FDA-research Related To Formulation & Pharmaceutical Product Stability

Research Related to Formulation and Pharmaceutical Product Stability
Advisory Committee for Pharmaceutical Science and Clinical Pharmacology April 14, 2010 Mansoor A. Khan, R.Ph., Ph.D.
CDER/OPS/OTR/DPQR
Stability
Drug substance and products could degrade by oxidation, hydrolysis, racemization etc. Factors such as temperature, humidity, light, pH, ionic strength, buffer strength, residual metals could enhance the degradation. It is expected that a well designed formulation and packaging protects the product from degradation
2 Mansoor Khan, FDA ACPS 2010
Stability Testing
Once a product is designed and developed, the stability of a finished product is required to be demonstrated for the shelf-life of a product Shelf life refers to the time for which the drug product retains the quality specifications Depending upon the clinical consequence, the Agency might tighten the potency/strength requirement- e.g. levothyroxine
Stability
If a product is stable for two years, a sponsor doesnt have to wait for that time to market a product with two years expiration dating. It can do stability studies in exaggerated/accelerated conditions of temperature and humidity (e.g.. 40C/75%RH) and get an ESTIMATE of real time stability The ESTIMATED/TENTATIVE shelf-life is backed by real time stability studies at controlled room temperature
Accelerated Stability Studies - Theoretical

Products degrade at various rates, e.g.. 0-Order, 1st Order, 2-nd Order. Co ln = k 25 * ShelfLife C
% Drug Remaining
37 oC 45 oC 55 oC 60 oC
We need Ea values
k1 E a T1 T2 ln = k2 R T1T2
TIME
We may able to use microcalorimetry or other methods for Ea Know the limitations of Ea
Mansoor Khan, FDA ACPS 2010
Ea ln k 25 = LnA RT
5
Current Stability Requirements

25C/60%RH, 40/75%RH and if necessary, 30/65%RH For SLEP Program, the conditions are 25/60%RH and 50/75%RH We may able to use microcalorimetry or other methods for Activation Energy
Solution state kinetics Solid state kinetics Other physical attributes

Stability indicating
HPLC, LC-MS, GC, GC-MS etc. Validation Analytical Methods
API Reaction Rate Order
Temperature
Moisture Environment & pH Formulation Light Factors Ionic strength Buffer conc. Dielectric constant Degradation mechanism
Oxidation
QBD studies and Shelf-life predictions
Stability
Product degradation studies

Physical attributes
Drug-Excipient interactions Packaging variable studies

Hydrolysis Reduction Decarboxylation Racemization Deamination Dehalogination
chemical degradation Activation energy determination
DSC, TgA, MicrocalorimetryHPLC, MS
studies etc to justify the use of excipients
Stability Test Attributes in Shelf-Life Extension Program

Solid Orals Potency Assay Impurities Dissolution Water Content Appearance Powders Potency Assay pH Water Content Appearance Injectables Potency Assay Impurities Preservatives pH Appearance Color Particulates Creams/Ointments Potency Assay pH Appearance Separation
8
Lyon et. al., J. Pharm. Sci., 2006, 95, 1549-1560.

SUMMARY

Results from 3005 lots (122 drug products) were evaluated. 88% of the lots were extended for an average of 66 months past the original expiration date. Of the 2650 lots extended, 18% were eventually terminated due to failure. The rest are still active or discontinued by the military. 40 Drug Products showed no signs of stability failure (at least 5 lots of each tested). 10 Drug Products were unstable with most lots failing initial extension.
9
120
Results: Example of Variability

Dormant Impurity Failure pH Recrystallization Failure Still Active
Length of Extension (months)
96
Diazepam Injectors
72
Average extension 54 months
48
24
0 A B C D E F G H I J K L M N O P Q R S T U V W X Y 10
Lot Designation
Example: Real-Time Stability

120
Diazepam Assay Test Results

HPLC Assay (% of Label)
110 Regression Line Test Results Limit Line 100
90
80 0 12 24 36 48 60 72 84
11
Time in Program (Months)

Repackaged Product Stability

Original packaging tablets Time 0 Original packaging tablets Stored at 25C 60%RH for 4 Weeks
Original packaging tablets Stored at 40C 75%RH for 4 Weeks
Repackaged tablets Stored at 25C 60%RH for 4 Weeks Repackaged tablets Stored at 40C 75%RH for 4 Weeks
Yang et al., Int. J. Pharm., 385, 92-97, 2010.
Levothyroxine Research
I
400 300
Peak area (mAU) Tyr The MIT DIT
I I I Levothyroxine structure
T0
T2
T3
200 100 0 -100 -200
T3AA 20
10
15
25
T4AA
T4
30
100 75 Weight (%) 50 25 0 0
Peak area (mAu)
P CP SSG A CCS CS CSD MCC
Time (min)
2000
1000
T4AA API T3AA
25
50 RH (%)
75
100
0 0 10 Time (days) 20 30
Shah RB et al. International Journal of Pharmaceutics, 360:77-82, 2008 Collier J etal. AAPS PharmSciTech, 2010, in press
13
Presentations in this Session

