drug provides a rough guide to its
pharmacokinetic dynamics
Log D at pH 7.4 Implications for drug development
Intestinal and CNS permeability problems
Below 0
Susceptible to renal clearance
May show a good balance between permeability and solubility
0 to 1
At lower values, CNS permeability may suffer
Optimum range for CNS and non-CNS orally active drugs
1 to 3
Low metabolic liabilities, generally good CNS penetration
3 to 5 Solubility tends to become lower. Metabolic liabilities increase
Low solubility and poor oral bioavailability, although potency may still
Above 5
be high
May 26, 2011 87
John Comer, Sirius Analytical Instruments Ltd

88. Why is Permeability Important?
Permeability, the rate at which a compound
will pass through a membrane
 Permeability (cm/sec) value
depends on the nature of
phases and API molecule
 Permeability of a molecule in
vitro study may relate to
absorbability in body fluid
 A relationship between
permeability and lipophilicity
 Ideal drug candidates fall on
curve
May 26, 2011 88
John Comer, Sirius Analytical Instruments Ltd

89. Why is Permeability Important?
 Drug permeability either by passive diffusion
(natural) or active / facilitated / ion-pair / pore
diffusion or pinocytosis transport
 High permeability is defined as human absorption
of 90% or more of administered dose
May 26, 2011 89
*Source: http://www.health.wits.ac.za/pharmacy/bio-adsorb.ppt#14

90. Why is Solubility Important?
Definition of Solubility
 The amount of a substance (solid) that dissolves in a
given (specified) volume (amount) of solvent (liquid) at a
specified temperature and pH or to form a saturated
solution at any temperature.
Significance of Solubility
 Drug’s physical entity need to be in solution form to
interact with biological systems.
 Active’s solubility is an important parameter for dissolution,
bioavailability, and therapeutic efficacy.
 Poorly soluble molecules rarely constitute successful drug
– difficult to absorb / formulate and analyze.
 It’s difficult to predict accurately - Early screening is vital
May 26, 2011 90

91. Why is Solubility Important?
Significance of Solubility
 Solubility is a property of API and its salt form.
 Solubility is determined by measuring. concentration of
equilibrated saturated solution at 37 ºC for 1 – 24 hrs.
 Equilibrium time depends on test duration time as well as
the physical and chemical stability (conversion of salt form
to free base in vitro) of the drug.
 Low-solubility compounds are compounds whose highest
dose is not soluble in 250mL or less aqueous media from
pH 1.2 – 7.5 at 37 ºC.
May 26, 2011 91

92. Solubility : Discovery vs Development
Solubility in Discovery Solubility in Development
Turbidimetric Solubility Thermodynamic Solubility
Non crystalline Crystalline
Solids not Characterized Polymorphs Characterized
Solubilized in DMSO Solubility measured in term of a solid
Added to stirred gavages medium Equilibrated with an aqueous medium
A time scale measured in tens of A time scale of 24-48 hours
minutes
Used for early in vivo SAR Used to determined the minimum
absorbable dose, dissolution rate, and
salt selection
Correlation with in vivo animal Correction with clinical dosage form
Better in early discovery Essential in development
May 26, 2011 92

93. Solubility at Equilibrium
Solubility of a molecule in solvents (and some oils if the molecule is
lipophilic) is determined by the equilibrium solubility method, which
employs a saturated solution of the material, obtained by stirring an excess
of material in the solvent for a prolonged period until equilibrium is
achieved.
Common solvents used for solubility determination are
Water Tweens Ethyl Alcohol
Polyethylene Glycols Castor Oil Methanol
Propylene Glycol Peanut Oil Benzyl Alcohol
Glycerin Sesame Oil Isopropyl Alcohol
Polysorbates Sorbitol
Buffers at Various pHs
May 26, 2011 93

94. Solubility Assay Methodology
Traditional Shake Flask Assay Method
 Costly, time consuming, polymorphic information required,
good for development
Kinetic Assay Method
 Relatively fast (96, 384 well plate) and automated
 Enhanced solubility and Kinetic due to DMSO
 Crystal lattice energy disappear and high energy state
solution
 Informative about rank of equilibrium solubility
May 26, 2011 94

