Post on 09-Jun-2020
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Dione Pompe disease Brazil
Case Study on Application of Analytical Life Cycle Management
and Risk Management Jianmei Kochling, Ph.D. Genzyme, a Sanofi Company
AAPS 2015
Outline
• Introduction of Concepts
− Analytical lifecycle management (ALCM)
− ALCM road map and phase-dependent activities
− Analytical quality-by-design (AQbD) methods development
− Overall ALCM elements
• Case Studies
− Clinical phase: 1 example
− Commercial phase: 1 example
• Analytical Lifecycle Knowledge Management
• Conclusion
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2
• Pharmaceutical Development − Drug substance development
− Formulation development (including container/closure system)
− Manufacture of investigational products
− Delivery system development (where relevant)
− Manufacturing process development and scale-up
− Analytical method development
• Technology Transfer − New product transfers during development through manufacturing
− Transfers within or between manufacturing and testing sites for marketed products
• Commercial Manufacturing − Acquisition and control of materials
− Provision of facilities, utilities, and equipment
− Production (including packaging and labeling)
− Quality control and assurance
− Release
− Storage
− Distribution (excluding wholesaler activities)
• Product Discontinuation − Retention of documentation
− Sample retention
− Continued product assessment and reporting
Product Lifecycle Includes the Following Technical
Activities for New and Existing Products
3 Reference: ICH Q10
• Sub-optimal methods lead to inaccurate and imprecise
data.
• Effort made to manufacturing process and product quality
improvement cannot be reflected.
• Huge cost already incurred, but quality-related problems
remains unclear whether they are solved or not.
• Analytical methods improvement must be synchronized
with product lifecycle management.
Continuous Improvement Requires Continuous
Improved Analytical Methods
4
Kochling
Analytical Lifecycle Management
• Ensures that the analytical methods from initial development to commercial use are best suited for their intended use at various stages
• A lifecycle approach
− Offers continuous strong science input
− Introduces up-to-date technology
− Implements balanced approach for risk and benefits assessment and control
− Combines with long-term business vision
Scope: Drug Substance, Drug Product, Raw
Material, and Reference Standards
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Analytical Method Lifecycle Road Map
Phase 1
- Method
development
- Appropriate for
use
Phase 2
- Method
development
- Method
qualification
Phase 3
- Method development
- Quality risk assessment
- Method qualification
- Method validation
Commercial
- Method routine use
- Method fit for purpose
assessment
- Risk benefits assessment
- Method improvement vs
redevelopment
- Method qualification
- Method validation
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Method Development
Method
Qualification
Method
Validation
Routine Use
Method
Assessment
Formulation and process development
CRO or internal QC
Method Transfer
Phase 1 Phase 2 Phase 3 Commercial
Formulation and
process
improvement
Ret
irem
ent
Analytical Quality by Design Approach
7
Kochling
Method
development
Study factors that affect
method performance, DOEs
for multivariants or
parameter screening. Use
Drylab® for chromatogr.
methods, etc. Reiterate the
process until meeting
method performance criteria
Sufficient statistical
data support of
design space for
analytical method.
Continuous
improvement
and lifecycle
management
Method
Scouting
Identify
“ATP”, e.g.,
accuracy,
precision, etc.
Define
Intended
purpose
Risk
Assessment
Method
Validation
Analytical Method
Implementation
AQbD within the Regulatory Quality System
Extension of QbD drug
development to analytical
methods
Systematic Method
Development
Strategy (MDS).
Help to obtain a
method with optimal
performance.
Incorporated ICH
Q8, Q9, and Q10
Comply with GMP
requirements
Kochling
GMP
Quality Risk Management, ICH Q9
Pharmaceutical Development (Quality by
Design, ICH Q8
Quality System, ICH Q10
cGMP
AQbD
Traditional Method Development
• Define a Method.
• Perform one experiment after another.
• Figure out problems during investigational experiments.
• Can easily diverge from original experimental plan.
• May take a long time to reach the goals for method
development.
• No guarantee of method robustness and other method quality
attributes.
Kochling
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• A systematic approach which examines every aspect of the method during
development.
