This Document describes (Standard Operating procedure) Sop for Stability Studies for Finished formulations.

Sop for Stability Studies for Finished formulations

 

I. Purpose & Scope:

• The purpose of this SOP is to lay down the procedure for performing the stability studies on finished dosage forms so that to ensure quality of the product throughout the shelf life & at the prescribed storage condition.
• This SOP is applicable in quality control department for the stability studies to be performed of all finished dosage forms manufactured.

II. Responsibilities:

• All Quality Control and Quality Assurance personnel’s shall be responsible to follow and implement this SOP.

III : MATERIALS AND EQUIPMENTS:

Stability chambers

IV : Definition:

Formal Stability Study:

Long term, accelerated and intermediate studies undertaken on primary and/or commitment batches according to prescribed stability protocol to establish or confirm the retest period of drug substances or the shelf life of the drug products.

Stability Tests :

A series of tests designed to obtain information on the stability studies of a pharmaceutical product in order to define its shelf life and utilization period under specified packaging and storage conditions.   

Long Term or Real Time stability studies:

Stability studies under recommended storage conditions to confirm or establish the re-test period or shelf life proposed (or approved) for labeling for drug product

Intermediate Testing :

Studies conducted at 30^oC ± 2°C/ 65% RH ± 5% or 30^oC ± 2°C/ 75% RH ± 5% and designed to moderately increase the rate of chemical degradation or at physical changes for a drug substance or product intended to be stored long term at 25^oC ± 2°C/ 60% RH ± 5%.

Accelerated Stability study :

Studies designed to increase the rate of chemical degradation and physical change of a drug by using exaggerated storage conditions as part of the formal stability-testing program.

Shelf Life :

The time period during which a drug product is expected to remain within the approved shelf life specifications provided that it is stored under the conditions defined on the container label.

Specification release :

The combination of physical, chemical and biological and microbiological tests and acceptance criteria that determines the suitability of the drug product at the time of its release.

Specification Shelf Life :

The combination of physical, chemical and biological and microbiological tests and acceptance criteria that determines the suitability of the drug product & drug substance meets throughout its shelf life.

Significant change :

• • 5% change in assay from its initial value; or failure to meet the acceptance criteria for potency when using biological or immunological procedures.
  • Any degradation product’s exceeding its acceptance criteria.
  • Failure to meet the acceptance criteria for appearance, physical attributes, and functionality test (e.g. colour, phase separation, re- suspendibility, caking, hardness, dose delivery per actuation); however, some changes in physical attributes may be expected under accelerated conditions.
  • Failure to meet the acceptance criterion for pH; if applicable.
  • Failure to meet the acceptance criteria for dissolution for 6 dosage units, if applicable.

 

V : Frequency of stability study:

• • Stability studies will be carried out as per stability schedule.
  • Monthly calendar will be prepared to track the stability testing which are due in that month.

• Special conditions:

  • Samples should be removed for analysis as per stability schedule.
  • The shrink wrap will be removed before charging the batches for stability studies.
  • Before charging all samples to be properly labeled with signature.
  • R & D samples & commercial batch as well as validation samples to be kept in separate rack with proper identity.
  • Stability chambers shall be opened by authorized persons.
  • In-case of product does not comply with specification after expiry date then OOS Procedure shall not be initiated.

VI : Criteria for keeping finish products under stability study :

• First three validation batches, other validation batches will be kept for stability studies for accelerated, long term and intermediate storage conditions.
• All Stability studies will be carried out as per stability schedule.
• The batches which have undergone critical process/ package deviations will be charged for stability studies. Batches which have undergone reprocessing will also be included in the stability studies program.
• After packing the batch will be placed for stability studies within one month.
• Retesting will be done in case the batches are not charged for stability studies within one month of release.
• Batches stored in bulk containers will be retested prior to packaging, if it is stored for more than 3 months.
• One commercial batch will be charged for stability study for long term & intermediate storage.
• Commercial batch will be charged for stability study for long term, accelerated & intermediate storage condition or as per customers requirement.

VII : Management of stability samples:

