Title:

STABILITY STUDY GUIDANCE PROTOCOL

Issue No.: 3
CODE No.: RDI-731-03 Issue Date: 01/4/2012
Page No.: 1 / 49
Distribution :
1 Management Representative 6 Human Resources 11 Promotion
2 Research and Development 7 Export 12 Health, Safety & Environment
3 Marketing 8 Production 13 Regulatory Affairs
4 Supply Chain 9 Engineering
5 Quality Assurance &Quality Control 10 R&D

Revision History :

Revision No. Page Description of change Process Effective

No. owner date

Approvals :
Prepared Revised Approved
Name: Michael Nabil Name: Manal Hamdy Name: Laila Gad Elrub
Job title: R&D Supervisor Job title: QA&QC Manager Job title: R&D Manager
Signature: Signature: Signature:
Date: Date: Date:

Pages Status

(49)

Rev. No.: 0 Department Name: R & D Dept.

Rev. Date: 01/05/2012
Title:
STABILITY STUDY GUIDANCE PROTOCOL
Issue No.: 3
CODE No.: RDI-731-03 Issue Date: 01/4/2012
Page No.: 2 / 49
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 and enabling 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: QUI-
824-08), 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

Rev. No.: 0 Department Name: R & D Department

Rev. Date: 01/4/2012
Title:
STABILITY STUDY GUIDANCE PROTOCOL
Issue No.: 3
CODE No.: RDI-731-03 Issue Date: 01/4/2012
Page No.: 3 / 49
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.

3.9 Significant change

In general “significant change” for a Finished Product is defined as OOS “out of
specification “:
1. A 5% or more change in assay from its initial content of API(s), or failure to meet the
acceptance criteria for potency when using biological or immunological procedures. If
justified, to certain products, such as multivitamins and herbal preparations.)
2. Any degradation product exceeding its acceptance criterion.
3. Failure to meet the acceptance criteria for appearance, physical attributes and functionality
test (e.g. colour, phase separation, resuspendability, caking, hardness, dose delivery per
actuation). However, some changes in physical attributes (e.g. softening of suppositories,

Rev. No.: 0 Department Name: R & D Department

Rev. Date: 01/4/2012
Title:
STABILITY STUDY GUIDANCE PROTOCOL
Issue No.: 3
CODE No.: RDI-731-03 Issue Date: 01/4/2012
Page No.: 4 / 49
melting of creams or partial loss of adhesion for transdermal products) may be expected
under accelerated conditions.
Also, as appropriate for the dosage form:
4. Failure to meet the acceptance criterion for pH. Or
5. Failure to meet the acceptance criteria for dissolution for 12 dosageunits.

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

Rev. No.: 0 Department Name: R & D Department

Rev. Date: 01/4/2012
Title:
STABILITY STUDY GUIDANCE PROTOCOL
Issue No.: 3
CODE No.: RDI-731-03 Issue Date: 01/4/2012
Page No.: 5 / 49
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 identify the drug product as well as the package
used
Table No. 1
Dosage form Name *Items of examination
Tablets Appearance- friability- hardness- color fading- odor- dissolution-
assay 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 granules Appearance- flowability- moisture- pH- assay of active substance -
related substances- color- odor
Syrup, drops, suspensions Color- odor- taste- assay of active substance - dissolution- assay of
and lotions preservative- antioxidant or other stabilizing additive-
sedimentation volume- cake formation- pH- related substances
Creams, ointments and Appearance- assay of active substance - related substances- pH-
gels viscosity- phase separation- bleeding
Suppositories Appearance- melting range- solidification point- hardness- assay of
active substance - dissolution- breaking test- disintegration- related
substances
Parenterals (injections Appearance- color- assay of active substance - clarity- pH- related
and solutions) substances- sterility- pyrogen- particulate matter
Aerosol Appearance- color- assay of active substance - dose content
uniformity- labeled no. of actuations per container- related
Rev. No.: 0 Department Name: R & D Department
Rev. Date: 01/4/2012
Title:
STABILITY STUDY GUIDANCE PROTOCOL
Issue No.: 3
CODE No.: RDI-731-03 Issue Date: 01/4/2012
Page No.: 6 / 49
substances - spray content- valve delivery
* Items are subjected to variability according to each individual case.
6.1.2.6 Storage conditions requested
6.1.2.7 Sample amount to be tested with the frequency of testing
6.1.2.8 Special needs or general comments
6.1.2.8 Signature of requester and date of requesting

6.1.7 Part 2 should be filled by the responsible stability team member and it defines the
following:
6.1.7.1 Literature survey (yes/no), important findings should be stated and an attachment
to this section can be added
6.1.7.2 Checklist indicating the availability of requirements to activate the study:
6.1.7.2.1 Initial analysis results from requester /date of receiving
6.1.7.2.2 Method of analysis:
Linearity data from validation of method of analysis items /date of receiving
Specificity of testing method (Performed by stability analyst) /date of application
Evaluation of reproducibility of method (analyst II compared to initial results of
requester) by statistical evaluation
Approval on applying method of analysis /date of application
6.1.7.2.3 Copy of registration license, if issued
6.1.7.2.4 Approval on sample size
6.1.7.2.5 Approval on starting stability study/signature /date
Notes:
1- 7 working days from receiving each checklist item should be needed to either evaluate the
point or to perform the next action
2- The analyst must ensure that there are enough samples to conduct all required testing under
all conditions. An additional quantity of samples, typically 50–100% of that required for the
study, should also be placed on stability for contingency testing; however, this quantity
depends greatly on the study purpose and also upon the materials available.

3- Initial release data could be used as Time Zero (TZ) if the samples are placed in the chambers
within 30 days of testing. Otherwise, Time Zero testing will be performed at the initiation of
the study. It is also recommended that Time Zero testing be done if the packaging process
could compromise the stability or quality of the drug product.
Rev. No.: 0 Department Name: R & D Department
Rev. Date: 01/4/2012
 Title:
STABILITY STUDY GUIDANCE PROTOCOL
Issue No.: 3
CODE No.: RDI-731-03 Issue Date: 01/4/2012
Page No.: 7 / 49
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
Rev. No.: 0 Department Name: R & D Department
Rev. Date: 01/4/2012
Title:
STABILITY STUDY GUIDANCE PROTOCOL
Issue No.: 3
CODE No.: RDI-731-03 Issue Date: 01/4/2012
Page No.: 8 / 49
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
16- The database will provide a unique unrepeated ID number for the stability study;
this ID should be used for any documentation of the relevant study.
17- For monthly check of the list to be analyzed, make sure that the date of the
computer clock is adjusted, and then press on “to be analyzed this month “button to view
the report.
18- Each form of the database can be printed and a backup for the database is stored on
company server by a secured process.

