Stability study of Pharmaceutical Products and Regulatory Requirements

TRAINER: MD. ZAKARIA FARUKI
Orion Pharma Limited
Dhaka, Bangladesh
TRAINING ON
Stability Study of
Pharmaceutical Products and
Regulatory Requirements
ORION
Slide 1 of 34

 A marketed product stability program fulfils registration
commitments and ensures that marketed product is
stable (potent) until expiry date stamped on product
label.
 The purpose of stability testing is to provide
evidence on how the quality of a FPP varies with
time under the influence of a variety of
environmental conditions such as temperature,
humidity and light and to establish a shelf-life for
the FPP, to determine the storage conditions and
the in-use stability.
 To know about length of the time and conditions
where efficacy, safety and quality of the FPP are
maintained.
Training on Stability Study of Pharmaceutical Products by Md. Zakaria Faruki Slide 2 of 34
ORIONPurpose of Stability Studies

ORIONStability Study to identify the
Potential instability issues of FPPs
 Loss or 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
Training on Stability Study of Pharmaceutical Products by Md. Zakaria Faruki Slide 3 of 34

Training on Stability Study of Pharmaceutical Products by Md. Zakaria Faruki
ORIONWhere, Why &
What are changes?
Stability Studies are preformed on ...
 Drug Substances (DS)  The unformulated drug substance
that may subsequently be formulated with excipients to
produce the dosage form.
 Drug Products (DP)  The dosage form in the final immediate
packaging intended for marketing……. controlled and
documented determination of acceptable changes of the drug
substance or drug product
 Physical changes
• Appearance, Melting point, Clarity and color of solution, moisture,
Crystal modification (Polymorphism), Particle size
 Chemical changes
• Increase in Degradation • Decrease of Assay
 Microbial changes
Slide 4 of 34

Common Terminology
 Long-term testing: Stability studies under the recommended storage condition for the retest
period or shelf-life approved for labelling
 Accelerated testing :Studies designed to increase the rate of chemical degradation or
physical change of active pharmaceutical product, medical device or pharmaceutical product
(I.e. drug product) by using exaggerated storage conditions as part of the formal defined
storage program
 Date of Manufacturing: The first day of compounding for pharmaceutical products. It is the
date of the final production step for chemical substances
 Retest Date: The date after which samples of the 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 pharmaceutical product
 Shelf life: The time interval that a pharmaceutical product (i.e. drug product) or medical
device is expected to remain within the approved specification provided that it is stored under
the conditions defined on the label in the proposed containers and closure
 Expiry date/Expiration date: The date placed on the container label of an API /
pharmaceutical product designating the time during which a batch of the API / product is
expected to remain within the established/approved shelf-life specification, if stored under
defined conditions, and after which it must not be used
 Bracketing: The design of stability schedule such that only samples on the extremes of
certain designs factors (e. g. strength, container size and/or fill) are tested at all time points
as in the full design. The design assumes that the stability of any intermediate levels is
represented by the facility of the extremes tested
 Matrixing: The design of a stability schedule that a selected subset of the total number of
possible samples for all factor combinations would be tested at a specified time point
 T0 : Initiation of the stability study (i.e. samples put in the climatic chambers)
Slide 5 of 34
ORION

ICH Climatic Stability Zone
Slide 6 of 34
ORION
Climatic Zone Temperature Humidity Minimum Duration
Zone I 21ºC ± 2ºC 45% rH ± 5% rH 12 Months
Zone II 25ºC ± 2ºC 60% rH ± 5% rH 12 Months
Zone III 30ºC ± 2ºC 35% rH ± 5% rH 12 Months
Zone IVa 30ºC ± 2ºC 65% rH ± 5% rH 12 Months
Zone IVb 30ºC ± 2ºC 75% rH ± 5% rH 12 Months
Refrigerated 5ºC ± 3ºC No Humidity 12 Months
Frozen -15ºC ± 5ºC No Humidity 12 Months
Climatic Zone Temperature Humidity Minimum Duration
Accelerated Ambient 40ºC ± 2ºC 75% rH ± 5% rH 6 Months
Accelerated Refrigerated 25ºC ± 2ºC 60% rH ± 5% rH 6 Months
Accelerated Frozen 5ºC ± 3ºC No Humidity 6 Months
Intermediate 30ºC ± 2ºC 65% rH ± 5% rH 6 Months
Long Term Testing Conditions
Accelerated and Intermediate Testing Conditions
Zone Type of Climate
Zone I Temperate zone
Zone II Mediterranean/subtropical zone
Zone III Hot dry zone
Zone IVa Hot humid/tropical zone
Zone IVb ASEAN testing conditions hot/higher humidity
ICH Stability Zones

