STABILITY STUDY GUIDANCE PROTOCOL

1) Purpose :
1.1 To provide evidence on how the quality of drug product varies with time when
subjected to different environmental conditions, namely temperature/humidity variation
andnabling the establishment of recommended storage conditions, re-test dates and/or
shelf life.
1.2 To select the formulation / primary package to be registered for production.
1.3 To determine shelf life and storage condition of the selected formulation for prospective
production batches. 1.4 To substantiate the claimed shelf life.
2) Scope Stability study is carried out on :
2.1 Product under formulation or development.
2.2 Selected formulation for registration.
2.3 Pilot scale batch –R&D batch (10% of production batch size).
2.4 Post marketing production batch (New products) / change control products.
2.5 Stability study in cases of a change control necessity including change in composition
(API or excipients), process upon an action taken by R&D for updating purposes for re-
registration or a product upgrade.
2.6 Stability study in cases where re-work of a product falling in OOS requisites (Code:
QUI824-08), refer to Corrective & Preventive Deviation Procedures (QUP – 850 – 01) upon a
request submitted by QA/QC or production to R&D.
3) Definitions :
3.1 Long Term (real time) Testing Stability evaluation of the physical, chemical, biological,
and microbiological characteristics of a drug substance and a drug product, covering the
expected duration of the shelf life, which is claimed in the submission and will appear on the
labeling.
3.2 Accelerated Testing / intermediate testing Studies designed to increase the rate of
chemical degradation or physical change of an active drug substance or drug product by
using exaggerated storage conditions as part of the formal, definitive, storage program;
where higher temperature affect the product intermediate analysis for a longer duration at
lower temperature/ humidity conditions is allowed..
3.3 Shelf –life; Expiration Dating Period The time interval that a drug product is expected to
remain within the approved shelf-life specification provided that it is stored under the
conditions defined on the label in the proposed containers and closure.
3.4 Stress Testing These studies are undertaken to elucidate intrinsic stability characteristics
3.5 In-use stability study The purpose of in-use stability testing is to provide information for
the labelling on the preparation, storage conditions and utilization period of multidose
products after opening, reconstitution or dilution of a solution, E.g. an antibiotic injection
supplied as a powder for reconstitution
3.6 Ongoing stability studies The study carried out by the manufacturer on production
batches according to a predetermined schedule in order to monitor, confi rm and extend
the projected re-test period (or shelf-life) of the API, or confi rm or extend the shelf-life of
the FPP
. 3.7 Statements and Labeling: Storage statement is established for labeling in accordance
with the stability evaluation of the product. 3.8 Specification A list of tests, references to
analytical procedures, and appropriate acceptance criteria, which are numerical limits,
ranges or other criteria for the tests described. It establishes the set of criteria to which an
API or FPP should conform to be considered acceptable for its intended use
4) References and Related documents
4.1 ICH guidelines

4.2 Egyptian MOH requirements issued by Central Pharmaceutical Administration

4.3 Stability guidelines – WHO

4.4 Handbook of stability testing in pharmaceutical development (Regulations, methodologies and

best practices) Kim Huynh-Ba : Editor

4.5 Pharmaceutical statistics – practical and clinical applications – fifth edition by Sanford Bolton &
Charles Bon

5) Responsibility

Stability team members and / or Product analyst

6) Procedure

6.1 Study Set-up

6.1.1 Study Set-up is typically triggered by a sample request (Form: RDF-733-15), either from the
formulation group. The Stability administrator must determine if a new study is necessary and if a
standard protocol can be used

. 6.1.2Stability protocols must be approved by a Quality group.

6.1.3 Each study must carry a unique, identifying (tracking) number that will contain information
necessary to enter the study into a specific tracking system. Lot-specific information is gathered by
contacting the appropriate personnel. Alert and test schedule information is determined with input
as necessary from appropriate analytical groups.

6.1.4 The purpose of the study must also be clearly stated and must be understood by the
stability studies team, who will need to determine the impact of the study data.
 6.1.5 RDF-733-15 lists information needed to initiate a stability study, stating the general
requirements needed from requester to start the study. It consists of 2 parts.
6.1.6 Part 1 should be filled by the requester of the stability study and it defines the
following
6.1.6.1 Drug Phase (Product under development / selected for registeration/post
registeration product /production batch)
6.1.2.2 Type of study (Accelerated / long term), should also mention if any in-use stability
testing is required
6.1.2.3 Product information (Product name / Dosage form / API and preservatives if
present / overages/primary package)
6.1.2.4 Selection of batches (batch no. /Mfg date for each batch to be tested)
6.1.2.5 Tested parameters (according to table no.1)
6.1.2.6 Registration procedure (old / new) These items are the requirements in order to
identi