95. Solubility Solkin Method
May 26, 2011 95

96. Compounds in DMSO
Factors Affect Stability / Solubility in DMSO
 Storage time, Temperature, Concentration, Freeze /
Thawing, Water Uptake
 Once a compound crystallizes from DMSO it will not
easily re-dissolve (crystallized compound is in a lower
energy less DMSO soluble form)
 Freeze thaw cycles increase the probability of
crystallization
 Narrow working window (time window) for keeping
most compounds dissolved in DMSO (1 to 2 days at
room temperature because compounds are active
when freshly made but not when stored
May 26, 2011 96

97. Compounds in DMSO
 Fresh DMSO is highly hygroscopic (5% water in 2hrs)
 DMSO has a high dielectric constant
 DMSO doesn’t solvate hydrocarbons e.g. hexane is
immiscible in DMSO
 DMSO solvates compound dipoles - almost all drugs
have dipoles
 Solvation is easier to do in DMSO than in water - no H-
bond donor / acceptor networks to disrupt
 DMSO containing 9% water is unfrozen in the typical
lab refrigerator
 Compounds Differ in DMSO Solubility Based on
Crystalline Form - Amorphous is the highest energy
form (most soluble in DMSO lowest melting point)
May 26, 2011 97

98. Solubility Kinetic Method

Kinetic
Solubility
 
May 26, 2011 98

99. Drug Solubilization: Decision Tree
May 26, 2011 99

100. Chemical Stability Profile
 Solid-State Stability
Elevated temperature Studies
Stability under High-Humidity Conditions
Photolytic Stability
Oxidative Stability
 Solution-Phase Stability
Light Stability
Oxidation
pH-Rate Profile
 Compatibility Studies: Stability in Presence of Excipients
Thin-layer chromatography
Differential thermal analysis
Diffuse reflectance spectroscopy
 Typical Stability Protocol for a New Chemical Entity
Next Slide….
May 26, 2011 100

101. Chemical Stability Profile
Stability Testing of New Drugs and Products
General Case for Drug Substances
Study Storage Conditions Minimum Time Period at Submission
Long Term 25 °C ± 2 °C / 60% RH ± 5% RH 12 months
Intermediate 30 °C ± 2 °C / 60% RH ± 5% RH 6 months
Accelerated 40 °C ± 2 °C / 75% RH ± 5% RH 6 months
Drug Substances Intended for Storage in a Refrigerator
Study Storage Conditions Minimum Time Period at Submission
Long Term 5 °C ± 3 12 months
Accelerated 25 °C ± 2 °C / 60% RH ± 5% RH 6 months
Drug Substances Intended for Storage in a Refrigerator
Study Storage Conditions Minimum Time Period at Submission
Long Term -20 °C ± 5 °C 12 months
May 26, 2011 101

102. Chemical Stability Profile
Stability Testing of New Drugs and Products
General Case for Drug Products
Study Storage Conditions Min. Time Period at Submission
Long Term 25 °C ± 2 °C / 60% RH ± 5% RH 12 months
Intermediate 30 °C ± 2 °C / 60% RH ± 5% RH 6 months
Accelerated 40 °C ± 2 °C / 75% RH ± 5% RH 6 months
Aqueous Based Products Packaged in Semi-Permeable Containers
Study Storage Conditions Min. Time Period at Submission
Long Term 25 °C ± 2 °C / 40% RH ± 5% RH 12 months
Intermediate 30 °C ± 2 °C / 60% RH ± 5% RH 6 months
Accelerated 40 °C ± 2 °C / NMT 25% RH 6 months (water loss after 3 months)
Aqueous Based Drug Products intended for Storage in a Freezer
Study Storage Conditions Min. Time Period at Submission
Long Term -20 °C ± 5 °C 12 months
May 26, 2011 102

103. Chemical Stability Profile
Stability Testing of New Drugs and Products
Aqueous Based Drug Products intended for Storage in a Refrigerator
Study Storage Conditions Min. Time Period at Submission
Long Term 5 °C ± 3 °C 12 months
Accelerated 25 °C ± 2 °C / 60% RH ± 5% RH 6 months
Relative Humidity Ratios Calculation
Alternative Humidity Nominated Humidity Ratio
40% RH 25% RH 2.4
60% RH 40% RH 1.5
75% RH 25% RH 3.0
May 26, 2011 103

