Post Approval Stability Studies - PowerPoint Presentation

Slide1

Post Approval Stability StudiesSlide2

LEARNING OBJECTIVES

Awareness of ICH /

EMA

/ other

Stability Guidelines

Understand

minimum requirements for

Routine Stability study

of

marketed products (for

API,

Drug Product

and

Medical Device)

Understand necessary studies/changes

that impact

marketed product stabilitySlide3

ICH Guidelines - Stability

Q1A(R2) - Stability Testing of New Drug Substances and Products (

Revision 2

) (August 2003) = CPMP/ICH/2736/99 : Zones I and II

Q1B –

Photostability

Testing of New Active Substances and

Medicinal Products

(January 1998) = CPMP/ICH/279/95

Q1C – Requirements for New Dosage Forms (January 1998)

= CPMP/ICH/280/95

Q1D – Bracketing and

Matrixing

Designs for Stability Testing of

Drug Substances

and Drug Products (August 2002) = CPMP/ICH/4104/00

Q1E – Evaluation of Stability Data (August 2003) = CPMP/ICH/420/02)

Q1F – Stability Data Package for Registration Applications in Climatic

Zones III

and IV (August 2003) = CPMP/ICH/421/02 :

Withdrawn on June 1st 2006.

Q5C – Stability Testing of Biotechnological/Biological Products (July 1996)

= CPMP/ICH/138/95Slide4

EMA Guidelines - Stability

Stability Testing of Existing Active Substances and Related

Finished Products

: CPMP/QWP/122/02, rev 1 (March 2004)

Declaration of Storage Conditions :

A : In the Product Information of Medicinal Products

B : For Active Substances : CPMP/QWP/609/96/Rev 1 (October 2003

)

(

Annex to ICH Q1 A (R2) and to CPMP/QWP/122/02, rev 1)

Stability Testing for Applications for Variations to a

Marketing

Autorisation

: CPMP/QWP/576/96 Rev 1 (01 December 2005)

DRAFT : Stability Testing for Active Substances and

Medicinal Products

manufactured in Climatic Zones III and IV to be marketed

in the

EU : CPMP/QWP/6142/03 – Consultation (August 2004)Slide5

Additional Guidelines (1)

EMA Guidelines

Start of shelf-life of the finished dosage form (Annex to NFG on the manufacture of the finished dosage form): CPMP/QWP/072/96 (December 2001)

EU Commissions Guidelines

Notice to applicants: Dossier requirements for Type 1A and type 1B notifications – Volume 2C (June 2006)

US FDA CDER 21 CFR Part 211.166

Current Good Manufacturing Practice

for Finished Pharmaceuticals-Stability Testing

US FDA CDER Guidance for Industry

Changes to an Approved NDA or ANDA

April 2004Slide6

Additional Guidelines

(2)

ASEAN Guideline on stability study of drug

product, updated

version February 22, 2005 : Drug products

: NCE

, Generics and

Variations

WHO Technical Report Series N° 863, 1996, Guidelines

for stability

testing of pharmaceutical products containing

well established

drug substances in conventional dosage

forms, revised

by technical Report Series N° 908, p 13, 2003 and N°

937, p

12, 2006.Slide7

Additional Guidelines

(3)

WHO Working document QAS/06.179/Rev.2

August-September 2007

: Stability testing of active pharmaceutical ingredients

and pharmaceutical

products.

Close to ICH Q1A(R2) and

EMA

CPMP/QWP/122/02, rev 1

New Chemical Entities and existing APIs and their

related pharmaceutical

products, not applicable for

biologicals

Specific items : In-use stability,

variations

,

o

ngoing

stability studies

Climatic Zones : I, II, III, IVA, IVB

Climatic Zones defined for some countries (less WHO

Eastern Mediterranean

Draft regional compared to Rev 1 April 2007)

WHO Eastern Mediterranean Draft regional guidelines on

stability testing

of active substances and pharmaceutical

products, August

2006 : NCE, existing active substances and

related pharmaceutical

products.Slide8

Additional Guidelines

(4)

Brazil : Guide for the Undertaking of Stability Studies

: Federative

Republic of Brazil ; National Press, Official

Gazette of

the Union Supplement to N°. 146 - Section 1 Brasilia -

DF, Monday

, August 1st,

2005.