Dosage form Name *Items of examination

Tablets Appearance- friability- hardness- color fading- odor-
dissolutionassay of active substance- related substances-
disintegration Microbiological examination
Capsules Appearance- color fading- dissolution- assay of active substance -
related substances- disintegration- brittleness- capsule
deformation- ( for soft gelatin capsule ; the fill medium should be
examined for precipitation, cloudiness and pH)
Oral powder and Appearance- flowability- moisture- pH- assay of active substance -
granules related substances- color- odor
Syrup, drops, Color- odor- taste- assay of active substance - dissolution- assay of
suspensions and preservative- antioxidant or other stabilizing
lotions additivesedimentation volume- cake formation-
Creams, ointments Appearance- assay of active substance - related substances-
and gels separation- pHviscosity- phase separation- bleeding
bleeding
Suppositories Appearance- melting range- solidification point- hardness- assay of
active substance - dissolution- breaking test- disintegration-
related substances
Parenterals Appearance- color- assay of active substance - clarity- pH- related
(injections and substances- sterility- pyrogen-
solutions)
Aerosol Appearance- color- assay of active substance - dose content
uniformity- labeled no. of actuations per
6.1.8 Stability study protocol is identified
: 6.1.8.1 For items 2.1, 2.2, 2.3, an Accelerated testing protocol using RDF-733-16 is
conducted (if not applicable to product, long term stability is conducted, justification for the
change should be included
) 6.1.8.2 For item 2.4, Long term stability study protocol using RDF-733-16 is conducted; any
requirements stated in MOH approval for production should be fulfilled and added to the
protocol
6.2 Samples are added to the appropriate incubator , the incubator logbook is updated ,
samples are scheduled to be pulled based on the time points listed in the stability protocol ,
data are added to the stability database by the stability responsible person , Two ways are
used to track stability program, the main way is through hard copies of the sheet in a file
(stability protocol ) the other way one is through the specific database (Ms access database )
, the file is secured by the responsible personnel who is in charge of handling samples in &
out of chambers and who also records results periodically. The process of recording stability
samples in the stability database is as follows
: 1- Ms access should be installed on the computer
2- Use stability database (stability.mdb), it is secured by a password only known to the head
of department and stability responsible person
3- Open the database , a preview of the startup form is as follows :
4- use (Stability new entry ) to open a new form for a new stability study
5- choose product name in the specified field from the dropdown list , if not included , press
add product button and add the name and description of new product
6- add batch number
7- choose the formulator(responsible person ) from dropdown list
8- choose analyst name (stability team ) from dropdown list
9- Choose type of product (production or R&D trial, etc) from the specific field along with
storage condition and type of stability study and duration.
10- state the amount of starting samples and identify the pack type
11- specify the starting date of study , verify that the calculation is accurate
12- mention the status of study
13- Components of the product are mentioned in the appropriate filed , save and click
refresh
14- for each pull , record in the appropriate field amount of sample pulled and specify the
date , press on remaining amount button to know the remaining amounts , verify the result
manually
15- to view time points intervals and added results , press on intervals and results button
6.5 Study or protocol amendment: Once the study is started, any change to the stability
protocol needs to be made with appropriate approvals. Justification must be recorded. The
Stability administrator must also check to assure that there are enough samples to test the
changes. An example of a study amendment could be an addition of testing time points to
more completely monitor out-of-trend stability data
. 6.6 study or protocol deviation: Deviation from a stability protocol can occur throughout
the study. There are two forms of deviations: planned and unplanned. Once a deviation
occurs, an investigation must be conducted. Corrective actions and preventive actions
(CAPA) may also be necessary to avoid recurrence. The impact of the deviation on the study
must also be assessed and documented.
6.7 Study completion: The study completion date is the point when the last sample was
pulled tested, and all results are reported. This time marks the end of the study. A study is
not considered complete if there is an open investigation on any result.
6.8 Study cancellation: If stability information is no longer needed, the study could be
cancelled. Appropriate approval must be secured in order to cancel a study. If the requester
wants to cancel a study, the approval of the R&D manager to cancel the study should be
documented.
6.20 OOS (Out-of specification): OOS results should be investigated. The procedures to be
followed and the responsibilities of various personnel are outlined below.
6.20.1 The first phase of the investigation occurs in the lab and is focused on the possible
identification of assignable laboratory errors. The responsibilities of the supervisor and the
analyst during this phase are listed below.
6.20.1.2 Analysts are responsible for

