Stability for Submission Purposes

AgendaStudy Design

Bracketing

Matrixing

Data Handling

The Basics

DefinitionsPull Date – The date a sample is taken out of a stability chamber for testing.

Testing Date – The date in which the last test was completed.

DefinitionsPilot Batch – 100,000 units or 10% of full commercial batch size, whichever is greater.

Small Scale Batch - Smaller than the 10 percent of the proposed production batch, but should not be less than 25 percent of the pilot scale batch.

DefinitionsSignificant Change – A change equal or greater than 5% in Assay; or, an out of specification result in any test for any single batch.

DefinitionsProportionally Similar –• When the active and inactive

ingredients are not in exactly the same proportion but the ratios of inactive ingredients to the total mass of the dosage form are within the limits defined by SUPAC guidelines.

• The difference in active ingredient content between strengths may be compensated for by mass changes in one or more of the IPIs provided that the total mass of the pharmaceutical product remains within 10 % of the mass of the pharmaceutical product on which the bioequivalence study was performed.

• Preserved drug products: Products containing antimicrobial preservatives, antioxidants or chelating agents.

• Commercial container: Any bottle, jar, tube, or other receptacle in which a drug product is held for distribution or dispensing to an ultimate user, and in addition, any box or package in which the receptacle is held for distribution or dispensing to an ultimate user.

Definitions• Bracketing: a stability testing

schedule where only samples on the extremes of certain design factors (e.g., strength, container size and/or fill) are tested at all time points.

• Matrixing: a stability testing schedule where a selected subset of the total number of possible samples for all factor combinations are tested at a specified time point. At a subsequent time point, another subset of samples for all factor combinations are tested.

The BasicsAll stability studies should follow a pre-written protocol.

The BasicsStability Conditions

Zone Temperature (°C) Relative Humidity (%)Zone II - Long term 25 ± 2 60 ± 5

Accelerated 40 ± 2 75 ± 5Zone IVa - Intermediate 30 ± 2 65 ± 5

Zone IVb 30 ± 2 75 ± 5

Stability Conditions

Long Term Stability Conditions

Zone IIZone IVaZone IVb• FDA will accept Zone IVa or IVb with no significant

change, in lieu of Zone II data.• If significant change is seen in Zone IVa or IVb,

then, Zone II samples can be subsequently tested from that time point on. Stability reports to be submitted to FDA would include Zone IVa or IVb data (up to the time point where significant change was observed), followed by Zone II data up to expiry date. Accelerated, intermediate and

long-term stability studies should start at the same time for any given batch.

Stability Batch Criteria

• Scaleo Three pilot scale batches or, two pilot scale batches and one small scale batch.

• Not less than two (2) drug substance lots must be used to manufacture each strength (i.e., 3 FP lots manufactured with NLT 2 API batches).

Stability Batch Packaging

Configurations to be packaged are high and low count and unit dose.

Stability Batch Criteria

• NLT 100,000 units must be packaged [high and low count and unit dose(if applicable)].

o Bulk is not considered a commercial packaging configuration.

o The batches should be packaged in the same number of containers per presentation.

Bottle Orientation• Irrelevant for Solid Dosage Forms

= =

• Inverted or side ways for liquids or suspensionso Upright only serves as control

= ≠

Alternate API Supplier• A single pilot scale batch per product strength

subject to BE studies

• If no BE studies were required, then a single pilot scale batch of the highest product dosage strength.

Alternate API Supplier• Same active moiety

• Same degradants

• Same degradation profile

• May have different impuritieso Different impurity profile does

not interfere with FP analytical methods

Alternate API SupplierNo annual batches need to be placed on stability studies for both, the primary and secondary source of API. Only one batch per strength, irrespective of API source, needs be placed on annual stability.

Time Points • Accelerated time

points: 0, 3, and 6 months

• Intermediate time points (0, 6, 9, and 12 months)

• Long-term time points (0, 3, 6, 9, 12, 18, 24, 36 months)

When to Pull SamplesThe stability protocol should establish a three (3) day range, centered about the pull due date, for pulling samples out of the stability chamber. The actual sample pull date should be recorded in the stability report.

Bracketing and Matrixing

A way to save resources.But BEWARE!!!

It’s all or nothing!!!

{[(Bracketing)]}Test only the samples on the extremes of certain design factors (container size/fill/strength) at all-time points as in a full design.

