Quality management system

1. M. Pharm Sem-I Presentations
Title- ICH Stability Testing Of New Drug Substance And Drug Product.
SUBMITTED TO
SAVITRIBAI PHULE, PUNE UNIVERSITY , PUNE
FOR
PARTIAL FULFILMENT OF REQUIREMENTS FOR THE AWARD OF
MASTER OF PHARMACY
IN THE SUBJECT
Pharmaceutical Quality Assurance
IN THE FACULTY OF SCIENCE AND TECHNOLOGY
Bhujbal Knowledge City,
MET’s Institute of Pharmacy,
Adgaon, Nashik, 422003.
Maharashtra, India
Academic Year-2021-22 1
Presented By- Mandlik Amruta
and
Thorat Prajakta.
Guided By- Dr. Sapna
Ahirrao.

2. Content:-
• Objective
• Scope
• General principle
• Drug substance
• Drug product
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3. Objective:-
• This guidelines defines the stability data package for new
medicine substance (API) or medicine product ( final product)
that’s necessary for a enrollment operation within the three
region of the Japan, European Commission, and the United
States
• . The guideline seeks to explain core stability data package for
new medicine substance and product but leaves sufficient
inflexibility to encompass variety of different partial situation
that may encounter due to specific scientific consideration and
characteristics of material being estimated
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4. Scope:-
• The guideline addresses the information to be submitted in
enrollment operation for new molecular realities and associate
the medicine product.
• This guideline doesn't presently seek to cover information to
be submitted for abbreviated operations, variation, clinical
trials operation,etc.
• Specific details of the slice and testing not covered in this
guideline.
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5. General principal:-
• The purpose of stability testing is to provide evidence on how
the quality of drug substance or drug product varies with time
under the influence of variety of environmental factor such as
temperature, humidity and light.
• These information help us to established a re-test period for
drug substance (API) or shelf life for final product and
recommended storage conditions.
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6. Guidelines for stability testing
Drug substance:-
1. General
2. Stress testing
3. Selection of batches
4. Container closure system
5. Specification
6. Testing frequency
7. Storage condition
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7. Generalities:-
• Stability of the drug substance is an integral part of the
systematic approach in stability evaluation.
Stress testing:-
• The stress testing may be carried out on a single batch of the
drug substance. It should include the effect of temperature,
humidity, oxidation and photo stability.
– Eg. The effect of temperature in 10 degrees increment
above that for accelerated testing (eg. 50°C to 60°C)
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8. • The testing should also estimate the vulnerability of the
medicine substance to hydrolysis across wide range of pH
values when in result or suspense.
• Helps to identify the declination product thus the declination
pathway and natural stability of patch, and validate the
stability indicating power of the logical procedure used.
•
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9. Selection of batches:-
• Data from formal stability studies should be handed on at lest
three primary batches of medicine substance.
• The batches should be manufactured to a minimum of airman
scale batches by the same system of manufacture and
procedure which is used for final product.
• Container check system-
• The stability study should be conducted on medicine substance
packed in vessel check system that’s same as packaging
proposed for storehouse and distribution
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10. Specifications:-
• Stability studies should include testing of those attributes of
the medicine substance that are susceptible to change during
storehouse and likely to impact quality, safety, and/ or
efficacity.
• The testing should cover the physical, chemical, natural and
microbiological attributes.
• Validated logical should be applied.
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11. Testing frequency:-
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Testing frequency
Long term studies
Accelerated storage
conditions
Intermediate storage
condition
Should be sufficient to
establish the stability
profile of the drug
substance.
Retest period of at least 12 months
Test every 3 months for 1st year
Every 6 month for 2nd year and
annually thereafter through the
proposed retest period
Minimum of 3 time points,
including the initial and final
time points.( Eg. 0,3 and 6
months)
Is needed as result of
significant change at
the accelerated
storage condition
minimum of 4 time
points of 0,6,9,12
month, from 12
month study is
recomanded

