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Stability Study of Drug Product as per ICH Q1A(R2)

Standard Operating Procedure (SOP) for Stability Study of Drug Product as per ICH Q1A(R2). The term (Stability Study) with respect to a drug dosage form refers to the chemical & physical integrity of the dosage unit & when appropriate, the ability of the dosage unit to maintain protection against microbial contamination.

Stability Study Guideline

1.0   Objective:

    • To lay down a procedure of stability study sample management to evaluate any physical, chemical, and microbiological changes with time under the influence of a variety of environmental factors to which drug products may be exposed during its shelf life.
    • To monitor the product and its shelf life and to determine whether the product can be expected to remain stable within the specification under the labeled storage condition.

2.0   Scope:

    • This SOP is applicable for sample management, testing, and result review with respect to stability studies carried out for Pharmaceutical Drug Products.

3.0   Responsibility:

Chemist QA :
  •  To collect and provide the samples to Stability study to section In-charge/Designee with “stability sample submission form” as per approved protocol.
Stability section In-charge /Designee                  :
  • Enter the detail of stability samples in the respective logbook.
  • Charge the sample as per defined condition as per protocol and withdrawal of samples as per predefined frequency.
  • Submission of the stability samples to QC for analysis.
  • Maintaining and monitoring the stability chambers.
  • Maintaining stability logbooks.
  • Labeling, storage, periodic withdrawal, and destruction of stability samples.
  • Maintaining the record of stability samples kept in the chambers and the Rack status of each chamber.
  • To combine and evaluate stability Data provided by QC at each station.
  • Review of the stability study protocol
  • Prepare the stability study planner Evaluation and interpretation of stability study results.
  • To co-ordinate the investigation of the Out of specification (OOS) and Out of trend result (OOT) if any.
Chemist QC :
  • To collect and provide the samples to Stability to section In-charge/Designee with “sample submission form” as per approved protocol.                   

4.0   Procedure for Stability Study as per ICH Guideline:

    • Stability:

    • The term with respect to a drug dosage form refers to the chemical & physical integrity of the dosage unit & when appropriate, the ability of the dosage unit to maintain protection against microbial contamination.

    • General Procedure for Stability Study:

    • At the end of the current year, the Stability section In-charge /Designee shall prepare the stability plan, for the samples of existing products to be subjected to stability studies during the next year.
    • The first batch of each product in the calendar year shall be kept for the ongoing stability study.
    • The quantity of sample required for stability studies shall be mentioned in the relevant stability study protocol.
    • The required sample quantity for one station shall be 2X where X is the sample quantity required for one complete analysis excluding micro-analysis.
    • For microbiological analysis, the sample quantity shall be equivalent to approx. 20g.

    • Different Situations where Stability Study to be initiated :

    • If the product is manufactured under different brand names but the formulation, strength, and manufacturing process, and primary packing remain the same, then the samples of anyone generic or brand name are subjected to the stability study.
    • If the manufacturing formulae of the product is the same but primary packaging materials are different, the product packaged in each packaging shall be kept for stability studies.
    • In case of pharmacopeia revision and In-house requirement (i.e. addition of test, change in method of analysis, change in the specification) the protocol shall be revised and the samples already kept on stability studies shall be analyzed as per amended analytical procedure as well as old procedure.
    • After evaluating the results by the analytical procedures, the revised specification and standard testing procedure shall be followed at the next due frequency.
    • Intermediate stability studies shall be performed when significant change is observed in the results for Accelerated stability studies.

    • Factors affecting the stability of the product:

    • Improper storage condition like:
      • Temperature:
      • The rate of chemical reaction increases exponentially for each 10°C increase in temperature.
      • Refrigeration may cause extreme viscosity in some liquid drugs and cause supersaturation in others.
      • Freezing may either break or cause a large increase in the droplet size of emulsions, it can denature proteins & in rare cases, it can cause less soluble polymorphic states of some drugs to form some dissolved carboxylic acid loses carbon dioxide from the carboxyl group when heated.
      • The resulting product has reduced pharmacological potency.
      • Light:
      • Exposure to primarily, UV illumination may cause oxidation (photo-oxidation) and scission (Photolysis) of covalent bonds.
      • Air:
      • Presence of oxygen.
      • Humidity (Moisture):
      • Esters & beta-lactams are the chemical bonds that are most likely to hydrolyze in the presence of water, e.g. the acetyl ester in aspirin is hydrolyzed to acetic acid and salicylic acid in the presence of moisture, but in a dry environment, the hydrolysis of aspirin is negligible.
    • Change in the formulation.
    • Change in primary packaging material (PPM).
    • Change in process or critical process parameters.
    • Change in critical manufacturing equipment