Pharmaceutical Stability: CMC Review Perspectives by Dr. Stephen Miller, ONDQA Predicting Product Stability During Process Development and Scale-Up by Dr. James Drennen NIPTE Opportunities to Modernize Pharmaceutical Stability Evaluation by Dr. Lee Kirsch NIPTE
Pharmaceutical Stability: CMC Review Perspectives

Stephen P. Miller, Ph.D. Branch Chief (acting) Office of New Drug Quality Assessment CDER / FDA
Advisory Committee for Pharmaceutical Science and Clinical Pharmacology April 14, 2010
1
Overview
Regulation & Guidance
IND Phase NDA Phase
Purposes and Practices Gaps Looking Forward Conclusions

2
Stability Requirements for INDs Code of Federal Regulations

CFR 312.23 (a)(7)(iv)(a): .and information sufficient to support stability of the drug substance during the toxicological studies and the planned clinical studies CFR 312.23 (a)(7)(iv)(b): and information sufficient to assure the products stability during the planned clinical studies
3
Stability Guidance IND

FDA Guidance for industry: Content and format of investigational new drug applications (INDs) for phase 1 studies of drugs, including well characterized, therapeutic, biotechnologyderived products
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInfor mation/Guidances/ucm074980.pdf
FDA Guidance for industry: INDs for phase 2 and phase 3 studies. Chemistry, Manufacturing and Controls information
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInfor mation/Guidances/ucm070567.pdf
4
Stability Regulations - NDA

CFR 314.50(d)(1)(i): Drug Substance - A full description of the drug substance including its physical and chemical characteristics and stability CFR 314.50(d)(1)(ii)(a): Drug Product - stability data with proposed expiration dating CFR 211.137(a): To assure that a drug product meets applicable standards of identity, strength, quality, and purity at the time of use, it shall bear an expiration date determined by appropriate stability testing described in 211.166 CFR 211.166: There shall be a written testing program designed to assess the stability characteristics of the drug products
5
Stability Guidance - NDA

Guidance for Industry: ICH Q1A(R2)-Stability testing of new drug substances and products Guidance for Industry: ICH Q1B-Photostability testing of new drug substances and products Guidance for Industry: ICH Q1C-Stability testing for new dosage forms Guidance for Industry: ICH Q1D-Bracketing and matrixing designs for stability testing of new drug substances and drug products Guidance for Industry: ICHQ1E-Evaluation of stability data
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/ Guidances/default.htm 6
Purposes for Stability Studies: Early Developmental Studies

Rational Formulation Appropriate Packaging
Identify chemical or physical interactions with excipients Understand need for protection from moisture, oxygen, etc. Understand photostability Identification of degradation pathways
Stress studies (thermal, pH extremes, oxidation) Select analytical procedures that can detect potential degradants
(Stability-Indicating Method)
7
Purposes for Stability Studies: Formal Stability Studies

Commercial product equiv or better than clinical studies
Assurance of efficacy (assay) Assurance of safety (degradant levels)

Toxicological Qualification of degradants at anticipated maximum level of exposure
Establish appropriate storage conditions Determine expiration dating period Assurance of safety and efficacy during use by patients
In-Use studies; length and conditions according to expected use
Resuspendability / dosing accuracy for suspension Thermal cycling (e.g., emulsions, dispersions)
Batch Selection per ICH Q1A

Drug substance # and size of batches Manufacturing and Container/ closure (CC) 3 batches, at least pilot scale Representative of proposed commercial material (same synthetic route) Stored in CC same as, or simulates, that proposed for commercial storage Drug product 3 batches, 2 at least pilot, one can be smaller with justification Manufactured using different DS batches Formulation, CC and manufacturing representative of commercial product Represent each strength and CC unless bracketing/matrixing applied
Additional
Any supportive batches. Any supportive batches.