TESTING FREQUENCY
Slide 7 of 34
ORION
 Long-term conditions : every 3 months over
the first year, every 6 months over the second
year and annually thereafter
 Accelerated storage conditions: minimum of 3
points including the initial and final time points
(e.g. 0, 3, & 6 months) from a 6-month study
 When testing at the intermediate storage
condition is called for as a result of significant
at the accelerated storage condition, a
minimum of 4 time points, including the initial
and final time points (e.g. 0, 6, 9 & 12
months) from a 12-month study is
recommended.
 Reduced designs i.e. matrixing or bracketing
can be applied, if justified

Types of stability studies ORION
 There are five types of stability that must be
consider for each drug
Slide 8 of 34Training on Stability Study of Pharmaceutical Products by Md. Zakaria Faruki

Stability studies at
different stages
 Stability on pre-formulation batches
 Accelerated and long term testing for registration
 On-going Stability testing
 Follow-up Stabilities
 For a drug substance, we need to study 3
categories of stabilities-
1. Solid state stability of drug only
2. Compatibility studies (drug+ excipients )
3. Solution phase stability
ORION

different stages
FORCED DEGRADATION STUDIES
 Acidic & Basic conditions.
 Dry heat exposure
 UV radiation exposure
 Influence of pH
 Influence of temperature
 Influence of ionic strength
PHYSICAL CHANGES/INSTABILITY
 Solubility
 pKa
 Melting point
 Crystal form
 Equilibrium moisture content.
Example- amorphous materials are less stable than their crystalline
counterparts.
ORION

different stages
CHEMICAL DEGRADATION STUDY
 Hydrolysis- usually drugs such as esters, amides and
lactams undergo hydrolysis.
 Oxidation Reduction- loss of electrons, gain of electrons.
Auto oxidation also is responsible. Eg-tetracyclines, vit A,
vit D, morphine.
 Photolysis- Compounds such as ascorbic acid, riboflavin,
cyanacobalamine, folic acid undergo degradation on
exposure to light. Sometimes coupled with thermal
reactions.
 Isomerisation-Compounds get converted into a less
effective form. Eg-Adrenaline solutions at low pH lose
activity since its levo form is more stable than dextro form
ORION

different stages
 Stability on pre-formulation batches
 Accelerated and long term testing for registration
 On-going Stability testing
 Follow-up Stabilities
 For a drug substance, we need to study 3
categories of stabilities-
1. Solid state stability of drug only
2. Compatibility studies (drug+ excipients )
3. Solution phase stability
ORION

IN-USE STABILITY TESTING ORION
 The content of multi-dose containers, due to repeated
opening and closing
 A minimum of 2 batches, at least pilot scale batches,
should be subjected to the test. At least one should be
chosen towards the end of its shelf-life
 Test design should simulate the use of the product in
practice including fill volume, dilution/constitution
before use
 The determined in-use shelf life should be stated on
the label

Impermeable & Semi-
permeable Containers
ORION
 Sensitivity to moisture or potential for solvent loss is not of concern
as there is a permanent barrier to passage of moisture or solvent
 Therefore stability studies for products stored in impermeable
containers can be conducted under any controlled or ambient
humidity conditions
 Aqueous based products packaged in semi-permeable containers
should be evaluated for potential water loss
 Studies should be carried out at low relative humidity to demonstrate
that container can withstand low relative humidity environments
 A 5% water loss is considered significant after an equivalent of
3months at 40±2ºC/ NMT 25%RH; however for small container i.e.
1ml or unit-dose products, this may be appropriate if justified

