Stability Studies

I.  PURPOSE:
    To provide the method of assessing for the stability  of  drug substances (activepharmaceutical ingredients) manufactured by the

 II. SCOPE:

The procedure is applicable to all the Products manufactured 

III.  RESPONSIBILITY:
It is the responsibility of the Quality Control to follow the procedures provided in this Standard Operating Procedure for conducting the Stability studies.

IV.  DOCUMENT REFERENCE:
          SOPs    :    Specifications and Standard Testing Procedures for Stability Studies
         Core procedure, Deviation – Investigation and Corrective Action
                 
          Forms    :    Stability Analysis workbook
          Stability Data Sheet
Stability sample label

V. DEFINITIONS :

Stability :  To provide evidence on how the quality of various Active Pharmaceutical Ingredients (APIs) varies with time under the influence by means of different of environmental factors such as temperature, humidity, light and to establish storage conditions and re-test period.
    
Active pharmaceutical ingredient (API) : Any substance with pharmacological activity intended for use in the manufacture of a drug product.

Long-term testing : Evaluation of the physical, chemical and microbiological(if required) characteristics of a drug substance over the expected duration of the shelf-life under recommended storage conditions and in the proposed container/closure system.

Accelerated (stress) testing : Studies designated to increase the rate of chemical degradation or physical change of a drug substance or drug product by using stress (exaggerated) conditions of storage.
 
Intermediate testing :  Studies conducted at intermediate storage condition of long term and accelerated testing designed to moderately increase the rate of chemical degradation or physical changes for a drug substance or drug product.

Established product : The drug substance manufactured using a standardised process and formula and showing no significant change after 24 months during long term stability testing and the completed  accelerated stability study.

Reprocessed product : Introducing an intermediate or API, including one that does not conform to standards or specifications, back into the process and repeating a crystallization step or other
appropriate chemical or physical manipulation steps (e.g., distillation, filtration, chromatography, milling) that are part of the established manufacturing process. Continuation of a process step after an in-process control test has shown that the step is incomplete is considered to be part of the normal process, and not reprocessing.
.
     Reworked product : Subjecting an intermediate or API that does not conform to standards or Specifications to one or more processing steps that are different from the established manufacturing process to obtain acceptable quality intermediate or API (e.g., recrystallizing with 
    a different solvent).Re-test period : The period of time after qualifying the substance to its specification during which a drug substance can be considered to remain within the specification and therefore acceptable for use in the manufacture of a drug product provided it has been stored under the defined conditions.

Stable product :  A product is considered to be stable when during long term stability testing the product is within specification limits and for accelerated testing there is no significant change in any parameters investigated up to its designated storage period.
     
   VI.  PROCEDURE:

1.0  Test Procedures and specification Criteria :

1.1   The testing should cover those features susceptible to change during storage and likely to Influence quality, safety and efficacy of the product.

1.2.  Stability information should cover as necessary the physical and chemical  characteristics.

1.3  The specifications should include   Description, Identification, Purity (known, unknown, total  impurities and degradation products) and Assay limits and where applicable, in case of polymorphs, methods indicating polymorphic stability. 

2.0    Significant change :  
2.1   At long term : Failure to meet the specification is considered as significant change for a drug substance (API) at long term.

2.2    At accelerated condition : Failure to meet the specification is considered as significant change for a drug substance (API) at accelerated condition.

2.3    At Intermediate condition: Failure to meet the specification is considered as significant change for a drug substance (API) at intermediate condition.

3.0   STORAGE CONDITIONS 

3.1. For the API’s to be stored at normal conditions (25°C ?  2°C)
         
    Long Term testing  : 25°C ?  2°C / 60 % ? 5 % RH 
      
     Accelerated testing : 40°C ? 2°C / 75 % ? 5 % RH

     Intermediate testing : 30°C ? 2°C / 60 % ? 5 % RH

   3.2.  For the API’s to be stored  at refrigerator conditions (2 to 8 °C) (Thermo liable products)
 Long Term  testing     : 5 + 3OC
 Accelerated testing     : 25 + 2OC and 60 + 5% Relative Humidity
 Elevated temperature testing: 30 + 2OC and 60 + 5% Relative Humidity

   3.3.    For the API’s to be stored at freezer temperature(- 15 + 5OC) (Thermo liable products)

            Long Term  testing    : 5 + 3OC
           Accelerated testing    : - 15 + 5OC
            Note:   The initial stability study should be carried out in all the three conditions mentioned  respectively for 3.1 and 3.2 and two conditions for 3.3.
3.4    Sample storage and maintenance: 
3.4.1    Stability samples shall be stored in  market-simulated containers at  the storage conditions of  the respective study  .
3.4.2    Any deviations in the specified storage conditions shall be recorded. If deviation is more than 24 hours,  should be provide other alternative chamber and it has to be reviewed thoroughly, as per the core procedure, “Deviation – Investigation and Corrective Action”. 
4.0    Selection of Batches &testing intervals :

  4.0 Selection of Batches &testing intervals  contd..:

The selection of the study and testing should be based on the conclusions obtained from the  respective investigation report

5.0    Packing and Labeling :
5.1  The batch should  be kept on stability within 21 days from the date of release of the batch.        

5.2     Collect  the samples by giving an IC to production department of  total quantity required  for stability study and sub-divide into quantities required for each interval to carry out the tests indicated in the stability testing protocols  and for the test intervals .

  5.3  Place at least three buffer samples (quantity sufficient to perform all the  stability tests    thrice) for the purpose of cross checking in case of any deviations in storage, spillage of the material.
   5.4  The samples shall be packed simulating the dispatch conditions including secondary packing and identified with a label showing the type of study. The packing shall be in double polythene  bags, which  are packed  and labeled subsequent to packing  The use of the type of double polythene bags shall vary depending on the type of product being packed i.e either two transparent polythene bags,  one transparent and the other black or two black bags.

