STABILITY PROTOCOLS FOR DIFFERENT DOSAGE FORMS

DEPARTMENT OF PHARMACY

Submitted by: Manish Kumar

INSTITUTE OF BIOMEDICAL EDUCATION AND RESEARCHMANGALAYATAN UNIVERSITY

04/09/20232

OVERVIEW1 • Introduction to stability

2 • Stability testing & product development

3 • Essential definitions4 • Stability testing protocols & report5 • Stability protocols of API6 • Stability protocols for diff. dosage forms7 • Evaluation of stability results8 • conclusion

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INTRODUCTION TO STABILITY

STABILITY :

Stability of a pharmaceutical product may be defined as the

capability of a particular formulation in a specific

container/closure system to remain within its

• Physical

• Chemical

• Microbiological

• Therapeutic

• Toxicological Specifications.

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POTENTIAL INSTABILITY ISSUES OF FPP’s

Loss/increase in concentration of API

Formation of (toxic) degradation products

Modification of any attribute of functional relevance

Alteration of dissolution time/profile or bioavailability

Decline of microbiological status

Loss of package integrity

Reduction of label quality

Loss of pharmaceutical elegance and patient acceptability

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STABILITY TESTING AND PRODUCT DEVELOPMENT

Stability testing is an integral part of pharmaceutical development.

It is an evolutionary concept covering the life cycle of pharmaceutical product

development.

In early discovery phase the primary focus is to generate stability

characteristics of a chemical /biological entity.

In later stages ,the goal is to establish shelf life for formulations packaged in

final package intended for commercial introduction.

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STABILITY TESTING PRINCIPLES CAN BE

SUBDIVIDED IN TO VARIOUS STAGES OF DRUG

DEVELOPMENT

Discovery phase

Pre clinical stage

Pre-IND stage

IND stage

Product development stage

NDA stage

Approved product stage

Revised product stage

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DISCOVERY PHASE

• To help select the most satisfactory chemical entity possessing the

right pharmacological, toxicological & pharmaceutical profile.

• The pharmaceutical profile is mostly focused towards the optimum

chemical and physical stability characteristics.

• To select the right physical form(base, salt ,ester).

• These studies help establish the boundaries with in which one must

operate to design formulations.

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PRE CLINICAL STAGE

• The development of early dosage form for pre clinical testing in

humans require an extensive stability evaluation.

• Preliminary stability testing on all formulations must be carried out

using stability indicating assays in accordance with GLPs.

• It requires an entrance assay prior to the initiation of toxicological

testing and an exit assay, must be performed at the end of the studies.

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PRE-IND STAGE

Pre-formulation & stability evaluation of chemical entity is

carried out according to ICH guidelines.

In addition to normal preformulation evaluations ,forced

degradation studies under highly stressed stability

conditions is under taken.

DOSAGE FORM PARAMETERS

SOLID Temperature, humidity,photo degradation.

Solutions pH, ionic strength, additives

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IND STAGE

• Accelerated and normal storage temperature testing of drug

substance and for clinical formulation must be initiated.

• The goal of these studies should be to generate information to

insure that the clinical formulations are likely to remain stable

during the planned clinical studies.

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PRODUCT DEVELOPMENT STAGE

• Intermediate stability testing is done in this stage.

• Interim stability testing is conducted to establish the

maximum time for which a drug product can be stored in

interim containers for further processing.

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NDA STAGE

• Formal stability program is established for generation of stability data for

registration applications.

• The stability of drugs should be evaluated in containers used for

marketing.

• Care should be exercised in selection of the size, surface-to volume ratio

of the container.

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APPROVED PRODUCT STAGE

• The goal of the stability evaluation program during this phase is to

confirm or extending the expiration date.

• The commitment in this stage mandates that any batch that is found

out of specification will be with drawn from the market.

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REVISED PRODUCT STAGE

• Most products undergo post approval changes.

• They may be internally driven or externally driven.

• Internally driven : changing size & shape of dosage forms, changes in

package design and others.

• Externally driven : deletion of dyes, formulation changed and others

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STABILITY PROTOCOL AND REPORT

1. Batches tested

2. General information

3. Container/closure system

4. Literature and supporting data

5. Stability-indicating analytical methods

6. Testing plan

7. Test parameters

8. Test results

9. Other requirements (post-approval commitments)

10. Conclusions

04/09/202316

ESSENTIAL DEFINITIONS

Re-test date

The date after which samples of an API should be examined to ensure that the

material is still in compliance with the specification and thus suitable for use in the

manufacture of a given FPP.

Shelf life (expiration dating period, conformance period)

The time period during which an API or a FPP is expected to remain within the

approved shelf-life specification, provided that it is stored under the conditions

defined on the container label.

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Formal stability studies

Long term and accelerated (and intermediate) studies undertaken on

primary and/or commitment batches according to a prescribed stability protocol

to establish or confirm the re-test period of an API or the shelf life of a FPP.

Stress testing – forced degradation (API)

Studies undertaken to elucidate the intrinsic stability of the API. Such

testing is part of the development strategy and is normally carried out under

more severe conditions than those used for accelerated testing.

Stress testing – forced degradation (FPP)

Studies undertaken to assess the effect of severe conditions on the

FPP. Such studies include photostability testing and compatibility testing on

APIs with each other in FDCs and API(s) with excipients during formulation

development.

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API (Active pharmaceutical

ingredient)

FPP(Finished pharmaceutical

product)

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STABILITY PROTOCOL - API

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Guidelines for drug substance (API) and drug product(FPP)

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STRESS TESTING IN API

Stress testing of the API can help identify the likely degradation products,

which, in turn, can help establish the degradation pathway. stress testing

may be carried out on a single batch of the API. It should include the effect

of temperature, humidity.