SPECIFICATIONS ORION
 Should include those attributes that are susceptible to change
during storage and are likely to influence quality, safety and/or
efficacy.
 Should cover as appropriate, the physical, chemical, biological and
microbiological attributes, preservative content and functionality
tests (e.g. for a dose delivery system)
 Analytical procedures should be fully validated and stability
indicating
 Shelf life acceptance criteria should be derived from consideration
of all available stability information
 Justifiable differences between the shelf life and release acceptance
criteria based on evaluation of stability data and changes observed
on storage
 Any differences between release and shelf life acceptance criteria
for antimicrobial preservative content to be supported by
development data
 A single, primary stability batch should be tested for antimicrobial
preservative effectiveness (in addition to preservative content)
whether there is a difference between the release and shelf life
acceptance criteria for preservative content or not

Stability-indicating quality
parameters
ORION
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 ♦ Degradants
♦ Assay ♦ Microbial purity

Testing scope for Solid dosage ORION
 Physical-chemical properties
– Appearance
– Elasticity
– Mean mass
– Moisture
– Hardness
– Disintegration
– Dissolution
 Chemical properties
– Assay
– Degradation
 Microbial properties
TAMC, TYMC, E. coli
 Container closure system properties
– Functionality tests (e.g. extraction from blister)

Testing scope for LIQUID FORMS
for inj. and PARENTRAL
ORION
– pH
– Loss on weight
– Color & clarity of solution
- Sterility Tests
– Assay
– Degradation products
– Degradation preservatives
– Content antioxidants
- Pyrogen Testing
– Functionality tests
- Leakage test

Testing scope for Oral liquid
form
ORION
– pH
– Color & clarity of solution
– Viscosity
– Particle size distribution (for oral suspensions only)
– Assay
– Degradation products
– Degradation preservatives
– Content antioxidants

Testing scope for SEMI
LIQUID FORMS
ORION
– Appearance, odor, homogeneity, consistency
– Loss on weight, Viscosity
– Content uniformity (within the container)
– Assay
– Degradation products & preservatives
– Content preservatives
– Degradation– Content antioxidants

Release and Shelf-life
Specifications
ORION
 It may be appropriate to have justifiable
differences between the shelf life and release
acceptance criteria based on the stability
evaluation and the changes observed on
storage.
 Shelf-life acceptance criteria should be derived
from consideration of all available stability
information.
 Release and shelf-life dissolution acceptance
criteria (Q and t) must be the same

ORIONSelection of Batches
 At the time of submission data from stability
studies should be provided for batches of
the same formulation and dosage form in
the container closure system proposed for
marketing.
 Stability data on three primary batches are
to be provided. The composition, batch size,
batch number and manufacturing date of
each of the stability batches should be
documented and the certificate of analysis
at batch release should be attached.
 Where possible, batches of the FPP should
be manufactured by using different batches
of the API.

ORIONSHELF LIFE EVALUATION
 Self life (referred to as expiration dating period) is the time period
during which a drug product is expected to remain within the
approved specification for use, provided that it is stored under the
conditions defined on the container label.

ORIONCalculation of shelf life
 Example:- self life of Aspirin suspension:
 A prescription for a liquid aspirin is called for, It contains
325mg/5ml or 6.5g/ 100ml.
 Solubility of aspirin at 250C is 0.33g/100ml. Therefore the
suspension will definitely be a suspension.
 Other ingredients in the prescription cause the product to have a
pH of 6.
 The first order rate constant for aspirin degradation in the solution
is 4.5×10-6 sec -1.
 Calculate the zero order rate constant.
 Determine the self life, t90 for the liquid preparation, assuming
that the product is satisfactory until at the time at which it has
decomposed to 90% of its original concentration (i.e 10%
decomposition) at 250C.

ORIONCalculation of shelf life
Ans:- K0 = K × [ aspirin in solution],
Thus K0 = [4.5 × 10-6 sec-1] × [0.33g/100ml]
K0 = 1.5 × 10-6 g/100ml sec-1
= 4.3×10 5 sec
= 5 days

ORIONSTABILITY CHAMBER ROOM

Significant Change & Pitfall ORION
 A 5% change in assay from its initial value.
 Any degradation product exceeding its acceptance criterion.
 Failure to meet the acceptance criteria for appearance, physical
attributes, and functionality test (e.g., color, phase separation,
hardness).
 As appropriate for the dosage form, e.g., failure to meet the
acceptance criteria for dissolution for 12 dosage units.
 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.

