2013-09-18 USP Stability 3 Operations

III. Critical Stability Operationsd St bilit P t land Stability Protocols

Critical Stability Systems

Regulations ProceduresRegulations(I)

Procedures(II)

Stability Systems

Operations(III)

Investigations(IV)

Copyright USP. All rights reserved.

Discussion Topics

3. Best Practices on Stability Operations

` Establish compliant stability protocols` Establish compliant stability protocols

` Define Stability Day-to-Day Operations

` Discuss best practices on these operations

` Discuss key factors of environmental chambers


Documentation Practices: Stability Protocol

1. Contents of a Stability Protocol2. Storage conditions3. Selection of batches4. Testing frequency5. Specifications / tests6. Reduced design (Bracketing and Matrixing)7. General considerations


Typical Global Stability Protocol

TEMP TZ 1 2 3 6 9 12 18 24 36HUMIDITY TZ Mo Mo3

Mo6

mo Mo Mo8

Mo mo36Mo

25 C25 C60%RH X X X X X X X X

30 C65%RH X X X X (X) (X) (X)

(30 C75%RH) X X X X X X X X

40 C75%RH X (X) X X (X) (X)75%RH ( ) ( ) ( )

50 C X

5 C H O L D

Handbook of Stability Testing in Pharmaceutical Development: Regulations, Methodologies and Best Practices, K. Huynh-Ba (ed.), Springer, November 2008, Chapter 2.

Special Storage Conditions

` Photostability: two types of studies: Forced degradation study to generate potential g y g p

degradation products

Confirmatory study to confirm product and package fperformance

` For liquids in semi-permeable package Long term: 25C/40%RH

Intermediate: 30C/65%RH

Accelerated: 40C/

Special Storage Conditions

` To support adverse shipping and unusual storage of samples (liquid)

Freeze Thaw Cycling (-10C to -20C four days, 25C or 25C/60%RH for three days)

Th l C li (40C f d ilib t t 25C Thermal Cycling (40C four days, equilibrate to 25C and then 5C for three days)


Contents of a Stability Protocol

Stability studies are initiated based on approved stability protocols:

Identity of product: name, strength Description of dosage form or formulation Purpose of study Manufacturing site, packaging and testing sites. Details of packages (container/closure) Instructions for receipt and allocation of material Shipping of material (if needed)


Contents of a Stability Protocol

Storage conditions, time-points, configuration, orientation (if applicable)

Testing information: tests and specifications

Each study has unique, identifying number for LIMS orEach study has unique, identifying number for LIMS or specific tracking system.

Global conditions for products which are expected to beGlobal conditions for products which are expected to be sold and used worldwide.

Change of protocols: Deviations vs Admendmentsg p


Specification / Tests

The testing covers physical, chemical and microbiological attributes, preservative content (e.g.

ti id t ti i bi l ti ) dantioxidant, antimicrobial preservative), and functionality tests (e.g. for a dose delivery system).

What tests at each time points? Which labs? What tests at each time points? Which labs?

Shelf life acceptance criteria derived from available stability information? Alert limits?y

Differences between the shelf life and release specs are justified based on the stability evaluation and the changes observed on storage.


Stability Practices

` Management of deviations and protocol amendments

` Chamber Monitoring System` Chamber Monitoring System

` Study Activation Procedure

` Sample Pulling and Testing Procedure

` Sample Custodian Procedure

` Sample Destruction Procedure

` Sample Shipping Procedure` Sample Shipping Procedure

` Study Cancellation


` Chamber Inventory Program

Critical Stability Dates

Expiration DateStudy Start DatePackaging

Date p(Study End Date)

ReleaseDate

Stability Pull DatesManufacturing

Date

yDate

Batch Manufactured

R l T ti

Stability Scheduled Testing

Drug Product Expiry

TZ* Testing

Release Testing

S

12

Stability Testing in Pharmaceutical Development Handbook: Regulations, Methodologies and Best Practices, K.Huynh-Ba, ed., Springer 2008.

Environmental Chambers

` Two basic types: Reach-In and Walk-In

Reach-in chambers can be a self-contained units with good profile control, but have limited space.

Walk-in chambers have more storage space but are more difficult to control and validate

All chamber units must have temperature and humidity control over a defined range with suitable tolerances tocontrol over a defined range with suitable tolerances to meet ICH specifications. Must have continuous monitoring of parameters to allow documentation of


chamber integrity at all times.

Environmental Chambers

Walk-inChambers

Courtesy of Luwa Americaswww.luwaamericas.com

14

Key Factors of Stability Chambers

` Chamber should be calibrated to appropriate technical specs.

` Chamber should be validated with profiling matrix.` Temperature and humidity should be recorded

ti lcontinuously.

` SOPs for operation of chamber should be prepared and controlledcontrolled.

` Units should have logbooks for maintenance and repairs.p


Key Factors of Stability Chambers

` Units should have secured access to prevent tampering.` If electronic information is collected, the system should

be compliant with 21CFR11 requirements.

