To lay down a procedure for carrying out stability studies of drug products.
This SOP is applicable for carrying out stability studies of drug products of pharmaceutical formulation plant.
QC Chemist or above
Head – Quality Control
Head – Quality Assurance
- ICH : International Conference on Harmonization
- USP : United State Pharmacopoeia
- QA : Quality Assurance
- QC : Quality Control
- SOP : Standard Operating Procedure
- ACC : Accelerated
- CRT : Controlled Room Temperature
- RH : Relative Humidity
- API : Active pharmaceutical Ingredient
- COA : Certificate of analysis
- R. No. : Analytical Reference Number
- ICDRA : International Conference of drug regulatory authorities
- SG : Sub-General
- GN : General
- SP : Specific
- NA : Not Applicable
- CAPA : Corrective and preventive action
- B. No Batch number
- No.: Number
- Deptt: Department
6.1 Stability study shall be carried out:
6.1.1 To understand any chemical, physical and microbiological changes in the Drug products during their shelf life when exposed under different storage conditions.
6.1.2 To confirm that drug products are assured for their efficacy and safety in marketed packs.
6.1.3 To compile data for confirming storage conditions and shelf life for finish products.
6.1.4 In support of product registration in different countries.
6.2 Initially three batches are kept for stability study (Initially “means the product is subjected for stability for first time at the location”) for long term, intermediate and accelerated stability. Subsequently minimum one batch per year of each product is subjected for Long Term condition. These samples shall be packed in marketed packs or simulated marketed packs.
6.3 The sample shall be charged to stability study for following change:-
6.3.1 Change in formulation-Accelerated and Long Term conditions-03 Batches.
6.3.2 Change in manufacturing process-Accelerated and Long Term conditions-03 Batches
6.3.3 Change in source of API-Accelerated and Long Term conditions-01 Batch.
6.3.4 Change in Batch size-Long Term condition-01 Batch.Change in Primary container-closure system-Accelerated and Long Term conditions –
6.3.5 Change in Primary container-closure system-Accelerated and Long Term conditions – 01Batch
6.3.6 Change in manufacturing equipment (s) having different operating procedure- Accelerated and Long Term conditions-03 Batches.
6.4 Additional Stability studies may be carried out as per the customer’s requirement based on the storage conditions and the frequencies of analysis as required by the
6.5 Additional stability studies may also to be carried out as per the directives received from Head-QA.
6.6 QA shall be responsible to identify reasons for performing stability studies, and shall send the stability study request as per Annexure No.-I to QC along with samples, placebo and finish product Certificate of Analysis.
6.7 Samples for stability study shall be collected by QA personnel during packing operation, representing start, middle and end of packaging.
6.7.1 Sample for stability study shall be charged into proper marketed packs or whenever necessary shall be charged using simulated packs which is identical to market packs. Label the samples of accelerated, Intermediate and Long Term condition as per Annexure No.-VI, Annexure No.- VII and Annexure No.- VIII respectively.
6.7.2 In case of dry powder injection and Dry syrup, half of the sample shall be charged in invert position and half of the sample in up-position.
6.7.3 Label for accelerated condition shall be in Red colour, Intermediate shall be in Brick colour and long term shall be in green colour.
6.8 Sample shall be charged to stability chamber within 15 days of release of batch and the results of initial analysis at the time of release of batch shall be considered as “0” month results. If this period exceeds 15 days, the sample shall be re-analyzed after allotting AR No. according to respective SOP treating sample as stability sample before charging to stability study to generate “0” month results. Sample shall be analyzed before charging to stability chamber for additional test if any.
6.9 The “Start date” of stability study shall be that date on which sample has been charged in stability chamber.
6.10 Subsequent time intervals shall be conducted on the basis of start date.
6.11 The due date at each interval (testing station) is the date that the sample shall be removed from the stability chamber.
6.12 Withdrawal of the stability sample shall be carried out as per monthly planner and Monthly planner shall be as per Annexure No. – XII. Reconciliation of the same shall be carried out during the withdrawal of the sample and record of the same shall be maintained as per Annexure No. – X.
6.13 Sample shall be withdrawn from stability chambers at different testing stations within +5 Days from due date for accelerated, Long Term and Intermediate conditions.
6.14 Place withdrawn sample at room temperature in a cupboard labeled as “Under Test” and initiate the analysis on the same day of withdrawal.
6.15 Batch specific protocol shall be prepared for performing the stability studies. The protocol covers stations (time intervals) and tests required during the stability studies of that product. Stability study protocol shall be prepared as per Annexure No. – XI. Stability Protocol shall be prepared for all batches, which shall be charged for stability study. Protocol shall be approved by Head-QA.