Ministry

of Health, National Agency of Health

Surveillance, Resolution

- RE N°. 1, of July 29, 2005

Guide for undertaking the stability tests of

pharmaceutical products

so as to predict, determine or follow-up their

validity term

Long-term conditions : Zone IVB : general case 30°C ±

2°C 75

% RH ± 5% RHSlide9

Purpose – Stability Studies

A marketed product stability program

fulfils registration

commitments and ensures that

marketed product

is stable (potent) until expiry date

stamped on

product

label

Post-approval stability testing is to

verify that

Active Pharmaceutical Ingredients (API

), Pharmaceutical

Products and Medical

Devices comply

during their retest period or shelf life with

the specifications

defined in the Marketing

authorisationSlide10

Stability Study….

Provides

evidence on how the quality of

an active

pharmaceutical product, medical

device, or

pharmaceutical product (i.e. drug

product) varies

with the time under the influence of

a variety

of environmental factors such

as temperature

, humidity and light and

enables recommended

storage conditions,

retest date/periods

or shelf life to be

established.Slide11

Common Terminology (1)

Long-term testing :

Stability studies under the recommended storage condition for the

retest period

or shelf-life approved for

labelling

Accelerated testing

:

Studies

designed to increase the rate of chemical degradation

or physical

change of active pharmaceutical product, medical device

or pharmaceutical

product (I.e. drug product) by using

exaggerated storage

conditions as part of the formal defined storage program

Climatic Zone :

Zones

into

which the world is divided based on the prevailing

annual climate

conditions. Zone I is temperate. Zone II is subtropical

and Mediterranean

with possible high humidity. Zone III is hot and

dry. Zone

IVa

is hot and humid. Zone

IVb

is hot and very humid.Slide12

Common Terminology

(2)

Date of Manufacturing :

The first day of compounding for pharmaceutical products. It is

the date

of the final production step for chemical substances

Retest Date :

The date after which samples of the API should be examined

to ensure

that the material is still in compliance with the specification

and thus suitable

for use in the manufacture of a given

pharmaceutical product

Shelf life :

The time interval that a pharmaceutical product (i.e. drug product)

or medical

device is expected to remain within the

approved specification

provided that it is stored under the conditions

defined on

the label in the proposed containers and closureSlide13

Common Terminology

(3)

Expiry date/Expiration date :

The date placed on the container label of an API /

pharmaceutical product

designating the time during which a batch of the API

/ product

is expected to remain within the established/approved

shelf-life specification

, if stored under defined conditions, and after

which it

must not be

used

Bracketing :

The design of stability schedule such that only samples on

the extremes

of certain designs factors (e. g.

strength,

container

size and/or

fill) are tested at all time points as in the full design. The

design assumes

that the stability of any intermediate levels is represented

by the

facility of the extremes tested

Matrixing

:

The design of a stability schedule that a selected subset of the

total number

of possible samples for all factor combinations would be

tested at

a specified time point

T

0

:

Initiation of the stability study (i.e. samples put in the

climatic chambers

)Slide14

Routine Post Approval Stability Testing

Routine stability monitoring

is performed to confirm

stability characteristics of

tested materials

during the routine production :

Verify the retest date/expiry date established

for active

substances and shelf life/expiry date for

drug products

and medical devices,

demonstrating current

product and process is under control

Stability studies on routine annual batchSlide15

Changes and Variations (1)

Whenever a change to product, pack, process or site is

made,

that

may affect

product stability (

assessed

by Change Control system

or stability

failure

investigation) stability testing is initiated to

:

Verify the established expiry period, including first 3 production batches

Support change in the source of active substance/excipient for existing product

Support change to product, package, process for existing product

Justify a bulk holding time

Support site transfer for existing product

Support a process/product deviation investigation

Support reworking/reprocessing

Support a change of storage conditions (for example to ICH conditions)

Support extension of the initially established expiry periodSlide16

Changes and Variations (2)

The decision regarding the classification

of any

change as a minor (Type IA and IB)

or major

(Type II) change should be made on

a scientific

basis and based upon the

EC Notice

to Applicants

Guideline

With respect to the existing registered formula

of known

stability profile.Slide17

Examples of Minor Changes – Little or no impact on product stability (1)

