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Determine Phase Appropriate Activities — A LifecycleApproach for Analytical Procedures and Methods Validation

Xiande (Andy) Wang, Ph.D.

Analytical Development

Janssen Pharmaceutical Companies of Johnson & Johnson

IVT Analytical Procedures and Validation, December 2015, Philadelphia

Outline

I. Life Cycle of Analytical Methods

II. Method Development/Validation at Early Stage (IND)

III. Method Development/Validation at Late Stage (NDA)

a. Notes on FDA Guideline

b. Systematic method development

c. Case studies of robust method development

IV. Analytical methods for post-marketing support

VII. Summary

Full Life Cycle of Pharmaceutical Products

CMC/R&DSupply Chain/

Operations

Full Life Cycle of Pharmaceutical Products

CMC/R&DSupply Chain/

Operations

NME

IND

NDA

LAUNCHTECH

TRANSFER

STABILITY

MONITORING

NEW

SYNTHESIS/

FORMULATION

Phase Appropriate Activities

• NME: Identification; isolation; purity profile

• IND: Method development/validation (abbreviated)

• NDA: Method development/validation (thorough)

• LAUNCH: Primary method transfer; stability studies

• TECH TRANSFER: Secondary method transfer

• STABILIY MONITORING:– Continuous stability studies

– Method re-evaluation

– Gap assessment (methods, validation, specifications)

– Method gap validation/re-development/re-validation

• New Synthesis/formulation– Method development/validation/approval/transfer

IND

Method Development to Support Early Formulation Development

• The chemistry, manufacturing and controls (CMC) aspect of drug development is focused on producing medicines suitable for human use with specified quality, safety and efficacy characteristics

• The drug development program is geared towards

– thorough understanding of the drug product’s performance

– identification of drug product’s critical characteristics

– demonstration of drug’s safety and efficacy

– ultimately leads to the review and approval of the drug

• Formulation development

– Proper API characterization (particle size, polymorph, bulk density)

– Solubility (intrinsic, pH dependent, saturation)

– Hygroscopicity study

– Impurity profile

– Drug excipient compatibility studies

– Probe stability studies

Validation at IND Vs. NDA

IND NDA

Method Development to Support Late Formulation Development

• Support the following studies:

– Use of overages

– Use of excipients, approved colors

– Adequate optimization study data on process controls

• Dissolution profile

• Stability studies

– Adequate batch size and number of batches

– Chamber temperature and humidity condition appropriate to the target market

– Adequate data at the time of submission

– Photo stability study

– Proper container orientation (specially for liquid products)

– Adequate stability study on bulk shipment pack (if intended to ship it for repackaging)

– Adequate parameters covered under stability protocol (e.g.: microbial testing)

Method Development in Formulation Development: Building-in Quality through Adequate Analytical Testing/Methods

• Meeting Pharmacopoeial requirement / ICH guidelines

• Second identification test

• Adequate impurities & residual solvent specification

• Testing for preservatives, anti-oxidants wherever used

• Test for breakability / content uniformity

• Test for establishing polymorphic conversions

• Test for water content in solid dosage form

• Analytical methods:

– Validated (e.g.: LOD, LOQ in RS method)

– Stability indicating (for stability studies)

– Forced degradation studies performed

– Method development report (adequate justification for choice / selection of method

and conditions)

Notes on New Guidance

• Supersedes 2000 draft guidance on Analytical Procedures and Methods Validation

• Will replace 1987 FDA guidance for industry on Submitting Samples and Analytical Data for Methods Validation

• Applies to DS and DP in NDA, ANDA, BLA and DMF.

• Not address:– IND

– biological and immunochemical assays

– revalidation of existing analytical methods

Notes on New Guidance: Method Robustness during Method Development

• During method development, parameters may be evaluated: specificity, linearity, LOD, LOQ, range, accuracy and precision.

• During early stage of method development, method robustness should be evaluated. Development data should be submitted if they support method validation.

• A systematic approach (e.g. DOE) should be used for method robustness evaluation.