• After receiving stability studies samples of commercial/Validation batches of finished products from Quality Assurance department, enter all the mentioned details in stability samples entry log book in Annexure-I
• At each storage condition samples equivalent to the quantity required
• For two analysis will be kept additionally as spare or buffer samples for investigational purpose if required in case of OOS generation
• Remove the shrink wraps, prepare sample bundles & label as per storage condition & stability interval as per stability schedule.
• Arrange stability sample in stability chamber at 25°C ± 2°C/ 60% RH ± 5% for long term stability study, 30°C ±  2°C /65% RH ± 5% or 30°C ±  2°C /75% RH ± 5% for intermediate stability study and 40°C ±  2°C & 75% RH ± 5% for accelerated stability study and maintain the location chart for the samples. And prepare stability schedule as Enter the details of the samples charged in the stability sample entry log book.
• Prepare stability summary data sheet for 40°C ± 2°C / 75% RH± 5%, 30°C ± 2°C/65% RH± 5% or 30°C ±  2°C /75% RH ± 5% and 25°C± 2°C / 60% RH ± 5% storage condition as per Annexure-V
• Withdraw the required quantity of sample as per schedule before starting the analysis. if the sampling activity is not carried out as per schedule the same will be conducted within +10 days from schedule date.
• After withdrawal make entry in stability sample inward register for analysis as per Annexure VI.
• Stability samples for microbial analysis removed from stability chamber as per stability schedule. In case of chemical analysis stability samples should not be stored more than 7 days at ambient condition of laboratory.
• Record the opening & closing record of stability chambers is maintained in the register’ Opening & closing record of stability chambers ‘as per Annexure VIII.
• Testing will be carried out as specified in STP and online recording of observations will be made into Test data sheet.
• Reconciliation of samples used for testing at each interval will be done against the samples charged for each test frequency and storage condition in stability samples entry log book. As per Annexure IX.
• After analysis destroy the remaining sample quantity.
• Note: – Following points will be considered during preparation of protocol.

VIII : Test procedure and test criteria:

• The testing will cover those features susceptible to change during storage and likely to have influence on quality, safety and/or efficacy as per
• The long term storage condition and studies will be performed as per protocol approved by customer.

IX : Specifications:

• • Limits of acceptance will relate to the shelf life specification and will allow acceptable and justifiable from the release specification.

X : Storage test conditions and monitoring:

• • The duration of the studies and the storage conditions will be sufficient to cover storage, shipment and subsequent use. The storage condition will be as follows;

	Long Term	Intermediate/ Long term (Zone IVA)	Intermediate/ Long term (Zone IVB)	Accelerated
Temperature	25°C ± 2°C	30°C ± 2°C	30°C ± 2°C	40°C ± 2°C
% Relative Humidity	60 % ± 5 %	65 % ± 5 %	75 % ± 5 %	75 % ± 5 %

 

• The storage condition and testing frequency as defined by the customer.
• Temperature and % Relative Humidity of Stability Chambers will be reviewed daily recorded.
• Temperature and humidity excursions beyond 24 hours will be   documented and will be informed to the Head QC and Head – Quality deviation from will   be filed.
• In case of multiple excursions occur in the accelerated storage condition lower than the acceptable humidity & temperature conditions, the stability study will be extended compensating for the period of unacceptable storage conditions.
• The stability protocol will be amended and communicated to the QP of the MA Holder.
• In case of any eventuality/major breakdown or maintenance of stability Chambers’, which will take more than 24 hours, then the samples, will be shifted to the other chamber, which will be routed through change control.

XI : Testing frequency:

• • Frequency of testing will be sufficient to establish the stability characters of the product.
  • For time zero (T0), the analytical data of finished product tested of the marketable pack will be considered, which will be valid for one month.
  • Stability studies samples having stability interval less than 12 months should be analyzed within 15 days from withdrawal date, in case of stability interval more than or equal to 12 months should be analyzed within 30 days from withdrawal date.
  • In-case of unavoidable circumstances if the stability testing is not carried out as per schedule the same will be documented through a deviation form with adequate justification. The impact of the change in the schedule will be assessed by Head – Quality.
  • The testing frequency for long term 25° C/ 65 % RH, intermediate 30°C / 65 % RH  or 30°C ±  2°C /75% RH ± 5% and accelerated 40° C / 75 % RH testing will be as follows.

 

Conditions	25°C ±  2°C 60 % ±  5 %	30°C ±  2°C 65 % ±  5 %	30°C ±  2°C 75 % ±  5 %	40°C ±  2°C 75 % ±  5 %
Frequency	Initial, 3, 6, 9, 12, 18, 24, 36 and 48 months OR 1 year more than the shelf life.	Initial, 3, 6, 9, 12, 18, 24, 36 and 48 months OR 1 year more than the shelf life.	Initial, 3, 6, 9, 12, 18, 24, 36 and 48 months OR 1 year more than the shelf life.	Initial, 1, 2, 3 and 6 months (or as per customer requirement)

 

• When the intermediate storage condition 30°C ± 2°C /65% RH ± 5% or 30°C ± 2°C /75% RH ± 5% will be considered as long term study Samples kept at 25°C ± 2°C/ 60% RH ± 5% will be analyzed only when there is significant change in the specification at intermediate storage condition. This change will be addressed in the deviation form.
• Matrixing / bracketing principles will be applied wherever required with proper technical justification. It will not be applied to the first three commercial validation batches.