Minor changes in synthesis of drug substances

where there is no

change in qualitative

and quantitative

impurity profile or in

physico

-chemical properties i.e. particle

size, apparent volume. The

active substance is not a biological

substance and the synthetic

route remains the

same

Change

in specification of an

excipient. The

change does not

concern adjuvant

for vaccines or a biological

excipient

Change

in test procedure for an

excipient. The

substance is not a

biological excipient

Change in the specifications of the

primary

packaging of the

finished product

Change in batch size of the finished product :

up/down by a

factor

of 10

times the size of the original approved

batch. Normally stability studies

are requested when batch size is up/down scaled more than

10 times

(biological active substances excluded).Slide18

Examples of Minor Changes – Little or no impact on product stability

(2)

Change to alternative equipment of the same design and

operating principles

(a minor change in the manufacturing process of

the finished

product

requires

stability studies).

Change in test procedures of drug product with no change

in specification

(i.e.,

optimisation

of methods).

Change in the dimensions of tablets, capsules, suppositories

or

pessaries

; without change in the quantitative composition

and mean

mass.Slide19

Examples of

Major Changes

–

Likely to impact

on product stability

(1)

Any

quantitative or qualitative excipient

changes

Change in the technical grade of an excipient

i.e. particle size

Change in manufacturer for drug substance

Major

changes in synthesis of drug

substance (change

in qualitative or quantitative impurity profile

)

Changes in the excipient ranges of low solubility

or low

permeability drugs.Slide20

Examples of Major Changes – Likely to impact on product stability

(2)

Change of storage

conditions

Change in specifications of the drug product or

API

Change in test procedures linked with a change in

specification

Change in dimensions of a sustained release

formulation

Major changes in manufacture of the drug

product

Change from wet granulation to direct compression of dry

powder

Site change to a contiguous facility on the same campus

or change

of the manufacturing site to a different

campus

Change in batch size beyond 10 times the size of the

original batch

Change to equipment of different design and different

operating principles

.Slide21

Responsibilities – Site Management (1)

Ensure procedures and systems for

Stability Programs

including review and approval

of stability

protocols and

reports

Ensure adequate storage, utilities,

equipment, security

and personnel to perform

stability programs

With Manufacturing representative, select

batches to

be put under stability including

campaign production.Slide22

Responsibilities – Site

Quality (2)

To optimise resources select

batches to be put in stability in

the event

of multiple

changes instead

of putting all batches

on stability

Rapidly

react and initiate follow-up actions (with Quality

Control)

in case of unusual observations : OOS or OOT

during testing

Ensure

SOPs

for Stability Programs

are

in place

and are consistent

with

company policies and

other

regulatory requirements

Ensure pharmaceutical products

manufactured, packaged or distributed by (or for) the

given site

are put under stability

Involved in the review and approval of potential changes

to product, manufacturing process or packaging that

may impact on product’s

stability profile and shelf-life.Slide23

Responsibilities – Site

Quality Control (3)

Written procedures for

initiating/conducting stability programs

Labelling

samples for stability studies in an

adequate manner

reporting/trending/archiving data

maintenance/calibration of storage/testing

equipment

Organise

periodical review of data

and reporting

trends that may result in

product failing

to meet specifications during

retest period

or shelf-lifeSlide24

Responsibilities –

Laboratory Manager/Analyst (4)

Laboratory

complete

review of laboratory actions leading

to stability

result and approve

laboratory investigations

reports, retest plans,

re-sampling justification

and plans, conclusion from

failure investigations

Analyst

identify OOS/atypical results (OOT)

– report them

to laboratory managementSlide25

General Points To Consider (1)

Approved protocols for each study (Routine

or post-approval

variations) in compliance with

the zone

in which the product is

marketed

In the event the

Manufacturing and Packaging operations are

performed at different sites, a

decision must

be taken as to which

site is

responsible

for routine

post-approval stability

study

Site Management/Quality

must be immediately

informed in case of result failure

: OOS/OOT.Slide26

General Points To

Consider – Storage Facility Control and Maintenance (2)

Use Robust systems where possible, for example continuous

power supply

: back-up generator, alarm, back-up climatic chambers

Prior to use, Storage Facilities mapped for temperature &

humidity with

typical load pattern. Re-map when significant changes to area

or controls

Storage Facilities calibrated regularly : temperature and humidity

Procedures to continuously monitor temperature and humidity

What actions in event of storage condition failure ?

