©2017 Waters Corporation 1
Adopting New Analytical Technology for
Method Modernization
Eric S. Grumbach
©2017 Waters Corporation 2
Highly competitive, regulated business environment
– Need to lower costs without compromising product quality while maintaining
regulatory and compliance requirements
– Decrease time to market while maintaining quality of information
Challenged to increase profitability
– Increasing regulatory pressures, price controls, increased quality
expectations, and competitive pressures
– Pressure to reduce manufacturing costs
– Harmonize approach across sites
o Simplify analytical method transfer
o Manage diversity of available platforms
Deliver sustainable competitive advantage
– Invest in the correct technologies to achieve business objectives
– Capacity to grow the business and anticipate that need
– Demonstrate fast return on investment
Business Drivers Towards Implementing a Change
©2017 Waters Corporation 3
Technology Transfer in the Pharmaceutical Industry
Technology Transfer
QA
Manufacturing production
QC Department
Packing Production
Engineering Department
Packing Development
Analytical Development
Formulation Development
©2017 Waters Corporation 4
Types of Technology Transfer
Transfer to a new user or laboratory
– Transfer to an identical instrument and column
LC instrument transfer
– Transfer of established method between different instruments with
the same or “equivalent” column
– Adjustment of method
o Certain parameters can be adjusted (within limits) in response to
meeting a procedure’s system suitability
– Method equivalency must be verified
Migration of method
– Substantial improvement in analytical quality and efficiency
– Significant change to method in which full validation is required
©2017 Waters Corporation 5
Analytical Method Transfer Workflow
Laboratory Evaluation
•Preparation of detailed analytical procedure
•Training of receiving unit and conduct trial run
•Identify issues and resolve
Method Transfer
•Verification of laboratory compliance with SOP
•Ensure transfer is in line with regulatory and guidance agencies
•Transfer of analytical procedure, development and validation reports to receiving unit
Post-Transfer
•Verification that method remains fit-for-purpose and acceptance criteria are met
•Transfer report written and approved
What are the regulations and guidelines being provided for analytical method transfer?
©2017 Waters Corporation 6
Life cycle management of analytical procedures:
Method should be continually assess to ensure it remains
fit for its intended purpose
– Optimize or revalidation necessary?
– Risk-based approach
“New technologies may allow for greater understanding
and/or confidence when ensuring product quality”
Analytical method transfer studies:
Comparative studies to be performed to assess inter-
laboratory variability
Analyze at originating and receiving labs if procedure is
also a stability-indicating method, forced degradation
sample or contains pertinent product-related impurities
– References USP Chapter <1224> Transfer of Analytical
Procedures
U.S. FDA Industry Guidance on Analytical Procedures
Issued July 2015
©2017 Waters Corporation 7
U.S. FDA Guidelines for Method Change
Reporting categories
– Minor (annual report – no fees)
– Moderate (supplement)
– Major (Prior approval supplement)
Changes are allowed to approved analytical
procedures
– Allowing implementation of new techniques while
maintaining standards and changes in methods but not
methodology
o Maintain original test methodology (i.e., HPLC to UPLC)
– Equivalent or increased assurance of identity, strength,
quality, purity or potency
– Acceptance criteria remains unchanged
What it means: If same methodology, equivalent or increased assurance, acceptance criteria remains unchanged, Full re-validation is not needed.
©2017 Waters Corporation 8
US Pharmacopeia (USP) USP Monograph Modernization Initiative
http://www.usp.org/usp-nf/development-process/monograph-modernization
©2017 Waters Corporation 9
Challenges in Methods Transfer
System dwell volume (i.e. gradient delay volume) – Matching gradients requires matching of dwell volume and mixing
behavior
– Can affect retention time, selectivity and resolution
Extra Column Dispersion – Resolution, sensitivity, separation efficiency and peak capacity
– Strong solvent effects (strong diluent effects)
Temperature Control and Related Effects – Matching the thermal environment of the column both oven temperature
and inlet preheating
– Thermal mismatch
– Transferability
Additional characteristics that can affect methods transfer include gradient formation, limits of detection, injection modes, etc.
