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©2017 Waters Corporation 1

Adopting New Analytical Technology for

Method Modernization

Eric S. Grumbach


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


Technology Transfer in the Pharmaceutical Industry

Technology Transfer

QA

Manufacturing production

QC Department

Packing Production

Engineering Department

Packing Development

Analytical Development

Formulation Development


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


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?


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


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.


US Pharmacopeia (USP) USP Monograph Modernization Initiative

http://www.usp.org/usp-nf/development-process/monograph-modernization









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.


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


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


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


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?


Case Study 1: Amoxicillin Oral Suspension

Amoxicillin Oral Suspension


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


http://tinyurl.com/WatersCC



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


What other analytical technologies can

benefit your current workflow?


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


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


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


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




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



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


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


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


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



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



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


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:



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:



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

adopting new analytical technology for method modernization...adopting new analytical technology for...

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