6.3 Samples pulled outside of the allowable windows will be audited. Justification must be
documented.
6.4 Sample testing turnaround is the time needed to complete testing of a stability sample.This
is the time from the point at which a sample is removed from the storage chamber until the time
that all the tests are completed and results are approved for submission. This time should be
defined based on available resources as well as the analyst’s sample workload. The industry
standard for completion of testing is 30 days; however, it depends on the nature of the samples
as well as the testing to be done. For samples stored at accelerated or stressed conditions, testing

Rev. No.: 0 Department Name: R & D Department

Rev. Date: 01/4/2012
Title:
STABILITY STUDY GUIDANCE PROTOCOL
Issue No.: 3
CODE No.: RDI-731-03 Issue Date: 01/4/2012
Page No.: 9 / 49
should be started as soon as the samples leave the chambers in order to stop the degradation
process.

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.

6.9 Sample destruction is necessary when excess stability samples are removed from the
storage. This task is usually part of chamber maintenance activities, and should be done when
the end of the study is reached. The lab usually schedules the end of the month, to remove all
leftover samples of studies completed or canceled in that month. Samples should not be
destroyed until all data are approved and the study is complete and the requester approves the
destruction of samples. As part of good laboratory practices, samples of cancelled or completed
studies should not be retained in the chambers.

6.10 Sample inventory is a critical activity in the stability program. All samples must be
accounted for at any time. Location and identification of samples is important information, and
Rev. No.: 0 Department Name: R & D Department
Rev. Date: 01/4/2012
Title:
STABILITY STUDY GUIDANCE PROTOCOL
Issue No.: 3
CODE No.: RDI-731-03 Issue Date: 01/4/2012
Page No.: 10 / 49
must be included on the stability label. When a study is completed or canceled, samples must be
moved out of the chambers. The number of samples removed must be recorded, and reconciled
annually with the inventory system; electronic tracking can be used in case needed.
Discrepancies must be promptly investigated and documented.

6.11 Personnel are a critical factor to a successful stability program; qualified individuals will
be trained on a continuing basis. All training must be documented. Training can be either in-
house training, outside training. New employee training curriculumcan include technique-
related as well as method related training. A new employee also needs to be trained on
fundamentals of cGMP, as well as relevant SOPs applicable to his or her responsibilities.

6.12 Report findings and test results in tables using RDF-733-17, stability protocol should
include the results to meet MOH requirements.
6.13 Retain forms and records in product file and stability file; identify the stability study ID
(e.g. accelerated 17, meaning the accelerated stability study number 17)
6.14 stability data required for registration is extracted from tabulated results in RDF-733-15
and thoroughly assessed for evaluation of results of the product under test.
6.15 Accelerated stability results are used for estimating shelf life of product based on
determining the reaction order and Q10 rule , using Ea = 18 Kcal/mol and B =0.05 , calculations
should be documented and verified , Arrhenius equation is used .
6.16 any other stress tests or extenuating condition or procedure other than usual is separately
reported
6.17 Stability report RDF-733- 16 and protocol should be completed and revised by document
control personnel and approved by R&D manager , all relevant documents are to be submitted
to regulator affairs for submission to authorities within 8 months from the issuance of product
pricing .
6.18 Commitment reports as per MOH regulations (Form :RDF-733-19 )are issued declaring
that the studies and results are done and approved by the responsible persons of the company ,
In the case of submitting a stability study whose period is shorter than the product shelf life a
commitment is issued to complete the stability study by :
6.18.1 Running and submitting a long-term and accelerated stability studies for products
whose stability was previously studied on 3 batches in a period less than shelf life.
6.18.2 Running and submitting a long-term and accelerated stability studies for products
whose stability was previously studied on less than 3 batches in a period less than shelf life.
Rev. No.: 0 Department Name: R & D Department
Rev. Date: 01/4/2012
Title:
STABILITY STUDY GUIDANCE PROTOCOL
Issue No.: 3
CODE No.: RDI-731-03 Issue Date: 01/4/2012
Page No.: 11 / 49
6.18.3 Running and submitting a long-term stability study for products whose accelerated
stability was only studied.

6.19 If any significant change is obtained, the following should be conducted:

6.19.1 For items of 2.1, 2.2 and 2.3, follow the procedure scheme under 6.20.
6.19.2 For item 2.4, follow the procedure of QC OOS investigation (Dealing with out-of-
specification result) QUI-824-08

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.
_ Examining the solutions, reagents, and standards to confirm that they were appropriate for use
during testing.
_ Evaluating the performance of the test method.
_ Documenting and preserving evidence of the assessment.
Prompt initiation of the investigation is essential for several reasons. Test solutions, reagents,
and standard solutions will still be available and may be re-analyzed if necessary. The analyst’s

Rev. No.: 0 Department Name: R & D Department

Rev. Date: 01/4/2012
Title:
STABILITY STUDY GUIDANCE PROTOCOL
Issue No.: 3
CODE No.: RDI-731-03 Issue Date: 01/4/2012
Page No.: 12 / 49
memory of all stages of the testing will be clearest on the day of the test, and equipment is more
likely to be in the configuration used for testing and can therefore be checked for errors.
Checklist for laboratory investigations form RDF-733-18
6.20.1.3 If the review does not reveal the root cause of the anomalous results, there may be a
need to test the final prepared solution, retained samples from earlier steps of the sample
preparation or tablet grinds to identify the root cause. The procedures for such testing must be
defined in an SOP and the testing must be supervised and approved by a supervisor, with a
review of the results at each stage before proceeding to the next.
6.20.1.4 When the laboratory phase of the investigation does not identify an assignable cause, a
full-scale investigation must be initiated. The functional groups involved, in addition to the
requester, should be included in the investigation team. The investigation should be initiated and
completed promptly.
6.20.1.5 Form RDF – 733-18 which will aid in documentation of investigations is provided:

6.20.1.6 A critical part of the investigation is a review of other related documents to identify the
root cause of the OOS result. Some of the documents to be checked include stability data of
other time points of the same lot, other lots of the same product; other pack sizes/pack
configurations of the same lot or the same product, and the batch production record for other
investigations on the same lot/same product.
6.20.1.7 The data can reveal if the anomalous data was developing at earlier time points or
whether the root cause discovered as a result of this investigation could impact other lots, other
pack sizes, and other time point data.
6.20.1.8 The investigation may also include experimental work to determine the root cause.
Such experimental work must be described approved and supervised by a responsible person.

