Topic:-Stability Studies (2) – an overview

• Stability: Fundamentals :-

The ability of a pharmaceutical product to retain its properties within specified limits throughout its shelf life. Aspects of stability that are to be considered include: Physical, Chemical, Microbiological & Biopharmaceuticals.

 

“It is It is a study on the evidence on how the quality of a drug substance or drug products varies with time under the influence of variety of environmental factors such as Temperature, Humidity and Light.”

 

• Objective – why stability

• To provide evidence on how the quality of a drug substance / product varies with the influence of variety of environmental factors such as temperature, humidity & light

• To recommend storage conditions

• To recommend retest period

• To assign shelf life

• To review the product quality

• To fulfill the regulatory requirement for dossier submission

• Why is stability testing an important issue ?

• In order to demonstrate that:

  • the clinical effect

  • the patient safety

  • the quality

  • of the drug is maintained during its maximal time of storage and intended use.

Starting a Study :-

Contents of a stability protocol

Setting the ‘start date’ for a stability study

Determining the ‘due dates’ for a stability study protocol The initial certificate of analysis at to for a stability study SOP Control

Format and layout of standard operating procedures Indexing procedure for stability studies

Index for stability sops

Study Parameters

Setting limits for check specifications in a stability study. Number and size of batches for stability testing.

Sampling

Number of samples required for performing stability tests Labeling of stability study samples

Storage configuration of samples in a stability environment

Storing the stability study samples under controlled conditions prior to analysis

Study Conditions

Intervals and climatic conditions for a development stability study Intervals and climatic conditions for a pivotal/bioequivalence stability study

Intervals and climatic conditions for a validation/pm stability study Placing the reference listed drug (RLB) on stability

Packaging procedures

Sampling and testing of pivotal batches – tablet & capsule dosage forms. Sampling and testing of pivotal batches – powder & syrups for reconstitution.

Container systems

Container-liner-closure systems for a stability study.

Certification of a container-liner-closure system.

Test methods

The control of analytical methods and  stability documentation

 

Test results

Reporting test results of a stability study.

Procedures for handling abnormal or OOS results in a stability study.

Audit and Review Raw Data

Auditing stability data in laboratory notebooks

Cross-referencing laboratory notebooks with computerized stability documentation

Chart Control

Recording stability study climatic conditions

Review and control of temperature and humidity recording charts

Validation and Sanitation

Periodic revalidation of climatic rooms and chambers

Sanitation and housekeeping requirements of climatic chambers

Corrective Action

Fault correcting procedures (after breakdowns) during a Stability Study Emergency procedures during a stability study

 

Stopping a Study

Conditions for stopping a stability study.

Self Inspection

Self inspection procedures in a stability department.

Job Description and Training

Job description of stability department personnel

Using stability SOPs and compliance program as stability training tools. The Do’s and Don’ts of a stability study – a department training tool.

Stability department compliance staff training

Reviewing Documentation

Review and auditing stability study documentation.

The layout and format of a regulatory stability report (a filed report)

Documentation requirements for a stability study – contents of a stability dossier

Closing a Study

Accepting and signing-off a completed stability study.

 

Stability protocol – contents:

 * Name of the product

• Batch size, type of batch and number of batches

• Source of API

• Type, size, source of containers and closures

• Storage condition

• Sampling schedule

• Container storage orientation

• Test parameters

• Test methods

• Acceptance criteria

 

• Stages of stability :

  • Pre-formulation / pre-experimental

  • Formulation / experimental stability

  • Pilot / post experimental stability

  • Production / commercial stability

Stability studies during product life-cycle

Development——> Submission and Approval—–> Post-approval

Development	Submission and Approval	Post-approval
•   Stress testing •   Photostability •  Studies to support process & product development •Clinical trial stability •  Shipping and In-use stability •Intermediates	•Formal studies for the application	•Commitment batches • Follow-up stability program • Stability studies initiated by: –   Changes –   Deviations

Guidelines for Stability Testing:

• ICH guidelines on Stability testing of new drug substances and drug   products

• USFDA guidelines on Stability testing

• CPMP guidelines on stability

• WHO guidelines on stability testing of pharmaceutical products

Global climatic zones:

 

Region	Zones I & II	Zones III & IV
European	All countries	–
American	Chile, Canada, United States	Brazil, Jamaica, Venezuela
Asian	China, Japan, Turkey	India, Philippines, Sri Lanka
African	South Africa, Zambia, Zimbabwe	Botswana, Ghana, Uganda
Australian / Oceanic	Australia, New Zealand	Fiji, Papua – New Guinea

 

Q1A : Stability Testing of New Drug Substances & Products.