6.16 Each stability Protocol number consist of alphanumerical characters and mentioned as SS-X-YYYY-ZZ.
6.16.1 First “two” (i.e. SS) character indicates code for stability study.
6.16.2 Next character “-“ is a separator.
6.16.3 Next character (i.e. X ) indicates the product code as per respective SOP.
6.16.4 Next Character “-“ is a separator.
6.16.5 Next four character ( i.e.YYYY) indicates the unique number in which first two Character indicates serial number increases sequencelly for a particular product and last two character indicate year of preparation.
6.16.6 Next character “-“ is a separator.
6.16.7 Next two character (i.e. ZZ) indicates the version number.
6.16.8 e.g. SS-PARAC-0117-00, in which SS for stability study, PARAC for PARACIN100 mg Tablets (USP), 01 for serial no. i.e. first protocol for Nepotel100 mg Tablets (USP), 10 for year 2017 and 00 for version number.
6.17 Each stability protocol consist of details as mentioned below:
6.17.1 Subject indicates subject of document i.e. ‘stability protocol’ shall be mentioned in the same.
6.17.2 Department indicates name of the department preparing the protocol i.e. ‘Quality Control’ shall be mentioned.
6.17.3 Product name indicates the generic name of the product for which the stability protocol shall be prepared.
6.17.4 Protocol number indicates the stability study protocol number as mentioned in point number 6.17.
6.17.5 Revision number indicates the version number of the stability study protocol. If it is prepared for the first time then “00” shall be mentioned. For any subsequent revision, the revision number “01” shall be mentioned.
6.17.6 Effective date indicates the date of effectiveness of stability protocol.
6.17.7 Supersedes indicates the previous version number. If protocol is prepared first time then NA shall be mentioned for every subsequent revision the revision number of previous protocol shall be mentioned.
6.17.8 Revise the protocol if required.
6.18 As per approved protocol, QC department shall charge the stability samples as per following procedure:
6.18.1 Segregate the packed containers for the stability conditions as mentioned in stability Protocol.
6.18.2 Affix the stability label as per stability condition as per Annexure No. – VI, VII & Annexure No. – VIII.
6.18.3 Quantity of sample required for the stability study shall be kept doubled the times of samples required for one complete analysis or as per specific requirement from customer. Approximate quantity required on each station has been summarized as per Annexure No. – XVI.
6.18.4 Charge the packed stability samples into the respective stability chamber. Ensure that door of stability chamber shall be locked before leaving.
6.18.5 Maintain the details of the product and scheduled station of stability products as per Annexure No. – II.
6.19 Stability study Conditions / Intervals:
6.19.1 Stability studies shall be conducted at conditions mentioned in table – I (References ICH (Q1A) and ICDRA) :
Table – I
|Long Term ( Zone-I & Zone-II)||25°C±2°C/60% ± 5% RH||Initial & 3,6,9,12,18, 24,36, 48 months|
|Intermediate*** ( Zone-I & Zone-II)||30°C±2°C/65% ± 5% RH||Initial & 3,6,9,12|
|Long term ( Zone IV a )||30°C±2°C/65% ± 5% RH||Initial & 3,6,9,12,18, 24,36, 48 months|
|Long term ( Zone IV b )||30°C±2°C/75% ± 5% RH||Initial & 3,6,9,12,18, 24,36, 48 months|
|Accelerated Stability||40°C ± 2°C/75 % ± 5% RH||Initial & 1,2,3,6 months|
| * The storage conditions to be decided as per product registration.
** The last frequency for Long term shall be either 12 months after shelf life of the product or 36 months whichever is greater.
*** Analysis of the intermediate samples shall be done only when samples charged at accelerated conditions shows a significant change
6.20 After withdrawal of samples, AR No. shall be allotted as per respective SOP and record shall be maintained as per Annexure No. – XV. Stability sample shall be given to analyst with worksheet and photocopy of Summary sheet upto pervious station. Stability samples shall be analyzed as per specification mentioned in the stability protocol of the specific batch.
6.21 Analyst shall record raw data of stability product in respective worksheet as per Annexure No. – IX for dry syrup / Injection and Annexure No. – VIII & X for Tablets / Capsules. And result shall be verified by analyst for any OOT or significant change with the help of the summary sheet upto previous station.
6.22 On Completion of testing after each station, stability data shall be reviewed and these results summarized in summary sheet for Long Term as per Annexure No. – III, For Intermediate as per Annexure No. – IV and For Accelerated as per Annexure – V. After that stability data shall be submitted in QA.
6.23 Inform any significant changes to the Head of Department which is mentioned below :
6.23.1 5% or more than 5% potency changes from the initial assay.
6.23.2 Any specified degradant not meeting specification limit.
6.23.3 pH not meeting specification limit.
6.23.4 Failure to meet specifications for appearance and physical properties i.e. colour, shape, hardness etc.
6.23.5 Dissolution not meeting specification limit for 12 dosage units.
6.24 Notify any “Out of specification” (OOS) or “Out of Trend” (OOT) results to Head of Department and perform the investigation as per the relevant SOPs (for handling of Out of specification, respective SOP and for Handling of Out of trend, respective SOP.