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.
Rev. No.: 0 Department Name: R & D Department
Rev. Date: 01/4/2012
Title:
STABILITY STUDY GUIDANCE PROTOCOL
Issue No.: 3
CODE No.: RDI-731-03 Issue Date: 01/4/2012
Page No.: 13 / 49
6.20.2.4 Where retesting of the original sample does not lead to the discovery of the root cause,
there may be a need to re-sample the lot. For stability studies, where the original time point
often cannot be resampled, due to the passage of time, a later time point sample is pulled and the
results are designated as such. For example, if in a study the 6-month sample test results are
under investigation, and additional containers at the 7-month time point are tested as part of the
investigation, the results are reported as belonging to the 7-month time point. The investigation
may conclude that either the original test result or the original sample tested was not
representative of the lot and may therefore be invalidated.
6.20.2.5 When faced with insufficient samples for testing of stability OOS investigations,
samples from other programs such as retention programs can be used for investigation only due
to difference in storage.

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.

Rev. No.: 0 Department Name: R & D Department

Rev. Date: 01/4/2012
Title:
STABILITY STUDY GUIDANCE PROTOCOL
Issue No.: 3
CODE No.: RDI-731-03 Issue Date: 01/4/2012
Page No.: 14 / 49

7) Flowchart
Trial Batches

Accelerated Testing Long Term Testing Stress Testing

View Results

Reports Unstable Formula

Stable Formula

Registration department

Production

Flowchart 1: Process Outline

Rev. No.: 0 Department Name: R & D Department

Rev. Date: 01/4/2012
Title:
STABILITY STUDY GUIDANCE PROTOCOL
Issue No.: 3
CODE No.: RDI-731-03 Issue Date: 01/4/2012
Page No.: 15 / 49
Flowchart 2: OOS flowchart

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 form
RDF-733-19 Commitment form

Rev. No.: 0 Department Name: R & D Department

Rev. Date: 01/4/2012
Title:
STABILITY STUDY GUIDANCE PROTOCOL
Issue No.: 3
CODE No.: RDI-731-03 Issue Date: 01/4/2012
Page No.: 16 / 49

10) Records

Title Retention period Retention Location

Stability study profile Unlimited -Product Registration file (R&D department)
-Documentation Master file (R&D department)
-Product stability file
Stability study protocol Unlimited Product Registration file (R&D department)
-Documentation Master file (R&D department)
-Product stability file
Stability study report Unlimited Product Registration file (R&D department)
-Documentation Master file (R&D department)
-Product stability file
OOS investigation Unlimited Product Registration file (R&D department)
form -Documentation Master file (R&D department)
-Product stability file
Commitment form Unlimited -Product Registration file (R&D department)
-Documentation Master file (R&D department)
-Product stability file

10) Performance Measure

None.

Rev. No.: 0 Department Name: R & D Department

Rev. Date: 01/4/2012
Title:
STABILITY STUDY GUIDANCE PROTOCOL
Issue No.: 3
CODE No.: RDI-731-03 Issue Date: 01/4/2012
Page No.: 17 / 49

Title:
STABILITY STUDY PROTOCOL
Issue No.:3
CODE No.: RDF-733-16 Issue Date:01/04/2012
Page No.: 1 / 49

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 ………………………… contains:
…………………………………………………….…………………………………………………….

4-Batches
Batch Number Manufacturing Date Expire date Packaging

5- Sampling Schedule and storage conditions

5.1 The samples were withdrawn at:…………………… months interval when stored at…………………………
: …………………………….. Product
Topic : …………………. Stability Study Protocol

Rev. No.: 0 Department Name: R & D Department

Rev. Date: 01/4/2012
Title:
STABILITY STUDY GUIDANCE PROTOCOL
Issue No.: 3
CODE No.: RDI-731-03 Issue Date: 01/4/2012
Page No.: 18 / 49

Title:
STABILITY STUDY PROTOCOL
Issue No.:3
CODE No.: RDF-733-16 Issue Date:01/04/2012
Page No.: 2 / 49
6- Acceptance Criteria
Item Specification
Physical parameters According to Reference method

Chemical parameters According to Reference method

Microbiological examination According to Reference method

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 ………………………………………… 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. ………..
Results ……………………………………………………………………………………….
Rev. No.: 0 Department Name: R & D Department
Rev. Date: 01/4/2012
 Title:
STABILITY STUDY GUIDANCE PROTOCOL
Issue No.: 3
CODE No.: RDI-731-03 Issue Date: 01/4/2012
Page No.: 19 / 49

Title:
STABILITY STUDY PROTOCOL
Issue No.:3
CODE No.: RDF-733-16 Issue Date:01/04/2012
Page No.: 19 / 49
10- stability study results
Accelerated stability results :
Table NO.:………..
Batch no: ……….. Manuf. Date: …………
Storage conditions**: 40°C ±2 75% RH
Initial 1 month 3 months 6 months

Item Specification
Estimated ………… ………… …………
month
Physical parameters according to ………. ………. ……….. ………..
RFM*
Chemical parameters according to ………. ………. ……....... ……......
RFM
Microbiological according to ………. ………. ……....... ………..
examination RFM

*RFM = Reference Method

**Liable to change according to individual requirement of pharmaceutical form

Rev. No.: 0 Department Name: R & D Department

Rev. Date: 01/4/2012
 Title:
STABILITY STUDY GUIDANCE PROTOCOL
Issue No.: 3
CODE No.: RDI-731-03 Issue Date: 01/4/2012
Page No.: 20 / 49
Title:
STABILITY STUDY PROTOCOL
Issue No.:3
CODE No.: RDF-733-16 Issue Date:01/04/2012
Page No.: 4/ 49
Long term stability study results
Table No..:………..
Batch No.: ……….. Manuf. Date: …………
Storage conditions : 30°C ±2 65% RH
First year Second year Third year
Third year
Initial 3rd 6th 9th 12th 18th 24th 36th
Item Specification month month month month month month month

Physical according to ………. …… ……

parameters RFM* …..
Chemical according to ………. ……... ……
parameters RFM ...
Microbiological according to ………. …… ……
examination RFM …..