XII : On-going stability studies:

• • One batch per year for product manufactured in the year in every strength and every primary packaging type will be included in the stability program.
  • The principles of matrixing and bracketing design may be applied if scientifically justified in the protocol.
  • The protocol for on-going stability studies will include the following parameters.
    • Number of batches per strength and different batch,if applicable.
    • Relevant physical, chemical and microbiological test methods.
    • Acceptance criteria.
    • Reference to the test method.
    • Description of the container closure system.
    • Testing (time points )
    • Description of the storage conditions.
    • Other applicable parameter specific to the drug product.
  • Out of specification/ out of trend results will be investigated and will be forwarded to the Marketing Authorization holder.
  • The possible impact on the batches on the market will be assessed by Head – Quality in consultation with Marketing Authorization holder.
  • Stability data generated will be trended. Summary of all data generated including interim conclusions will be written and maintained. This will be reviewed during annual product review.

XIII : Evaluation:

• • After testing the results will be entered into stability data record.
  • Where product fails to meet specifications during accelerated stability study/ intermediate storage conditions or there is significant change the stability studies will be communicated to Marketing Authorization holder. Long-term stability studies will be continued.
  • For OOS of stability samples follow respective OOS procedure.

 

XIV : Stability Protocol numbering system given below:

Protocol No. : SS/XX/NNN-YY

SS: Stands for stability study

XX: Stands for product code

NNN: Stands for serial number

YY: Stands for version number 

       

XV : ANNEXURE

Annexure I- Stability Sample log book

Annexure II- Stability Sample Label

Annexure III- Long term / Accelerated Stability summary data sheet

Annexure IV- Stability inward register

Annexure V – Stability sample reconciliation (Accelerated)

Annexure VI – Customer wise storage condition and testing frequency

Annexure VII – List of products to be placed for stability. 

Annexure VIII- Opening and closing record of stability chambers.

Annexure IX – Stability sample reconciliation (Long term)

 

ANNEXURE-I

Stability Sample Log Book

 

Date

Product name

Batch.No

Mfg. date

Exp. Date

Date of receipt

Qty. received

Sample charging date

3M

6M

9M

12M

18M

24M

36M

48M

 

 

             ANNEXURE-II                                                                                                        

      Stability Sample Label

STABILITY SAMPLE

Temp:                                           RH:   Sample kept on :                         Kept By :

 

                                       ANNEXURE-III                                                                                                        

LONG TERM/ ACCELERATED STABILITY SUMMARY DATA SHEET

Name of Product	:					Charging date	:
Batch No.	:		Mfg. Date	:		Exp. Date	:
Pack Profile	:		Batch Size	:		Storage condition	:
Reason for keeping	:					Type of Batch	:

 

Tests	Specifications	Months
		Initial	3	6	9

 

Remarks:

 

	Prepared By	Checked By	Approved By
Sign/ Date
Name
Designation

                                                                                                                       

    ANNEXURE-IV   

STABILITY INWARD REGISTER

 

Sr. No.

Date of Receipt

Name of the Product

stage

Batch No.

Batch Size

Mfg. Date

Expiry Date

Sampled on

Sampled by

(A.R. No.)

Status (Approved or Rejected)

Date of Approved or Rejected

Analyzed by

Checked by

Remark

 

 

 

 

 

ANNERURE -V

Stability Sample RECONCILIATION (ACCELERATED )

 

Name of Product	:
Batch No.	:		Stability Condition	:
Batch Size	:		Charged sample Qty.	:
Mfg. Date	:		Sample Charging Date	:
Exp. Date	:		Pack Profile	:

Month wise sample quantity distribution:

Month→	1	2	3	6
Std. Qty. kept in Nos→

 

Sr. No	Date of withdrawal	Stability study due point (in Month)	Opening Qty.	Withdrawal Qty.	Balance Qty.	Withdrawal By	Checked By
1		1 Month
2		2 Month
3		3 Month
4		6 Month
5

 

Annexure -VI

Customer wise storage condition and testing frequency

 

CUSTOMER NAME	STABILITY SAMPLES STORAGE CONDITION and testing frequency
	25°C / 60 % RH	30°C / 65 % RH	30°C / 75 % RH	40°C / 75 % RH

 

 

 

 

 

 

Annexure –VII

List of products to be placed for stability

 

Sr.No.	Product name	Party	B. No	Condition/ Stage	Chamber No.	Rack No.

 

 

Annexure -VIII

 

Opening and closing record of stability chambers

Sr.No.	Opened on Date	Reason of opening	Opened at (Time)	Closed at (Time)	Opened by	Checked by

 

 

ANNERURE –IX

 STABILITY SAMPLE RECONCILIATION

 

Name of Product	:
Batch No.	:		Stability Condition	:
Batch Size	:		Charged sample Qty.	:
Mfg. Date	:		Sample Charging Date	:
Exp. Date	:		Pack Profile	:

Month wise sample quantity distribution:

Month→	3	6	9	12	18	24	36	48	60	72
Std. Qty. kept in Nos→

 

Sr. No	Date of withdrawal	Stability study due point (in Month)	Opening Qty.	Withdrawal Qty.	Balance Qty.	Withdrawal By	Checked By
6		3 Month
7		6 Month
8		9 Month
9		12 Month
10		18 Month
11		24 Month
12		36 Month
13		48 Month