©2017 Waters Corporation 10
USP <621> Chromatography Defines “Allowable Adjustments”
“Adjustments to the specified chromatographic system may be
necessary in order to meet system suitability requirements.”
Adjustments permitted only when:
– Suitable standards are available for all compounds used in suitability test
– Adjustments (or column change) yields results that meet all system suitability
requirements specified in official procedure.
Must use the same L-designation of column
USP 40 NF 36
- Official until August 1, 2017
- Significant changes to General Chapter <621> Chromatography in August 2014 USP 37 NF 32
©2017 Waters Corporation 11
USP 37-NF 32 through First Supplement - August 1, 2014
Parameter USP 36-NF 31 USP 37-NF 32 Through first supplement
Isocratic Gradient
Particle Size -50% L/dp Ratio Constant
or -25% to + 50% of L/dp ratio
No changes allowed
Column Length ±70% No changes
allowed
Flow Rate F2=F1 (d22/d1
2) and ± 50% F2 = F1 x [(dc2
2 x dp1)/(dc12 x dp2)]
and ±50% No changes
allowed
Column ID Any allowed if linear velocity is
constant Any allowed if linear velocity is
constant No changes
allowed
Injection Volume Any reduction consistent with precision and detection limits;
no increase permitted
Can be adjusted as consistent with precision, linearity and detection limits
Column Temperature ±10 0C ±10 0C
Mobile Phase pH ±0.2 unit ±0.2 unit
F=Flow rate; d = internal column diameter; dc = column diameter, dp = particle size
©2017 Waters Corporation 12
Guidance on ‘Allowable Adjustments’ Stated within USP General Chapter <621>
Isocratic Methods - Improve analysis speed and quality with UPLC and sub-2µm columns
- Improve methods with 2.x µm on HPLC and UHPLC systems
- No re-validation required
Gradient Methods - Duration of initial isocratic hold and/or dwell volume adjustments are allowed.
- Fully optimize methods using sub-2-µm particles and UPLC if investing in re-validation
- Develop better methods with more confidence by incorporating mass detection and photodiode array
System - Choose instrumentation suitable for maximizing the LC asset utilization
- Manage options by impact and future goals
Software - Scaling calculators for proper transfers
- Emulation tools
©2017 Waters Corporation 13
Improve resolution
Improve selectivity
Reduce run time
Reduce solvent consumption
Increase analytical efficiency
Employ modern methodology
Employ modern instruments and
column technology
Why Improve a Compendial Method?
©2017 Waters Corporation 14
Case Study 1: Amoxicillin Oral Suspension
Amoxicillin Oral Suspension
©2017 Waters Corporation 15
Method Parameters:
Diluent: 50 mM potassium phosphate,
monobasic in water – pH 5.0
with potassium hydroxide
Mobile phase: 98:2 diluent:acetonitrile
Separation: Isocratic
Detection: UV at 230 nm
Sample Preparation:
Amoxicillin oral suspension powder,
reconstituted in water (50 mg/mL), dilute to 1
mg/mL in diluent
Amoxicillin standard 1 mg/mL in diluent
Filter through 0.2 µm nylon syringe filter
Compendial HPLC Method:
Column: L1 4.6 x 250 mm, 5 µm
(µBondapak C18 or equiv.)
XBridge Shield RP18
Flow rate: 1.5 mL/min
Inj. Vol.: 10 µL
UPLC Method (Scaled using Columns
Calculator Version 2.0):
Column: L1 2.1 x 100 mm, 1.7 µm
ACQUITY UPLC BEH Shield RP18
Flow rate: 0.4 mL/min
Inj. Vol.: 0.8 µL
Case Study 1: Amoxicillin Oral Suspension
http://tinyurl.com/WatersCC
©2017 Waters Corporation 16
Case Study 1: Amoxicillin Oral Suspension
Benefits:
70% decrease in analysis time, faster throughput for routine sample analysis
92% reduction in solvent usage and sample injected
Adopt modern UPLC Technology while remaining within USP guidance
©2017 Waters Corporation 17
What other analytical technologies can
benefit your current workflow?