Strength 50 mg 75 mg 100 mg Batch 1 2 3 1 2 3 1 2 3

Container Size 15 ml T T T T T T 100 ml 500 ml T T T T T T

Key: t = Sample Tested

Matrixing • Matrixing is applicable

to long-term protocols.o Degree of Matrixing depends

on:• Data variability• Known product stability• Amount of R&D data• Stability significant

difference between product strengths

• Number of combinations in the study

o Matrixing should attempt to reduce NMT 25% of full testing

o Factors that can be matrixed:• Common blends• Identical formulations• Container sizes• Fill sizes• Similar formulations

(colors and flavors)o Factors that should not be

matrixed:• Initial and final time points• Test parameters• Dosage forms• Storage conditions• Proportionally similar

formulations

Matrixing Designs for a Product With Three Strengths and Three Container Sizes

Matrixing on Time PointsStrength S1 S2 S3Container Size A B C A B C A B C

Batch 1 T1 T2 T3 T2 T3 T1 T3 T1 T2Batch 2 T2 T3 T1 T3 T1 T2 T1 T2 T3Batch 3 T3 T1 T2 T1 T2 T3 T2 T3 T1

Matrixing on Time Points and FactorsStrength S1 S2 S3Container Size

A B C A B C A B C

Batch 1 T1 T2   T2   T1   T1 T2Batch 2   T3 T1 T3 T1   T1   T3Batch 3 T3   T2   T2 T3 T2 T3  

Key: Time-point (months) 0 3 6 9 12 18 24 36

T1 T T T T T T T T2 T T T T T T T3 T T T T T T

S1, S2 and S3 are different strengthsA, B and C are different container sizesT = Sample tested

Matrixing Designs Common Granulation/Blend

• Manufacture three (3) common granulations/blend lots.

• Use one common granulation/blend lot to manufacture all product strengths.

• The second and third common granulation/blend lots will be used to manufacture the highest, lowest and any other strength used in BE studies

Strength S1 S2 S3 S4 S5Batch #1 X X X X XBatch #2 X       XBatch #3 X       X

Key:X – ManufacturedX – Stability tested

Designs outside the examples provided should be submitted to FDA for approval before implementation.

Scored Tablets

Tablets must be split

The split tablets must be bottled in proposed CCS – not sealed, no filler/dessicant.

Need 90 days in long term conditions

One batch per strength

Preserved ProductsIn addition to chemical assay of preservatives, one exhibit batch needs to be subjected to preservative efficacy testing at expiry date.

Testing• Batches should be placed

in stability within 30 days of manufactured.

• Time zero data should not be older than 30 days from the day the batch is placed on stability.

• Sample testing should be completed within 15 days of pull date.

• Reports should be updated within 30 days of pull date.

In Use Stability• For products for

reconstitution or dilution.• Performed once on two

batches:o One batch tested after 6 month

accelerated (if no significant change) or 6 month long term storage..

o Second batch tested at expiry date.

• To cover product at initial reconstitution, at end of use time and intermediate points.

Data Reporting• Always report the actual numerical value of those

tests which yield numerical values as results. Do not use conforms.

• For degradants:o Results below limit of quantitation should be reported as ≤ LOQ.o Results below limit of detection should be reported as ND.o Results below specifications but above LOQ should have the actual

result reported.• Dissolution results should not have decimal

values reported.

Data ReportingSignificant changes should be accompanied by a failure analysis to provide understanding and clarity to the cause of the failure/significant change.

Trend Analysis• Procedures to identify Out

of Trend (OOT) results should be in place:o OOT analysis procedures should first

establish what is expected• Within a batch• Across historical stability

batcheso OOT identification methods should

discriminate between substantive events and spurious values expected from the inherent randomness.

o If an OOT result is found, then steps need to be delineated to determine the presence of an underlying cause and if present, the consequence that it has for the batch under consideration.

Data• Minimum stability data in support of an original

submission:o Accelerated Stability

• With no significant change: 6 months Accelerated Conditions• With significant change: 6 months Intermediate Conditions

o Ambient Temperature (Zone II, IVa or IVb): Six monthso Scored tablet stability report.o In use stability report including data from 6 month samples.

• Stability conclusions need to be written up by R&D, verified by QC/QA and approved by RA before the study reports are submitted to FDA.

RetentionSubmission stability batches should be retained for 1 year after application approval, or one year after the conclusion of the stability study, whichever comes later.

Data Reporting

Questions