*RFM = Reference Method

11- Conclusion
After storage of three batches NO.: …………/……………/………….for …… months at
…………………………………………:
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 ……………………………………. justifies the shelf life of
……………………. for the product.
13- Storage condition
………………………………………………………………………………….
Analyzed by :
Compiled by :
Approved by :

Rev. No.: 0 Department Name: R & D Department

Rev. Date: 01/4/2012
Title:
STABILITY STUDY GUIDANCE PROTOCOL
Issue No.: 3
CODE No.: RDI-731-03 Issue Date: 01/4/2012
Page No.: 21 / 49

Title:
STABILITY STUDY PROFILE
Issue No.:3
CODE No.:RDF-733-15 Issue Date:01/04/2012
Page No.: 21 / 6
PART 1
Section 1 : Section2
Filled by stability study requester Filled by stability administrator
Formulator :…………………………………… Checked by
Analyst : :……………………………………………….
Approved Not Comments
approved
1- Drug phase

1.1 Product under development

1.2 Product selected for registration
1.3 Pilot scale batch –R&D batch (10% of production batch size )
1.4 Production batch

2-Type of study

2.1 Accelerated
2.2 Long term

4-Product information
3.1 Product Name: ……………………….

3.2 Dosage form : ……………………….

3.3 fill components to be studied table (s) (concentration/unit dose)

Content
Component strength Unit Assay Dissolution
Overage uniformity
  
 Acceptance Acceptance Acceptance
………..% limit limit limit
… % - …% … % - …% … % - …%
  
 Acceptance Acceptance Acceptance
………..% limit limit limit
… % - …% … % - …% … % - …%
  
 Acceptance Acceptance Acceptance
………..% limit limit limit
… % - …% … % - …% … % - …%

Rev. No.: 0 Department Name: R & D Department

Rev. Date: 01/4/2012
 Title:
STABILITY STUDY GUIDANCE PROTOCOL
Issue No.: 3
CODE No.: RDI-731-03 Issue Date: 01/4/2012
Page No.: 22 / 49

Title:
STABILITY STUDY PROFILE
Issue No.:3
CODE No.:RDF-733-15 Issue Date:01/04/2012
Page No.: 2 / 6
Section 1 : Section2
Filled by stability study requester Filled by stability administrator
Approved Not Comments
approved
3.4 Underline the items for examination
Dosage form Name *Items of examination
Tablets Appearance- friability- hardness- color fading- odor-
dissolution- assay 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 granules Appearance- flowability- moisture- pH- assay of active
substance - related substances- color- odor
Syrup, drops, suspensions and lotions Color- odor- taste- assay of active substance - dissolution-
assay of preservative- antioxidant or other stabilizing
additive- sedimentation volume- cake formation- pH-
related substances
Creams, ointments and gels Appearance- assay of active substance - related
substances- pH- viscosity- phase separation- bleeding
Suppositories Appearance- melting range- solidification point-
hardness- assay of active substance - dissolution-
breaking test- disintegration- related substances
Parenterals (injections and solutions) Appearance- color- assay of active substance - clarity-
pH- related substances- sterility- pyrogen- particulate
matter
Appearance- color- assay of active substance - dose
Aerosol content uniformity- labeled no. of actuations per
container- related substances - spray content- valve
delivery
3.4 Primary Packaging ………………………………………………………….
4-Selection of Batches
Batch No……………… Manuf. Date : …………
Batch No……………… Manuf. Date : …………
Batch No……………… Manuf. Date : …………

5- Frequency of testing
5.1 Program : ………………………………………………………………………
5.2 Duration of study : ……………………………………………………………..

Rev. No.: 0 Department Name: R & D Department

Rev. Date: 01/4/2012
Title:
STABILITY STUDY GUIDANCE PROTOCOL
Issue No.: 3
CODE No.: RDI-731-03 Issue Date: 01/4/2012
Page No.: 23 / 49

Title:
STABILITY STUDY PROFILE
Issue No.:3
CODE No.:RDF-733-15 Issue Date:1/04/2012
Page No.: 23 / 6

6- Storage conditions
6.1 Temperature : ………………………..
6.2 Humidity : ………………………..
7.3 Light : ………………………..

Section 1 : Section2
Filled by stability study requester Filled by stability administrator
Approved Not Comments
approved
7- Registration regimen
7.1 Old
7.2 New
8.Documents to be submitted by formulator :
8.1 Registration file
8.2 Procedure of stability sample preparation
8.3 Initial analysis results
8.4 Linearity of MOA
8.5 copy of registration license , if issued
9. sample size
Amount :…………………………………………………

10. Signature and request date

……………………………………………………………..

Rev. No.: 0 Department Name: R & D Department

Rev. Date: 01/4/2012
 Title:
STABILITY STUDY GUIDANCE PROTOCOL
Issue No.: 3
CODE No.: RDI-731-03 Issue Date: 01/4/2012
Page No.: 24 / 49

Title:
STABILITY STUDY PROFILE
Issue No.:
CODE No.:RDF-733-15 Issue Date:
Page No.: 24 / 6

PART 2
Stability plan checklist
Item Done Not yet Date of fulfillment

1.Literature survey

2. Method of analysis :
2.1. Validation items
2.1.1 Reproducibility
2.2 .1specificity of method to dosage form

2.2. TZ (Time zero ) analysis

2.2.1 Performed (yes/ No)
2.2.2 conforming to the analyst results ( if not ,mention actions taken , date )
………………………………………………………………………………

3. stability study protocol :

3.1Determined
3.2 written
3.3 revised and approved
4. stability data evaluation (after ending of intervals )

5. stability study report

Manager ………..

Rev. No.: 0 Department Name: R & D Department

Rev. Date: 01/4/2012
 Title:
STABILITY STUDY GUIDANCE PROTOCOL
Issue No.: 1
CODE No.: RDI-731-03 Issue Date: 01/4/2012
Page No.: 25 / 49

Title:
STABILITY STUDY PROFILE
Issue No.:3
CODE No.: RDF-733-15 Issue Date:1/04/2012
Page No.: 25 / 49
Long Term Stability Study
Design & Outline

1-Representative samples of batches are examined physically and analyzed chemically

before storage Yes NO

2-Storge according to individual requirement as follows

2.1 A portion of the sample is stored in a refrigerator at 15 °C
2.2 A portion of the sample is stored in an incubator at 30 °C
2.3 A portion of the sample is stored on shelf

3- Samples are withdrawn for physical and chemical evaluation at time intervals
3.1 At 3,6, 9,12 months interval for first year Yes NO
3.2 Yearly thereafter (18 , 24 months ) Yes NO
3.3 36 months Yes NO
4-Validation of method of analysis
.…………………………………………………………………………………………
………………………………………………………………………………………….
…………………………………………………………………………………………..
5- Interpretation of results
…………………………………………………………………………………………..
…………………………………………………………………………………………..
…………………………………………………………………………………………..

6- Statements and Labeling

……………………………………………………………………………………………
……………………………………………………………………………………………
……………………………………………………………………………………………

Approval
…………………….