    • Procedure for preparation of stability study protocol:

    • The stability study protocol (Annexure-VI) shall contain the following points :
      • Protocol Approval
      • Objective
      • Scope
      • Responsibility
      • Batch Selection
      • Product Details
      • Packaging Details
      • Stability Condition & Testing Period
      • Sampling
      • Analytical Method
      • Testing Frequency & Sample Quantity
      • Testing Parameters
      • Deviation/Incident, Change Control and OOS
      • Documentation and Reporting
      • Conclusion
      • Revision History
      • Abbreviation
    • Master copies of the stability study protocol shall be kept in the product file in QA and the controlled copies of the master copy shall be issued to QC along with the stability sample.

    • Significant changes at accelerated stability study for critical parameters are given below:

    • Assay – 5% change from the initial value. (except Vitamins & enzymes)
    • Related Substances / Degradation Products – exceeding its acceptance criteria.
    • Failure to meet the acceptance criteria for appearance, physical attributes, and functionality test (e.g., color, phase separation, resuspendibility, caking, hardness, dose delivery per actuation);
    • however, some changes in physical attributes (e.g., softening of suppositories, melting of creams) may be expected under accelerated conditions; and, as appropriate for the dosage form
    • Failure to meet the acceptance criteria for pH.
    • Failure to meet the acceptance criteria for disintegration time & dissolution for 12 dosage units.

    • Container Closure System:

    • Pack selected for stability studies should be the marketed pack or simulate the actual pack used for storage and distribution.

  • Classified Climatic Zones (Stability Study Zones):

    • Drug product should be evaluated under storage conditions (with appropriate tolerances) that test its thermal stability and its sensitivity to moisture.
    • The design of the stability program should take into account the intended market and the climatic conditions in the country in which the product shall be distributed.
    • The climatic zones with their definition and storage conditions are given below:
Climatic Zone Definition Condition (MKT)
I Temperate climate 21°C / 45% RH
II Subtropical and Mediterranean climate 25°C / 60% RH
III Hot and Dry climate 30°C / 35% RH
IVA Hot and Humid climate 30°C / 65% RH
IVB The hot and very humid climate 30°C / 75% RH
    • The following table provides the stability storage conditions for accelerated, Long Term Stability Study, and intermediate stability storage conditions for all climatic zones (Stability Study Zone).
Stability Condition

(Climatic Zone) —>

 I II III IVA IVB
Accelerated 40 ± 2°C / 75 ± 5%RH
Real-Time/long time 25 ± 2°C / 60 ± 5%RH 30 ± 2°C / 65 ± 5%RH 30 ± 2°C / 75 ± 5%RH
Intermediate 30 ± 2°C / 65 ± 5%RH Not applicable

    • Storage Conditions & Testing Frequency for drug products:

    • The storage condition & testing frequency are given below:
Study Condition Frequencies (Months)(or as specified in Stability Study Protocol)
Long Term 30ºC ± 2ºC, 65% ± 5% RH30ºC ± 2ºC, 75% ± 5% RH25ºC ± 2ºC, 60% ± 5% RH 0, 3, 6, 9, 12, 18, 24, followed by annually till                     shelf-life + one year
Accelerated 40ºC ± 2ºC, 75% ± 5% RH 0, 3 & 6
*Intermediate 30ºC ± 2ºC, 65% ± 5% RH 0, 6, 9, 12
On going 30ºC ± 2ºC, 65% ± 5% RH30ºC ± 2ºC, 75% ± 5% RH25ºC ± 2ºC, 60% ± 5% RH 0, 6, 12, followed by annually till shelf-life

*It is applicable when long-term stability study will be done at 25 ºC ± 2ºC, 60% ± 5% RH, and study will be performed if the significant change occurs at the accelerated stability condition.

Remarks: Sample at Accelerated shall be charged for 6 months if there is a significant change or significant deviation to the processor package or any reworking, reprocessing, or recovery operation.

Indian market long term/on-going stability samples shall be charged on 30ºC ± 2ºC, 75% ± 5% RH as per respective protocol.

For all other markets, WHO-TRS 953 Appendix-I shall be referred as per respective country requirements.

