Dive Inside the Stability IcebergRegulatory & Scientific Affairs of

Harmonized Guidance

Obaid AliCivil Service Officer, Member, ISPE, PDA

26 March 2017

Not the view of DRAP

Current judgment

No obligation on DRAP

Regulatory experience

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References US-FDA WHO ICH NRAs

What's the harm to give shelf life

without stability study while we have

experience of innovator drugs and

manufacturing of other drugs?

Duration

Conditions

Safety

Efficacy

Quality

How the quality varies with time

under the influence of conditions

(temperature, humidity, light)

DSDP

Selection Container Closure Specification Testing Frequency

Storage Conditions

Commitment Evaluation Claim

Stress Photo

DS

• 3 Primary Batches of pilot scale

• Same synthetic route

DP

• 3 Primary Batches, two, of pilot scale, one may be smaller

• Same formulation & CC

Batch Selection

DS

• Packaging may be simulated

DP

• No, should be identical

Container Closure

DS

• Physical, Chemical & Microbiological tests

DP

• + Preservative, Functionality Tests

Specifications

Should Content Uniformity be done in

Stability Study?

Should Sterility Test be done in

Injectable dosage forms?

Should Dissolution be done as a Drug

Delivery Performance Test?

Specifications

Finished Pharmaceutical Product

Specifications special for FDCs

Remember

Degradation products must be calculated in % with reference

to the parent API, not the sum of APIs,

For

FDCs

Rifampicin / isoniazidtablets

• Rifampicin quinone(degradant) as % of rifampicin

Lamivudine + Stavudine + Nevirapine

tablets

• Thymine (degradant) as % of stavudine

Example

Remember

If 2 APIs react with each other, then the degradant to be

stated with respect to worst case

Rifampicin / isoniazid tablets

• Isonicotinyl hydrazone forms from the 2 APIs.

• Specification: % hydrazonewith respect to rifampicin(worst-case in mass balance)

Example

Remember

Unknown degradants – with respect to worst case

Testing Frequency

For API with proposed re-test

period/shelf-life of at least 12

months

Every 3 months over first year,

every 6 months over next 12

months and annually

thereafter.

DS

DP

Testing Frequency

Accelerated condition

Minimum of 3 time

points, including initial

and final time points

(e.g. 0, 3 & 6 months)

DS

DP

Testing Frequency

Intermediate condition (due to

significant change under

accelerated condition)

Study design should include 4

time points (e.g. 0, 6, 9 and 12

months

DS

DP

DS

• Bracketing, Matrixing not applicable

DP

• Bracketing, MatrixingApplicable

Testing Frequency

Storage Conditions

Accelerated40⁰C+2⁰C

75% +5%RH6 months

1 of 3

DS

DP

Storage Conditions

Long term

25⁰C+2⁰C 60%+5%RH or

30⁰C+2⁰C

65% +5%RH

12 months

2 of 3

DS

DP

Storage Conditions

Intermediate30⁰C+2⁰C

65% +5%RH6 months

3 of 3

DS

DP

Storage in a Refrigerator

Accelerated25⁰C + 2⁰C

60% + 5% RH6 months

DS

DP

Long term 5⁰C + 3⁰C 12 months

Storage in a Freezer DS

DP

Long term- 20⁰C +

5⁰C12 months

Storage below - 20⁰C : Case by case basis

Retest (DS)

• Compliance of attributes

• Suitability of use

Expiry (DP/DS)

• Expected within compliance

• No retesting

Stress (DS)

Shocks exposure

Intrinsic stability

PD

Stress (DP)

Photosensitivity

Specific products

QIB

• Must be stability indicating e.g.

• Assay of API

• Determination of Degradants

• Determination of Preservatives

Analytical Methods

• May not be suitable (e.g. non-specific like titration) i.e. Non-specific

• May not exist for the particular purpose (e.g. degradants)

CompendialMethods

Significant Change

Drug Substance

Failure to meet

specifications

>5% change in assay from the initial results

Any degradation product exceeding its acceptance

criterion

Failure to meet acceptance criteria for appearance,

physical attributes and functionality tests

Failure to meet acceptance criteria for pH

Failure to meet acceptance criteria for dissolution of 12

dosage units

Pitfall/Downside

The assay value is still within the limits

but the change during stability is

more than 5.0%Example

Release assay limit: 95.0 –

105.0%

Stability assay limit: 92.5 –

105.0%

Release assay:101.0% (within

spec)

24-Month assay: 93.0% (within

spec)

Loss in potency: 8.0% !!This is a significant change !!

Points to be noted

Manage knowledge from R&D to plan

stability study

Stress study for intrinsic behavior & real time for retest

Review

Stability testing is an

essential part of the process

of ensuring that the patient

receives a product that

meets established standards

of safety, efficacy and

quality

Review

Give attention to

analysis and

calculation of

degradation products

especially in FDCs

Review

Adopt Science & Risk

based Approach

Map Product

Attributes for Stability

during Development

Review

Sound planning and execution of stability studies are important:

•Valuable time may be lost if the data are insufficient

•Always include all attributes which may change with

time (e.g. water content, friability & tablet strength in the

case of uncoated tablets) – pay upfront and save later