Manish Kumar Mangalayatan University

1. STABILITY PROTOCOLS FOR DIFFERENT
DOSAGE FORMS
Submitted by: Manish Kumar
DEPARTMENT OF PHARMACY
INSTITUTE OF BIOMEDICAL EDUCATION AND RESEARCH
MANGALAYATAN UNIVERSITY

2. OVERVIEW
1 • Introduction to stability
2 • Stability testing & product development
3 • Essential definitions
4
• Stability testing protocols & report
5
• Stability protocols of API
6
• Stability protocols for diff. dosage forms
• Evaluation of stability results
7
8
• conclusion
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3. 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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4. 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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5.  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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6. 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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7. 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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8. 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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9. PRE-IND STAGE
Pre-formulation & stability evaluation of chemical entity
is carried out according to ICH guidelines.
DOSAGE FORM PARAMETERS
SOLID Temperature, humidity,
photo degradation.
Solutions pH, ionic strength,
additives
In addition to normal preformulation evaluations ,forced
degradation studies under highly stressed stability
conditions is under taken.
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10. 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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11. 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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12. 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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13. 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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14. 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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15. 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
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16. 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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17. 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
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development.

18. API FPP
(Active pharmaceutical (Finished pharmaceutical
ingredient) product)
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19. STABILITY PROTOCOL - API
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20. Guidelines for drug substance (API) and drug
product(FPP)
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21. 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
21 H2O2, 0.1-2% at neutral pH, room 2 weeks
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temperature

22. 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.
Minimum time period
Type of study Storage condition
covered by data at submission
25°C ± 2°C/60% RH ± 5% RH
Long term or 12 Months
30°C ± 2°C/65% RH ± 5% RH
30°C ± 2°C/65% RH ± 5% RH 6 Months
Intermediate
22 Accelerated 40°C ± 2°C/75% RH ± 5% RH 6 Months5/25/2012

23. 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
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24. 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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25. Testing frequency
To establish the stability profile of drug substance
For long-term storage
12 month study
◦ Testing frequency
For intermediate storage
0 3 6 9 12
12 month study
For accelerated storage - Testing frequency
6 month study
0 6 12
◦ Testing frequency
0 3 6
(initial) (final) If significant change occur
- A 4th time point can be included
If significant change occur
◦ Increase the testing by adding
sample at final time point
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◦ Include 4th time point in study design

26. STORAGE CONDITIONS AND STABILITY ZONES
Based on the analysis the world is divided in to 4 climatic zones.
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27. 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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28. 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
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29. 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
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30. 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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31. 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 Appearance,clarity,colour,homgeneity,odour,ph,resus
s,gels,solutions. pendibility,viscosity,particle size
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distribution,assy,degraation
products,preservatives,microbial limits, weight loss.

32. 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.
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33. 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)
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