Notes on New Guidance:Details on Chemicals/Materials

Notes on New Guidance:Combination of Challenges to Demonstrate Specificity

Notes on New Guidance:Notification to FDA; Robustness Data Required

Notes on New Guidance:Compendial Methods

Notes on New Guidance:Statistical Analysis and Models

Notes on New Guidance:Life Cycle Management of Methods

Notes on New Guidance:Changes to Methods

Notes on New Guidance:Revalidation

Notes on New Guidance:Method Comparability Study (1)

Notes on New Guidance:Method Comparability Study (2)

Notes on New Guidance:Method Comparability Study (3)

Notes on New Guidance:Method Transfer

Notes on New Guidance:Report Post-marketing Changes

Analytical Techniques/Methods

• Titration• HPLC• GC• CE• AAS• Loss on Drying• Karl-Fisher • UV-VIS• Sulfate ash• Heavy metals• Insoluble matter

• Color and clarity

• Dissolution

• Appearance

• IR

• DSC

• Optical rotation

• Melting point/Melting profile

• NMR

• MS

Stability-indicating Method

• A stability-indicating assay is a validated quantitative analytical procedure that can detect the changes with time in the pertinent properties of the drug substance and drug product.

• A stability-indicating assay accurately measures the active ingredients, without interference from degradation products, process impurities, excipients, or other potential impurities

• Key characteristics of a stability-indicting method:

– Accuracy

– Precision

– Sensitivity (LOD/LOQ)

– Specificity

• Peak purity

• Mass balance

• Resolution

• Forced degradation

• Orthogonal method

Systematic Method Development Process

Samples are stressed

under different

conditions

Stressed samples

are analyzed with

a generic method

Representative

stressed samples are

chosen

Method screening is

conducted with

selected samples

A primary method

and an orthogonal

secondary method

are identified

The methods are

optimized

Stressed samples are

analyzed with

optimized methods

The primary method is ready for

further optimization / validation

Process impurities and/or

excipients are obtained

Stressing of API

• Purposes:

– To facilitate method development/validation

– To aid in development of the first API specification

– To understand the degradation pathways of the API to facilitate rational

product development

– To screen for possible formation of potential genotoxins

– Provides a control baseline for excipient compatibility studies

– Target 5-15% degradation with secondary degradation minimized

• Typical conditions for API might be:

– Solid under light or heat/humidity

– In acid, base or buffered media of pH 1-10

– with peroxide (and/or free radical initiator)

– With water under light or heat

Stressing of Formulations

• Purposes:

– To facilitate method development/validation

– Pre-formulation investigations

– To confirm the mass balance

– Solid state degradation and stability assessment

– Role of excipients in API instability

• Typical conditions might be:

– Solid under light or heat/humidity

– In acid, base or buffered media of pH 1-10

– with peroxide (and/or free radical initiator)

– With water under light or heat

– Different grade/source of excipients

32

A Generic HPLC Method

•Column: Endcapped C18, 15x0.46cm, 3.5um (or 1.7 um)

•Mobile phase A: 0.05%TFA in H2O

•Mobile phase B: 0.05% TFA in MeCN

•Flow rate: 1.2mL/min

•Run time: 25 min90/10,A/B

10/90, A/B

20min

5min

Ref: X Wang, “Generic HPLC Methods for Pharmaceuticals”, Nov 14, 2006, EAS, Somerset, New Jersey.

33

Representative Stressed Samples

• Deploy the right technique

– LC-MS or LC/MS/MS

• Establish the appropriate threshold

– 0.01% or 0.03%

• Preparation of degradants

– Purchase

– Preparative separation

– Organic synthesis

HPLC Column Screen Set: An Example

Orthogonal Screening – Columns

Stationary Phase Column pH Rangea

Manufacturer Part Number

C18 – Twin Technology Gemini C18, 5 m, 110A, 4.6 x 150 mm 1-12 Phenomenex 00F-4435-E0

Phenyl with Hexyl (C6) linker,

endcapped Luna Phenyl-Hexyl, 3 m, 4.6 x 150 mm 1.5-10 Phenomenex 00F-4256-E0

C18-20% C loading Discovery HS-C18, 3m, 4.6 x 150 mm 2-8 Supelco 569252-U

C18 – polar embedded, hybrid

particle with Shield Technology XTerra RP18, 3.5 m, 4.6 x 150 mm 1-12 Waters 186000442

C18– silica Sunfire C18, 3.5 m, 4.6 x 150 mm 2-8 Waters 186002554

Pentafluorophenyl Curosil PFP, 3 m, 4.6 x 150 mm 2-7.5 Phenomenex 00F-4122-E0 aColumns were screened only against mobiles phases within their compatible pH range.