• Can be used as a stand-alone to probe existing old methods or,
• Can be easily broaden to a platform applications (one type of method for
multiple products or multiple methods from the same product) where strong
scientific knowledge can be fully realized.
• Method validation for traditional method is a key activity. In AQbD, method
validation becomes predictable.
• Great level of confidence is gained using QbD developed analytical methods
for spec setting with improved data quality.
Benefits of AQbD Approach for Methods
Development
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Analytical Method Qualification
• Provide authorities with first results on method
performance and the setting of validation
acceptance criteria for future ICH validation.
•A study to find out sticky points, e.g., certain steps
are not well designed for routine QC testing.
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Analytical Method Validation
• The objective to validate an analytical method is
to demonstrate that the method is suitable for
intended purpose.
• ICH Q2 (R1): Validation of Analytical
Procedures: Text and Methodology
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Analytical Method Transfer
Sending Unit Team
• Project Manager
• Analytical Technical Team
(including statisticians)
• Quality Control
• Quality Assurance
• Regulatory Affair
Receiving Unit Team
• Project Manager (CRO)
• Analytical Technical Team
• Quality Control
• Quality Assurance
• Regulatory (if not in the
same country)
USP <1224> The transfer of analytical procedures (TAP), also referred to as method transfer, is the documented
process that qualifies a laboratory (the receiving unit) to use an analytical test procedure that
originated in another laboratory (the transferring unit), thus ensuring that the receiving unit has the
procedural knowledge and ability to perform the transferred analytical procedure as intended.
FDA Draft Guidance, 2014 Guidance for Industry Analytical Procedures and Methods Validation for Drugs and Biologics
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Kochling
Method Transfer Continuation
• Transfer assessment: Scope definition, gap analysis and risk assessment
for readiness check before transfer.
• Transfer approach: Comparability, co-validation, complete or partial
validation, or transfer waiver.
• Transfer requirements: Transfer plan, transfer protocol, transfer statistical
design, and transfer results acceptance criteria.
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• Valuable new findings using new labs and naive users.
• It is advantageous to have 2 labs involved in 3 steps,
Development, Qualification, and Validation to enhance
method reproducibility
Analytical Method Transfer from Development
to Qualification and Validation
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Kochling
Analytical Method Routine Use
• Methods to be used for release and stability testing need to monitored
for
− OOT and OOS results
− Data accuracy
− Data variability
− Failure rate of method execution
− Easiness of method operation
− Cost of operation
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Analytical Method Assessment
• During routine use, the testing lab does periodic assessment to determine
whether changes, improvement, additional validation, etc. are necessary.
• Assessment Trigger
− Frequent analytical failures
− Process or formulation change (clinical phase)
− Periodic product review (PPR) (commercial phase)
• Test Method Assessment
− Is this method suitable for intended use for supporting drug
development or for QC testing?
− Phase dependent effort based on regulatory requirements, e.g.,
validation status. Kochling
17
Case 1: Methods in Support of Clinical
Phase Studies
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Example 1: Developing a RP HPLC-UV method
for a Phase 3 Product A
U
-0.020
-0.010
0.000
0.010
0.020
0.030
0.040
0.050
0.060
0.070
0.080
0.090
Minutes 1.00 2.00 3.00 4.00 5.00 6.00 7.00 8.00 9.00 10.00 11.00 12.00 13.00 14.00 15.00 16.00 17.00 18.00 19.00 20.00
Imp 1 Imp 2 Imp 3
Imp 4 Imp 5
API
CMA: baseline
CMA:
baseline CMA:
baseline
CMA: rlsn
CMA: K’
Reference: Jianmei Kochling, QbD sunrise section at AAPS 2008
CMA=Critical method attributes
Kochling
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• If the product continues to the later phase, the
analytical method needs to be improved for better
accuracy, precision, impurity quantitation, method
robustness, and other QC method requirements.
Method Assessment
Kochling
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Identification of Method Analytical Target Profile
ATP Must Have Details
Stability-indicating Can detect changes using forced-degradation samples
Quantitative Assay for API Quantitate API in the range of 80-120%
Quantitative Assay for
Impurities Quantitate each individual impurity
Precision Precision and intermediate precision for API and
impurities
Specificity No interference. For stability-indicating methods, peaks
of interest with required resolution
Accuracy For both API and impurities
Reproducibility Analysts, days, and labs
Robustness Method parameters operate in a flexible design space
Linearity and Range Linear regression for API and impurities
QL must be able to quantitate impurities at 0.05%
QC method consideration System suitability, operation easiness, procedures leads to
minimal operational errors, working reference standard,
reagents, expiration date, column, etc.