` Alarm and backup systems should be in place to detect f il d t t ti f hipower failures and prevent station from crashing.

` Procedures should be in place for man-made or natural disastersdisasters.


B k ti d M t i iBracketing and Matrixing

What is Bracketing?

` The design of a stability schedule such that at any time point only the samples on the extremes of certain d i f t ( t th k i ) t t ddesign factors (e.g., strength, package size) are tested at all time points as in a full design. The design assumes that the stability of the intermediate levels is represented by the extremes tested


What is Bracketing?

` ...Where a range of strengths is to be tested, bracketing designs may be particularly applicable if the t th id ti l l l l t d istrengths are identical or very closely related in

composition (e.g., for a tablet range made with different compression weights of a similar basic granulation, or a capsule range made by filling different plug fill weights of the same basic composition into different size of capsule shells) capsule shells).


Bracketing

` Bracketing can be applied to different container sizes of or different fills in the same container closure

tsystem...

` The use of a bracketing design would NOT be appropriate if it can not be demonstrated that theappropriate if it can not be demonstrated that the strengths or container sizes and fills selected for testing are indeed the extremes.


Bracketing and Matrixing

o Example of simple bracketing design

Strengths 10mg 20mg 30mg

Batch 1 2 3 1 2 3 1 2 3

100s T T T - - - T T T100 s T T T T T T

Fill size 500s - - - - - - - - -

1000s

T T T - - - T T T


Rationale for Matrixing

Long term trends are approximately linear Can design so that the effect of each factor may beCan design so that the effect of each factor may be

determined Can evaluate comparative stability of each

presentation Each storage condition has its own matrix Each testing can have its own matrix Each testing can have its own matrix Can revert to full testing Resource savingResource saving

22

What is Matrixing?

` The statistical design of a stability schedule such that a selected subset of the total number ofthat a selected subset of the total number of

possible samples are tested for all factor

combinations is tested at a specified time point. At

a subsequent time point, another subset of sample

for all factor combinations is tested. The design

assumes that the stability of each subset of

samples tested represent the stability of all samples

at a given time point


at a given time point.

What is Matrixing?

` The differences in the samples for the same drug product should be identified as for example coveringproduct should be identified as, for example, covering

different batches, different strengths, different sizes of

the same container and closure, and in some cases,

different container/closure systems.


Matrixing

o Example of one half factorial designTime point Months on stabilityTime point Months on stability

Batch 0 3 6 9 12 18 24 36

10 mg 1 T T - T T - T T10 mg 2 T T T T T T10 mg 2 T T - T T T - T10 mg 3 T - T - T T - T20 mg 1 T - T - T - T T20 mg 1 T - T - T - T T20 mg 2 T T - T T T - T20mg 3 T - T - T - T T

25

20mg 3 T T T T T

Matrixing

o Example of two third factorial design (1/3 reduction)Time point Months on stability

Batch 0 3 6 9 12 18 24 36

10 mg 1 T T - T T - T T

10 mg 2 T T T - T T - T10 mg 2 T T T T T T10 mg 3 T - T T T T T T20 mg 1 T - T T T T T Tg20 mg 2 T T - T T - T T20mg 3 T T T - T T - T


g


Example of a complete complex designStrengths 10mg 20mg 30mg

Container size

X Y Z X Y Z X Y Z

Batch A T1 T2 T3 T2 T3 T1 T3 T1 T2

Batch B T2 T3 T1 T3 T1 T2 T1 T2 T3

Batch C T3 T1 T2 T1 T2 T3 T2 T3 T1

Time point

Months on stability

0 3 6 9 12 18 24 36T1 T - T T T T T TT2 T T - T T - T T

27

T3 T T T - T T - T


o Example of an incomplete complex designStrengths 10mg 20mg 30mg

Container size

X Y Z X Y Z X Y Z

Batch A T1 T2 - T2 - T1 - T1 T2Batch A T1 T2 T2 T1 T1 T2

Batch B - T3 T1 T3 T1 - T1 - T3

Batch C T3 - T2 - T2 T3 T2 T3 -

Time point

Months on stabilityp

0 3 6 9 12 18 24 36T1 T - T T T T T T

2

28

T2 T T - T T - T TT3 T T T - T T - T

Limitations of Matrixing

` All presentations must be set-up on storage` Realistically only the Long-Term storage is matrixedy y g g` May not pick up as much on differences` Data evaluation can be more complex` Data evaluation can be more complex` Confidence intervals may be wider` Regulatory experience is limited` Regulatory experience is limited



` of complete removal of some presentations from testing and then reduced testing of those that remain. This is a

j d ti d d j tifi timajor reduction and needs justification.

` Not very common. Definitely need to work with the Agency to do this, unless there is lots of supportive data.

` Reduction of batches of all presentations

` Matrix different tests to different extents


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2013-09-18 USP Stability 3 Operations

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