Q1B : Stability Testing : Photostability testing of New Drug Substances & Products.

Q1C : Stability Testing for New Dosage Forms.

Q1D : Bracketing & Matrixing Designs for Stability Testing of Drug Substances & Products.

Q1E : Evaluation of Stability Data.

 

Q3A : Impurities in New Drug Substances.

Q3B : Impurities in New Drug Products.

Q3C : Impurities: Guideline for Residual Solvents.

Q3C(M): Impurities: Guideline for Residual Solvents (Maintenance).

 

Specifications :

• List of Tests

• Testing procedure

• Acceptance criteria (at the time of release / shelf life).

• Reference standard

• In-process tests

• Physical tests such as particle size distribution

• Parametric releases

• Various decision trees

• Impurities

• Micro Limits

 

The testing should cover as appropriate : chemical, physical, biological & microbiological parameters. Validated analytical method should be adopted.

 

• Stability Specification

• Product relase specifications: ”…include those attributes of the drug product/drug substance that are susceptible to change during storage and likely to influence quality, safety and/or efficacy”

  End shelf life ( Stability) specification The likely changes on storage and the rationale for the selection of attributes to be tested in the formal stability studies should be stated”

 

• Stability Testing Frequency

• Long Term :

• First year     : Every 3 Months

• Second year : Every 6 months.

•  Thereafter    : Annually.

• Intermediate : 0, 3, 6, 9, 12 (Months)

• Accelerated : 0, 3, 6 (Months)

Storage Condition :  General case:

Study	Storage condition	Minimum time period covered by data at submission
Long Term	25 ± 20C / 60 ± 5% RH	12 months
Intermediate	30 ± 20C / 65 ± 5% RH	6 months
Accelerated	40 ± 20C / 75 ± 5% RH	6 months

Any “significant change” occurs during 6 month accelerated study, additional testing at intermediate storage should be conducted. The initial application should include a minimum of 6 moths data from 12 month study of intermediate storage condition.

“Significant change” for a drug substance is failure to meet specification. For drug product, it is given separately.

Storage Condition :

Drug Substance / Drug Product intended for storage in refrigerator :

Study	Storage condition	Minimum time period covered by data at submission
Long Term	5 ± 3°C	12 months
Accelerated	25 ± 2°C / 60 ± 5% RH	6 months

If   “significant  change”   occurs   between   3   &   6     months  of accelerated study, data on long term study should be submitted.

If “significant change” occurs within 3 months of accelerated study, it is unnecessary to continue further testing.

• Storage Condition Drug Substance / Drug Product intended for storage in freezer :

 

Study	Storage condition	Minimum time period covered by data at submission
Long Term	– 20 ± 5°C	12 months

 

There is no accelerated study for above case.

Drug substance intended for storage below – 20°C should be treated case by case.

 

 

Ø COMMITMENT

• Initial long-term data on primary batches may not cover the proposed shelf life granted at the time of approval.

• Commitment is made to continue the post approval studies in order to firmly establish the shelf life.

• If the submission includes data from studies on less than 3 production batches, a commitment is made to continue the long term studies during the proposed shelf life and place additional production batches to make a total of at least 3 on long-term studies through the proposed shelf life.

• If the submission does not include stability data on production batches, a commitment should be made to place the first 3 production batches on long term studies during the proposed shelf life and accelerated studies for 6 months.

 

EVALUATION OF STABILITY DATA TO ESTABLISH SHELF LIFE – For Drug Products RE-TEST DATE – For Drug Substances

If accelerated stability data for 6 months is OK.