    • For samples kept under stability study, analysis at the time of release (Finished Product analysis), is considered as initial or “0” month analysis.
    • In case the finished product analysis date and sample charging date differs by more than one month, 0 month’s analysis shall be done prior to charging the samples in the stability chamber.
    • Samples of Validation batches shall be analyzed at Accelerated and Real/long term conditions.
    • If the product does not comply with respect to laid down standards or specification at 40°C ± 2°C, 75 % ± 5 % RH condition, stability studies shall be continued at 30°C ± 2°C, 75 % ± 5 % RH up to the shelf life.
    • The matrix and bracketing can be done for the products of different strengths and identical container closure systems, as per the design mentioned in product-specific stability protocols.

    • Bracketing Approach during Stability Study:

    • Bracketing can be applied to different container-sized or different fills in the same container closure system.
    • It can be applied to the strengths of identical or closely related formulations.
    • Bracketing can be applied with justification where the relative amounts of drug substance and excipients change in a formulation.

    • Matrixing Approach during Stability Study:

    • Matrixing can be applied for the samples of the same drug product covering different batches, different strengths, and different sizes of the same container closer system and in some cases different container closer systems.
    • While designing bracketing and matrixing ensure a minimum of three test points including initial analysis for all storage conditions on stability.

  • Selection of Batches & Stability Commitment:

    • The first three batches (i.e. the product manufactured first time or new products) are subject to stability study at Accelerated Long Term and Intermediate (if applicable).
    • This is also applicable if primary packaging materials are changed.
    • Ongoing stability studies shall be carried out only at Long-term stability conditions.
    • One batch of each product shall be kept for ongoing study every year.
    • Subsequent stability studies required due to various changes in the existing process and product are carried out as described in the process validation protocol.
    • All details for stability studies shall be mentioned in the respective validation protocol and stability study protocol.

  • Procedure to provide the samples for stability studies to stability section:

    • During issuance of BMR/BPR, the Authorized QA personnel shall affix the sticker on file shall write the quantity of stability sample against the type of study required i.e. ACC, long term / ongoing/intermediate from stability study protocol and shall issue the stability study protocol.  
    • QA-Chemist shall collect the quantity of the defined samples and submit samples along with Stability Sample Submission Form (Annexure-I) to the Stability section Incharge/Designee along with stability study protocol.
    • Stability section Incharge/Designee shall verify the details of the sample against the “Stability Sample Submission Form.
    • After receipt duplicate copy of the sample request form shall be retained by the QA chemist in the batch record.
    • Stability section Incharge/Designee shall charge the sample for stability study following the below procedure.
    • Till charging the samples shall be kept under a controlled environment (i.e. temperature NMT 25°C.) under monitoring.
    • Stability section Incharge/Designee shall make an entry in the “Stability study Planner’’ as per Annexure-II and shall enclose the stability sample submission form in the file.

  • Procedure for charging of samples into the stability chamber:

    • Stability section Incharge / Designee shall divide the sample quantity according to the sample required for accelerated, long term, and intermediate condition (or any other condition as applicable) against the approved stability study protocol.
    • Stability section Incharge/Designee shall prepare “stability sample label (Annexure-V)” and shall affix on each unit pack/container.
    • Charge the samples as per the recommended storage condition and shall make entries in the respective Stability study Planner (Annexure-II).
    • The date of the charging of the sample shall be considered as the start date of the stability study.
    • After entry, the stability section in-charge shall complete the planner i.e. stability interval in months, and scheduled date.
    • Charging of individual batch samples shall be avoided and samples shall be charged at least once a week and charging details shall be recorded in respective Stability study Planner. (Annexure-II).
    • The sample shall be charged in the stability chamber within 30 working days of the batch released by Quality Control.
    • In case, if the samples are not charged into the stability chamber within the scheduled time, then the sample can be subjected to stability studies after reanalysis of the batch.

  • Preparation of Stability Monthly Planner

    • Stability study section In-charge / Designee shall prepare the “Stability Monthly Planner (Annexure-III) for the next month in the last week of the current month and records shall be maintained.
    • Authorized QA Personnel shall review the stability, monthly planner.
    • As per the planner, the Sample shall be handover to QC for analysis.

