STABILITY STUDY MANAGEMENT
Stability Study Management – To lay down the procedure to conduct stability studies of the drug product (dosage forms)/ Drug substances (API). This Procedure describes the procedure for assigning the stability of drug substances (Active pharma ingredients) and drug products (Packed finished dosage forms).
The purpose of stability studies is to obtain evidence on how the quality of drug substance and drug product varies with time under the influence of a variety of factors such as temperature, humidity, light, and enables the establishment of recommended storage conditions retest period (for drug substances and Intermediates) and shelf life for (drug products).
SCOPE STABILITY STUDY:
This Procedure is applicable for the Stability Study of the drug products (dosage forms)/ Drug substances (API) manufactured.
RESPONSIBILITY STABILITY STUDY :
Concerned Quality Control personnel shall be responsible for the preparation of stability protocol, to conduct a Stability Study (i.e. Sample preparation, Charging, and Withdrawal of sample, monitoring of stability chambers, testing & preparation of stability reports) as per laid down procedure.
Concerned Quality Assurance personnel shall be responsible for the collection of the sample for stability charging. Review and Approval of Stability Protocol and stability Test Report summary & to ensure that the Study is executed as per laid down procedure.
Reviewer: The reviewer is responsible for the review of the stability testing form, and the completed stability testing report.
Head Quality Control is responsible for reviewing of Stability Test Report, and verification of Stability protocol and is accountable for the implementation and Compliance of the laid down procedure.
Head RA /Designee shall approve the stability study protocol.
Head QA: The Head QA is responsible for Reviewing and approval of Stability Protocol and Final approval of the Stability Testing Form Ensuring that the procedure for the Stability Study is followed as specified in this document.
DEFINITION:
Stability:
To provide evidence on how the Quality of a drug substance or product varies with time under the influence of a variety of environmental factors such as temperature, humidity, and light and to establish a retest period for the drug substance or a shelf life for the drug product and recommended storage condition.
The capacity of a drug substance or a drug product to comply with the specification laid down for the duration of the shelf-life assigned to it when stored under the conditions stated on the label of the containers.
Formal stability studies
Long-term and accelerated (and intermediate) studies undertaken on primary and/or commitment batches according to a prescribed stability protocol to establish or confirm the re-test period of a drug substance or
the shelf life of a drug product.
Product stability studies
The stability of the product monitored which is manufactured analyzed and packed as per the established procedure and under the established container closed system.
Intermediate testing
Studies conducted at 30°C +/- 2°c /65% RH+/- 5 % RH and designed to moderately increase the rate of chemical degradation or physical changes for a drug substance or drug product intended to be stored long term at 25°C. +/- 2°C I 60% RH+/- 5 % RH.
Note:
1.0 If the Long term storage condition is 30°C +/- 2°C /65% RH+/- 5 % RH/ 30°C +/- 2°c; / 75% RH+/- 5 % RH there is no intermediate condition required .
2.0 For the semipermeable packs 30°C +/- 2°C /35% RH+/- 5 % RH is to be considered as a suitable alternative long-term storage condition to 30°C +/- 2°C /40% RH+/- 5 % RH
Long-term testing: Evaluation of the physical, chemical, and microbiological characteristics of a drug substance or drug product over the expected duration of the shelf-life / retest period under the recommended storage conditions and in the proposed container/closure system.
Stress Testing (Substances)
Studies undertaken to elucidate the intrinsic stability of the drug substance. Such testing is part of the development strategy and is normally carried out under more severe conditions than those used for
accelerated testing.
Stress Testing (Drug products):
Studies were undertaken to assess the effect of severe conditions on the drug product. Such studies include photo-stability testing and specific testing on certain products, (e.g., metered dose inhalers, creams; emulsions, and refrigerated aqueous liquid products.
Accelerated testing:
Studies designed to increase the rate of chemical degradation or physical change of a drug substance or drug product by using stress (exaggerated) storage conditions as part of the formal stability studies. Data from these studies, in addition to long-term stability studies, can be used to assess longer-term chemical effects at non-accelerated (real-time) conditions and to evaluate the effect of short-term excursions outside the
label storage conditions that might occur during shipping. Results from accelerated testing studies are not always predictive of physical changes.
Bracketing:
The design of a stability study plan is such that only samples on the extremes of certain design factors, e.g., strength, and package size, are tested at all time points as in a full design. The design assumes that the stability of any intermediate levels is represented by the stability of the extremes tested.
Where a range of strengths is to be tested, bracketing is applicable if the strengths are identical or very closely related in composition (e.g., for a tablet range made with different compression weights of a similar basic granulation, or a capsule range made by filling different plug-fill weights of the same basic composition into different size capsule shells). Bracketing can be applied to different container sizes or different fills in the same container closure system.
Matrixing
The design of a stability study plan is such that a selected subset of the total number of possible samples for all factor combinations is tested at a specified time point. At a subsequent time, point, another subset of
samples for all factor combinations are tested. The design assumes that the stability of each subset of samples tested represents the stability of all samples at a given time point. The different factors for the selection of the
samples in the subset include different batches, different strengths, and different sizes of the same container closure system, and, possibly in some cases, different container closure systems.
Container closure system
The combination of packaging components, which together contain and protect the dosage form is defined as a container closure system. This includes primary packaging components and secondary packaging
components, if the latter are intended to provide additional protection to the drug product.
Semi-permeable containers: Containers that allow the passage of solvent, usually water, while preventing solute loss. The mechanism for solvent transport occurs by absorption into one container surface, diffusion
through the bulk of the container material, and desorption from the other surface. Transport is driven by a partial-pressure gradient. Examples of semi-permeable containers include plastic bags and semi-rigid, low-density polyethylene (LOPE) pouches for large-volume parenteral (LVPs), and LOPE ampoules, bottles, and vials.