9
Drug Product Stability Studies per ICH Q1A

Proposed Study Type Storage
Long term Controlled room temp. Intermediate Accelerated Refrigerator Long term Accelerated Freezer Long term
Storage Condition
25C 2C / 60% 5% RH 30C 2C / 65% 5% RH 30C 2C / 65 5% RH 40C 2C / 75% 5% RH 5C 3C 25C 2C / 60 5% RH -20C 5C
Time
12 months
6 mo (of 12) 6 months 12 months 6 months 12 months

10
Stability Commitments
Provide appropriate post-approval stability commitment so that a total of three commercial batches have acceptable long-term and accelerated stability data to confirm the assigned expiration period Annual stability commitment
Provide commitment to put one annual batch of each marketed strength in each packaging configuration (unless bracketing/matrixing is proposed) on longterm stability
Report stability failures for the marketed batches as per 21CFR314.81(b)(1)(ii)

11
Gap Analysis
Without sufficient product knowledge
Unanticipated stability issues may occur Usually encountered and resolved during IND Can delay approval or impact availability
Drug development incorporating QbD

Considers intrinsic stability of drug substance Selects formulations to improve or maintain stability in the dosage form
12
Risk-Based CQAs
Example : The Levothyroxine Story Narrow therapeutic index; low dose; multiple tablet strengths (25-150 g); intermediate strengths separated by 10% of dose Marketed without approved NDAs prior to 2000, many with overages due to stability issues Many products approved since 2000 showed
History of sub-optimal stability profile Significant loss (5-10%) of potency over shelf life Inconsistent stability profiles within an individual manufacturers drug product line
13
Risk-Based Regulatory Approaches

Current NDA/ANDA specification and USP monograph permit assay of 90 to 110% labeled claim Theoretically, a tablet can degrade to contain less levothyroxine than a lower strength tablet Levothyroxine is labile to heat, moisture, oxidative conditions, chemical reactions
Apply science & riskbased approach

Understand factors affecting stability Design formulation and process to minimize degradation Tighten assay limit to 95-105% to ensure efficacy
14
Conventional versus QbD Approaches

Reduce expiration Change packaging Reduce storage temperature Reformulate and begin stability studies again Drug recalls and compliance challenges Possible negative impact on availability Understand DS stability
solid-state form(s)
Formulate to meet quality target product profile [QTPP, ICH Q8(R2)] Maximize expiry
Earlier start on primary stability studies
Incorporate knowledge from commercial experience Assure quality and availability for patients
15
Developments Underway
HL-7 [Health Level 7]
(http://www.hl7.org)
Developing standards for health care information Goal: Standardized model for stability data
XML-based approach based on model created by FDAs Jon Clark & Naiqi Ya Industry-FDA working group established to test standard and associated Implementation Guide
Zeneth (https://www.lhasalimited.org/index.php/vitic/FDA_Vitic/)
Goal: Predicting degradation pathways
CDADA (Cooperative Research and Development Agreement) with CDER and CFSAN
16
Conclusions
Many appropriate regulatory and scientific tools are available for understanding stability of drug substances and dosage forms Drug development based on QbD principles should:
increase assurance of quality including stability avoid surprises during IND development
17
18
Predicting Product Stability During Process Development and Scale-Up
James K. Drennen, III, Ph.D. Associate Dean, Research and Graduate Programs Duquesne University Graduate School of Pharmaceutical Sciences
What is NIPTE?
NIPTE is a multi-university nonprofit organization federally funded to address fundamental research and education on the science of pharmaceutical development & manufacturing. NIPTE will develop new science & engineering to create a paradigm shift in how pharmaceutical products are designed, developed and manufactured after the new molecules are discovered.
Duquesne University Illinois Institute of Technology Purdue University Rutgers University University of Puerto Rico University of Connecticut University of Iowa University of Kansas University of Kentucky University of Maryland University of Minnesota
NIPTE Scope
Discovery of New Molecules
Product Development
Manufacturing
Safety & Clinical Studies
NIPTE Scope
FDA Project: Development of QbD Guidance Elements on Design Space Specifications across Scales with Stability Consideration
Project Objectives
Improve pharmaceutical product quality, maximize process innovation & continuous quality improvements, and reduce manufacturing costs by developing:
QbD guidance elements on process design space, scale-up and process validation Framework for optimizing design space specifications across scales with considerations to stability
Unit Operations Team

High Shear Granulation
Purdue
Initial Development and Regime Map Characterization
Blending
Duquesne
PAT: Online NIR Method Development Process Optimization (DOE)
Duquesne
Granulation Transfer Process Optimization (DOE)
Rutgers
Final Blend Characterizations
Fluid Bed Drying

Duquesne
Hybrid Control (Thermodynamic and PAT) Process Optimization (DOE) Scale-up Experimentation
Tablet Compression
Rutgers
Small Scale Compression Optimization
FDA/University of Maryland
Full Scale Tablet Feasibility/Optimzation
Illinois Institute of Technology (IIT)

Computation Fluid Dynamics (Optimizing Scale-up DOE)
Note: Abbott is scale-up partner

