Stability Studies - Evaluation of Outcomes and Development of Documentation For Regulatory Submissions

Bob Seevers

Outcomes of Stability Studies

• Retest date or shelf-life for APIs• Shelf-life for drug products• Stability-indicating analytical methods• Appropriately protective packaging for API and

drug product• Understanding the impact of temperature

excursions during distribution

ICH Q1E Evaluation of Stability Data

• Presentation of data• Extrapolating from existing data• Decision Trees

ICH Q1E

• Stability data from 3 lots of drug substance or drug product may used to establish a shelf-life or retest date.

• This is a statistical prediction– Increased variability among lots means less

confidence in the shelf-life/retest date– More lots provide greater confidence– Extrapolation from available data is limited

ICH Q1E: Data to Provide

• Results from the physical, chemical, biological, and microbiological tests such as: – Dissolution– Degradants– Assay– Preservative content

• The adequacy of the mass balance should be assessed. Factors that can cause an apparent lack of mass balance should be considered– Mechanisms of degradation– Stability-indicating capability of analytical methods

ICH Q1E Extrapolation

• Can extend expiration dating or retest date beyond available long-term stability data if– Sufficient long-term data is available to assess any

trends– No significant change is observed under accelerated

conditions• This process is spelled out in Q1E decision trees• Shelf-lives/retest dates established based on

extrapolation must be confirmed by long-term data when available

ICH Q1E Additional Analysis•For each parameter set a regression line with 95% confidence interval

ICH Q1E Additional Analysis

• Testing if data from all batches can be pooled to determine shelf-life/retest date– Slopes and intercepts for each batch should be the same to be

pooles– Analysis of Covariance used

• Analysis of Bracketing studies– Assumes stability of the intermediate strengths or sizes is

represented by the stability at the extremes.– If the statistical analysis indicates that the stability of the

extreme strengths or sizes is different, the intermediate strengths or sizes should be considered no more stable than the least stable extreme.

ICHQ1E Additional Analysis• Matrixing

– Important to ascertain that all factors and factor combinations that can have an impact on shelf life estimation have been appropriately tested.

– Statistical analysis should clearly identify the procedure and assumptions used.

• Assumptions underlying the model in which interaction terms are negligible should be stated.

• If a preliminary test is performed for the purpose of eliminating factor interactions from the model, the procedure used should be provided and justified.

• The final model on which the estimation of shelf life will be based should be stated.

• Use of a matrixing design can result in an estimated shelf life shorter than that resulting from a full design.

ICH Q5C

• Stability Testing of Biotechnological/Biologic Products• Applies to well-characterised proteins and

polypeptides, their derivatives and products of which they are components, and which are isolated from tissues, body fluids, cell cultures, or produced using rDNA technology.

• Does not provide specific data analysis recommendations

• Therefore the principles of ICH Q1E should be applied to biotech/biologic drugs

Curent WHO Guidance

• Annex 2 Stability testing of active pharmaceutical ingredients and finished pharmaceutical products (2009)

• Provides limited recommendations for data evaluation that are consistent with ICH Q1E

Documentation For Regulatory Submissions

RHS Model Stability QOS 15

Which is Better: This?

RHS Model Stability QOS 16

And This…

RHS Model Stability QOS 17

And So On for Page After Page…

RHS Model Stability QOS 18

Or This?Figure 1. API degradation rate (%/ 12 mo) vs. change in mean moisture @ 25°C/60% RH.

15-Al/Al 15-Bot500 15-Bot090 15-Bot01015-Aclar 60-Al/Al 60-Bot500 60-Bot09060-Bot010 60-Aclar UCL 15-Aclar UCL 60-AclarSpline 15 mg Spline 60 mg

Deg

rada

tion

Rat

e (%

/ 12

mon

ths)

-0.05

0.00

0.05

0.10

0.15

0.20

Change in Mean moisture over 12 months

0.0 0.1 0.2 0.3 0.4 0.5 0.6

RHS Model Stability QOS 19

And This

Figure 2. API degradation rate (%/ 6 mo) vs. change in mean moisture @ 40°C/75% RH

15-Al/Al 15-Bot500 15-Bot090 15-Bot01015-Aclar 60-Al/Al 60-Bot500 60-Bot09060-Bot010 60-Aclar Spline 15 mg Spline 60 mg

Deg

rada

tion

Rat

e (%

/ 6

mon

ths)

-0.02

0.00

0.02

0.04

0.06

0.08

0.10

0.12

0.14

0.16

0.18

Change in Mean moisture over 6 months

0.0 0.1 0.2 0.3 0.4 0.5 0.6

RHS Model Stability QOS 20

And ThisDrug Product Degradation Product CurrinA @ 25C/60%RH. Results of ICH Q1E analysis. All pkg studied; only worst case shown.

15-Aclar Pred. 15-Aclar 95% UCL 15-Aclar60-Aclar Pred. 60-Aclar 95% UCL 60-Aclar

Deg

rada

tion

Pro

duct

1 (C

urrin

A),

%

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

1.1

1.2

1.3

1.4

1.5

Age, Months

0 3 6 9 12 15 18 21 24 27 30 33 36

RHS Model Stability QOS 21

Graphical Presentation of Data

• All data presented as points on graphs• Full data tables available if requested• Important convention: Y-axis of data plots

scaled to – either the upper bound of the acceptance criteria– or to accommodate the maximum value of the data

if it exceeds the acceptance criteria. • Rationale for specifications becomes very clear

How Has This Worked?

• Regulators have asked for the tables of data• There is an FDA-Industry group working on a

data standard for submitting stability results• Some state that they want to do their own

analysis of the stability data• In practice this is extremely rare

What is Needed

• Stability data in tables or graphs or both– 2nd person verified– Be prepared to submit electronically

• Statistical analysis• Justify parameters tested• Validation reports for analytical methods• Conclusions

– Retest date for drug substance– Shelf-Life for drug product

Immediate Release Solid Orals

• Assay• Appearance• Degradants• Dissolution• Moisture

Modified Release Dosage Forms

• Enteric coated to release in intestine not stomach

• Delayed release• Assay• Appearance• Degradants• Dissolution• Moisture

Parenteral Products

• Assay• Appearance• Preservative Content• Degradation Products• Particulate matter• pH

Creams, Ointments, and Suppositories

• Assay• Appearance• Degradants• pH• Resuspendibility for lotions• Viscosity• Particle size• Preservative and Antioxidant Content

Non-parenteral Liquids

• Assay• Degradants• Preservative Content• Degradation Products• Particulate matter• pH