©2017 Waters Corporation 18
New Technology Adoption Beyond LC: Mass Detection
Sample complexity continues to increase
– Ability to detect unexpected components
– Ability to detect co-eluting components
Need for characterizing compounds at lower limits of
quantitation
– Ability to detect unknown components
– Ability to detect known critical components
Expedite peak identification
– Information used in identification
– Track peaks across method development experiments
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ACQUITY QDa Mass Detector Integrating Mass Information into Your Existing Workflow
Provides mass information to
compliment your optical data
Compact & robust design for
constant use with wide variety of
chromatographic conditions
Orthogonal detection for the
broad range of applications that
benefit from the extra
information
Seamlessly integrates with your
Waters HPLC, UHPLC and UPLC
©2017 Waters Corporation 20
Case Study 2: Metoclopramide and Related Substances
USP specified Related Compounds
Monoisotopic Mass (Da)
Impurity A 341.15
Impurity B 257.05
Impurity C 201.02
Impurity D 223.08
Impurity F 285.12
Impurity G 315.14
Impurity H 195.05
Impurity 9 181.07
Metoclopramide C14H22ClN3O2 Monoisotopic mass: 299.14 m/z
CH3
CH3
N
O
NH
CH3ONH2
Cl
Antiemetic used in the treatment of nausea and vomiting
©2017 Waters Corporation 21
Metoclopramide
Metoclopramide Impurity G
272.8
309.1
212.9
272.8 309.1
nm
250.0 300.0 350.0
m/z =
m/z =
300.1
316.1
Case Study 2: Metoclopramide and Related Substances
©2017 Waters Corporation 22
Case Study 2: Metoclopramide and Related Substances
Compare both UV and MS spectral information
AU
-0.004
0.000
0.004
Minutes0.00 0.50 1.00 1.50 2.00 2.50 3.00 3.50 4.00 4.50 5.00
286.1
– I
mp. F
300.1
- A
PI
342.1
– I
mp. A
316.1
– I
mp. G
182.1
– I
mp. 9
196.0
– I
mp. H
202.0
– I
mp. C
224.1
– I
mp. D
258.0
– I
mp. B
Imp. F - 1.344 - QDa
Apex
213.5 272.8 311.0
368.0
286.1
288.1
API - 1.608 – QDa
Apex
213.5 272.8 309.1
300.1
302.0
Imp. A - 1.825 – QDa
Apex
212.9 263.0
306.0 392.9
342.0
343.9
Imp. G - 1.923 – QDa
Apex
211.0 271.5 307.9
372.4
316.0
317.9
UV Spectra
MS Spectra
©2017 Waters Corporation 23
Case Study 2: Metoclopramide and Related Substances
UV Peak Purity Plot
Imp.
A -
1.8
26 -
342.0
3
PurityAuto Threshold
AU
Degre
es
0.0000
0.0036
0.0072
0.0108
0.0144
0.00
10.00
20.00
30.00
40.00
50.00
60.00
70.00
80.00
90.00
Minutes1.802 1.819 1.836 1.853 1.870
* Accuracy sample
Demonstrate peak homogeneity
AU
0.00
0.02
0.04
Minutes1.50 1.55 1.60 1.65 1.70 1.75 1.80 1.85 1.90 1.95 2.00
UV at 270 nm
Imp. A - 1.826 - QDa 1: MS Scan
Leading Apex Trailing
213.5
266.6309.1
359.3
212.9
266.0306.6
212.9
266.6309.1
391.0
342.0
343.9
342.0
344.0
342.0
343.9
UV Spectra
MS Spectra
©2017 Waters Corporation 24
Other Opportunities to Implement Mass Detection
EARLY PHASE OF DEVELOPMENT
LATE PHASE OF DEVELOPMENT
QUALITY CONTROL
ASSAY TECH
TRANSFER
TROUBLESHOOTING
METHOD VALIDATION
STABILITY TESTING
CLEANING VALIDATION
GTI ANALYSIS
METHOD OPTIMIZATION
SCREENING
OF ANALYTICAL METHODS
FORCE DEG.