 Ensuring that the equipment used is calibrated and meets the required acceptance
criteria.
 Reporting data only if the required system suitability tests pass acceptance criteria
 Checking the data for compliance to specifications before discarding any test
solutions
 Informing the supervisor if any unexpected results are obtained
 Stopping testing if an obvious error occurs; they should not knowingly continue
testing when they expect to invalidate the data at a later time for an assignable
cause, except when the sole purpose is to see what results are obtained when
obvious errors are known. The supervisor is responsible for
 Performing an objective and timely assessment.
 Confirming the analyst’s knowledge and performance of correct procedures
 Examining the raw data and identifying anomalous or suspect information.
 Confirming the performance of the instruments.
6.20.2 Retesting
6.20.2.1 Retesting is performed using the same homogenous material as the original
sample.
6.20.2.2 The concept of retesting does not apply to some tests such as content uniformity
and dissolution.
6.20.2.3 Re-testing should not be applied over 3 times. Each testing step must be approved
and supervised by a responsible person. It is important that the retesting be performed by a
second analyst if available. Repeating testing until a passing result is obtained and then
discarding the originally obtained data is commonly referred to as testing into compliance
and is objectionable under the cGMPs.
6.20.4 Outlier Test
6.20.4.1 Outlier testing is a statistical procedure to determine if a value obtained is different
than others in a series.
6.20.4.2 The outlier test cannot be applied to data when the variability in the product is
being assessed, such as dissolution or content uniformity testing.
6.20.4.3 Dixon’s Test for Extreme Values is used to evaluate the outlier
6.20.5 When the OOS Result Is Confirmed If the investigation described above does not
identify a laboratory error as a root cause, then the OOS result is considered representative
of the lot being tested.
8) Forms

Form Number Title

RDF-733-15 Stability study profile
RDF-733-16 Stability study protocol
 RDF-733-17 Stability study report
RDF-733-18 OOS investigation
RDF-733-19 Commitment form

9) Records :

Title: STABILITY STUDY PROTOCOL

1-Objective:
To provide evidence of the quality of product with respect to time when subjected to
different environmental conditions, namely temperature/humidity variation, enabling the
establishment of recommended storage conditions, re-test dates and/or shelf-life.
2-Purpose:
2.1 To determine shelf-life and storage conditions for prospective production batches.
2.2 To substantiate the claimed shelf life.
3- Composition
3.1 Each …Asprin 75mg……
contains
4-Batches

Batch Number Manufacturing Date Date Expire Packaging

59000011 08/2020 07/2022 Alu - Alu
5- Sampling Schedule and storage conditions
5.1 The samples were withdrawn at:……6…… months interval when stored at………15 c…… :
……………….. Product Topic : ……aspirin 75mg…. Stability Study Protocol.
6- Acceptance Criteria

Item Specification Physical parameters

Physical According to Reference method
parameters
Chemical According to Reference method
parameters
Microbiological According to Reference method
examination

7- Method of analysis

7.1 Label Claim

7.2 Limit

7.3 Equipment

7.5 Analytical conditions

7.4 Procedure

7.5 Calculations

8. Validation of method of analysis

The assay of ………Aspirin 75mg TAblet… as per Attachment has been tested for:

8.1 Analytical validation according to validation protocol: Accuracy Precision Specificity Quantitation
limit Detection limit Linearity and Range System suitability Robustness

8.2 A placebo of ……………---…… showed no interference with the method

. 9- Method Findings:

Refer to results tabulated in the attached tables no. ……2….. Results …………………………
PASS………………………………………

10- stability study results

Accelerated stability results

Table NO.:……1….. Batch no: …59000011.. Manuf. Date: 08/2020……

Storage conditions**: 40°C ±2 75% RH

Item Specification 1 month 3 month 6 month

Physical according to RFM CHECK CHECK CHECK
parameters
Chemical according to RFM CHECK CHECK CHECK
parameters
Microbiological according to RFM CHECK CHECK CHECK
examination

*RFM = Reference Method **Liable to change according to individual requirement of

pharmaceutical form

11- Conclusion

After storage of three batches NO.: 59000011…/…59001232…………/…59000056…….for …6… months

at ……Room temperature…………………………

1- The product did not show any significant difference with respect to initial control analysis
regarding all physico-chemical parameters studied.

2- The product showed some significant difference with respect to the following items
…………………………………----…………………………………………………………

12-Shelf life Results from stability study of ……Aspirin 75mg…………. justifies the shelf life of ……24
months………………. for the product.

13- Storage condition ………At room temperature…………………………………………………………………………

Analyzed by : Manish Shankarpure

Compiled by : Dr.Madhuri shelar

Approved by : Dr. Sonia singh