Lab Scale to Pilot Scale Pilot Scale to Full Scale
OH
Case Product Formulation

Gabapentin: crystalline, anhydrous, form II;
Intra/ Extragranular
Intragranular Intragranular
NH2
Material
Gabapentin Hydroxypropylcellulose
Function
API Syntheticbinder,addedto promotecohesiveness, drymixingbeforeadding water Disintegrant Disintegrant Lubricant Diluent Glidant Syntheticbinder
Amount
600mg 40mg
Crospovidone,NF Pregelatinizedcorn starch,NF Magnesiumstearate,NF
Extragranular Extragranular Extragranular
22mg 60mg 7mg 100mg 9mg 40mg
Microcrystallinecellulose, Extragranular NF(AvicelPH102) Talc,USPExtrafine Hydroxypropylcellulose Extragranular Extragranular
Basic Processing Sequence
Binder
Excipients
Lubricants
API
Wet Granulation
Fluid Bed Drying
Blending
Tabletting
Key Technical Issues

Stability
Analytical methods to detect degradation products Understanding of degradation factors & conditions Processing induced stresses favorable to degradation Long term stability factors
Design Space Development

Risk assessment of product & manufacturing process Determination of critical quality attributes for product & intermediates Development of on-line sensing protocols Model assisted development of unit & process design spaces Prediction of effects of scale-up on design space Confirmation via laboratory & larger batch experiments
Scope of Activity
Characterization of gabapentin:
Chemical & physical characterization of gabapentin Development of stability-indicating analytical methods Studies of degradation products & conditions Determination of CQAs of intermediates and final product via multistage FMEA Review & identification of relevant models & scale-up relations Granulation trials to confirm base formulation & nominal processing conditions Scoping experiments to confirm processing scheme Definition & implementation of on-line instrumentation for tracking CQAs and controlling end points Design of lab scale experimental program for processing line Completion of lab scale manufacturing
Risk Assessment:
Unit-operations:
Scope of Activity
Modeling:
Use lab scale data to evaluate /improve model fidelity Use model-guided experimental program to define design space for unit ops and process Execute larger batch experiments to confirm capability to translate design space under scale-up Analysis of larger batch experiments to confirm design space provides assurance of stability under processing Execute selected experiments demonstrating approach to design space refinement with additional data Complete shelf-life stability studies Report results & formulate guidance elements
Scale-up:

Design Space Refinement:

Provide Guidance Elements:
Stability Investigation
Development of physical & chemical property base for API
Identification of forms Full range of analytical tools: SSNMR, Raman, DSC, TGA, XRD, BET, Water vapor sorption, HPLC
Development of stability indicating methods & protocol for processed material (HPLC) Studies of degradation products & conditions
API degradation produces lactam (limit 0.5%) Temperature, processing stress, humidity
Preliminary studies of longer term stability issues

Observation of some anomolous behavior
See paper 166d
Anomalous Behavior
2
2
Details reported at 2009 AAPS mtg
sealed % la c ta m (m o la r)
% lact am ( m o lar)
1.5
1.5
31% RH
0.5
sealed
0.5
47% RH 74% RH 81% RH
31% RH 47% RH 74% RH 81% RH

0 20 40 60 80 100
0 0 20 40 60 80 100
Hours
Hours
Lactam formation for milled API (45 min) stored at 50C at various humidity environments
Lactam formation for milled API (15 min) stored at 50C at various humidity environments
Lactam formation decreases with increasing relative humidity Effect greater for longer stress times ( milling)
Determination of CQA
Establish quality Target Product Profile Identify Critical Quality Attributes (product,
substance & excipients)
Develop Ishikawa (cause & effect) diagrams for product CAQs Identify process variables key to stability Develop FMEA analysis Establish critical process parameters & CQAs for intermediate materials
Ishikawa
Cause & effect diagram for chemical stability CQA
Unit Operations Models

Intensive assessment of literature completed Identified approach appropriate for each unit operation
Response surface model Dimensionless variable modes Semi-empirical /reduced order model Rigorous simulation model
Preliminary assessment of appropriate scale-up methodology

Dimensionless quantities Similarity rules & tests Rigorous simulation
Preliminary experiments
Gabapentin + HPC
1.9 %
25.00
28.5 g
3.8 %
5.7 %
20.00
Mass%
57.1 g 85.7 g
15.00 10.00 5.00 0.00 10
100 Particlesize( m)
1000
Figure 3. The effect of binder liquid content on the size distribution of the Gab+HPC granules. The label shows the total amount of water added to the system
Microscope image of granulated gabapentin + HPC
APPROACH
Nucleation regime map

10 Hapgood, Litster & Smith, AIChE J, 49, 350-361, 2003
Spray Flux
& 3V a = & 2 Ad d
Drop . Pen .Time Drop Penetration Time p = 1 .35 V
2/3 drop 2
LV . cos
R eff eff
Growth Regime Map

1.0E+1
Iron Ore in M ixer
1.0E+0
U / 2Y (-)
Na2SO4 in M ixer
Tardos et al . (1998)
Crumb Steady Growth

