Data Evaluate, Set Specifications and Prepare Reports 11 –Stability Data –Evaluate, Set Specifications and Prepare Reports Dan Willingmyre, Neha Frantz, Philip Pue-Gilchrist, Donnie

SESSION 11 – Stability Data – Evaluate, Set Specifications and Prepare Reports

Dan Willingmyre, Neha Frantz,

Philip Pue-Gilchrist, Donnie

Pulliam, Ketan Shah, and Brian K

Nunnally

Agenda

• Introduction

• Inputs and Outputs

• Case Study: Laboratory Variability

• The specification process

• Case Study: Setting Stability Specifications

2

Purpose of Stability Studies

• Evaluate Quality of DS and DP under Environmental Influences:

› Temperature

› Humidity (if applicable)

› Light

› Outcome: Establishment of recommended storage conditions, retest or

expiry periods for DS and shelf life for DP.

• Evaluate Quality based on Product-related factors:

› Interaction of DS with excipients

› Product in container closure systems and packaging materials

3 3

Inputs

• The goal is to set a DP

expiration date on the

label

• Many inputs are needed to

set the DP expiration date

• Within each input are

many more inputs

• Considering each one of

these inputs will allow for a

comprehensive stability

strategy to be developed.

4

Drug Substance

5

Drug Substance: General

Assumptions

• Detail the assumptions being made

• What is the final formulation for the DS?

• What storage temperature(s) will be used?

• What shelf life is desired?

• What container closure(s) will be used?

6

Development Studies

• Does not replace real-time stability

• Provides insight into stability-indicating attributes

Protocol-driven Accelerated Stability Assessment Program (ASAP) Studies1,2

• Impurities

Forced degradation / characterization

• 6M / accelerated condition on development material to support clinical DP shelf-life.

Real-time stability on feasibility

1: Waterman, K.C., et al (2007), Pharmaceutical Research, Vol. 24, No. 4 April 2007.

2: Waterman, K.C. (2010), AAPS Short Course on Stability Testing in Pharmaceutical Development.

Phase Specific Stability Protocol

Considerations (Small Molecule)

# of Batches 1 1 3a 0-3b

Storage

Conditions

per ICH Q1A (R2)

25°C (Zone II) or 2-8 °C Globally

30°C (Intermediate)

40°C (Accelerated)

Target

Retest/Expiry60 Months

Minimum Data at

submission

Development data (as

applicable) and

3M, minimum

12M real timeN/A (Post-approval

updates)

Initial Retest

Claim

(ICH Q1E)

6M, minimum 24M, minimumExtensions with real-

time data

Storage label

ClaimCRT (20-25 C) or 2-8 C CRT (20-25 C) or 2-8 C

a: at least 1 batch at commercial scale from intended site of mfg

b: depending on # of full scale registration batches, a total of 3 batches at commercial scale.

Phase IPhase

II

Phase

III/RegPVR/

PostApp

Phase Specific Stability – Special

Studies (Small Molecule)

9

Special Study

Description

Photostability

(ICH Q1B)

Evaluate at Ph1 for DS handling /

pack (1 batch)Conduct in PhIII if process / packaging

changes (1 batch)

Temperature cycling/

Short-term excursion

studies

N/A – support handling / TE with

stability data up to 40 C

(accelerated)

Conduct to support supply chain and

handling of drug substance (1 batch)

Temp range = -20oC to up to 70oC

Stability of RSM and

Process Intermediates

N/A unless required or need

determined during early phase.

Conduct prior to registration or during

PVRs

(1 batch)

Phase IPhase

II

Phase

III / RegPVR/

PostApp


Considerations (Large Molecule)

# of Batches 1 1 3 / 3 0-3

Storage

Conditions

per ICH Q1A (R2)

Frozen or 2-8 °C

25°C (Accelerated)

Target Expiry 24 Months (minimum)

Minimum Data at

submission


applicable) and 6M (min)12M real time

N/A (Post-approval

updates)

Initial Expiry

Claim (ICH Q1E)12M, minimum 24M, minimum

Extensions with real-

time data

Storage label

ClaimFrozen or 2-8 °C Frozen or 2-8 °C

Phase IPhase

II

Phase

III/PVPostApp

Methods

11

Phase Specific Stability Tests (Small

Molecule DS)

Test List (ICH Q6A)

Appearance Verify consistency and free from foreign matter

XRPD

Chiral

Evaluate as applicable per

ICH Q6A decision trees 4

and 5Specifications as applicable

Assay Required: ICH Q6A

ImpuritiesEvaluate from development studies and ICH Q6A Decision Tree 2;

