sop for stability policy

1.0 OBJECTIVE  
1.1 The objective of this SOP is to define the procedure for stability study policy for formulated products because quality of a formulated product varies with time under the influence of a variety of environmental factors such as temperature, humidity and light. Stability Study enables recommended storage conditions, retest periods, and shelf life to be established.
2.0 SCOPE
2.1 This procedure is applicable for Stability Study of all the products manufactured
3.0 RESPONSIBILITY
3.1 Officer / Executive – Quality Assurance: Prepare the SOP and follow up the standard operating procedure accordingly.
3.2 Head – Quality Assurance: Provide the support to the implementation of SOP and maintaining the record.
4.0 ACCOUNTABILITY
4.1 Head – Quality Assurance / Chief Executive Officer
5.0 REFERENCE(S)
5.1 ICH Guidelines

6.0 PROCEDURE
6.1 The methodology followed and selection of the test conditions indicated in this SOP is based on the below mentioned
6.1.1 ICH – Guidelines on Stability testing of New Drug Substances and Products.
6.1.2 WHO Guidelines for Stability testing of well-established drug substances and their products.
6.2 Stability study will be Performed in the following conditions:
6.2.1 New product Manufactured for the first time in the Facility.
6.2.2 Existing product’s process/equipment deviation.
6.2.3 Change in manufacturing site.
6.2.4 Change in manufacturing process/equipment.
6.2.5 Change in source of any of the key raw materials.
6.2.6 Addition of new strength for the product.
6.2.7 Change in batch size.
6.2.8 Reprocessing of the product.
6.2.9 Change in primary packaging material.
6.3 Stability study will be carried out for formulated products with generic name in the following circumstances:
6.3.1 To select an optimum formulation and container closure system. An optimum formulation shall retain it’s identity, purity and strength for it’s entire shelf life. This will be done during the development phase and for this accelerated stability study will be under taken.
6.3.2 To determine shelf life and storage conditions for the drug product. Once the formulation and the packing have been established, both accelerated and real time stability study will be carried out. To verify that the established formulation and the manufacturing process will produce a stable product till further it’s shelf life consistently. For this ongoing stability study on the commercial batches will be done.
6.4 Stability study will be carried out in following phases:
6.4.1 Development Phase
This is the phase in which manufacture selects an optimum formulation, manufacturing process and packing for the product. Accelerate studies will be carried out to determine tentative shelf life and storage condition of the product. Real time studies will be started at the same time to substantiate the claimed shelf life.
6.4.2 For Registration Dossier
Various drug authorities require stability data of the drug product. For this purpose, both the accelerated (at temperature 400C ± 2° C & %R.H. 75% ± 5%) and real time (at temperature 300C ± 2° C & % R.H. 75% ± 5%) data will be submitted. Stability data of the API and shelf life of similar market products will be given as supportive data.
6.4.3 Ongoing Stability Study
In the post registration period, ongoing stability study of products being manufactured will be carried out in real time conditions to verify the expiry date and storage condition of the product. Real time stability study is conducted one year later after the shelf life of the product.
At least one representative sample of each product will be kept annually for stability study. In case of products having same composition and packaging but different brand names, any-one brand may be termed as a representative sample. If any change is made in the inactive ingredients or manufacturing process or packing, additional stability study will be carried out to verify that the changes shall not affect the stability of the product.
6.5 Intended Market
The climatic conditions of the place where the products are to be marketed will be considered while designing stability studies. For this, the world has been divided in four different zones as per the general prevalent climatic conditions. Zone IV further divided in two sub-zones i.e. zone IVA and IVB.
a) Zone I : Temperate
b) Zone II : Subtropical
c) Zone III : Hot & Dry
d) Zone IVA : Hot & Humid
e) Zone IVB : Hot & Very Humid
As the intended market for CLS Products fall in zone IVA, the stability study will be carried out based on the conditions of zone IVA climate.
6.6 Sampling Considerations
For registration purposes test samples will be taken from at least three different production / pilot plant batches. The selection of containers from the batches selected for stability study should be carried out so as to ensure that the samples chosen represent the batch as a whole. As a rule, dosage units should be sampled randomly, with each unit having an equal chance to be included in the sample.