Iron Ore in Drum
1.0E-1
Ballotini & PEG in M ixer
Induction Nucleation Steady Grow th Rapid Grow th
St def =
1.0E-2 Nucleation Region 1.0E-3

Ballotini & Glycerol in Drum Ballotini & Water in Drum Chalcopyrite in Drum
Rapid Growth
Induction 0.800 1.000 1.200 1.400
1.0E-4 0.600
Stokes Max Pore gU 2 w s (1 min ) ; S = Deformation St def = Saturation

2Y
Pore Saturation (-)
l min
High Shear Wet Granulation Studies

Comparison of PSDs Produced at Purdue and Duquesne The transfer of the high shear wet granulation process from Purdues Diosna (bottom driven) system to Duquesnes GEA (top driven) system was successful based on similar particle size distributions. The regime map characterization by Purdues team allowed this process to be completed in only 4 experiments.
Purdue Granulation; 2.0% H2O
2.0% H2O; 2 M in We t M as s 30
DCPT Granulation; 2.0% H2O
25
20 M a s s%
15
10
0 < 63 63-88 88125 125177 177250 250354 354500 500707 7071000 > 1000
Size Fraction (um )
Scale-up Suggestions
Scale impeller speed with constant tip speed and constant shear rate rules provided that the impeller speed is above the critical Froude number (Fr). The change from bumping to roping flow occurs at 250 rpm at the smallest scale, then the impeller speeds at the critical Fr number for the other scales will be calculated with the following equation: N2 D1
N1 = D2
where N is the impeller speed and D is the impeller diameter. Impeller speed for constant tip speed rule will be calculated with the N 2 D1 following equation: = N 1 D2 Impeller speed for constant shear stress rule will be calculated with 0. 8 the following equation: N2 D1
= N 1 D2
The spraying time and the dimensionless spray flux will be kept constant
4l BatchSize(kg) Wateramount(g) Waterflowrate(g/min) 0.6 30 15
10l
75l
1.8 90.9 45.5
17.7 883.6 441.8
Ratio of fill height to granulator diameter at all three scales should be same.
4l BatchSize(kg) Diameterofthegranulatorbowl(cm) Fillheight/Diameter 0.6 17 0.27
10l
75l
1.8 24.6
0.27
17.7 52.5
0.27
Fluid Bed Instrumentation & Control

Duquesne Installation
Fluid Bed PAT scheme Pressure drop across
bed to control air flow NIR for granule moisture control end point Model based EEF factor to control inlet air T Control software: Emerson Delta V
Hybrid Controls (First-Principles and Empirical)

Establish a thermodynamic environment inside the dryer that ensures a constant drying mechanism and product properties.
Manages environmental fluctuation by adjusting process parameters that are easily controlled to maintain a constant drying environment
Uses empirical measurements to define meaningful phase endpoints and observe process changes quickly. The first-principles modeling enables the reduction of input variables for efficient experimental designs.
The thermodynamic environment variable (environmental equivalency factor (EEF)) accounts for 4 of the input variables (airflow, input temperature, environmental humidity, starting material moisture content) to reduce the necessary number of experiments.
The thermodynamic environment is directly scaleable. (Theoretically)
Environmental Equivalency Factor

A single calculated value that represents the environmental condition in the bowl at which the process take place 2 mechanisms control drying
Heat Transfer driven by temperature Mass Transfer driven by differences in vapor pressure
Mpw Mp [ ]htg RTw RT AH = AM C p (T TB )
EEF is equal to the ratio of the heat-transfer surface area to the mass-transfer surface area
Regressed against quality attributes. Potentially useful scale factor
1Ebey
GC. 1987. A thermodynamic model for aqueous film-coating. Pharmaceutical Technology 11(4): 40-50.
Hybrid Controls
EEF Input Factors over a Drying Run 90 80 70 60 Process Units 50 40 30 20 10 0 -10 0 200 400 600 800 1000 1200 Time (sec.) 1400 1600 1800 2000 Inlet Temperature Product Temperature Outlet Temperature Inlet Humidity Outlet Humidity Airflow Velocity Spray Rate Environ. Temp. (Inlet) Environ. Temp. (Outlet)
The EEF Calculation over a Drying/Cooling Run 25

100
Inlet Air Temperature to Control EEF over a Drying Run
5 EEF 0 -5 -10 -15
X: 410 Y: 0.1916
Temp. Calc
Temperature (oC)
EEF Calc. 10
1 .
20 15
Cooling Begins
90 80 70 60 50 40 30 20
-20 -25 0 200 400 600 800 1000 1200 Time (sec.) 1400 1600 1800 2000
200
400
600
800 1000 1200 Time (sec.)
1400
1600
1800
2000
NIR Reflectance Spectra from an FBP Drying Run 1.4