6.25 The stability study shall be discontinued in case of failure to comply the specification. Stability study discontinuation shall be done as per Annexure No. – XIII after approval of Head-QA.
6.26 The investigation for failure shall be conducted with the help of Head-QA. Head QA shall decide whether investigation shall be extended to other batches manufactured under similar condition and or other batches, which are likely to be affected. Record of the same shall be maintained as per Annexure No. – XVII.
6.27 Any failure in stability chamber generate an alarm on stability chamber as well as on security gate. At the time of duty hours stability In-charge shall rectify the problem with the help of engineering person. If any failure in stability chamber happened on Holiday or during off duty hours, Security person shall intimate to Engineering deptt. and stability In-charge. Engineering person shall rectify the problem with the help of stability In-charge.
6.28 Alarm system of stability chamber shall be handled as respective per SOP.
6.29 In case the failure of stability chamber prolonged to more than 24 hours, initiate a deviation as per Annexure No. QAGN005/A01. If required, samples from respective stability chamber shall be removed and stored at room temperature and Record shall be maintained as per Annexure No. – XIV.
6.30 Stability chamber failure investigation report shall be prepared as per Annexure No – XVIII. with the help of engineering and Quality Assurance.
6.31 After completion of rectification of chamber, samples shall be charged again in the respective original stability storage condition and rescheduling of the charging and withdrawal station shall be done by adding number of days for which sample stored at room temperature to the existing due dates for withdrawal of samples and close the deviation.
6.32 Temperature / RH Monitoring of Stability Chambers:
6.32.1 Temperature / RH of stability chamber shall be recorded by stability chemist or above on manually basis on the interval of 2 hours as per Annexure No. – IX.
6.32.2 Temperature / RH shall be monitored through software on the interval of 1 hour and print out shall be taken on daily basis by stability chemist or above. This printout shall be reviewed by Executive stability / Nominee.
6.32.3 If any failure in Temperature / RH of Stability Chambers found, investigation shall be done and note down in the Stability chamber failure investigation report as per Annexure No. – XVIII and CAPA shall be generated as perrespective SOP.
5.33 Executive summary Report:
5.33.1 Product specific Executive summary report shall be prepared as per Annexure No. – XIX at the time of requirement.
5.33.2 Executive summary report shall be assigned as ESR-X-YY-ZZ
First two characters (i.e. ESR) indicate for Executive summary report
Next character ( – ) is a separator
Next characters X is for product Code as per respective SOP.
Next two character YY is for report number which is a serial number, increases sequencelly for a particular product.
Next character ( – ) is a separator
Next two characters ZZ is for version number of the report.
6.33.3 Each executive summary report consist of details as mentioned below:
Subject indicates subject of document i.e. ‘Executive Summary Report’ shall be mentioned in the Same.
Department indicates name of the department preparing the Report i.e. ‘Quality Control’ shall be mentioned.
Product name indicates the Brand name of the product for which the Executive summary report shall be prepared.
Report number indicates the executive summary report number as mentioned in point number 6.33.2
Revision number indicates the version number of the Executive summary report. If it is prepared for the first time then “00” shall be mentioned. For any subsequent revision, the revision number “01” shall be mentioned.
Effective date indicates the date of effectiveness of Executive summary Report. Supersedes indicates the previous version number. If report is prepared
Supersedes indicates the previous version number. If report is prepared first time then NA shall be mentioned for every subsequent revision the revision number of previous report shall be mentioned.
6.34 Prepare separate charging schedule, monthly planner and A. R. number register for exhibit batches.
7.0 List of Annexure / Formats:
Stability sample Requisition Slip : Annexure-I
Schedule for charging and analysis of stability samples : Annexure-II
Summary of Long Term stability data : Annexure-III
Summary of Intermediate stability data : Annexure-IV
Summary of Accelerated stability data : Annexure-V
Label for samples of Accelerated Condition : Annexure-VI
Label for sample of Intermediate condition : Annexure-VII
Label for sample of Long term condition : Annexure-VIII
Temperature and RH monitoring record : Annexure-IX
Reconciliation of stability samples : Annexure-X
Stability Protocol : Annexure-XI
Monthly Planner : Annexure-XII
Stability study discontinuation statement : Annexure-XIII
Record of sample taken at room temperature during stability chamber failure : Annexure-XIV
Stability samples AR No. Register : Annexure-XV
Quantity of samples required for stability study : Annexure-XVI
Stability Product Failure Investigation Report : Annexure-XVII
Failure Report of stability chamber : Annexure-XVIII
Executive Summary Report : Annexure-XIX
8.0 References (if any).
USP, ICH (Q1A), ICDRA
7.1 Master Copy : Documentation Cell (Quality Assurance)
7.2 Controlled Copies : Quality Assurance, Quality Control
|Date||Revision Number||Reason for Revision|
Record of Sample Taken at Room Temperature During Stability Chamber Failure