6.7 Container Orientations
Products should be stored in both the upright and either inverted or on-the side positions until contact with the container/ closure system has been shown not to impact on drug product quality.
The evaluation should include the set of test parameters that are listed for specific dosage form.
Upright versus inverted/on-the-side stability study should be performed during the pre- approval and post-approval verification stages of the stability program.
Once it has been demonstrated that the product in maximum contact with the primary pack does not have a significantly greater impact on drug product quality than the upright orientation, stability study may be continued instead of most stressful orientation, which is generally the inverted or on the side position.
6.8 Test Criteria and Test Procedures
The testing should cover those features susceptible to change during storage and likely to influence quality, safety, and/or efficacy. Stability information should cover as necessary the physical, chemical, and microbiological test characteristics. Validated stability indicating testing methods should be applied.
6.9 Specifications
The product under stability shall meet the shelf life specification, to ensure that any product under stability will meet the domestic as well as regulatory requirement at any point of time in its complete shelf life.
6.10 Storage/ Test Conditions
6.10.1 Long Term Stability
If recommended storage condition for formulated product is general condition, long term stability studies are carried out (at temperature 30⁰ C ± 2°C and % RH 75% ± 5%) in a temperature & humidity-controlled stability chamber.
If recommended storage temperature for formulated Product is in refrigerator, Long Term Stability Studies are carried out (at temperature 5⁰ C ± 3°C) in a Refrigerator.
6.10.2 Accelerated Stability
If recommended storage condition for formulated product is General condition, accelerated stability studies are carried out(at temperature 40⁰C ± 2°C and % RH 75% ± 5%) in a temperature and humidity-controlled stability chamber.
If recommended storage condition for formulated Product is in refrigerator, accelerated stability studies are carried out (at temperature 30⁰C ± 2°C and % RH 75% ± 5%) in a temperature and humidity-controlled oven.
“Significant change” at the accelerated condition is defined as:
6.10.2.1 A ≥ 5% potency loss from the initial assay value of a product batch.
6.10.2.2 Any specified degradation products exceeding its specification limit.
6.10.2.3 The product is exceeding its pH limits.
6.10.2.4 Failure to meet specifications for appearance and physical properties, Physical attributes functionality test (e.g. colour, phase separation, sedimentation/ precipitation, turbidity etc).
6.10.2.5 Failure to meet specifications for pH / Sterility/ Bacterial Endotoxin Test etc.
6.10.2.6 In case, significant change occur at temperature 40°C & R.H.75% then the initial Registration Application should include a minimum 06 months data and ongoing 1-year real time stability study data i.e. at temperature 30°C & RH: 75% then the same significant change criteria will be applied.
6.11 Testing Frequency
Frequency of testing should be sufficient to establish the stability characteristics of the product.
The testing frequency to be followed for Accelerated and long-term stability study has been described below.
6.11.1 Long Term Stability
It is a real time testing carried out for a sufficient time to cover shelf life. Testing under the defined long-term conditions will normally be every 03 months over the first year, every 06 months over the second year, and then annually.
The test for sterility and BET will be carried out initially after every 12 months at expiry date and after 12 months from the date of expiry.
6.11.2 Accelerated Stability
Accelerated stability is carried out for 06 months. The testing frequency will be after 01, 02, 03 and 06 months.
The test for Sterility and BET will be carried out initially and at the end of stability studies.
6.12 Stability samples shall be collected by IPQA person and requisition with sample to be submitted to QC department for stability testing.
6.13 Stability Study Report should be prepared as per stability protocol.
6.14 Conclusion
Based on the evaluation of the stability data appropriate conclusion will be concluded to support the expiration dating, product labeling and any other aspect of the product Quality, which could be influenced based on the stability data.
A summarized report on stability Study will be prepared to indicate the objective, methodology followed, compiled data and graphical representation of the data and final conclusions in brief.

8.0 ABBREVIATIONS

SOP : Standard Operating Procedure
QA : Quality Assurance
Mfg. : Manufacturing Date
Exp. : Expiry Date
MLT : Microbial Limit Test
RH : Relative Humidity
BET : Bacterial Endotoxin Test