Report, Identify, Qualify per thresholds stated in ICH Q3A (R2)

Water ContentRequired: ICH Q6A unless otherwise justified

MLTN/A due to

rationale*TBD per ICH Q6A Decision Tree 6

Phase IPhase

II

Phase

III/RegPVR/

PostApp

* PAD control strategy for Phase 1

*

*

Methods validation

*

Specs Proposal/SRB

*

Methods: Large Molecule DS

• Additional methods

for process

impurities (e.g. HCP,

DNA, Leachate(s),

Viral inactivation

surfactants, etc) may

be added

Type of tests Assay Attribute

General

AppearanceColor

Clarity

pH pH

Osmolality Osmolality

Quantity Protein Concentration Total protein concentration

IdentityBinding Assay Identity

icIEF Identity

Biological

ActivityBinding Assay Potency

Purity and

Impurities

SEC Aggregate

Non Reducing CE-

SDS

Total Purity

Single Highest Impurity

icIEFLower pI Isoforms

Main Peak

Safety

Endotoxin (USP,EP) Endotoxin level

BioburdenTAMC

TYMC

13

Phase Specific Stability Tests (Small

Molecule Drug Product)

Test List (ICH Q6A)

Appearance Verify Product Appearance Conforms to Specification

Dissolution /

DisintegrationEvaluate per ICH Q6A Decision Tree 7

Specifications as applicable

Assay Required: ICH Q6A

ImpuritiesEvaluate from development studies and ICH Q6A Decision Trees 2 and 5;

Report, Identify, Qualify per thresholds stated in ICH Q3B (R2)

Water ContentRequired: ICH Q6A unless otherwise justified

MLTN/A due to

rationale*

Per ICH Q6A

Decision Tree 6

Per ICH Q6A Decision Tree 6 and also

required in some markets

(minimally on limited number of batches)

Phase IPhase

II

Phase

III/RegPVR/

PostApp

*PAD control strategy for Phase 1

* *

*

Methods validation

*

Specs Proposal/SRB

Methods: Large Molecule DP

• CCI is only tested on

stability

Type of tests Assay Component

General

Appearance

Color

Clarity

Particulates

pH pH

Osmolality Osmolality

QuantityProtein Concentration Total protein concentration

Extractable Volume Volume in container

IdentityBinding Assay Identity

icIEF Identity

Biological Activity Binding Assay Potency

Purity and

Impurities

SEC Aggregation

Non Reducing CE-

SDS

Total Purity

Single Highest Impurity

icIEFLower pI Isoforms

Main Peak

Safety

Endotoxin Endotoxin level

Sterility Sterility

CCI Container closure integrity

Particulates≥10µm Particles

≥25µm Particles

15

0

5

10

15

20

25

30

1 2 3 4 5 6 7 8 9

Ran

ge

Accuracy or Precision?

• Problem statement

– Yield for the material was outside

the 2σ Processing Limits.

– Yield was above 100%.

– Analytical and manufacturing

investigation revealed the

problem was likely to due to an

assay issue.

• Solution

– The problem was the variability

(not the accuracy, per se) of the

quantity assay, so there was a

need to reduce the variability of

the quantity assay.

60

80

100

120

1 2 3 4 5 6 7 8 9

1-P

oin

t A

verag

e

Accuracy versus Precision

What do you do?

Are these the right answers?

Maybe, maybe not?

How do you know????

Run more samples!

Run more replicate injections!

Step 1: Determine your precision

Four common methods

• Use of validation data

• Stability data

• Control data

• Blind control data

19

Use of validation data to determine

precision

Advantages

• Easy to acquire

• Provides variance component

analysis (even if only for a

‘moment in time’)

• Best accepted method

Disadvantages

• Rarely gives accurate assessment

of true variability

• Spotlight effect

› Underestimation of variability

due to intense concentration

and the use of highly skilled

analysts during special

studies such as validations

• Lack of long term variability

Example of using validation data

Analyst Day/Assay Instrument Capillary Result

1/1 6.5

1/2 7.2

1/3 6.7

2/1 8.1

2/2 7.6

1

2/3 8.2

1/1 7.8

1/2 7.6

1/3 7.3

2/1 7.4

2/2 7.0

2

2/3

1 1

7.0

1/1 7.4

1/2 7.6

1/3 7.2

1/4 7.4

1/5

2

7.1

2/1 6.2

2/2 6.6

2/3 6.7

2/4 6.1

3

2/5

2

3

7.1

Mean 7.2

Std 0.55

%RSD 7.7%

RSquare

RSquare Adj

Root Mean Square Error

Mean of Response

Observations (or Sum Wgts)