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Risk Assessment: Fishbone Diagram and
Scores
Kochling
Score =Probability x Impact x Detectability CMA: critical method attributes
CMA
Sample preparation
Weighing error (100)
Pipetting error (100)
Dilution solvent type (500)
Dilution vol. (1)
Mobile phase composition (1000)
Mobile phase pH (1000)
Organic modifier (1000) Column type (1000)
Column brand (1000)
Wavelength (1000)
HPLC UV Analysis
Standard preparation
Weighing error (100)
Pipetting error (100)
Dilution solvent type (500)
Dilution vol (100).
22
HPLC Method Development
Column
Mobile Phase
Wavelength
pH Systematic
Approach
DOE studies to understand method robustness, set
control ranges for method
Factors: organic modifier content,
organic% in gradient, temp., and
flow rate
Responses: Assay value and RT for
API, Impurity RT window,
Resolution
Analytical Target Profiles
Perform forced degradation using DS and DP
Check the resolution of impurities and degradants
DOE studies to determine influencing
factors to method parameters
Evaluate critical method parameters e.g., Assay
value range, RT window and Resolution for
impurities
Tool: API spiked with impurities
PAR
NOR
Parameter
Variation Range
Parameters
A Robust Method
Parameter
Variation Range NOR=normal operating range, PAR=proven acceptable range
Kochling
Reference: Jianmei Kochling, QbD Sunrise Session at AAPS 2008 23
Columns and Buffer Screening
Response: Chromatographic UV Appearance
0.15M T
FA
0.15M A
cetic Acid
0.15M P
hosp
horic A
cid
0.15M F
orm
ic Acid
0.15M A
mm
oniu
m F
orm
ate
0.15M A
mm
oniu
m A
cetate
Waters Atlantis T3 + 0 0 + 0 0
YMC ODS A + 0 0 0 0 +
TSKgel ODS-100V + + 0 + 0 0
Agela Venusil ASB C18 + 0 0 0 0 +
Ace C8 + 0 0 + 0 +
Ace 3 C18 + 0 0 0 0 +
+ Good Chromatography
0 Poor Chromatography
Reference: Jianmei Kochling, QbD Sunrise Session at AAPS 2008
Kochling
Risk Assessment and Risk Control Strategy:
- Perform experiments for parameters with high risks (HPLC method)
- DOE studies for parameter design space or control range.
24
A Robust HPLC Method Developed for API Assay and
Critical Impurities and Degradation Products
AU
-0.04
-0.02
0.00
0.02
0.04
0.06
0.08
0.10
0.12
0.14
0.16
0.18
0.20
0.22
0.24
0.26
0.28
Minutes
1.00 2.00 3.00 4.00 5.00 6.00 7.00 8.00 9.00 10.00 11.00 12.00 13.00 14.00 15.00 16.00 17.00 18.00 19.00 20.00
New
Method
(280 nm)
Old Method
(210 nm)
Imp 1
Imp 2
Im
p 6
Imp 3
Imp 4
Imp 5
Imp 1
Imp 2
Imp 3
Imp 4
Imp 5
isom
er
API
AU
-0.010
0.000
0.010
0.020
0.030
0.040
0.050
0.060
0.070
0.080
0.090
0.100
0.110
0.120
0.130
0.140
0.150
0.160
0.170
0.180
0.190
0.200
Minutes
1.00 2.00 3.00 4.00 5.00 6.00 7.00 8.00 9.00 10.00 11.00 12.00 13.00 14.00 15.00 16.00 17.00 18.00 19.00 20.00
Old Method
Interference from
Capsule shell
DP
New Method
Clean Baseline
Reference: Jianmei Kochling, QbD sunrise section at AAPS 2008
Method accuracy: 98.0-102.0%
Precision: RSD<=2.0%
Method is accurate and precise for
Assay determination.