  • Procedure for withdrawal of samples from stability chamber:

    • Stabilitysection Incharge/Designee shall withdraw the sample as per “stability study monthly planner”.
    • After sample withdrawal, Stability section Incharge / Designee shall update the details in respective Stability study Planner (Annexure-II) shall write the:
      • The date under the withdrawn date column
      • Quantity withdraws under the withdrawn qty.
      • Reconcile the sample and write the balance quantity under balance qty. column
      • Signature of withdrawn by and verified by (QA) shall be done under the respective column.
      • Any comment shall be written under the remark column, if not write NA.
    • After the withdrawal of the last station quantity, the balance quantity shall be destroyed after receipt of analysis data and details shall be written under the remark column.
    • The withdrawal of the sample shall be carried out within + 3 working days of the scheduled date.
    • The sample shall be stored in the control room temperature.
    • For Stability samples regarding testing on a weekly or monthly basis (less than three months), the sample shall be withdrawn one working day prior to the schedule withdrawn date.

  • Submission of stability study samples to QC, and Receipt, review & compilation of data:

    • Stability Section In-charge shall submit the samples to QC along with duly filled and signed “Intimation for Analysis of Stability Study Samples” (Annexure-IX).
    • Authorized QC personnel shall acknowledge the sample and handover the signed receipt to Stability Section In-charge for follow-up.
    • After receipt of the analysis results from QC, Compilation of data shall be done in the Stability study summary report (Annexure-VII).
    • If stability data at any time is required by any regulatory authorities, the datasheet will be prepared in the approved format in the computer system as per Annexure-VII.
    • After the approval of the report, the scan or hard copy shall be sent to the regulatory authority and one copy shall be attached with the respective file.
    • If stability data shows significant change at accelerated stability study for critical parameters as defined in the protocol,

    • The results shall be investigated as per SOP and the QA department shall be informed about such observations.

    • After completion of the stability study for the product, the Stability study report shall be prepared by Stability study section Incharge / Designee on Annexure-VIII.
    • If any activity is not completed within a defined timeframe then the same shall be handled as per the SOP for “Deviation/Incident Management”.
    • In event of any stability failure, Head-QA shall discuss with technical groups comprising of Head-QC, Head-Production, and Operation / Site Head Joint decision shall be taken for recall/revision of formulation or other corrective action.
    • If a significant change occurs during testing at the accelerated storage condition, Head-QC, Head-QA, Head-Production, and customer (if required) shall review the proposed shelf-life period based on the long-term data available.
    • The storage condition may be reviewed accordingly.

    • Authorization procedure for discontinuation of stability study:

    • In case of stability, the study needs to discontinue, QA shall initiate the Stability study discontinuation form (Annexure-IV) and Head QA shall approve the request.
    • After approval for the same Stability Study Section In-charge shall attach the stability study data sheet with the respective stability sample submission form and keep in the respective file.

    • Procedure for stability study of contract manufacturing product:

    • For contract manufacturing, a product stability study shall be carried out as per customer requirement if provided.     
    • Destruction of Stability Samples:
    • On completion of the stability schedule analysis (all intervals) of the product batch, remaining quantities shall be destroyed as per respective SOP and the details shall be updated under remark column of respective Stability Study Planner.

    • Action to be taken in case of Malfunction of humidity chamber:

    • In case of failure of the humidity chamber the samples shall be transferred to another humidity chamber which is adjusted to the same condition (Temp & %RH).
    • If any excursion in the operation is notified, intimation shall be raised to the Engineering department for the rectification of the problem.

5.0   Reference (S):

    • WHO Technical Report Series No. 953.Annexure -2
    • Guide to good manufacturing practice for medicinal product (PIC’s) part-I: PE009-9
    • ICH Q1A(R2): Stability testing of New drug Substances and Products.
    • USP <1150> Pharmaceutical Stability.
    • SOP for Handling of Out of trend (OOT) results.
    • Deviation/Incident Management SOP
    • SOP for Equipment Breakdown Maintenance.

6.0   Annexures – Stability Study:

Annexure I: Stability Study Sample Submission Form

Product Name  

 
Generic Name  

 
Batch No.: Batch Size
Mfg. Date Exp. Date
Total

Sample Qty.

 Market  

 

1

 Reason for Stability Study :

2

 Stability Study Condition:

3

 Stability Study Protocol: Attached/Not Attached

Reason If not attached:

4

 Description of Pack:

5

 Remarks:

6

 Stability Sample Submitted By (QA):

Sign/Date.

 Stability Sample Received By:

Sign/Date.
For Stability Study Section Purpose Only

1

 Date of Release:

2

 Stability Sample Charged on: Sign/Date

Annexure-II: Stability Study Planner

Sr.

No

 Product

Name

 Batch

No.