Rev. No.: 0 Department Name: R & D Department

Rev. Date: 01/4/2012
 Title:
STABILITY STUDY GUIDANCE PROTOCOL
Issue No.: 1
CODE No.: RDI-731-03 Issue Date: 01/4/2012
Page No.: 26 / 49

Title:
STABILITY STUDY PROFILE
Issue No.:3
CODE No.:RDF-733-15 Issue Date:1/04/2012
Page No.: 6 / 6

Accelerated Stability Study

Design & Outline

1-Representative samples of batches are examined physically and analyzed chemically

before storage Yes NO

2-Storage according to individual requirement as follows

2.1 A portion of the sample is stored in an incubator at 40 °C RH 75%
2.2 A portion of the sample is stored in a refrigerator at 15 °C
according to requirement of each individual case

3- Samples are withdrawn for physical and chemical evaluation at time intervals
3.1 At 1, 3, 6, months Yes NO
3.2 Other conditions …………………………………………………..

4-Validation of method of analysis

.…………………………………………………………………………………………
………………………………………………………………………………………….
…………………………………………………………………………………………..

5- Interpretation of results
…………………………………………………………………………………………..
…………………………………………………………………………………………..
…………………………………………………………………………………………..

6- Predicted shelf life

……………………………………………………………………………………………
……………………………………………………………………………………………
Approval

…………………….

Rev. No.: 0 Department Name: R & D Department

Rev. Date: 01/4/2012
Title:
STABILITY STUDY GUIDANCE PROTOCOL
Issue No.: 1
CODE No.: RDI-731-03 Issue Date: 01/4/2012
Page No.: 27 / 49

Title:
Stability Study Protocol
Issue No.:3
CODE No.: RDF-733-16 Issue Date:1/04/2012
Page No.: 27 / 49

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 ………………………… contains:
…………………………………………………….…………………………………………………….

4-Batches
Batch Number Manufacturing Date Expire date Packaging

5- Sampling Schedule and storage conditions

5.1 The samples were withdrawn at:…………………… months interval when stored at…………………………

Rev. No.: 0 Department Name: R & D Department

Rev. Date: 01/4/2012
Title:
STABILITY STUDY GUIDANCE PROTOCOL
Issue No.: 1
CODE No.: RDI-731-03 Issue Date: 01/4/2012
Page No.: 28 / 49

Title:
Stability Study Protocol
Issue No.:3
CODE No.: RDF-733-16 Issue Date:1/04/2012
Page No.: 28 / 49
Product : ……………………………..
Topic : …………………. Stability Study Protocol
6- Acceptance Criteria
Item Specification
Physical parameters According to Reference method

Chemical parameters According to Reference method

Microbiological examination According to Reference method

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 ………………………………………… 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. ………..
Results ……………………………………………………………………………………….
Rev. No.: 0 Department Name: R & D Department
Rev. Date: 01/4/2012
 Title:
STABILITY STUDY GUIDANCE PROTOCOL
Issue No.: 1
CODE No.: RDI-731-03 Issue Date: 01/4/2012
Page No.: 29 / 49

Title:
Stability Study Protocol
Issue No.:3
CODE No.: RDF-733-16 Issue Date:1/04/2012
Page No.: 29 / 49
10- stability study results
Accelerated stability results :
Table NO.:………..
Batch no: ……….. Manuf. Date: …………
Storage conditions**: 40°C ±2 75% RH

Initial 1 month 3 months 6 months

Item Specification
Estimated ………… ………… …………
month
Physical parameters according to ………. ………. ……….. ………..
RFM*

Chemical parameters according to ………. ………. ……....... ……......

RFM
Microbiological examination according to ………. ………. ……....... ………..
RFM

*RFM = Reference Method

**Liable to change according to individual requirement of pharmaceutical form

Long term stability study results

Table No..:………..
Batch No.: ……….. Manuf. Date: …………
Storage conditions : 30°C ±2 65% RH

First year Second year Third year

Third year
Initial 3rd 6th 9th 12th 18th 24th 36th
month month month month month month month
Item Specification

Physical parameters according to ………. ……….. ……

RFM*
Chemical parameters according to ………. ……...... ……
RFM
Microbiological according to ………. ……….. ……
examination RFM

Rev. No.: 0 Department Name: R & D Department

Rev. Date: 01/4/2012
 Title:
STABILITY STUDY GUIDANCE PROTOCOL
Issue No.: 1
CODE No.: RDI-731-03 Issue Date: 01/4/2012
Page No.: 30 / 49

Title:
Stability Study Protocol
Issue No.:3
CODE No.: RDF-733-16 Issue Date:1/4/2012
Page No.: 30 / 49

*RFM = Reference Method

11- Conclusion
After storage of three batches NO.: …………/……………/………….for …… months at
…………………………………………:
1- The product did not show any significant difference with respect to initial control analysis regarding all
physic-chemical parameters studied.
2- The product showed some significant difference with respect to the following items
……………………………………………………………………………………………
12-Shelf life
Results from stability study of ……………………………………. justifies the shelf life of
……………………. for the product.
13- Storage condition
………………………………………………………………………………….

Analyzed by :
Compiled by :
Approved by :

Rev. No.: 0 Department Name: R & D Department

Rev. Date: 01/4/2012
Title:
STABILITY STUDY GUIDANCE PROTOCOL
Issue No.: 1
CODE No.: RDI-731-03 Issue Date: 01/4/2012
Page No.: 31 / 49

Title:
STABILITY STUDY REPORT
Issue No.:3
CODE No.: RDI-733-17 Issue Date: 01/4/2012
Page No.: 31 / 14

-Name of the Product: …………………

-Applicant: …………………
-Manufacturer: …………………
-Licensor (for under license products): …………………
-Dosage form: …………………
-Composition (To be Presented or Attached):

Quantity Overage
Material Name Unit Reference
[Per Tablet] (%)
Active Substance (s)

Inactive Substance (s)

Rev. No.: 0 Department Name: R & D Department

Rev. Date: 01/4/2012
Title:
STABILITY STUDY GUIDANCE PROTOCOL
Issue No.: 1
CODE No.: RDI-731-03 Issue Date: 01/4/2012
Page No.: 32 / 49

Title:
STABILITY STUDY REPORT
Issue No.: 3
CODE No.: RDI-733-17 Issue Date: 01/4/2012
Page No.: 32 / 14

-Literature and supporting data:

-Information about the specification of active pharmaceutical ingredient (API) either presented
or attached
**The product contains …………………
API 1:
Chemical Name (1…………………
Chemical structure (1):

Molecular formula (1) : …………………

Molecular weight (1) : …………………
CAS # (1) : …………………

-References:
1- …………………

2- …………………

3-…………………

Title:

Rev. No.: 0 Department Name: R & D Department

Rev. Date: 01/4/2012
 Title:
STABILITY STUDY GUIDANCE PROTOCOL
Issue No.: 1
CODE No.: RDI-731-03 Issue Date: 01/4/2012
Page No.: 33 / 49

STABILITY STUDY REPORT

Issue No.: 3
CODE No.: RDI-733-17 Issue Date: 01/4/2012
Page No.: 33 / 14

-Specification of the batch tested:

Item Batch1
Batch number
Date of manufacture
Site of Manufacture

Batch size (Kg)

Batch size (number of units)

Primary packaging material

Date of initial analysis

Batch number, Manufacturing date and Expiry

date of the active pharmaceutical ingredient
(API)

- Container/ closure system.