Method is specific, stability-
indicating for quantitation of
impurities and degradants
Kochling
Method Improvement
- Flat baseline for accurate integration
- Satisfactory recovery of impurities
- Column optimized
- Sample preparation procedure optimized,
proper solvent not to degrade API
- Rigorous system suitability for final QC
method
25
Im
p 6
• Assay is run by determining potency of drug against a reference standard.
• Purity is run by HPLC-UV, normalizing all peaks to 100%. Can over report high UV-absorbing peaks.
• Check method mass balance
− Check peak purity-UV spectra using the online UV detector
− Use LC-MS as an orthogonal method, identify impurities and determine correction factors (response factors can be vary different for different impurities)
What Else Is Not Checked?
If Potency (assay) = 98% while Purity = 90%, What
is missing?
Kochling
26
Use Forced Degradation Study Samples
Good agreement was found for % Purity vs % Assay across
various possible degradation pathways for drug product. Kochling
27
Forced-degradation level : <20%
Lot Degradation
Condition
RSD%
(method)
% Difference (Assay
vs Purity)
1 Control 1.5 0
1 Photo-exposure 0.6 -0.3
1 Heat 0.3 2.3
1 pH 3 1.8 -1.7
1 pH 7 1.0 0.5
1 pH 9 1.3 -0.6
1 pH7/H2O2 1.3 2.9
1 H2O2-Fe 1.8 -0.1
2 Control 0.6 0.8
2 Heat/Moisture 1.3 0.4
2 pH 3 0.7 -1.7
2 pH 6.9 3.2 -1.2
2 pH 6.9/H2O2 0.7 -0.9
2 pH 8/H2O2 0.2 -1.2
New Method Implementation
•Bridging study (study protocol, study design, and
study report).
• Ensure all new issues are addressed, e.g., new
impurities and specifications.
•Data for regulatory submission for the new method.
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Case 2: A commercial phase product method
development and change
Kochling
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A Platform Analytical QbD Methods
Development Strategy
One Product : same QbD method
development strategy for different
methods
Method 1
Method 2
Method 3
Multiple Products: minimal method
development effort with small
variations
A method
Product 1
Product2
Product3
Product 4
One Product
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• A balanced approach: risks and benefits
− Comparability studies are required when substituting approved procedures with alternative analytical procedures.
− FDA requires that the change provides the same or increased assurance of the identity, strength, quality, purity, or potency of the material being tested as the analytical procedure described in the approved application.
Ref: FDA draft guidance: Industry Analytical Procedures and Methods Validation for Drugs and Biologics
• Fully assessment (minimally every five years) to each test method
• Test methods full assessment
− Usability: performance in QC testing labs
− Adequacy: meet the requirements, proper technology strong scientific rationale, and designed for intended use
− Purpose: Fit for intended use
− Validation: comply to current regulatory standards
− Regulatory commitment: audit, filing, post-marketing commitments
Commercial Phase Analytical Method
Assessment
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31
AQbD Platform Approach to 4 Analytical
Methods Development for 2 Drug Products
32
Kochling
Risk Assessment for 2 Methods for Protein X
33
Kochling
Risk Assessment for 3 Protein Methods
34
Kochling
Initial Statistical DOE to Guide Decision Making for
Method Conditions
35
Missed
cleavage ≥ 5%
AU
0.00
0.02
0.04
0.06
0.08
Minutes24.00 26.00 28.00 30.00 32.00
AU
0.00
0.02
0.04
0.06
0.08
0.10
Minutes24.00 26.00 28.00 30.00 32.00
BT9-10
BT9 % BT9-10 = 11.8%
BT9-10
BT9 % BT9-10 = 2.6%
BT9-10
BT9 % BT9-10 = 3.5%
Kochling
Final DOE Study-Surface Response
Pattern Temp (C) Time (hr) Missed cleavage (%)
−− 33 3 10.33
a0 33 4 17.91
−+ 33 5 2.42
0a 37 3 8.33
0 37 4 3.4
0 37 4 4.82
0 37 4 3.84
0A 37 5 2.21
+− 41 3 8.1
A0 41 4 4.54
++ 41 5 2.98
Method
Operable
Design
Region
Finding Root Cause for Uncertainty in UPLC-MS
Oxidation Quantitation Method: Potential Artifacts
Kochling
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-HPLC analysis
- Residual metal effect
-Mass spectrometry analysis
- Ion source artifacts
- Stable ionization signal
- Charge state distribution for
quantitation consideration
-Sample preparation steps
- Enzyme quality
- Glassware wash
- Reagent quality
- Buffer type
-Sample storage
- Solution stability
Which step can cause artifacts of oxidation which leads to inconsistent
oxidation measurement?
