| www.genzyme.com

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

Kochling

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• 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.

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9

• 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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13

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

15

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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18

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

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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

20

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

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29

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

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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.

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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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