 

	x	y
Accelerated (6months)	Long Term  (9 months OK)	y = 2x Shelf life / re-test date is 18 months
Accelerated (6months)	Long Term (12 months OK)	y = 2x Shelf life / re-test date is 24 months
Accelerated (6months)	Long Term (18 months OK)	y = x + 12 Shelf life / re-test date is 30 months
Accelerated (6months)	Long Term (24 months OK)	y = x + 12 Shelf life / re-test date is 36 months
Accelerated (6months)	Long Term (36 months OK)	y = x No extrapolation beyond 36 months

 

 

EVALUATION OF STABILITY DATA TO ESTABLISH SHELF LIFE For Drug Products RE-TEST DATE For Drug Substances

If accelerated stability data for 6 months is NOT OK.

	x	y
Accelerated (6months)	Intermediate 12 months OK	y = 1.5x Shelf life / re-test date is 18 months
Accelerated (6months)	Intermediate 9 months OK	y = 1.5x Shelf life / re-test date is 13.5 months
Accelerated (6months)	Intermediate 9 months NOT OK & if long term 9 months OK	y = x + 3 Shelf life / re-test date is 12 months

STABILITY DATA EVALUATION 

  

• Consider assay, degradation products & other appropriate attributes for evaluation of stability study data.

• Use formal   statistical  analysis   for   data showing substantial variability & degradation.

• Do not apply this statistical analysis for stability data showing little degradation / variability.

• The nature of degradation relationship determines whether it should be converted for linear regression analysis.

SIGNIFICANT CHANGE

 

What does significant change means… For Drug Substance : Failing to meet its specification. For Drug Products :

• 5% assay variation from its initial

• Failure to meet the acceptance criteria for potency when using biological / immunological procedures.

• Any degradation products exceeding acceptance

• Failure to meet acceptance criteria with respect to :

  • Appearance l Color l Phase separation

  • Re-suspendibility l Caking l Hardness

  • pH l Dissolution on 12 units

Some acceptable factors such as softening of suppositories & melting of creams may be accepted at accelerated conditions.

 

 

 

LABLELING CONSIDERATION FOR

DRUG PRODUCTS & DRUG SUBSTANCES

Statement / Labeling :

• A storage statement should be based on the stability evaluation. Wherever applicable, specific instructions should be provided. For eg.: drug substances that cannot tolerate freezing.

• Avoid use of “ambient condition” or “Room temperature”.

• Need direct   link   between   the   label   storage           statement    &             the

demonstrated stability.

• A retest period for drug substance & expiration for the drug product should be derived from stability information, and should be displayed on the container label as appropriate.

LABLELING CONSIDERATION FOR DRUG PRODUCTS & DRUG SUBSTANCES

	Testing conditions where stability has been shown	Required labeling statement	Additional labeling statement, where relevant
	25 ± 20C / 60 ± 5% RH (long term) 40 ± 20C / 75 ± 5% RH (accelerated) or 30 ± 20C / 65 ± 5% RH (long term) 40 ± 20C / 75 ± 5% RH (accelerated)	None	Do not refrigerate or freeze.
	25 ± 20C / 60 ± 5% RH (long term) 30 ± 20C / 65 ± 5% RH (intermediate) or 30 ± 20C / 65 ± 5% RH (long term)	Do not store above 30 0C or Store below 30 0C.	Do not refrigerate or freeze.
	25 ± 20C / 60 ± 5% RH (long term)	Do not store above 25 0C or Store below 25 0C.	Do not refrigerate or freeze.
	5 ± 30C (long term)	Store in a refrigerator or Store & transport refrigerated.	Do not freeze.
	Below zero	Store in a freezer or Store & transport frozen	—

 

OTHER SPECIFIC STORAGE STATEMENTS

 

Sr. No	Storage problem	Additional labeling statements* depending on the packaging
1.	Sensitivity to moisture.	Keep the container*** tightly closed.
2.	Sensitivity to moisture.	Store in the original package.
3.	Sensitivity to light.**	Store in the original package.
4.	Sensitivity to light.**	Keep the container*** in the outer carton.

*An :explanation for the labeling statement should be given in the package leaflet (e.g. “in order to protect from light”) and on the outer packaging, where space permits.

 

BRACKETING ICH REFERENCE: Q1D

OBJECTIVE

To provide guidance on application of Bracketing and Matrixing for stability studies of Drug product and Drug substance.

 

What is Bracketing ?

Bracketing is the design of stability schedule such that only samples of extremes of certain design factors (strength / container size & / or fill) are tested at all points a sin full design. The design assumes that the stability of any immediate levels is represented by the stability of extremes tested.