0.46645

0.377525

0.436357

7.172727

22

Summary of Fit

Model

Error

C. Total

Source

3

18

21

DF

2.9963030

3.4273333

6.4236364

Sum of Squares

0.998768

0.190407

Mean Square

5.2454

F Ratio

0.0089 *

Prob > F

Analysis of Variance

Intercept

Instrument

Capillary

Day

Term

6.66

1.3233333

-1.166667

0.3666667

Estimate

0.596177

0.59083

0.373674

0.251931

Std Error

11.17

2.24

-3.12

1.46

t Ratio

<.0001 *

0.0380 *

0.0059 *

0.1628

Prob>|t|

Parameter Estimates

Response Result

Use of stability data to determine

precision

Advantages

• Provides long term variability

• Relatively immune to Spotlight

effect

• Minimal contribution of

sampling variability

• No contribution due to

manufacturing variability

Disadvantages

• Material must be unchanging

or have a predictable rate of

change

• Can take a long time to

acquire the data set

• Lacks ability to show day to

day variability

• Periodicity can be invisible

Example of using stability data

Timepoint Potency Lot

1 39.06 A

2 42.70 A

3 46.53 A

1 39.86 B

2 40.48 B

3 39.79 B

4 42.14 B

5 37.06 B

1 36.13 C

2 39.36 C

3 37.66 C

4 38.97 C

5 35.20 C

6 40.18 C

1 40.22 D

2 41.34 D

3 40.72 D

Lot

A B C D

Mean 42.76 39.86 37.92 40.76

Standard

Deviation 3.74 1.83 1.95 0.56

RSD (%) 8.74 4.60 5.13 1.38

Estimated Method RSD (%) 5.0

Use of control data to determine

precision

Advantages

• Easy to do, if control data is

available


analysis

• Provides long term variability

Disadvantages

• Spotlight effect

› Especially when there are

acceptance criteria or system

suitability criteria associated with

the control

• Control must be run identically

to sample

Example of using control

data

12

12.5

13

13.5

14

14.5

15

15.5

16

0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75

Indiv

iduals

0

0.5

1

1.5

2

2.5

0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75

Mo

vin

g R

an

ge

s = 0.326s = 0.132

s = 0.578

Use of blind control data to determine

precision

Advantages

• Best way to understand true

analytical variability

• Eliminates the Spotlight effect


analysis

Disadvantages

• Takes more organization than

other means

• Usually does not show long

term variability

Example of using blind control data

0

1

2

3

4

5

6

7

8

9

10

0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75

Indiv

iduals

0

1

2

3

4

5

6

7

0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75

Movin

g R

ange

Laboratory expanded

Step 2: Reduce variability

• So now you know your precision, what’s next

• (Ruthlessly) reduce variability!!!

› The exercise will give an example of the effects of reducing

variability

• Steps

› Identify sources of variation (e.g. reagents, equipment, techniques,

practices, knob twisting, etc.)

› For reagents and equipment – take the randomness out of the

process and standardize

› For techniques and practices – decide on one-way of doing things

› Implement changes

28

Case Study: Variability reduction

project

• Purpose

› Reduction of controllable variability within all critical assays.

› Provide data that is irrefutable within the inherent variability of the

method.

› Build a relationship of trust between the laboratory and the

customers.

• Execution

› Scientist driven [CRITICAL]

› Step by step review of each method

› Identification of agreed upon best practices

› Published minutes documenting best practices

› Training Syllabus

Present Future

29

Concentration DOE Data Summary

• Scientist portion of the total

variability dropped over 72%

for the drug substance and

47% for the intermediate

• Overall variability dropped

50% for the drug substance

• No drop for the intermediate

– This is due to variability in

dilutions

Assay Control

(Intermediate)

Drug Substance

Total Analyst/

Assay

Total Analyst

Pre-

project

DOE

92.7 79.2 30.6 22.2

Post-

project

DOE

96.5 41.6 15.3 6.2

% Drop

in s

0% 47% 50% 72%

Intermediate – Before = 5.1%; After = 5.6%

Drug Substance – Before = 6.3%; After = 3.2%

Proposed replication strategy

• Two scientists run the assay

independently

› Keep n = 4 replicates, but they must be

independent draws from the sample. This

will also help if there is any homogeneity

variability.