- Give a detailed description of the container/closure system(s), including any liner or wadding, and provide details of the
composition of each component. Describe other (e.g. outer) packaging, and state what material they are made from
.Provide the specifications for any part of the container / closure system(s), which comes into contact with the product or is
protective.
Primary container: ……………………………………
Secondary container: ………………….

Storage conditions
Accelerated stability study

- Temperature / humidity : …………………/ …………………

Sampling intervals : …………………months interval

Rev. No.: 0 Department Name: R & D Department

Rev. Date: 01/4/2012
Title:
STABILITY STUDY GUIDANCE PROTOCOL
Issue No.: 1
CODE No.: RDI-731-03 Issue Date: 01/4/2012
Page No.: 34 / 49

Title:
STABILITY STUDY REPORT
Issue No.: 3
CODE No.: RDI-733-17 Issue Date: 01/4/2012
Page No.: 34 / 14

Analysis method:
………………… Method of …………………
Label Claim: Each tablet contains ………………… label claim

Limit:
 ………………… with a deviation of …………………of label
Equipment: …………………
Chromatographic conditions : …………………
Standard Preparations
…………………
Test preparation
…………………
Procedures
…………………Calculation

…………………

Rev. No.: 0 Department Name: R & D Department

Rev. Date: 01/4/2012
 Title:
STABILITY STUDY GUIDANCE PROTOCOL
Issue No.: 1
CODE No.: RDI-731-03 Issue Date: 01/4/2012
Page No.: 35 / 49

Title:
STABILITY STUDY REPORT
Issue No.: 3
CODE No.: RDI-733-17 Issue Date: 01/4/2012
Page No.: 35 / 14

Microbiological Method
Bacterial Count (Eur. Ph., Category 3.A-2.6.12)
Sampling
…………………
Procedure
…………………
…………………
Interpretation of Results:
…………………
Accepted Limits:
Aerobic bacteria : …………………
Fungi : …………………
Pathogens : …………………
Test For Pathogens (Eur. Ph., Category 3.A-2.6.13)
Detection of objectionable microorganism

Gr.
Organism Media Batch # Organism Media Batch # Gr. stain
stain
MacConkey Staph. Vogel
E.coli:
EMB agar aureus: Mannitol
Absent
Absent Coagulase
Present Indole test Present test
Selenite broth Ps. Cetrimide
aeruginosa:
Absent Oxidase
XLD agar
Present test
Salmonella:
Brilliant agar Candida
Absent
albicans :
Present SDA
TSI Absent
Present
LB TSB
Acceptance criteria : absence of objectionable microorganisms

Rev. No.: 0 Department Name: R & D Department

Rev. Date: 01/4/2012
Title:
STABILITY STUDY GUIDANCE PROTOCOL
Issue No.: 1
CODE No.: RDI-731-03 Issue Date: 01/4/2012
Page No.: 36 / 49

Title:
STABILITY STUDY REPORT
Issue No.: 3
CODE No.: RDI-733-17 Issue Date: 01/4/2012
Page No.: 36 / 14
Stability Indicating Analytical methods (HPLC Method):-
(Items for assay validation)
Non Official
Accuracy The accuracy of an analytical procedure expresses the closeness of agreement
between the value, which is accepted as true value, and the value found.
Procedure :
accuracy is determined by application of the analytical method to a mixture of the
drug product components to which known amounts of analyte have been added
within the range of the method ( i.e. prepare solution of 80 % [samples 1-3], 100 %
[samples 4-6] & 120 % [samples 7 -9] of label claim) and proceed according to
analytical procedure.
Calculation :
Calculate mean recovery sample and standard deviation for each sample of the
stated, diluted or spiked sample.
Results of nine samples weighed and analyzed are summarized in table 1 with
attached charts

Table (1)

Found value % of
Sample
No.

1
2
3
4
5
6
7
8
9

Rev. No.: 0 Department Name: R & D Department

Rev. Date: 01/4/2012
 Title:
STABILITY STUDY GUIDANCE PROTOCOL
Issue No.: 1
CODE No.: RDI-731-03 Issue Date: 01/4/2012
Page No.: 37 / 49

Title:
STABILITY STUDY REPORT
Issue No.: 3
CODE No.: RDI-733-17 Issue Date: 01/4/2012
Page No.: 37 / 14

Precision The precision of an analytical procedure expresses the closeness of agreement

(degree of scatter) between a series of measurements obtained from multiple
sampling of the same homogenous sample under the prescribed analytical conditions
, precision may be considered at two levels: repeatability & intermediate precision
(ruggedness)
Repeatability
Precision of the method when repeated by the same analyst, same test method and
under same set of laboratory conditions, the only difference being the sample weight
Procedure:
Repeatability assessed using a minimum of six determinations at 100 % of the test
concentration
Calculation:
The precision of an analytical procedure is expressed as the variance, standard
deviation or coefficient of variation of six determinations
Refer to results in table 2 and attached charts and reports

Table (2)

Sample No. Found value % of

1
2
3
4
5
6

Rev. No.: 0 Department Name: R & D Department

Rev. Date: 01/4/2012
 Title:
STABILITY STUDY GUIDANCE PROTOCOL
Issue No.: 1
CODE No.: RDI-731-03 Issue Date: 01/4/2012
Page No.: 38 / 49

Title:
STABILITY STUDY REPORT
Issue No.: 3
CODE No.: RDI-733-17 Issue Date: 01/4/2012
Page No.: 38 / 14

Specificity The selected methods are chosen so as to selectively measure the active substance
without any interference from other excipients in the dosage form.

The method is applied to a placebo, which is prepared as an authentic sample

containing all ingredients except the active substance; the placebo is treated in
exactly the same manner for assay considering the highest range of detection and
applied during stability study of drug product.