104. Permeability Assay Methods

  PAMPA - Parallel Artificial Membrane
Permeability Assay: Same size
chamber separated by filter coated
with lipid in organic solvent
 Results vary if lipid selection varies.
 Easy and results are comparable
with Caco-2
 Coco-2: Different compartmental
volume separated by a monolayer of
cells grown on a filter.
 Stable monolayer preparation time
and cost consuming.
 Results agree with human in vivo
 jejunal permeability experiments
May 26, 2011 104
http://pubs.acs.org/subscribe/journals/mdd/v06/i01/pdf/103toolbox.pdf

105. Drug Delivery : Solid Dosage Forms
Molecular Transport and Cellular Controlled Diffusion
Dosage
Form
Drug
Drug
Disintegration In
GI Membrane
Absorbed
Dispersed
Granules
Dissolution
“Solution”
into
in
Dispersion Systemic
Primary Drug
GI
Particles
Circulation
Media
May 26, 2011 105
Modified from Michael J. Hageman, Pfizer Global R&D, NJ, USA

106. Permeability Assay Methods
≈? K
D
≠?
≡? C0
Donor
solution
Cd C1 h
Cr
Donor C2
Receptor
Do excipients alter or affect permeability / Absorption?
May 26, 2011 106

107. Drug Diffusion
May 26, 2011 Anand Sistla in Mol. Dev. Intern Symp 2003 107

108. Solubility Decision Trees
Solubility? ?
300
low high
200
? 100
Dose? ?
<200 >200
0
High Low
?
May 26, 2011 108

109. Basic Powder Properties
May 26, 2011 109

110. PSD for DS : Decision Tree
Is the drug product a solid dosage form NO
or liquid containing un-dissolved drug
No drug substance
substance?
particle size
acceptance criterion
YES
required for solution
1. Is the particle size critical to dissolution, dosage form
solubility or bioavailability?
2. Is the particle size critical to drug If NO to All
processability?
No acceptance
3. Is the particle size critical to drug product
criterion required
stability?
4. Is the particle size critical to drug product
content uniformity? If YES to All
5. Is the particle size critical for maintaining Set Acceptance
product appearance?
Criterion
May 26, 2011 110
ICH Q6A : Particle Size Distribution (DS) Acceptance Criteria

111. Influence of Particle Size Reduction
on Material Characteristics
 Homogeneity – Increases
 Crystallinity – Decreases
 Bulk density – Decreases
 Flow characteristics – Worsens
 Solubility – Increases
 Reactivity – Increases
 Taste – Increases
 Explosiveness – Increases?
May 26, 2011 111
Source: Elizabeth B Vadas Inscitech Inc

112. Drug Excipient Interactions
Effect on Dissolution, Solubility and Stability
 Processing factors – Micronization, grinding, milling, spray
drying, lyophilization, compaction force.
 Physical factors – Temperature, humidity, and pressure.
 Chemical factors – Solvation (Formation of agglomerates,
inclusion complex and hydrophobic film.
 Dissolution in vivo will not likely to be rate limiting, if
excipients are well characterized under various conditions.
High permeability attribute reduces the risk of bio-in-
equivalence.
The changes in drug structure and dynamics over time needs
to be verified by solid-state NMR, FTIR, Raman, X-ray
diffraction, and DS calorimetric techniques.
May 26, 2011 112

113. Brodie’s pH Partition Theory
Biophysical Significance of Theory in ADMET
Solvation – Ionization – Diffusion - Receptor – Interaction
 The pKa of the drug and pH of the GI tract fluid and the pH
of blood stream control the solubility of drug i.e. rate of drug
transfer or absorption through membranes
 Only non-ionized drug get through lipid membrane i.e.
unionized drugs have higher lipid solubility
 Brodie’s distribution is related to Henderson - Hasselbach
equation for weak acids and bases
 Ci   Cu 
pKa  pH  log   for bases pKa  pH  log   for acids
 Cu   Ci 
Henderson - Hasselbach Equation
May 26, 2011 113

114. Package Compatibility
 Types of packaging systems – storage, shipping, or
marketing.
 Applicable cGMPs – equipment construction,
qualification applies regardless of holding time.
 Description information – construction material, label
information.
 Suitability information – protection, compatibility,
safety, performance.
 Quality control information – chemical composition,
physical characteristics, acceptance criteria.
 Stability information – shelf life stability, expiration
date, CMC documentation.
May 26, 2011 114

115. Thank You
May 26, 2011 115

116. “If we can’t describe scientifically and technologically what we are
doing as a process, we don’t know what we’re doing”
May 26, 2011 116