Record failures : Review and assess by senior stability person

Deviations must be documented and require investigation(s)

Keep Durable Records of storage conditions

Archive 1 year minimum beyond expiration date of any

products

stored.Slide27

General Points To Consider –

Stability Protocol (3)

Each approved protocol must contain :

Purpose: objective

of study

Specifications:

tests and associated acceptance limits/criteria

Storage Conditions/Test

Schedules:

correlate condition with test interval

and test

performed at that interval

Sample

Requirements:

number of samples for each time point and

for the study

as

a whole

Follow regulatory and product license requirements

Approved protocols are

binding

Changes are discouraged - if necessary through approved

change control procedure

Use stability indicating methods, in case of method

change: new method

must be validated,

and approved.

A

nalytical results

from new

methods should be

proven through comparison to

previous results.Slide28

General Points To Consider – Stability Protocol

(4)

Studies conducted on samples manufactured at

the site;

in the event manufacturing, packaging

or distribution

performed at different sites >>

decision must

be taken which site is responsible for

follow-up stability testing

Studies on at

least one lot per

year

High volume products

(e.g. >50

batches per

year) requires studies on more

than one batch per

year

All marketed products included in a stability

program: strength/packaging.Slide29

General Points To Consider – Stability Protocol

(5)

Not every primary packaging presentation but

the most

sensitive/vulnerable

The use of « Bracketing » and/or «

Matrixing

» permitted

but must be justified

Consideration must be given to storage

conditions between

the time the sample is taken and the

analysis is performed: minimise

degradation process

Bulk storage, holding-times, time out of

refrigeration or

freezing, storage of intermediates, in-use

and transportation

stability, as appropriate must

be studied.Slide30

General Points To Consider – Stability Protocol

(6)

For initiation of stability study (T

0

) after date

of manufacturing:

within 3 months

For withdraw from storage : between 2 weeks of

planned time point

and at the same time samples must be

retrieved just

prior to analysis. If time point not met, samples kept

in climatic

chambers and report bears actual retrieval

and testing

dates

For finishing analysis after having retrieved samples

: within

30 calendars days (unless test duration is >

30 days

), if additional time is

required,

the

original retrieved samples must be stored

at conditions

that minimise

the

degradation process.Slide31

General Points To Consider –

Criteria's to be Monitored (7)

Change

in

Colour,

Appearance of Product/Package (

including labelling)

Potency and Purity at each time point – Impurity Profile

/ Degradation impurities:

Any new observed impurities

?*

Pharmaceutical Properties, some examples :

Disintegration/Dissolution for solids

Dose Delivery/Unit Spray Content for Aerosols

*

Refer to ICH

NFG:

Q3

A(R)

Impurities

in New Drug Substances (

August 2002

) = CPMP/ICH/2737/99; Q3 B ( R )

Impurities

in New Drug

Products (August

2003) = CPMP/ICH/2738/99 and European Pharmacopoeia

Monograph: “

Substances for Pharmaceutical Use” 01/2005Slide32

General Points To Consider – Criteria's to be Monitored

(8)

Microbial contamination

Parenterals

: Sterility test,

Pyrogens

, Endotoxins

(tested at least

at expiry date)

Products normally stored upright

consider additional orientations, for example change

to container/closure

Photo-stability & Freeze-Thaw

studies. These are

usually not

performed for Follow-up or

after variations

Note: Programs

conducted in Final Market Primary Package for

DP, API

or Bulk DP sold in large drums may be placed

in smaller/equivalent containers for stability studies, based on a justified rational. Slide33

General Points To Consider –

Contract Laboratories and Transfers (9)

Satisfactory audit prior to any start of testing

Analytical procedure (method) transfer successfully concluded

In case of production transfer, routine post marketing stability

testing transferred

to receiving site

Stability program must be established as part of product

transfer process

If manufacture is in the situation of terminating, stability program

must be

continued to end of shelf life

If a solid dosage form is produced at one site and packaged at

another, stability

program may be reduced at one site if stability is not

critical and

packaging materials and processes are

equivalent.Slide34

General Points To Consider –

Data Review and Reporting (10)

Quality management must review

stability results

at

least annually

Trend analysis of data must be undertaken. Trends

that would

predict a failure for product/medical device

to meet

shelf life specifications is

to be managed through a quality alert reporting procedure

OOS and OOT must be investigated according to

the corresponding procedure

In case of a confirmed OOS, local requirements must

be considered

for

reporting

to regulatory

authorities.Slide35

General Points To Consider – Data Review and Reporting (

11)

All results presented in stability

reports

Must be approved by senior stability

personnel

Suitable quality for submission to regulatory authorities

Issued at each significant milestone of study

Contain conclusions and shelf-life recommendation

Based upon full review of data and statistical analysis,

as appropriate

.