Results
…………………

Linearity & The linearity of an analytical procedure is its ability to obtain test results, which are
Range directly proportional to the concentration of analyte in the sample

Procedure:
Serial dilutions of …………. working standard ranging from …………………and ………..
working standard ranging from …………………are analyzed. Data of the curves show
linearity over the tested ranges.

Refer to attached Standard Calibration curves and its' statistical data analysis.
Ruggedness Intermediate precision expresses within-laboratories variation (different days different
analysts, different equipment)
Procedure:
Intermediate precision is assessed by using a minimum of six determinations at 100% of
the test concentration of the same homogenous sample by two analysts
Calculation:
Intermediate precision of an analytical procedure is expressed as the variance,
standard deviation or coefficient of variation of six determinations
Refer to results in table 3, attached charts and reports
Table (3)

Rev. No.: 0 Department Name: R & D Department

Rev. Date: 01/4/2012
 Title:
STABILITY STUDY GUIDANCE PROTOCOL
Issue No.: 1
CODE No.: RDI-731-03 Issue Date: 01/4/2012
Page No.: 39 / 49

Title:
STABILITY STUDY REPORT
Issue No.: 3
CODE No.: RDI-733-17 Issue Date: 01/4/2012
Page No.: 39 / 14

Findings % of
Sample
No.

1
2
3
4
5
6

It is identified in ICH guidelines as a measure of the method's capability to remain

Robustness unaffected by small but deliberate variations in method parameters. It can also be
partly assured by good system suitability specifications.
The method was successfully tested for robustness through change of column
temperature & mobile phase pH.
Very slight changes in system suitability parameters were observed.
Is the lowest concentration of analyte in a sample that the method can detect but is
Detection not necessarily quantitated. Detection limit is determined by the analysis of samples
Limit with known concentrations of analyte and then consequently establishing the
minimum level at which the analyte can be detected. Refer to results in table 4
Table (4)
Name Minimum Detection limit

Rev. No.: 0 Department Name: R & D Department

Rev. Date: 01/4/2012
 Title:
STABILITY STUDY GUIDANCE PROTOCOL
Issue No.: 1
CODE No.: RDI-731-03 Issue Date: 01/4/2012
Page No.: 40 / 49

Title:
STABILITY STUDY REPORT
Issue No.: 3
CODE No.: RDI-733-17 Issue Date: 01/4/2012
Page No.: 40 / 14

Quantitation The quantitation limit of an individual analytical procedure is the lowest amount of analyte in a
Limit sample, which can be quantitatively determined with a suitable precision and accuracy i.e.
the lowest concentration shown on a linear curve. Refer to results in table 5

Table (5)
Name Minimum quantitation limit

System Once a method or system has been validated, the task becomes one of routinely checking
suitability test the suitability of the system to perform within the validated limits. The simplest form of an HPLC
system suitability test involves a comparison of the chromatogram trace with a standard trace.
This allows a comparison of the peak shape, peak width, and baseline resolution. Alternatively,
these parameters can be calculated to provide a quantitative system suitability test report.
There are numerous guidelines, which detail the expected limits for chromatographic methods.
In the current FDA guidelines on Validation of Chromatographic methods, the following
acceptance limits are proposed as initial criteria. Refer to Limits & results in table 6

Table (6)
Result
Parameters Limits

Capacity factor
K´ > 2
K´
Injection
RSD < 1 % for n ≥ 5
Precision
Resolution BP Rs > 2
Tailing factor T≤2
Theoretical
N > 2000
plate BP
Detailed method and validation reports signed by the authorized person and stamped by the
manufacturer should be attached.
Attachment I
Rev. No.: 0 Department Name: R & D Department
Rev. Date: 01/4/2012
Title:
STABILITY STUDY GUIDANCE PROTOCOL
Issue No.: 1
CODE No.: RDI-731-03 Issue Date: 01/4/2012
Page No.: 41 / 49

Title:
STABILITY STUDY REPORT
Issue No.: 3
CODE No.: RDI-733-17 Issue Date: 01/4/2012
Page No.: 41 / 14

 Product characteristic studied:

For each dosage form, parameters to be studied shall be applied according to the supplied
stability study guideline of Ministry of Health – Egypt.
(Issue number 1 authorized in 4/10/2007).
Batch 1
Batch no. : …………………
Mfg. Date: …………………
Exp. Date: …………………
Container: …………………
Assay limit:
…………………with a deviation of 90.0- 110.0 % of label claim
(Limit: 90 - 1100 mg w/w per tablet)

………………… Assay of ………………… Assay

………………… (%) of ………………… (%)
Storage Conditions
Limit: [ 90 -110 % w/v of Limit: [ 90 -110 % w/v of
label claim] label claim]
Initial Values
1 month, …………………/…………………
3 months, …………………/…………………
6 months, …………………/…………………

Rev. No.: 0 Department Name: R & D Department

Rev. Date: 01/4/2012
 Title:
STABILITY STUDY GUIDANCE PROTOCOL
Issue No.: 1
CODE No.: RDI-731-03 Issue Date: 01/4/2012
Page No.: 42 / 49

Title:
STABILITY STUDY REPORT
Issue No.: 3
CODE No.: RDI-733-17 Issue Date: 01/4/2012
Page No.: 42 / 14

Batch 1
Batch no. :
Mfg. Date:
Exp. Date:
Container:
Physical Data

Dissolution Average
weight of tablet
Description (% w/w recovery) Disintegration
Storage (mg) Friability:
Conditions
at 37 ºC Hardness:
Limit:

Initial
Values

…………
………/
…………

…………
………/
…………

…………
………/
…………

Rev. No.: 0 Department Name: R & D Department

Rev. Date: 01/4/2012
Title:
STABILITY STUDY GUIDANCE PROTOCOL
Issue No.: 1
CODE No.: RDI-731-03 Issue Date: 01/4/2012
Page No.: 43 / 49

Title:
STABILITY STUDY REPORT
Issue No.: 1
CODE No.: RDI-733-17 Issue Date: 01/4/2012
Page No.: 43 / 14

Batch 1
Batch no. : …………………
Mfg. Date: …………………
Exp. Date: …………………
Container: …………………
Microbiological attributes:

Storage Bacterial Count Fungi Count Pathogen Microbes

Conditions Limit: NMT 1000 cfu/g Limit: NMT 100 cfu/g Limit: absent

At the beginning
At the end

Rev. No.: 0 Department Name: R & D Department

Rev. Date: 01/4/2012
Title:
STABILITY STUDY GUIDANCE PROTOCOL
Issue No.: 1
CODE No.: RDI-731-03 Issue Date: 01/4/2012
Page No.: 44 / 49