6
Drying Run Moisture Profile
1.2
Predicted Moisture Content (%)
Absorbance
0.8
PLS
0.6
0.4
2 .
0.2
0 1000
1200
1400
1600 1800 Wavelength (nm)
2000
2200
2400
200
400
600
800 1000 1200 Time (sec.)
1400
1600
1800
2000
1. The thermodynamic (EEF) calculations use 9 input variables to predict the necessary inlet air temperature to maintain a constant drying environment. 2. The NIR spectra are used to identify a moisture endpoint for drying.
Hybrid control modeling is used to control the drying process PAT defines phase endpoints and enhances process understanding
CFD Modeling
Simulated three different particle size
150 micron, 225micron, 350 micron (Inlet velocity: 0.876m/s, Auxiliary: 0.03m/s)
Umf =0 .067m/s Ut = 1.12m/s
Umf =0 .143m/s Ut = 2.03m/s
Umf =0 .312m/s Ut = 3.24m/s
1s
2s
3s
4s
5s
6s
Summary
NIPTE project to enable framework for optimizing design space specifications across scales with considerations for stability Risk-based development and manufacturing is possible improve pharmaceutical product quality maximize process innovation continuous quality improvements reduce manufacturing costs
Thank you!
Opportunities to Modernize Pharmaceutical Stability Evaluation and Prediction

Lee E. Kirsch University of Iowa National Institute of Pharmaceutical Technology and Education
lee-kirsch@uiowa.edu (4/14/10)
The Pharmaceutical Stability Predicament

Manufacturing stress Storage stress Shipping stress Product use stress
catastrophic Probability of failure (multimodal gradual
Performance Drug release kinetics Potency Safety Utility Acceptability
critical failure
stable
Accumulative stress and time

Current and Future Paradigm

Deterministic
stable or not
Stochastic
based on probability
Measurability-based
significant change based on detection
Performance-based
significant change based on performance
Impact arbitrary
historical rather than situational-based
Therapeutic impact
evaluation of the effects dose regimen, patient population, in vivo performance on stability limits
Prediction based on post-assembly stress

storage environment and time
Prediction includes design, assembly and post-assembly stress
Research Opportunities
Designofmodelstolinkdesignspacestabilityto clinicalperformanceinrelevantpatientpopulations basedonintendedtherapeuticuseregimens Methodologiesforincorporating designspacemodelsintostability predictionmodels
Future state
Toolstoassemblescientificallyrational stabilitydesignspacemodels Fundamentalphysicalandbiophysicalstudiesof exemplarydruginstabilityprocessesincomplexsystems
Current state
Overarching objective: integrating stability in QbD

1.Physical and Chemical Markers 2. Design Space Model
L0&F0
3.Post-Manufacturing Degradation Model

Lt
4. Therapeutic Utility/Safety Model

NIPTE Project Team for Gabapentin Case Study

Research H.Arastapour,ChE,IIT
Fluidization&multiphasesystems
J.Litster,ChE&IPPH,Purdue
Granulation&PowderTechnology
E.Munson,PhSci,Kansas
Characterizationofsolidpharmaceuticals
R.Bogner,PhSci,UCONN
Drugrelease,soliddosageforms
F.Muzzio,ChE,Rutgers
Powdermixing&flowbehavior
A.Cuitino,ME,Rutgers
Materialmechanics,Multiscale modeling
G.Reklaitis,ChE,Purdue
Processsystemsengineering
J.Drennen,PhSci,Duquesne
PATandRiskManagement
R.Suryanarayanan,PhSci,UMinn
Materialscienceofpharmaceuticals
S.Hoag,PhSci,Umaryland
compressionmodeling
M.Khan,PhSci,FDA
PharmaceuticalTechnology
NIPTEAdministration P.Basu,ExecDirector,NIPTE
QbD&Pharmaceuticaleconomics
L.Kirsch,PhSci,Iowa
Drugstability&quality
V.Gurvich,AssocDirector,NIPTE
Medicinalchemistry&organictechnology
1. Exploring the molecular basis for instability

case study: gabapentin
gabapentin Form I:hydrate

Chemically stable Desolvates
gabapentin-lactam Form II: API

Chemically & physically stable
Form III
Less chemical stability and readily converts to Form II
Physical and Chemical Probes

Method NIPTE/FDA project assignment Kansas Minnesota Minnesota Iowa
1 2 3 4
SolidStateNMR Powderxraydiffraction(XRD) Calorimetry HPLC
Multiphasic lactam kinetics of stressed-gabapentin

3.5 3
Lactam (mole %)
2.5 2 1.5 1 0.5
Long-term lactam formation consistent with autocatalytic model Initial lactam formation from process-damaged crystals
Manufacturing-stress 0 induced lactam
10
20
30
40
50
60
days
Determination of lactam and crystal-disordered gabapentin by chemical/kinetic analysis