› Averages across scientist

› Averages across two standard curves

(key component of variability)

• No acceptance criterion for agreement

between replicates or between scientists

› The point of the replication strategy is to

average out variability

1 2 3 4

Sample Replicates

Analyst 1

Result Result Result Result

1 2 3 4

Sample Replicates

Analyst 2

Result Result Result Result

A

Concentration

A

Concentration

31

Does it work?

0.6

0.7

0.8

0.9

1

1.1

1.2

1.3

1 6 11 16 21 26 31 36

1-P

oin

t A

vera

ge

0

0.05

0.1

0.15

0.2

0.25

0.3

0.35

0.4

0.45

0.5

1 6 11 16 21 26 31 36

Ran

ge

RSD pre-improvement = 10.3%

RSD post-improvement = 1.9%

Formulation

33

Formulation: Studies

• The various buffer combinations are studied to determine the impact on

quality attributes:

› DOEs to optimize the formulation.

› Short term stability to justify selection.

• Formulation lock

› Research different formulations leading to the selection of a lead

candidate

› Confirming final concentration

› 6 months of stability data will be collected to confirm stability

34

Drug Product

35

Drug Product: General Assumptions


• What is the final formulation for the DP? Is it the same as DS?

• What storage temperature(s) will be used?


• What container closure(s) will be used? Are there multiple

presentations?

36


Considerations (Small Molecule)

# of Batches 1 / strength 1 / strength 3a 0-3b

Storage Condition

per ICH Q1A (R2)

30°C (Zone IV) Globally

25°C (Zone II) – Back-up condition to 30°C (Zone IV)

40°C (Accelerated)

Target Shelf-life 36M, minimum

Minimum Data at

submission


applicable) and

1 month 40°C (min)

12M LT + 6M Acc.N/A (Post-approval

updates)

Initial shelf-life

6M, min

(with 6M development data,

initial shelf-life 12M)

24M, minimum Extensions with real-

time data

Storage label

Claim

Store below 30°C

(Store below 25°C, if applicable)

Store below 30°C

(Store below 25°C, if applicable)

a: at least 1 batch at commercial scale

b: depending on # of full scale registration batches, a total of 3 batches at commercial scale.

Phase IPhase

II

Phase

III/RegPVR/

PostApp


Studies (Small Molecule)

Special Study

Description

Photostability

(ICH Q1B)

If DS photosensitive,

evaluate at Ph1

(1 batch)

Conduct in Ph3 / final

commercial image in open dish

and commercial package (as

applicable)

Temperature cycling


studies

N/A – support handling / TE with

stability data

Conduct to support supply chain

and handling of drug product,

and unmonitored shipping of

drug (1 batch)

Bulk Hold Studies N/A through phase 2

Conduct on 1 batch per ICH

conditions in bulk container (or

smaller, comparable container).

In-use stability

(for multidose

containers)

EU Guidance:

CPMP/QWP/2934/99

N/A through phase 2

Conduct on 2 batches in worst-

case commercial multidose

container; with one batch at end

of shelf-life.

Phase IPhase

II

Phase

III / RegPVR/

PostApp


Considerations (Large Molecule)

# of Batches 1 1 3a 0-3b

Storage Condition

per ICH Q1A (R2)

2 - 8°C

25°C (Accelerated)

40°C (Stressed)

Target Shelf-life 36M, min

Minimum Data at

submission


applicable) and

6M (min)

12M LT + 6M Acc.N/A (Post-approval

updates)

Initial shelf-life 12M, min 24M, minExtensions with real-

time data

Storage label

ClaimStore at 2-8°C

Store at 2-8°C

(X months outside of refrigeration, if

applicable)

Phase IPhase

II

Phase

III/PVPostApp


Studies (Large Molecule)

Special Study

Description

Photostability

(ICH Q1B)

Conduct in final commercial

package

Temperature cycling


studies


and handling of drug product (1

batch)

Secondary CCS

Conduct many of the same studies needed for the

original CCS (omit photostability, End to End,

Cycling studies)

End to End

Conduct on 1 batch; Need DS at

expiry and then longterm,

accelerated, stress DP studies

Phase IPhase

II

Phase

III / PVPostApp

Drug Product: Needs

• Final packaging for Photostability studies

• Pstab data for Cycle 2 and Cycle 3 concentrations

• Final formulation

• Specifications

• Confirmation of no method changes

• # vial sizes (assumption is 3) and fill volumes

• “Worst case” justification

• Ask agencies for the ability to use statistics (CMC question)

• Patient convenience needs?