 Mfg Date Exp

Date

 

 Initial testing

done on

 Date of charging

of sample
Reason for the stability study Qty *____ Months
Scheduled Withdraw Qty Withdraw by Verified By

Remarks

Withdraw date

 Balance Qty

 

    

Annexure III: Stability Study Monthly Planner

Sample for Month ………………                                                                  Year ………………
Product Batch No. Chamber No. Date of withdrawn Station Withdrawn By & Date Updation of chamber log

Annexure-IV: Stability Study Discontinuation form

From Quality Assurance To: Stability Study Section In-charge
Please discontinue the stability study of the product mentioned below:
Product Batch No.
Stability Condition:
Reason for Discontinuation of Stability Study:
Prepared By (QA) Approved By (Head QA)
To be filled by Quality Control:
Stability Stations Remaining
Qty. to be Destroyed
Destruction Procedure Followed
Remarks
Prepared By / Date: Approved By / Date:

Annexure V: Stability Study Label

Test Station
Date of Charging
Date Withdrawn
Signature

Annexure-VI: Stability Study Protocol

Sr. No. Subject
1. Protocol  Approval
2. Objective
3. Scope
4. Responsibility
5. Batch Selection
6. Product Details
7. Packaging Details
8. Stability Condition & Testing Period
9. Sampling
10. Analytical Method
11. Testing Frequency & Sample Quantity
12. Testing Parameters
13. Deviation/Incident, Change Control and OOS
14. Conclusion
15. Documentation and Reporting
16. Revision History
17. Abbreviation

Annexure-VII: Stability Study Summary Report

Sr. No. Description

1

 Purpose

2

 Scope

3

 Composition

4

 Details of API

5

 Details of Packing Material

6

 Accelerated Stability Study

7

 Long Term Stability Study

8

 Summary and Conclusion

9

 Recommendation

Purpose:

The purpose of this study is to assess the physical, chemical, and microbiological stability of ………………………  in the proposed primary pack and formula when exposed to different environmental conditions. The stability study is conducted on the following conditions:

Study Sr. No. Storage Condition Testing

Period
Temperature (°C) Relative Humidity (%)
Accelerated
Long term

  •  Scope:

This report is applicable to compile and review the stability data of ……………………. The stability study is conducted on the following batches:

Product Name Batch No. Batch Size Mfg. Date Exp. Date

  • Composition:

  • Details of API:
Sr. No. Active Pharmaceutical Ingredient Item Code Manufacturer Name

  • Details of Packing Material:

Sr. No.

 Packing Material Item Code

Manufacturer Name
 

  • Accelerated Stability Studies:

B. No.: Primary Packing
Storage Condition Stability Start Date

 

Sr. No. Test Limit ………. (Storage Condition)
Initial ….. Months ….. Months

*Description:……………….

Inference:

  • ………… OOS / OOT results or incident has been observed during the analysis of samples.
  • The parameter of different tests ……………………………… are/are not well within the specification limit during the study up to ………. months.
  • Microbial growth is/is not also found well within specification during the study up to ……… months.

  • Long Term Stability Studies:

B. No.: Primary Packing
Storage Condition Stability Start Date
Sr. No. Test Limit (Storage Condition)
Initial Months Months

*Description:……………….

Inference:

  • ………… OOS / OOT results or incident has been observed during the analysis of samples.
  • The parameter of different tests ……………………………… are/are not well within the specification limit during the study up to ……. months.
  • Microbial growth is/is not also found well within specification during study up to ……… months
  • Summary and Conclusion:

The above data shows that the:

  • …………. signification change is observed in all three batches at Accelerated stability study
  • …………….. OOS / OOT results or incident has been observed during the study.
  • The product remains stable / doesn’t stable throughout the shelf life when stored at …………°C and ………………. %RH and ………….°C and ………………% RH

Above stability, data shows that the formulation of ……………………….. is/is not stable when packed in ……………… ………………………

  • Recommendation:

Based on the above data it is stated that the product ……………………………  in ………….. pack is/is not stable up to ……………. months in the long term and we will continue/assign…………months shelf life of the product.

Annexure-VIII: Intimation for analysis of Stability study samples

Product Name Batch No.
Station No. Storage Condition
Sample Quantity Date
Reference Protocol No. & Rev. No.  
Sample sent By:

(Sign/Date)

 Sample received by (Sign/Date)

 ——————————————————————————————————————–

 Acknowledgment Slip :

We have received ………………………………  of the sample after completion of  …………. Month for the analysis of stability sample on ……………………….. condition of Product ……………………….. and batch No. ……………….

The report will be shared till ………………….

Sign. & date of Received By.

Janki Singh

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