The case of bracketing design would be considered appropriate if design factors selected for testing are indeed the extremes.

BRACKETING Design Consideration and Potential risk:

If the stability of the extremes is not satisfactory, the intermediate should be considered NO more stable than the extremes.

 BRACKETING Where it can be applied:

1. Capsules / tablets of different strengths, manufactured using the same granules / powder (linear formulation) varying in different quantity.

Examples :

Strength               Powder fill / wt. of tab.

10 mg      =     100 mg

20 mg      =     200 mg

50 mg      =     500 mg

II.   When the container size & fill volume vary. However, care should be taken to select the extremes by comparing the various characteristics of the container & closure system that may affect the product stability, such as –

• Composition of container

• Wall thickness

• Head space to volume ratio

• Water vapor penetration rate,

III. BRACKETING – REDUCED DESIGN STUDY

 Example 2 :

Tablet range made with different compression weights of linear formulae.

Strength/tab.

25 mg

50 mg

100 mg

200 mg

Batch No.

B1

B2

B3

B4

B5

B6

B7

B8

B9

B10

B11

B12

Container Size

100 s

ü

ü

ü

X

X

X

X

X

X

ü

ü

ü

250 s

X

X

X

X

X

X

X

X

X

X

X

X

500 s

ü

ü

ü

X

X

X

X

X

X

ü

ü

ü

ü : Data required (test to be performed)

X

Bracketing (test not necessary)

 

 

WHAT IS MATRIXING ?

1. It is a stability schedule

2. It is a selection of subset of the total number of samples.

3. It assumes all factor combinations tested at a specified time point.

4. The various factor combination to be considered:

Ø Different batches.

Ø Different strengths.

Ø Different sizes of same containers.

Ø Different closure system.

•   MATRIXING

When a secondary packing system contributes to the stability the drug product matrixing can be performed across the packing system.

Design factors to be considered for Matrixing:

1. Strength of the dosage

2. Container size

3. Container fill.

In a matrix approach, a supporting data with respect to the effect due to:

• Moisture

• Light

• Oxygen

is required to prepare a design close to the ideal one.

Matrixing has a limited use in stability testing of Drug substance but it will have significant applicability in drug products depending on strength, container, closure fill volume, supporting data etc.

 

BRACKETING v/s. MATRIXING

• Bracketing and Matrixing is compliment to each other. Both the techniques helps to reduce the design of various combination factors based on strength, containers/ closures, fills and point of testing time.

• Both Matrixing and Bracketing is a reduced design on different principles.

• The use of Bracketing and Matrixing is generally applied together.

• The design should be scientifically justified.

• BRACKETING IS GENERALLY NOT APPLICABLE TO DRUG SUBSTANCE

• Bracketing is  applicable  to  Drug  product  based  on  different strengths, containers, closures and fill volumes.

Ø CONCLUSION

• Bracketing & Matrixing is a stability schedule & a reduced design. The number of test to be performed on a different size, pack & strength should be logically justified to reduce the analytical load. Bracketing and Matrixing is more applicable for drug

 

 

IMPURITIES IN NEW DRUG SUBSTANCES

Classification of impurities:

1. Organic impurities (Process & Drug related).

2. Inorganic impurities

3. Residual Solvents

 

Identification Threshold:

A limit above which an impurity should be identified.

Qualification Threshold:

A limit above which an impurity should be qualified. Qualification is the process of acquiring and evaluating data that establishes biological safety of individual impurity level specified. The level of any impurity present in a new drug substance that has been adequately tested in safety and / or clinical studies would be considered qualified.

 

IMPURITIES IN NEW DRUG SUBSTANCES

Thresholds: (Drug substances)

Maximum daily dose (1)	Reporting Threshold(2,3)	Identification Threshold (3)	Qualification Threshold (3)
< 2 gram per day	0.05%	0.1% or 1 mg per day intake ( whichever is low)	0.15% or 1.0 mg per day intake (whichever is low)
>2 gram per day	0.03%	0.05%	0.05%

 

1. The amount of the drug administered per

2. Higher reporting threshold should be scientifically

3. Lower threshold can be appropriate if the impurity is unusually toxic.

 

 

CONCLUSION

• Reporting, identifying & qualifying of impurities are based on the total daily intake & the same has been detailed in the ICH guideline.