In process lactam (L0)
Change in lactam levels during specific treatment or unit operation in % lactam/gabapentin on molar basis
Initial Rate of Lactam Formation (V0)

Daily rate of lactam formation upon thermal stress at 50C under 0% RH
Fraction of damage crystal (F0 )

V0 = k AD F02 F0 = V0 k AD
k AD (50o C ) = 0.37 / %day

Essential research questions for addressing instability mechanisms

What are the relevant structural probes for identifying and quantifying reactive forms? What is the relationship between physical and chemical transitions? Are there underlying rules that can be used to predict instability based on inherent chemical and physical properties of drug substances and excipients in complex milieu (e.g. solid state formulations) or for complex drugs (e.g. biopolymers)?
2. Integrating stability probes into design space models: Traditional approach using response surface (e.g. milling)
2 2 SA, Stability = 0 + 1 P + P + P P + P + P 1 2 2 12 1 2 11 1 0 2
SurfaceArea
8
8
Stability
Milling Speed
Milling Speed
10
10
0.6 0.8 1.0 1.2 1.4 1.6 1.8
Batch Size
Batch size
5 10 15 20 25 30
Predicted Degradation (%mole)
Design Space: acceptable surface area and stability

8
Milling speed
10
Batch Size
Essential research questions for advancing design space

What are sophisticated modeling approaches that move away from the flashlight in the cave syndrome?
Methods that incorporate prior knowledge (e.g. Bayesian approaches) Methods that make realistic parameter distribution estimations Modeling methods that incorporate our understanding of unit operations physics and material properties
Dr. Drennens review of recent approaches
3. Linking shelf-life and manufacturing models

L0 = fraction (%) of chemically degraded API at end of manufacturing F0 = fraction (%) of undegraded process - altered API at end of manufacturing Ftotal = L0 + F0 = total fraction of process - stressed API
Intact API Degraded API Altered API
STORAGE STRESS CONDITIONS

Formulation Shelf-life
Degraded API
Post-Manufacturing Stability
Degraded API Intact API Altered API
Degradation Model
Lt (degraded API) = L0 + f ( Ft , t , storage conditions) Ft (undegraded process - altered API) = f (t , storage conditions)
Autocatalytic Solid-state Degradation Model

Deg _ Rate [ API ]x[ Defects] Defects : Degradation product
100
RealisticPerspective
80
14
% degradation
60
% degradation product
12 10 8 6 4 2 0 TIME
40
20
TIME
What if manufacturing causes un-degraded defects?

Deg _ Rate [ API ]x[ Defects] Defects : Degradation product and Crystal Defect
14 12 10 8 6 4 2 0
Multiphase lactam kinetics of process-damaged gabapentin

3.5 3
Lactam (mole %)
2.5 2 1.5 1 0.5 0 0 10 20 30 40 50 60
days
Lactam Formation: Storage effects

Effectoftemperature
2
Effectofhumidity
3.5 3
1.5 gaba-L (% mole)
60 C
2.5 gaba-L (% mole) 2
0% RH
50 C 40C
1.5
31% RH 47% RH
0.5
0.5
0 0 20 40 60 hours 80 100 120
81% RH
74% RH
0 0 20 40 hours 60 80 100
RecoverykineticsbasedonXRDdata
XRDchangesforprocessdamagedgabapentin at31%RHand40C
XRDpeakat16.1(FormIII)decreasesandpeakat16.8(FormII) increases
ModifiedDegradationModel forPostmanufacturingStability
kID
Intact API
Degraded API kR
kAD
Recovered
API
Altered API
Lt (degraded API) = L0 + k AD Ft + k ID FID where Ft is undegraded process - altered API and FID is intact API including F0 to account for crystal defect sites lee-kirsch@uiowa.edu (4/14/10)
Key research questions: linking DS to stability prediction models

What are effective methods for incorporating the output of design space models (stability-relevant material characteristics) into shelf-life prediction models ?
Application of Bayesian approaches to estimate parameter distributions rather than single-point estimation Development of biomolecule and small molecule stability models based on isoconversional concepts Determination of key manufacturing induced physical changes that form the basis for subsequent physical and chemical instability under environmental stress Assessment of excipient roles in shelf-life prediction models : Do they catalyze/stabilize chemical or physical transformations
Incorporating Stability in Design Space

Physical and Chemical Markers Design Space Model
L0&F0
Post-Manufacturing Degradation Model

Lt
Therapeutic Utility/Safety Model

What is a meaningful stability specification?