HPLC Screening Conditions: An Example

Orthogonal Screening Method Description

Time (min) %Water %Acetonitrile

% Modifiera Flow Rate (ml/min)

0 85 10 5 1.0

40 10 85 5 1.0

45 10 85 5 1.0

45.10 85 10 5 1.0

60 85 10 5 1.0

Injection Volume 5 L

Detection 280 nm; DAD (190 – 400 nm)

Column Temperature Ambient

Sample Temperature 5oC

aModifier stock solutions are prepared at a concentration 20 times higher than the desired mobile phase concentration since mobile phases are prepared at time of use

with the HPLC quaternary pump.

Modifier Mobile Phase

Concentration

Approximate pH

Trifluoroacetic Acid (TFA) 0.05% 2

Formic Acid 0.1% 2.8

Ammonium Acetate + Acetic Acid 8 mM + 0.1% 4

Ammonium Acetate 8 mM 7

Ammonium Acetate + Ammonium

Hydroxide

8 mM + 0.05% 10.2

Ammonium Hydroxide 0.05% 10.8

Method Optimization

• Examples of optimization parameters:– Organic modifier

– Gradient slope

– pH

– Buffer (type, concentration)

– Flow rate

– Colum temperature

– Gel lots of column

– Sample solvent

– Injection volume

• Typically monitored characteristics:– Retention time

– Resolution

– Tailing factor

• General approaches:– One factor at a time

– Design of experiments (DOE)

37

min6 8 10 12 14 16 18 20

mAU

0

25

50

75

100

125

150

175

min6 8 10 12 14 16 18 20

mAU

0

25

50

75

100

125

150

175

Active HPLC methodYMC Pro C18 pH 2.5

Orthogonal HPLC methodXTerra RP18 C18 pH 7

Example of Primary and Secondary Method

Ref. H. Rasmussen et al, “HPLC method development”, in S. Ahuja and M.W. Dong, ed,

Handbook of Pharmaceutical Analysis by HPLC, Elsevier, Amsterdam, 2005, Chapter 6.

Approaches to Maximize Method Orthogonality

• Separation mode

– Reversed phase (RP)o Different stationary phase

o Buffer/pH

– Normal phase (RP)

– Hydrophilic interaction Chromatography (HILIC)

• Detection

• Different UV wavelength

• Mass spectrometry

• Charged aerosol detector (CAD)

Case #1. Complementary Selectivity of Different Separation Modes: Reversed Phase at -Low PH A

U

0.00

0.25

0.50

0.75

Minutes

0.0 10.0 20.0 30.0 40.0 50.0

A BC

D

Col: 250 3mm 5m Nucleosil 100-5 Protect-1;

MPA: 0.3% H3PO4;

MPB: MeCN;

Gradient:

Time(min) MPA(%) MPB(%)

0 100 0

26 100 0

35 20 80

40 20 80

41 100 0

Flow-rate: 0.3 ml/min;

Column temp: 40C

Case #1. Reversed Phase at High pH

Col: 250 4.6mm 5m Gemini C18;

MPA: 0.3% Triethylamine;

MPB: MeOH;

Gradient:

Time(min) MPA(%) MPB(%)

0 50 50

5 50 50

20 10 90

21 50 50

Flow-rate: 1.0 ml/min;

Column temp: 40C

Case #1. Normal Phase

Col: 250 4.6mm 5m YMC-Pack SIL;

MPA: EtOH;

MPB: Hexane;

Gradient:

Time(min) MPA(%) MPB(%)

0 10 90

25 55 45

26 10 90

Flow-rate: 1.5 ml/min;

Column temp: 30C

Case #1. Hydrophilic Interaction Chromatography (HILIC)

Col: 250 4.6mm 5m YMC-Pack DIOL;

MP: 94/6, MeCN/50mM NH4OAc;

Flow-rate: 1.5 ml/min;

Column temp: 30C

Case #1. Complementary Selectivity of Different Separation Modes

Method Elution Order

Observations Run time

(min)

Reversed phase – Low pH

A, B, C, D Difficult to resolve A & B on most columns

55

Reversed phase – High pH

B, C, A, D Limited selection of columns at pH ~12

Higher risk of interference

30

Normal Phase D, A, B, C Low peak efficiency

Challenging sample preparation

35

HILIC D, B, A, C Short run time, better peak shape and efficiency

10

Case #2. Complementary Selectivity of Different Separation Modes (RP vs. HILIC)

Compd Functional Groups

1 Aromatic, -NH2,

-OH

2(API) Aromatic, -NH2,

-O-CONH2

3 Aromatic, -OH,

-NH-CONH2

4 Aromatic,

-O-CONH-

Ref: X. Wang, W. Li, H. Rasmussen, J. Chromatogr. A, 1083 (2005), 58.