Commitment to conduct
Additional or New Stability Study
ORION
 For confirmation of provisional (tentative) shelf-life, real-
time data are required
 First 3 production batches on stability
 Follow up stability testing (FUST) – one batch per year
 Variations affecting one or more steps of the same route of
synthesis of an API
 Change in the route of synthesis of an API
 Change in composition of the FPP
 Change in immediate packaging of the FPP

ROLE OF STABILITY TESTING ORION
 Provides evidence on how the drug substance or product quality varies
with time under environmental conditions during distribution.
 Helps to recommend storage conditions including establishment of shelf
life, expiry date or retest period
 Key assurance of quality of pharmaceuticals.
STAGES OF DRUG AND PRODUCT DEVELOPMENT AND
STABILITY TESTING
 Pre-clinical studies
 Clinical studies
 Pre- formulation
 Formulation development
 Scale up
 Commercial manufacturing
 Distribution and shipping
 Post approval changes
 Market surveillance

ICH GUIDELINES (QUALITY) ORION
 Stability Testing in Climatic Zone I and II (Q1A)
 Photostability Testing (Q1B)
 Stability Testing for New Dosage Forms (Q1C)
 Bracketing and Matrixing Designs (Q1D)
 Evaluation of Stability Data (Q1E)
 Stability Testing in Climatic Zones III and IV (Q1F)
 Validation of Analytical Procedures (Q2)
 Impurities (Q3)
 Q4- Pharmacopoeial Harmonization
 Biotechnological Products (Q5)
 Specifications (Q6)

Explanatory Note on the Withdrawal
of ICH Q1F
ORION
 ICH Q1 F Stability Data Package for Registration Applications in Climatic Zones III and IV defined
storage conditions for stability testing in countries located in Climatic Zones III (hot and dry) and IV (hot
and humid), i.e. countries not located in the ICH regions and not covered by ICH Q1 A (R2) Stability
Testing for New Drug Substances and Drug Products. ICH Q1 F described harmonised global stability
testing requirements in order to facilitate access to medicines by reducing the number of different storage
conditions. In the course of the discussions which led to the development of the guideline, WHO
conducted a survey amongst their member states to find consensus on 30 °C/65% [relative humidity] RH
as the longterm storage conditions for hot and humid regions. As no significant objections were raised in
this survey, 30 °C/65% RH was defined as the long-term storage condition for Climatic Zone III/IV
countries in ICH Q1F. The document was adopted by the ICH Steering Committee in February 2003 and
subsequently implemented in the ICH regions.
 Based on new calculations and discussions, some countries in Climatic Zone IV have expressed their wish
to include a larger safety margin for medicinal products to be marketed in their region than foreseen in
ICH Q1F. As a consequence, several countries and regions have revised their own stability testing
guidelines, defining up to 30 °C/75% RH as the long-term storage conditions for hot and humid regions.
Due to this divergence in global stability testing requirements, the ICH Steering Committee has decided
to withdraw ICH Q1F and to leave definition of storage conditions in Climatic Zones III and IV to the
respective regions and WHO
 In assessing the impact of the withdrawal of ICH Q1F on intermediate testing conditions defined in ICH
Q1A (R2), the decision was reached to retain 30 °C/65%RH. However, regulatory authorities in the ICH
regions have agreed that the use of more stringent humidity conditions such as 30 °C/75% RH will be
acceptable should the applicant decide to use them.

HIGHLIGHTS ORION
 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
must be evaluated by the manufacturer in
order to propose a retest date or expiry date.

References
 Drug Stability: Principles and Practices, 3rd Edition, edited
by Jens T. Carstensen and C. T. Rhodes (Marcel Dekker, Inc.,
New York, 2000)
 http://www.ich.org/fileadmin/Public_Web_Site/ICH_Product
s/Guidelines/Quality/Q1F/Q1F_Explanatory_
 Note.pdf.
 Silke Klick and others: Toward a Generic Approach for
Stress Testing of Drug Substances and Drug Products
(Pharmaceutical Technology, February 2005)
 Raphael Bar: 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)
ORION

ORION
“Success is walking from failure to
failure with no loss of enthusiasm”.
~Winston Churchill

Stability study of Pharmaceutical Products and Regulatory Requirements

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