•  WHAT IS A SUPAC GUIDANCE?

 

• A communication that represents the best scientific judgement of the Agency at this time regarding certain scale-up and post- approval issues:

• TYPES OF SUPAC CHANGES

1. Components and Composition

2. Site Changes

3. Batch Size (Scale-Up/Scale-Down)

4. Manufacturing (Equipment/Process)

• Level I changes:

Which are unlikely to have any detectable impact on formulation quality and performance.

• Level II changes:

Which may have significant impact on formulation quality and performance.

• Level III changes:

Which have a significant impact on formulation quality and performance.

SUPAC – Components and Composition changes:

  

Level	Classification	Documentation	Supplemen t
I	·        Complete or partial deletion of colour / flavour ·        Change of excipient ranges upto 5 %	1st production batch on LTSS	AR
II	·        Change in technical grade or specification of excipient ·        Change of excipient ranges upto 10%	1 batch with 3 month Acc data and LTSS data on 1st production batch	PAS
III	·        Change of excipient ranges exceeding 10 %	3 batches with 3 months Acc data and LTSS data on 1st 3 production batches	PAS

 

SUPAC – Site changes:

 

Level	Classification	Documentation	Supplem ent
I	·      Same facility ·      Common personnel	1st production batch on LTSS (optional, but recommended)	AR
II	·      Same contiguous campus Common personnel	LTSS data on 1st production batch	CBE
III	·      Different campus ·      Different personnel	3 batches with 3 months Acc data and LTSS data on 1st 3 production batches	CBE

 

SUPAC – Batch size changes:

 

Level	Classification	Documentation	Supple ment
I	·        Scale up of biobatch / pivotal clinical batch (less than 10 X)	1st production batch on LTSS	AR
II	·        Scale up of biobatch / pivotal clinical batch (More than 10 X)	1 batch with 3 month Acc data and LTSS data on 1st production batch	CBE

 

SUPAC – manufacturing equipment changes:

Level	Classification	Documentation	Supple ment
I	·        Equipment changes (same operating principle)	1st production batch on LTSS	AR
II	·        Equipment changes (different operating principle)	3 batch with 3 month Acc data and LTSS data on 1st 3 production batch	PAS

 

SUPAC – Manufacturing process changes:

 

Level	Classification	Documentation	Supple ment
I	·      Adjustment within operating conditions (e.g. Mixing time, speed with in validated range)	1st production batch on LTSS (Optional, recommended)	AR
II	·      Adjustments outside operating conditions (outside the validated range)	LTSS data on 1st production batch	CBE
III	·      Change of process (e.g. Wet granulation to direct compression)	3 batches with 3 months Acc data and LTSS data on 1st 3 production batches	PAS

 

Photo stability – Light source:

• Option 1: Artificial daylight fluorescent lamp combining visible and UV outputs, xenon or metal halide lamp. or

• Option 2: A cool white fluorescent lamp & a near UV fluorescent lamp having a spectral emission range from 320 nm to 400 nm

Level of exposure for stability study:

• Overall illumination of not less than 2 million lux hours and an integrated near UV energy of not less than 200 watt hours/m2. This can be monitored by either Quinine actinometry, calibrated radiometers or lux meters.

• To exclude the thermal effect, a protected control sample (wrapped in aluminum foil) may be exposed side by side.

 

1. Scientific and Regulatory Aspects

• Importance of preparing and training personnel
• Significance of studies conducted
• Definition of shelf life, expiration dating, developmental, and marketed product stability
• Determination of the storage conditions stability
• Definition of the roles of temperature, humidity, and light
• Key elements of stability testing

 

• 2. Stability Storage Chambers: Calibration, Monitoring, and Maintenance

• Stability chambers and rooms used in the industry

• Installation, Operation, and Performance Qualifications

• Principles of calibration frequency and documentation

• Principles of monitoring frequency and documentation

• Maintenance of stability chambers

3. Stability Storage and Testing as Defined in cGMPs, ICH, and FDA Guidelines

• CGMP requirements for stability storage and testing.

• ICH stability guidelines’ expectations.

• FDA guidelines’ expectations.

• Photo stability studies.

• Forced degradation (stress) and stability-indicating methods.

 

 

 

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