Is 90 or 95 % potency relevant for the therapeutic use of all drugs irrespective of therapeutic use and index, population variability, pharmacokinetics or pharmacodynamics? Is 1% or 2% level of a specific related substance meaningful irrespective of the drug-like properties, pharmacokinetics, dosage regimen, or toxicokinetics of that related substance? Does it make sense from a QbD-standpoint to fix the impurity profile of a drug product based on toxicology studies on preclinical drug product batches? How can we meaningfully address the potential safety and efficacy issues that relate to drug product stability as determined by product design, manufacturing and storage?
Integrating design-space, shelf-life and population-based therapeutic models

Formulation design API Physical properties Dosage Parameters Molecular-basis for instability Manufacturing Design Drug Substance
Stability DS Model
Meaningful DEGRADANT Specification
Post-manufacturing stability model
Drug-like properties of critical DEGRADANT
Virtual Patient Population (PBPK, PDPK)
Dosage Regimen, Patient population parameters
Degradant Toxicokinetics
Simplified model for illustration

Dosage Regimen Ranges
Degradation product profile
Average Steady-state Concentration
Response Model Variation
Probability of Mild Adverse Effects
Clearance Variation
Monte-Carlo simulation and logistical regression

Meaningful Degradation Product Specification
1.00
Probability of MAE
0.75
0.50
0.25
Maximum acceptable risk

0.00 0 .01 .02
fraction of degradation product
Essential research issues in development of population-based clinical product stability models

Options for model design and structure in silico, in vitro and in vivo evaluation of drug-like properties of degradation products and API and their incorporation into meaningful therapeutic models Improved approaches to estimate parameter distributions and account for new genomic information
Summary of Suggested Stability Research Investments

1. Molecular basis of instability pathways for complex molecules or for simple molecules in complex formulation milieus 2. Development of quantitative frameworks for relating the effects of product design variation and manufacturing stress on stability-relevant material characteristics 3. Methodologies for incorporating the output of design space models shelf-life prediction models 4. Design and development of population-based clinical product performance models to link design spacestability models to clinical performance in relevant patient populations based on intended therapeutic use regimens

FDA-research Related To Formulation & Pharmaceutical Product Stability

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Research Related to Formulation and Pharmaceutical Product Stability

Accelerated Stability Studies - Theoretical

Current Stability Requirements

Solution state kinetics Solid state kinetics Other physical attributes

HPLC, LC-MS, GC, GC-MS etc. Validation Analytical Methods

API Reaction Rate Order

QBD studies and Shelf-life predictions

Product degradation studies

Drug-Excipient interactions Packaging variable studies

Hydrolysis Reduction Decarboxylation Racemization Deamination Dehalogination

chemical degradation Activation energy determination

DSC, TgA, MicrocalorimetryHPLC, MS

studies etc to justify the use of excipients

7 Mansoor Khan, FDA ACPS 2010

Stability Test Attributes in Shelf-Life Extension Program

Lyon et. al., J. Pharm. Sci., 2006, 95, 1549-1560.

Mansoor Khan, FDA ACPS 2010

Results: Example of Variability

Length of Extension (months)

Average extension 54 months

Example: Real-Time Stability

Diazepam Assay Test Results

Time in Program (Months)

Repackaged Product Stability

Original packaging tablets Stored at 40C 75%RH for 4 Weeks

Yang et al., Int. J. Pharm., 385, 92-97, 2010.

200 100 0 -100 -200

100 75 Weight (%) 50 25 0 0

Peak area (mAu)

P CP SSG A CCS CS CSD MCC

T4AA API T3AA

Mansoor Khan, FDA ACPS 2010

Presentations in this Session

Pharmaceutical Stability: CMC Review Perspectives

Purposes and Practices Gaps Looking Forward Conclusions

Stability Requirements for INDs Code of Federal Regulations

Stability Guidance IND

Stability Regulations - NDA

Stability Guidance - NDA

Purposes for Stability Studies: Early Developmental Studies

Purposes for Stability Studies: Formal Stability Studies

Assurance of efficacy (assay) Assurance of safety (degradant levels)

Batch Selection per ICH Q1A

Any supportive batches. Any supportive batches.

Drug Product Stability Studies per ICH Q1A

6 mo (of 12) 6 months 12 months 6 months 12 months

Report stability failures for the marketed batches as per 21CFR314.81(b)(1)(ii)

Drug development incorporating QbD

Risk-Based Regulatory Approaches

Conventional versus QbD Approaches

Predicting Product Stability During Process Development and Scale-Up

Discovery of New Molecules

Safety & Clinical Studies

Unit Operations Team

Fluid Bed Drying

Illinois Institute of Technology (IIT)

Note: Abbott is scale-up partner

Case Product Formulation

Crospovidone,NF Pregelatinizedcorn starch,NF Magnesiumstearate,NF

Extragranular Extragranular Extragranular

22mg 60mg 7mg 100mg 9mg 40mg

Microcrystallinecellulose, Extragranular NF(AvicelPH102) Talc,USPExtrafine Hydroxypropylcellulose Extragranular Extragranular

Basic Processing Sequence