45

Case# 2: HILIC Method Validation Summary

Category Results

Specificity All peaks of interest are separated. The peaks are free of co-elution as demonstrated by RP-HPLC orthogonal method and peak purity analysis on the UV spectra.

Accuracy The recovery from multiple sample preparation is within the range of 99.2% to 100.6%.

Limit of Quantitation

3.75 ng; or 0.05% of standard concentration (0.75mg/mL, 10L injection, S/N =10)

Linearity In the range of 0.05% to 120% of standard concentration (0.75mg/mL), the curve composed of 7 data points is linear (R2=0.9999).

Precision 5 injections of the same standard solution (0.75mg/mL) have a relative standard deviation of 0.4%; 3 individual sample preparations at different concentration levels have a relative standard deviation of 0.8%.

Summary of Phase Appropriate Method Development

• Systematic method development process

– Stressed sample

– Method screen

– Primary/secondary method

– Method optimization

– Method validation

• Approaches to enhance method orthogonality

– Separation mechanism (HILIC vs. RS for R331333)

– Detection (UV vs. CAD for paclitaxel and gentamicin/proclin)

• Phase appropriate development and validation

– Build up knowledge base for DS/DP in early phase

– Establish robustness (define design space) in late phase

Triggers of Post-market Method Changes

• New submission (renewal) to worldwide markets

• Compendial updates

• New Guidelines

• Development of new formulations (combination products) / new API synthetic route

• Change of manufacturing process

• Change of source/chemistry of raw materials/intermediates

• Method transfer to different sites

• New analytical techniques/improved methods

• Inspections

• Events/Observations: stability monitoring; complaints; counterfeits

• Periodic review/monitor

Analytical Method Transfer

• Types of method transfer:

– Comparative testing

– Co-validation between two laboratories

– Method validation/re-validation

– Transfer waiver

• Steps towards successful method transfer:

– Discussions initiated

– Method and validation reviewed

– Laboratory evaluated

– Transfer protocol written and approved

– Experimental data generated

– Transfer report written and approved

• Is the method inadequate by today’s scientific standard or regulatory requirement?

• Is sufficient data available to permit simplification of the method?

• Does monitoring of laboratory deviation suggest a need for method improvement ?

• Do newer method for similar products significantly outperform?

• Is the volume of testing justify further method optimization or automation?

Method Change Triggered by Periodic Monitor/Review of Methods in Testing Labs

Life Cycle of Post-approval Analytical Methods

AssessmentId gap

Open Change Control

Validation TransferReport to authority

Implementation

Method development

Close change control

Periodic review

monitoring

Change Control Process Flow

Pre-CoCmeeting

Open CoC

Site/functional approval

QA/Board approval

Authority approval

Site/functional Implementation

Site/funtional assessment

Close change control

Change Control

• Request for change

• Change control No.

• Date

• Type/category of change

• Change related to product/document/system/facility

• Concerned documents with number

• Description of change

• Reason for change

• Impact of change

• Assessment of Impacted sites/functions

• Proposed methodology for Implementation

• Closure

Why Is Change Control Critical?

• Compliance risks due to no/ineffective change control

o Method not aligned with Local regulatory filing

o Local regulatory filing not consistent with global regulatory filing

o Global regulatory filing not consistent with latest version of methods

o Translation to local language is not accurate

o Wrong version of test method is used at different sites

o Methods not validated

o Method not validated according to today’s standard

o Missing information

o Calculation error

o Inappropriate system suitability

o Compendial changes in each country

• Effective change control system provides evidence of compliance to FDA.

• It is invaluable to maintain a history of the lifecycle of all change requests.

Summary

Analytical methods are essential part of product life cycle

Method development/validation activities should be phase appropriate: IND, NDA, post

approval

New FDA guideline on analytical methods reflects current thinking of agencies and industry

trend: to proactively address method issues

Robust method development is the best investment in life cycle of analytical methods

It is important to manage post-market changes to analytical methods