Confirmed:
Not introducing oxidation artifacts
Need to be confirmed.
Not introducing oxidation artifacts
DOE Studies for UPLC-MS Method Optimization
38
R2=0.94 for model fitting
Expected 100% recovery
Recovery results
Two Methods with 2 Different Intended Purposes
39
Kochling
Injection Id: 4916 SampleName: TSH_tryptic_4hr_07Feb14_S1 Channel Id: 4917
Injection Id: 4941 SampleName: TSH_tryp_300uL_totalV_07Feb14_S3 Channel Id: 4942
AU
0.00
0.05
0.10
0.15
0.20
0.25
0.30
0.35
0.40
0.45
0.50
0.55
0.60
Minutes
0.00 4.00 8.00 12.00 16.00 20.00 24.00 28.00 32.00 36.00 40.00 44.00
10min 40min
MS
UV UV
SIM MS Oxidized
peptide
6.0 10.00 min
6.0 10.00 min
Identify peptides that represent the sequence of a protein
Quantify the Oxidative Peptide in a protein
Use Simulation Software DryLab® to Help
Method Development
A B
C D
E
F G H
I
Wei Wu. Poster W4255
Just these 4 methods will save $500K per year.
More method per product will same more $$$
41
Reduction: 30 ± 5 min at 60
± 5 ºC
Alkylation: 60 ± 10 min at 23
± 3 ºC
Desalting: 10 min using 6K spin
columns
Trypsin Digestion: 4 – 4.5 h at 37
+ 4 ºC, pH 7.6
Analysis: 30 min
UPLC-MS for
Protein 1 oxidation
quantitation
Analysis: 55 min
UPLC-UV for
Protein 1 peptide
mapping
Analysis: 50 min
UPLC-UV analysis for
Protein 1 C-terminal
truncation
Asp-N Digestion: 2 h at
37 + 4 ºC, pH 8.0
Analysis: 75 min
UPLC-UV for
Protein 2 peptide
mapping and
oxidation
Kochling Saved $250-300K per method during method development and validation
Method Quality is Built-in During Method
Development Following an AQbD Approach
Kochling
Method is ready to be
qualified and validated
in QC laboratory.
Method validation becomes a predictable exercise
Method Quality Built in
During the Development
• Specificity
• Linearity
• Accuracy
• Precision
• Range
• QL
• Robustness
• Solution Stability
42
Analytical Lifecycle Knowledge Management
• A systematic approach to acquiring, analyzing, storing, and disseminating
information related to products and manufacturing processes, and components
• Establish a knowledge repertoire
− Development activities
− Transfer activities
− Method knowledge repository which contains the information from the
various stages of the method lifecycle
− Validation study knowledge (lifecycle of the analytical procedures and
changes)
• Ensure product quality control in a controlled and consistent manner
• Knowledge management is an important factor in ensuring ongoing
effectiveness of the control strategy
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43
Conclusion
• Analytical Lifecycle Management
− A systematic approach for ensuring that methods are properly developed, qualified
or validated, and managed at different stages of lifetime.
• Analytical Quality by Design Methods Development
− Ensures that methods are developed for intended purpose and the method quality
is built-in during development.
− A quality method enhances its performance and reduces cost at each step of
analytical lifecycle management.
• The elements of quality risk management and knowledge
management
− Ensures ongoing quality control and improvement of the analytical methods.
Kochling
44
Acknowledgements
• Genzyme
− Yimin Hua, PhD
− Wei Wu, PhD
− Qian Guan, PhD
− Juan Castaneda-Merced
− Natalya Atlasevich, PhD
− Pilsoo Kang, PhD
− Jane Chen
− Zhongyu Xie, PhD
− Sam Burns
− Chris Willis
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