Storage conditions Testing period*

pH ± 2, room temperature 2 weeks

pH ± 7, room temperature 2 weeks

pH ± 10-12, room temperature 2 weeks

H2O2, 0.1-2% at neutral pH, room

temperature

2 weeks

04/09/202322

FORMAL STABILITY STUDIES

In general an API should be evaluated under storage conditions (with appropriate

tolerances) that test its thermal stability and, if applicable, its sensitivity to

moisture. The storage conditions and the lengths of studies chosen should be

sufficient to cover storage and shipment.

Type of study Storage conditionMinimum time period

covered by data at submission

Long term

25°C ± 2°C/60% RH ± 5% RH

or

30°C ± 2°C/65% RH ± 5% RH

12 Months

Intermediate 30°C ± 2°C/65% RH ± 5% RH 6 Months

Accelerated 40°C ± 2°C/75% RH ± 5% RH 6 Months

04/09/202323

Photostability testing of new drug substances & products

Photostability testing studies include:

• Test on drug substance.

• Test on exposed drug product outside the immediate pack.

• Test on drug product in the immediate pack.

• Test on drug product in the marketing pack.

Light source

Option 1: Artificial daylight lamp combining both visible & UV

output similar to D65 & ID65.

Option 2: Cool white fluorescent & near UV lamp

04/09/202324

CONTAINER CLOSURE SYSTEMS

The containers should be tested in all directions i.e. up

right ,inverted ,on the side positions.

This is done for long term and accelerated stability testing.

This is to ensure that there are no adverse effects from any

interaction is produced.

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Testing frequency To establish the stability profile of drug substance

For intermediate storage

12 month study

- Testing frequency

0 6 12

If significant change occur

- A 4th time point can be included

For long-term storage

12 month study

◦ Testing frequency

0 3 6 9 12

For accelerated storage

6 month study

◦ Testing frequency

0 3 6

(initial) (final)

If significant change occur

◦ Increase the testing by adding

sample at final time point

◦ Include 4th time point in study

design

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STORAGE CONDITIONS AND STABILITY ZONES

Based on the analysis the world is divided in to 4 climatic zones.

04/09/202327

STABILITY RESULTS

• A storage statement should be proposed for the labeling (if applicable), which

should be based on the stability evaluation of the API.

• A re-test period should be derived from the stability information, and the

approved retest date should be displayed on the container label.

• An API is considered as stable if it is within the defined/regulatory

specifications when stored at 30±2oC and 65±5% RH for 2 years and at

40±2oC and 75±5%RH for 6 months.

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EVALUATION – BEST CASE

1. No significant change at accelerated conditions within six (6) months.

2. Long-term data show little or no variability and little or no change

over time.

3. Accelerated data show little or no variability and little or no change

over time.

4. Statistical analysis is normally unnecessary.

5. Proposed retest period or shelf life = double of period covered by

long-term data

6. A retest period or shelf life granted on the basis of extrapolation

should always be verified by additional long-term stability data

04/09/202329

Stability-indicating quality parameters

Stability studies should include testing of those attributes of the FPP that are

susceptible to change during storage and are likely to influence quality, safety

and/or efficacy. For instance, in case of tablets:

♦ appearance ♦ hardness

♦ friability ♦ moisture content

♦ dissolution time ♦ degradation

♦ assay ♦ microbial purity

04/09/202330

DOSAGE FORM CONSIDERATION

Dosage form Evaluation

Tablets Appearance,colour,odour,assay,degradation products,dissolution,moisture and friability.

Hard gelatin capsules Appearance,colour,odour,assay,degradation products,dissolution,moisture and microbial

limits

Soft gelatin capsules Appearance,colour,odour,assay,degradation products,dissolution,moisture and microbial

limits,pH,leakage.

Emulsions Appearance,colour,odour,assay,degradation products, microbial

limits,PH,viscosity,preservative content and distribution of dispersed phase globules.

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Dosage form Evaluation

Oral solutions Appearance,colour,odour,assay,degradation products,

PH,microbial limits, preservative content.

Oral suspensions Appearance,colour,odour,assay,degradation products,

PH,microbial limits, preservative

content,redispersibility,rheological properties, mean

size and distribution of particle.

Oral powders Appearance,colour,moisture,and reconstitution time.

Inhalations and nasal sprays Appearance,colour,odour,assay,degradation products,

dose content uniformity, microscopic evalution,water

content, leak rate, microbial limits.

Topical,opthalamic,ointments,creams,lotions,paste

s,gels,solutions.

Appearance,clarity,colour,homgeneity,odour,ph,resus

pendibility,viscosity,particle size

distribution,assy,degraation

products,preservatives,microbial limits, weight loss.

04/09/202332

CONCLUSION

Stability studies should be planned on the basis of pharmaceutical R&D and

regulatory requirements.

Forced degradation studies reveal the intrinsic chemical properties of the

API, while formal stability studies establish the retest date.

The shelf life (expiry date) of FPPs is derived from formal stability studies.

Variability and time trends of stability data mustbe evaluated by the

manufacturer in order to propose a retest date or expiry date.

33 04/09/2023

REFERENCES

Drug Stability: Principles and Practices, 3rd Edition,

edited by Jens T. Carstensen and C. T. Rhodes

Statistical Evaluation of Stability Data: Criteria for

Change-over-time and Data Variability (PDA Journal of

Pharmaceutical Science and Technology, Vol. 57. No.5,

Sept./Oct. 2003, pp. 369-377)