• In use stability data

• Will excipient to protein ratio be the same across all strengths

• Agency agreement on stability strategy

41

Packaging and Device

42

Packaging and Device: General

Assumptions


• Is the container the same or is a switch needed for the device?


• What container closure(s) will be used? Are there multiple

presentations?

43


Considerations (Devices)

# of Batches N/A N/A 3 0

Storage Condition

per ICH Q1A (R2)

2 - 8°C

25°C (Accelerated)

40°C (Stressed)

Target Shelf-life 36M, min

Minimum Data at

submission12M LT + 6M Acc. N/A

Initial shelf-life 24M, minExtensions with real-

time data

Storage label

Claim

Store at 2-8°C

(X months outside of refrigeration, if

applicable)

Phase IPhase

II

Phase

III/PVPostApp


Studies (Devices)

Special Study

Description

Photostability

(ICH Q1B)

Conduct in final commercial

package

Temperature cycling


studies


and handling of drug product (1

batch)

End to End

Conduct on 1 batch; Need DS at

expiry and then longterm,

accelerated, stress DP studies

Phase IPhase

II

Phase

III / PVPostApp

Specifications

46

The Specification Process

• Specifications are reviewed by a committee with a chairperson as the lead

› Committee is a standing cross-functional team with other ad-hoc

members brought in as needed

› Additional Executive committee is available for new modalities,

specification strategy, and higher level discussions.

• Intent is to infuse and maintain consistency of approach for specification setting

and rationale

• The Specification report is the internal technical report supporting the proposed

specifications/strategy; intended to be a more detailed version of the 32S45 and

32P56 filing documents (e.g. extensive explanation of stats where applicable)

47

The Specification Process: Scope

• Specification review process applies to all stages, but is phase-

appropriate

• Platform specifications have been developed for early stage

compounds based on standardization

› Action limits have been added at release while we are still learning

about the molecule

• Inquiries impact specs, this is also in scope of SRB review and

endorsement

48

Specifications: Assumptions

• Clinical specifications are the maximum ever submitted (likely lower)

• Best support for any specification is clinical data

• Manufacturing capability will drive final specifications as well

• Japan only allows one specification; so stability specification is licensed

specification

49

Specifications: Drug Substance

Type of

testAssay Component Release Limit Stability Limit

General

AppearanceColor <YX Same as Release

Clarity < A NTU Same as Release

pH N/A TBD (equal tail tolerance) Same as Release

Osmolality N/A TBD (equal tail tolerance) N/A

Quantity Concentration N/A TBD (equal tail tolerance) N/A

Identity

Binding Assay N/AMeets Biological Activity

SpecificationN/A

icIEF N/AComparable to reference

standardN/A

Biological

ActivityBinding Assay N/A

TBD (equal tail tolerance) +

clinical experienceSame as Release

Safety

Endotoxin

(USP,EP)N/A ≤ Z EU/mL N/A

BioburdenTAMC ≤ Y CFU/10mL N/A

TYMC ≤ Y CFU/10mL N/A

50

Specifications: Drug Substance

(cont’d)

Type of

testsAssay Component Release Limit Stability Limit

Biological




Purity and

Impurities

SEC N/ATBD (equal tail tolerance) +

clinical experience

= DS release spec + D X

mos

Purity

Total PurityTBD (equal tail tolerance) +

clinical experience


mos

Single Highest ImpurityTBD (equal tail tolerance) +

clinical experience


mos

pI

Lower pI IsoformsTBD (equal tail tolerance) +

clinical experience


mos

Main PeakTBD (equal tail tolerance) +

clinical experience


mos

• For highlighted parameters, if DS is stored frozen, there is no need for a different stability

limit as there are no trends over time for frozen material.