STUDIES
MASS BALANCE
Excipient compatibility studies
©2017 Waters Corporation 25
Case Study 3: Streamline Sample Characterization
Polysorbate 80 (PS80) is a common excipient and solubilizing
agent used in the pharmaceutical industry
– Used as an emulsifier, solubilizer and stabilizer
– Can contain numerous impurities and different fatty acid residues
Janssen utilizing PS80 as part of a mAB formulation to prevent
aggregation
– Need to assess interaction of proteins and surfactant
©2017 Waters Corporation 26
The challenge
Uncontrolled heterogeneity can impact stability, safety
and efficacy of the formulation
Aging multi-vendor instrumentation required for full
characterization leading to service challenges
Significant cost to Janssen associated with running
multiple methods and awaiting results
– Multiple methods were required for full characterization
– Methodology was very lengthy, resulting in a 2-3 day
turnaround time to test 10 samples.
– Delays in testing resulted in delayed production of final
product
Case Study 3: Streamline Sample Characterization
©2017 Waters Corporation 27
Polysorbate Quality Analysis
Determine PS80 residuals
isolated from mAb formulations
Original HPLC Analysis
– Alliance 2695 HPLC with 2996 PDA and
PL-2100 ELSD
– Analysis time = 70 minutes
UPLC Analysis
– ACQUITY UPLC with ACQUITY QDa Mass
Detector and Waters ELSD
– Analysis time = 7 minutes
The Impact to Janssen
Analysis time 10 X faster per sample
Full characterization of multiple samples reduced from 2-3 days to only 4 hours by consolidating multiple methods
– Reduced sample preparation
– Reduced analysis time
– Reduced data analysis
Faster batch release of PS 80 into formulation production
$450,000 USD annual savings
Case Study 3: Streamline Sample Characterization
©2017 Waters Corporation 28
Guidance on Genotoxic Impurities
EMEA
‒ Guidelines on the limits of Genotoxic
Impurities (2006)
U.S. FDA
– Guidance for Industry, Genotoxic
and Carcinogenic Impurities in Drug
Substances and Products:
Recommended Approaches (2008)
ICH M7
– Assessment and Control of DNA
Reactive (Mutagenic) Impurities in
Pharmaceuticals to Limit Potential
Carcinogenic Risk (2014)
Case Study 4:
Genotoxic Impurities
©2017 Waters Corporation 29
MSN Laboratories – India
Research-based Pharmaceutical company
(API, formulation and research partner)
Challenged in sensitivity for impurity
analysis
– Utilizing LC-UV
Increased sample loading on UV based
systems to meet required LOQs. 100
mg/mL API concentration injected to
achieve adequate sensitivity of GTI
o Reduction in column life time
o Distorted peak shape
o Solubility challenges
Multiple analytical tools used to analyse
all impurities in manufacturing process
– Challenge for method support
– Challenge for user training
– Challenge for data integrity
Case Study 4:
Genotoxic Impurities
©2017 Waters Corporation 30
The Impact
Confidence in meeting regulatory
requirements
UV methods being replaced with ACQUITY
QDa Mass Detector
Consolidating multiple methods on a single
platform
Improved column lifetimes
Less delay through fewer solubility challenges
Case Study 4:
Genotoxic Impurities
©2017 Waters Corporation 31
Summary
New technology adoption is beneficial towards
maintaining a sustainable competitive advantage
Ability to lower costs without compromising product quality
while maintaining regulatory and compliance requirements
Decrease time to market while maintaining quality of
information
Investment in modern technologies can help achieve
business objectives
Builds in future capacity needed to grow the business
Adding Mass Detection to your existing workflow provides
improved confidence in your results while streamlining the
sample preparation, sample analysis and data interpretation
©2017 Waters Corporation 32