   5.5  The label shall contain details such as Product, Batch No., Weight packed, Sample No., Packing date, To be analyzed on, and also the instructions regarding storage temperature and relative humidity.
  5.6   Enclose the labeled packets in a miniature HDPE drum or other specified container,  in a manner that simulates the proposed packing in which it will be marketed.

6.0 Testing : 

6.3    After completion of incubation period, withdraw the selected samples from stability chamber  as per the time point window for sample pull-out as given below.  

6.4  For long term condition

 6.5 For Accelerated and Intermediate conditions

* For intermediate condition samples 

6.6     If the samples are not being planned for analysis as per the testing frequency, transfer the samples to self-sealing polyethylene bag, seal it, label it and pack in a Triple Laminated High Barrier bag and heat seal or pack in an air tight container, seal it and store at 2 to 8°C till the samples are taken for analysis.

6.7    Withdraw the samples stored at intermediate stability study at each interval.  Transfer the samples to self-sealing polyethylene bag, seal it, label it and pack in a Triple Laminated High Barrier bag and heat seal or pack in an airtight container, seal it and store at 2 to 8°C.  If any significant change is observed at accelerated stability study at any interval, analyse all the samples of previous interval of intermediate stability study  which are stored at 2 to 8°C and continue the intermediate stability study up to 12 months or as per the stability protocol. 

6.8     If no significant change is observed during accelerated stability study, then discard the samples of intermediate stability study , after completion of all designated accelerated stability study intervals.

6.9     After withdrawing samples from their storage places, allow the samples to  come to ambient temperature before proceeding with the testing.    
6.10   Carry out the tests specified in the relevant stability testing protocol, following the current stability study specification.

6.11         In case of any sample missed for analysis, as per schedule, then, intimate the same to Quality Assurance and take appropriate action as suggested by Quality Assurance.

7.0 Documentation: 
7.1 Prepare separate protocol for long term, accelerated, intermediate, Elevated conditions as per selection of Batches & testing intervals 

  7.2  Stability analysis work book shall be prepared according to the STP. The analysis  workbook shall contain details such as Product name, batch number, batch quantity, date  of  manufacture, date of analysis, analysis details, signature of analyst and date for each  test and finally checked by and date. A bound book shall be used for each  batch placed on  stability.

7.3     The results shall be recorded in the corresponding stability analysis workbook.

7.4     The results shall be tabulated in the respective data sheets from the workbook.
 
8.0  Review of Stability Studies :
 8.1 Review of the results from the stability studies shall be carried out after completion of every  interval testing  as the samples are affected by the impact of the conditions under which they are stored or not.
8.2     Initial review shall be carried out after completion of the accelerated studies and the subsequent reviews shall be carried out on a scheduled basis.

8.3     Re-test dates for the products under question shall be fixed based on the results obtained.

8.4     In case of any sample placed on stability failing to meet its specifications, an investigation on the lines of investigating Out-of-specification results shall be carried out to evaluate the reasons and to determine subsequent actions to be taken.
8.5    The reasons normally for the failure may be
-    The temperature condition
-    The relative humidity
-    The packing used for the product

8.6     A review shall be carried out and the changed conditions for the stability studies should be  fixed.

9.0    Re-test date evaluation
9.1    Data Evaluation for Retest Period or Shelf Life Estimation for Drug Substances or Products Intended for Room Temperature Storage 
          (25 ± 2OC and 60 ± 5% Relative Humidity).

    9.1.1    No significant change at accelerated condition Where no significant change occurs at the accelerated condition, the retest period
            or shelf life would depend on the nature of the long-term and accelerated data.   
?     Long-term and accelerated data showing little or no change over 
                 time  and little or no variability
Y= 2X           (Not exceeding 12 months)

•    Long-term or accelerated data showing change over time  and/or variability
?    Data not amenable to statistical analysis 
                      Y= 1.5X (Not exceeding 6 months)
?    Data amenable to statistical analysis
                    Y= 2X (Not exceeding 12 months)

     9.1.2    Significant change at accelerated conditionWhere significant change occurs at the accelerated condition, 
    the retest period or shelf life would depend on the outcome of stability testing at the intermediate condition, as well as at the long-term condition.

•        No significant change at intermediate condition
?     Data not amenable to statistical analysis
                        Y= X + 3 Months
?     Data amenable to statistical analysis
                             Y= 1.5X (Not exceeding 6 months)
•    Significant change at intermediate condition  
?      Y=  X

 
9.2    Data Evaluation for Retest Period or Shelf Life Estimation for Drug Substances or Products Intended for Storage Below 
    Room Temperature ( 5 ± 30C)Drug substances or products intended for storage in a refrigerator 

9.2.1     No significant change at accelerated conditionY= 1.5X (Not exceeding 6 months)
•     Long-term or accelerated data showing change over time and/or 
             variability
?     Data not amenable to statistical analysis 
                          Y= X + 3 Months
•         Data amenable to statistical analysis
?    Y= 1.5X (Not exceeding 6 months)
?    
9.2.2    Significant change at accelerated condition

?    If significant change occurs within the first 3 months’ testing at the accelerated 
       storage condition.

                  Y= X

?    No significant change occurs within the first 3 months’ testing at the 
accelerated storage condition.
                  Y= X
9.3   Tabulate and/or plot stability data on all attributes at all storage conditions and evaluate each attribute separately. 

9.4 Follow the logic tree given below for the retest date estimation.
 

Stability, pharmacological, manufactured, intended