• X months is the shelf life of DS

51

Specifications: Drug Product

Type of


General

Appearance

Color <YX Same as Release

Clarity < A NTU Same as Release

Particulates Essentially Free of Particles Same as Release

pH N/A TBD (equal tail tolerance) Same as Release

Osmolality N/A TBD (equal tail tolerance) N/A

Quantity

Concentration N/A TBD (equal tail tolerance) N/A

Extractable

VolumeN/A ≥ X mL N/A

Identity

Binding Assay N/AMeets Biological Activity

SpecificationN/A

icIEF N/AComparable to Reference

StandardN/A

Biological




Safety

Endotoxin N/A ≤ Z EU/mL N/A

Sterility N/A No Growth N/A

CCI N/A N/A Pass

Particulates≥10µm Particles ≤6000 Particles/Container Same as Release

≥25µm Particles ≤600 Particles/Container Same as Release

52

Specifications: Drug Product (cont’d)

Type of


Purity and

Impurities

SEC N/ATBD (equal tail tolerance) +

clinical experience

= DS release spec + D Y mos

+ DP Mfg

Purity

Total PurityTBD (equal tail tolerance) +

clinical experience


+ DP Mfg

Single Highest

Impurity


clinical experience


+ DP Mfg

icIEF

Lower pI IsoformsTBD (equal tail tolerance) +

clinical experience


+ DP Mfg

Main PeakTBD (equal tail tolerance) +

clinical experience


+ DP Mfg

• For highlighted parameters, if DS is stored frozen, the formula will be DP release specification + D Y

months + DP Mfg

53

Label

54

Label

• Label will include expiry and storage temperature

• Package insert will include patient convenience details

55

Setting Specifications for Stability: Case Study

Approach

• Product quality attributes for this compound demonstrate significant change as

a function of storage time and temperature:

• Global Stability collaborated with several groups to set release and stability

specifications.

• DS stability specification calculation = (DS release specification) + (maximum

predicted change over storage)

• DP stability specification calculation = (DS release specification) + (change

predicted during DP manufacturing) + (maximum predicted change over DP

storage)

57

Widening Stability Specifications: Case Study

Case Study: Specification Widening

• A new manufacturer for the DP

was being added for a biotech

product

• As part of the submission, a

specification was widened.

• At the 5±3°C long-term storage

condition, a biphasic trend exists

• Appropriate statistical model was

applied to fit the data set

• The change was then calculated

between the intercept of the

common slope line at T=0 and the

plateau of the upper 99.9%

confidence interval at shelf life.

The resulting value represents the

worst case on stability.

59

• The widening was supported by a

tox/safety assessment.

• The proposed widening was

accepted!

A word about the Regulatory filing…

CTD

Module 3Quality

3.0

CTD Table of Contents 2.1

CTD Introduction 2.2

Quality

Overall

Summary

2.3

Nonclinical

Overview 2.4

Nonclinical Written

and Tabulated

Summaries 2.6

Clinical

Summary

2.7

Clinical

Overview

2.5

Module 2

Not Part of the CTDModule 1Regional

Administrative

Information

1.0

Module 4Nonclinical

Study Reports

4.0

Module 5Clinical Study Reports

5.0

CTD Structure

CMC Granularity

• Granularity depends on the product and life cycle decisions

› Defines how the completed document is broken down, tagged and stored for reuse

› Determines smallest piece of information that is reusable

› Changing granularity during lifecycle is difficult, therefore must be planned at the

beginning.

• More complex products, such as biotech, typically benefit from greater

granularity

• Granularity beyond the ICHM4 granularity annex can be used, such

as sub-sections or attached reports; these are separate

documents/leaves

62

Stability Information (32S7 and 32P8)

• Summary and Conclusions (32S71 and 32P81)

› This includes a summary and analysis of the stability data, including figures

• Post-approval Stability Protocol and Commitment (32S72 and 32P82)

› This includes the post-approval stability protocol, with analytical methods,

specifications, and timepoints tested

• Stability data (32S73 and 32P83)

› This includes the stability data tables

• Additional stability documents (e.g. in-use stability, clinical stability,

stress testing, etc.) may be included as separate documents (e.g.

additional granularity)

• Legacy programs may have slightly different set-ups

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Specification Information

• DS Specifications are listed in 3.2.S.4.1; DP Specifications in 3.2.P.5.1

• Justification of these specifications are presented in 3.2.S.4.5 (DS)

and 3.2.P.5.6 (DP)

• Justification for method stability indicating behavior can be put in

several places in the dossier – pick one and put hyperlinks in the

other places

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Managing Multiple Versions

• Ideally, there is only one version of the filing used for all markets

• In practice it is difficult to have a single version (if not impossible)

› Japan requires more detail in the manufacturing and testing sections than any

other market

› Specifications between markets can be difficult to align

• For 32S7 and 32P8, it is often easy to have one version of the stability

data and stability conclusion sections

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Documents

Data Evaluate, Set Specifications and Prepare Reports 11 –Stability Data –Evaluate, Set Specifications and Prepare Reports Dan Willingmyre, Neha Frantz, Philip Pue-Gilchrist, Donnie