12. Testing frequency and storage condition:-
General case study Storage condition Minimum time
period covered by
data at submission.
Long term 25°c ± 2°c/ 60% RH
± 5% RH or
30°c ± 2°c or 65%
RH ± 5% RH
0, 3, 6, 9,12 months
18, 24 months
36 months and
annually.
12 months
Intermediate 30°c ± 2°c or 65%
RH ± 5% RH
0, 6, 9, 12 months 6 months
Accelerated 40°c ± 2°c or 75%
RH ± 5% RH
0,3,6 months 6 months
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13. Drug substance / Drug product:-
Stability commitment
When available long term stability data on primary batches don’t
cover the proposedre-test or shelf life granted at time of blessing
from at least three product batches, a commitment should made to
continue the stability study post blessing in order to forcefully
establish the stability
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14. Statement / labelling:-
• Storage statement should be established for labelling based on
stability study of the drug substance or product according to
national or regional requirements.
• Re test date or expiration date should be display on container
labels.
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15. Drug product:-
1. General
2. Selection of batches
3. Container closure system
4. Specification
5. Testing frequency
6. Storage condition
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16. Drug product:-
Generalities:-
Stability studies grounded on the conclusion of medicine
substance stability.
Attributes to test are those susceptible to change during
storehouse and likely to impact on quality, safety or efficacity.
Physical, chemical, natural and microbiological
. Preservative content fore.g. Antioxidant, antimicrobial.
Functionality teste.g. Dissolution rate for lozenge form.
Antimicrobial preservative effectiveness on primary batch at
proposed shelf life.
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17. Selection of batch:-
• At lest 3 primary batches (pilot scale)
• Same formulation
• Same container closer system as proposed for marketing
including secondary package and container label.
• The manufacturing process used for primary and production
batch should be similar
• It should provide same quality and meeting the specification as
that intended for marketing.
• 2 of the 3 batch should be pilot scale and 3rd one can be
smaller.
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18. • If possible batches of drug product should be manufactured by
using different batches of drug substances.
• Stability studies should be performed on each individual
strength and container size of drug product unless bracketing
or matrixing is applied.
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19. Container closure system:-
• Stability testing should be conducted on dosage form packed
in container closer system proposed for marketing.
• Any available studies carried out on drug product out side its
immediate container or other packaging material can form a
useful part of stress testing of dosage form.
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20. Specification:-
• Stability study should include those attributes of drug product
that are susceptible to change during storage and are likely to
influence quality, safety, and efficacy.
• The test should cover the physical, chemical, biological,
microbiological attributes, preservative content and
functionality test.
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21. Testing frequency and storage conditions:-
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General case study storage condition Minimum time
period covered by
data at submission.
Long term 25°c ± 2°c/ 60% RH
± 5% RH or
30°c ± 2°c or 65%
RH ± 5% RH
0, 3, 6, 9,12 months
18, 24 months
36 months and
annually.
12 months
Intermediate 30°c ± 2°c or 65%
RH ± 5% RH
0, 6, 9, 12 months 6 months
Accelerated 40°c ± 2°c or 75%
RH ± 5% RH
0,3,6 months 6 months

22. Significant change:-
• The significant change for drug product is defined as
1. A 5% change in assay from its initial value or failure to meet
acceptance criteria for potency when using biological or
immunological procedure.
2. Any degradation product exceeding its acceptance criteria.
3. Failure to meet acceptance criteria for appearance, physical
attributes and functionality test.
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23. Types of container
• Impermeable container
– No sensitivity to moisture or potential solvent loss
– Stability study under any control or ambient humidity.
• Semipermeable container
– Determine the water loss at low RH condition
– 5% water loss after 3 months at accelerated condition is
significant change
– Small container (1ml or less), 5% or more of water loss
may be appropriate.
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24. Testing frequency storage conditions for semipermeable
container :-
General case study Storage condition Minimum time period
covered by data at
submission
Long term 25°C ± 2°C / 40% RH ± 5%
RH
30°C ± 2°C / 35% RH ± 5%
RH
12 months
Intermediate 30°C ± 2°C / 35% RH ± 5%
RH
6 months
accelerated 40°C ± 2°C / NMT 25%RH 6 months
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25. Approach for determining water loss
The ratio of water loss is calculated by following formula
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100 – reference % RH
100 – alternative % RH
Ratio of water loss =
Alternative relative
humidity
Reference relative
humidity
Ratio of water loss at
given temperature
65% RH 35% RH 1.9
75% RH 25% RH 3.0

26. Testing frequency storage conditions:-
• Storage in refrigerator
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General case study Storage condition Minimum time period
covered by data at
sumission
Long term 5°C ± 3°C 12 months
accelerated 25°C ± 2°C or 60% RH ±
5% RH
6 months
• Storage in freezer
General case study Storage condition Minimum time period
covered by data at
sumission
Long term -20°C ± 5°C 12 months

27. Conclusion
• Stability studies of pharmaceutical substance helps in
developing the pharmaceutical dosage form and new
Formulation.
• From these studies it is easy to predict the shelf life of the
drug including effect of environmental factors for the
degradation of the product.
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28. Case study:-
• the medicine substance stability data were used to support medicine
in capsule (DiC) product. The compass of the design gauged across
5 small motes with medicine in capsule phrasings. The FDA
Guidance for Industry, cGMP for Phase l Medicines (U.S. Food and
Drug Administration, 2008) allows representative samples of phase
1 investigational medicines to be used to cover stability and quality.
In the case of DiC phrasings it was determined that the medicine
substance stability data was representative of the DiC stability. The
defense in the Clinical Trial Operation (CTA) included representing
the Common Technical Document (CTD) SectionS. 7 in SectionP. 8.
The CTA also included reference to accelerated stability data on the
medicine substance as part of the defense.
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29. Case study:-
Regulatory cessions were performed in the US, France and Spain.
Challenges were entered in two cases (US and Spain) and the
agencies requested that the DiC be placed on long- term stability
concurrent with the clinical study. Due to timing considerations,
further specialized discussion wasn’t pursued, and the DiC was
placed on long- term stability. The primary benefit was still
realized by this approach; time savings in not staying for the one-
month medicine product stability data previous to IND or CTA
form.
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30. Conclusion
The case studies presented here described how the combination
of scientific rationale and product knowledge have been hold
successfully to develop stability strategies that were robust and
efficient. It is evident that there are a multiple of opportunities
for scientifically sound lean stability approaches to be adopted.
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31. Reference:-
1. Stability Testing of New Drug Substances And Products
Q1A(R2). ICH Harmonised Tripartite Guideline. Step 4
version. 6 February 2003 18
2. https://www.researchgate.net › fulltextLean Stability Case
Studies—Leveraging Science
3. https://www.ich.org
4. https://www.researchgate.net/publication/333236574_STABI
LITY_STUDIES_OF_PHARMACEUTICAL_PRODUCTS
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