Title:
STABILITY STUDY REPORT
Issue No.: 1
CODE No.: RDI-733-17 Issue Date: 01/4/2012
Page No.: 44 / 14

 Contact person in applicant company

1. Technical person
Name : …………………
Qualification : …………………
Position in company : …………………
Postal address : …………………
Telephone number : …………………
Fax number : …………………
E-mail address : …………………
2. Other:

Name : …………………
Qualification : …………………
Position in company : …………………
Postal address : …………………
Telephone number :…………………
Fax number : …………………
E-mail address : …………………

Approved by: ………………… Prepared by: …………………

Signature : ………………… Signature : ……………….…
Date : Date :

Rev. No.: 0 Department Name: R & D Department

Rev. Date: 01/4/2012
 Title:
STABILITY STUDY GUIDANCE PROTOCOL
Issue No.: 1
CODE No.: RDI-731-03 Issue Date: 01/4/2012
Page No.: 45 / 49

Title:
OOS INVESTIGATION FORM
Issue No.:3
CODE No.: RDF-733-18 Issue Date:1/04/2012
Page No.: 45 / 1
OOS investigation form
OOS no. Issued date Close Out date

Product name : Batch no. Stability study no.

Stability storage Stability time Analyst Name

condition point
Instrument used Test date

Observation leading to investigation :

Repeated testing of sample : Yes No

 
Result of repeated testing of sample Conform
Yes No
 
Lab error identified Yes No
 
Previous results investigation / comment Yes No
 
Done by
Specify lot number
Re-sampling authorization Stability study no.
Storage condition
Time point
Re-sampled amount
Result of re-sampled testing Conform
Yes No
 
Specify lot number
Mention any related products that
might be affected :
Stability study no
Comment /recommended actions
Investigation close up approval

Signature

Rev. No.: 0 Department Name: R & D Department

Rev. Date: 01/4/2012
Title:
STABILITY STUDY GUIDANCE PROTOCOL
Issue No.: 1
CODE No.: RDI-731-03 Issue Date: 01/4/2012
Page No.: 46 / 49

‫تعهدات دراسة الثبات‬

: ‫اصدار رقم‬
CODE No.: RDF-733-19 : ‫تاريخ االصدار‬

‫شهادة‬
:‫يشهد مصنع"ايفا فارما" بأنه قام بعمل دراسة الثبات الخاصة بمستحضر‬
…………………………………….

:‫و مسئول عنها مسئولية كاملة و هذه الدراسة تمت بمعرفة فريق العمل المكون من‬

Performed by (R&D analyst):

Checked by (R&D Supervisor):

Authorized by (R&D Section Head):

Stamp: ………

Rev. No.: 0 Department Name: R & D Department

Rev. Date: 01/4/2012
 ‫‪Title:‬‬
‫‪STABILITY STUDY GUIDANCE PROTOCOL‬‬
‫‪Issue No.: 1‬‬
‫‪CODE No.: RDI-731-03‬‬ ‫‪Issue Date: 01/4/2012‬‬
‫‪Page No.: 47 / 49‬‬

‫تعهدات دراسة الثبات‬

‫اصدار رقم ‪:‬‬
‫‪CODE No.: RDF-733-19‬‬ ‫تاريخ االصدار ‪:‬‬

‫إقرار‬

‫أقر أنا الموقع أدناه مدير قطاع األبحاث و التطوير‬

‫بشركة‪ :‬إيفا فارما لألدوية والمستلزمات الطبية‬

‫بأن االسطوانة المدمجة (‪ )CD‬المقدمة لدراسة الثبات الخاصة‬

‫بمستحضر‪:‬‬

‫‪……………………………………………………..‬‬
‫من إنتاج شركة‪ :‬إيفا فارما لألدوية والمستلزمات الطبية‬

‫و التي تم تقديمها إلى اإلدارة المركزية للشئون الصيدلية بتاريخ ‪ --/--/----‬هي صورة طبق األصل من النسخة الورقية‬
‫للدراسة وأنه في حالة طلب استكماالت من قبل اللجنة العلمية المتخصصة لتقييم دراسات الثبات يتم تقديم نسخة ورقية و‬
‫اسطوانة مدمجة (‪ )CD‬باالستكماالت المطلوبة‪.‬‬

‫مدير قطاع األبحاث و التطوير‬

‫‪........................‬‬

‫‪Rev. No.: 0‬‬ ‫‪Department Name: R & D Department‬‬

‫‪Rev. Date: 01/4/2012‬‬
 ‫‪Title:‬‬
‫‪STABILITY STUDY GUIDANCE PROTOCOL‬‬
‫‪Issue No.: 1‬‬
‫‪CODE No.: RDI-731-03‬‬ ‫‪Issue Date: 01/4/2012‬‬
‫‪Page No.: 48 / 49‬‬

‫تعهدات دراسة الثبات‬

‫اصدار رقم ‪:‬‬
‫‪CODE No.: RDF-733-19‬‬ ‫تاريخ االصدار ‪:‬‬

‫تعهد بظروف التخزين المقترحة‬

‫بالنسبة للمستحضر اآلتي ‪:‬‬
‫‪……………………………………..‬‬

‫تم عمل دراسة الثبات المعجلة عند درجة حرارة ‪ ٤٠‬درجة مئوية ورطوبة نسبیة ‪ % ٧٥‬لمدة ستة أشهر‪.‬‬

‫وسوف تستكمل دراسة الثبات طويلة المدى عند درجة حرارة ‪ ٣٠‬درجة مئوية و رطوبة نسبیة ‪ % ٦٥‬و ذلك طبقا للقواعد‬
‫المنظمة لدراسات الثبات‪.‬‬
‫و تقر الشركة بأن ظروف حفظ المستحضر المقترحة ھي درجة حرارة التتجاوز ‪ ٣٠‬درجة مئوية طوال مدة الصالحیة‪.‬‬

‫رئیس مجلس إدارة الشركة‬

‫‪……………………..‬‬
‫عنه مدير قسم البحوث و التطوير‬
‫‪………………….‬‬

‫‪Rev. No.: 0‬‬ ‫‪Department Name: R & D Department‬‬

‫‪Rev. Date: 01/4/2012‬‬
Title:
STABILITY STUDY GUIDANCE PROTOCOL
Issue No.: 1
CODE No.: RDI-731-03 Issue Date: 01/5/2012
Page No.: 49 / 49

11.Biennial revisions:

Rev. no. Planned revision date Actual revision date Department manager DC &R
Signature Signature
1 4/2014
2 4/2016

Rev. No.: 0 Department Name: R & D Department

Rev. Date: 01/4/2012