See Guidance from ICH Q1E (Evaluation of Stability Data)

Several statistical treatments possible - not specified here

End with Stability Report DesignSlide36

Example Stability Report Format (1)

I

Cover & Approvals signatures

II

Introduction Purpose

of study, products, packages, site and any other information

III

References Protocol

number, approval date and indication as to

whether the protocol

is included in the corresponding (A)NDA.

IV

Results should be tabulated

by lot/study

V

Analysis A

. Statistical

Analysis Regression

Analysis (with tests for

similarity

of slopes

by strength

, package and lot), as

appropriate any other Analysis.

B

. Protocol

Deviations*

*

Note:

all deviations from the protocol or acceptance

criteria must

p

rovide

justification

for accepting

the deviation or out of specification

result where applicable.Slide37

Example Stability Report Format (2)

VI

Conclusions

, Study

meets/fails acceptance

criteria, references

to other supportive

data/studies

VII

Recommendations,

Study

support and expiration date (of

xx

months)

and any

other Recommendations.Slide38

Example Stability Report Format (2)

VI

Conclusions

, Study

meets/fails acceptance

criteria, references

to other supportive

data/studies

VII

Recommendations,

Study

support and expiration date (of

xx

months)

and any

other Recommendations.Slide39

Long Term Stability Storage Conditions (1)

Storage conditions

Zone I

25

°

C

+/- 2°C / 45% RH +/- 5% RH

Zone II

25

°

C

+/- 2°C / 60% RH +/- 5% RH

Zone III

30

°

C

+/- 2°C / 35% RH +/- 5% RH

Zone IVa

30

°

C

+/- 2°C / 65% RH +/- 5% RH

Zone

IVb

30°C +/-2°C / 75% RH +/- 5% RH

Temperature sensitive products (intended for storage in

a refrigerator

) 5°C

+/- 3°C

Temperature sensitive products (intended for storage in

a freezer

) - 20 °C

+/- 5°C

Products in semi permeable containers 25 °C

+/- 2 °C

/ 40 %

RH

+/-

5 % RH

or 30 ° C

+/- 2 °C

/ 35 % RH

+/- 5 % RHSlide40

Long Term Stability Storage Conditions

(2)

Relaxing

measures:

To keep the number of storage chambers for the

respective manufacturing

site at

a

minimum necessary, studies planned

for Zone

I might also be

performed

at Zone II conditions (25 °C +/- 2 °C

/60

% RH +/- 5 % RH

)

For products in impermeable containers, relative

humidity is

not a relevant parameter.Slide41

Long Term Stability Storage

Conditions – Post Variation Studies (3)

Accelerated Storage Conditions

+ 40° C ± 2ºC/ 75% RH ± 5 % RH

For products intended for storage in a

refrigerator: 25°C

+/- 2°C / 60 % RH +/- 5 % RH

For products packaged in semi-permeable

containers: 40

°C +/- 2 °C RH max 25

%

See next

slide

for summary table on routine

s

tability monitoring and sampling and testing requirements for qualifying changes. Slide42
Slide43

Table A – Sampling and Testing Frequency

=

release or shelf

life specification

X

=

mandatory time point with reduced risk based

testing

permitted

= optional

additional time point depending on earlier time point stability resultsSlide44

Table B – Sampling and Testing Frequency

=

release or shelf

life specification

X

=

mandatory time point with reduced risk based

testing

permitted

= optional

additional time point depending on earlier time point stability resultsSlide45

Conclusion – Stability Studies (1)

If a risk-based

approach to stability is followed during development, then the stability characteristics of an API and drug product

would

be properly understood and

mapped

Although the resource and cost requirements of this approach may be greater initially, it should ensure that product failures due to unexpected stability results are avoided

further in the product life cycle.

Adopting a science and risk-based approach, combined with an accelerated predictive model leads to >>Less routine, non value added studies during development and commercial phases

Facilitates in the continuous improvement of processes without the need to wait for unnecessary long-term data before changes could be

implemented.Slide46

Thank You

Any Questions