Impermeable containers: Containers that provide a permanent barrier to the passage of gases or solvents, e.g., sealed aluminum tubes for semi-solids, and sealed glass ampoules for solutions. Glass containers are impermeable only if there is a good seal between the container and the closure.
Immediate (primary) pack: Immediate (primary) pack is that constituent of the packaging that is in direct contact with the drug substance or drug product and includes any appropriate label.
Marketing pack: The marketing pack is the combination of the immediate pack and the other secondary packaging such as a carton.
Drug substance or Active Pharmaceutical Ingredient
The unformulated drug substance may subsequently be formulated with excipients to produce the dosage form. An Active Pharmaceutical Ingredient is any Substance or mixture of substances intended to be used
in the manufacture of a drug (medicinal) product and that, when used in the production of a drug, becomes an active ingredient of the drug product.
Such substances are intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure and function of the body.
Intermediate: A material produced during steps in the synthesis of an API that must undergo further molecular change or processing before it becomes an API.
Dosage form
A pharmaceutical product type, for example, tablets, capsules, solutions, or creams, that contain a drug substance, generally, but not necessarily, in association with excipients.
Drug Product (Finished Product)
The dosage form in the final immediate packing is intended for marketing.
Excipients:
Any ingredient other than the drug substances used in the manufacturing of a drug product in the dosage form.
Placebo:
A Mixture of ingredients of formulation without drug substance.
Established Product:
The drug substance/drug product shows no significant change up to its shelf life during long-term stability testing.
Primary batch: A batch of a drug substance or drug product used in a formal stability study, from which stability data are submitted in a registration application to establish a re-test period or shelf life, respectively. The primary batch may also be referred to as the Exhibit batch or Test batch. A primary batch of a drug substrate should be at least a pilot-scale batch. For a drug product, the number of primary batches and their batch sizes will be based on the requirements of the respective countries where the dossier is to be submitted. A primary batch may be a production batch.
Production batch
A batch of a drug substance or drug product manufactured at a production scale by using production equipment in a production facility as specified in the application.
Subsequent Batch:
The batch of drug substance/drug product is manufactured after the initial three batches till the product is established.
Atypical:
The Batch that shows out-of-trend results or the batch that does not show characteristics as those of historical batches manufactured routinely.
Expiration date
The date placed on the container/labels of an API designates the time during which the API is expected to remain within the established shelf life specifications if stored under defined conditions, and after which it should not be used.
Tentative Expiration Dating Period (Provisional Expiry):
A provisional expiration dating period is based on acceptable accelerated data, statistical analysis of available long-term data, and other supportive data for an NOA product, or acceptable accelerated data for an ANDA product, but not on full long-term stability data from at least three production batches.
Shelf life (Expiry period)
The period during which a drug product is expected to remain within the approved shelf-life specification provided that it is stored under the conditions defined on the container label.
Re-test date
The date after which, samples of the drug substance should be examined, to ensure that the material is still in compliance with the specification and thus suitable for use in the manufacture of a given drug product. provided that the drug substance has been stored under the defined conditions.
Re-test period
The period during which the drug substance is expected to remain within its specification and, therefore, can be used in the manufacture of a given drug product, provided that the drug substance has been stored
under the defined conditions. After this period, a batch of drug substance destined for use in the manufacture of a drug product should be re-tested for compliance with the specification and then used immediately. A batch of drug substance can be re-tested multiple times and a different portion of the batch used after each re-test, as long as it continues to comply with the specification.
Significant change:
Significant Change for a drug substance is defined as failure to meet the specifications. A significant change for a drug product is defined as a 5% change in assay from its initial value; failure to meet the acceptance criteria for potency when using biological or immunological procedures; or Any degradation product 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, m·elting 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 dissolution for 12 dosage units.
Climatic Zone:
The four zones in the world are distinguished by their characteristic prevalent annual climatic conditions.
| Zone No | Zone ID | The area covered under the zone |
| Zone-I | Temperature (21 ‘C, 45 %RH) | United Kingdom, northern Europe, Canada, Russia, United States, Japan |
| Zone-II | Mediterranean and subtropical (25’C, 60 %RH) | United States, Japan, Southern Europe (Portugal- Greece). |
| Zone-III | Hot and Dry climate Temperature (30’C, 35 %RH) | Australia, Argentina, Egypt, Iran, Iraq Sudan, |
| Zone-IVA | Hot and Humid (30’C, 65 %RH) | Uganda, Namibia, Gambia |
| Zone-IVB | Hot and very Humid (30’C,75 %RH) | Brazil Ghana, Indonesia Zimbabwe, India |
Also read STABILITY TESTING OF NEW DRUG SUBSTANCES Q1A(R2)
PROCEDURE
Stability studies provide evidence of impact on the quality of drug substances or drug products or drug Product varied with time under the influence of a variety of factors such as temperature, humidity, and light and enable the establishment of recommended container closure systems, storage conditions retest periods (for drug substances and own manufactured intermediates), and shelf-life (for drug products).
Monitoring the stability study for every drug substance/drug product manufactured is essential
Stability Includes
(a-) Product stability i.e. stability of a product that is manufactured, analyzed, and packed as per the established procedure and under an established container closure system.
(b) The stability monitored due to exceptional cases e.g. delayed packing of the product after exposure to the same beyond the established hold period, change in compression machine, deviation observed during manufacturing, etc.
In the case of an established product, the subsequent batch which is monitored in stability once a year should be charged for Product Stability i.e. only that batch that is manufactured, analyzed, and packed as per the established procedure and under the established container closure system. Do not consider the batch with deviations or exceptions as the Product Stability batch.
A required number of batches of every product should be incubated for stability at appropriate stability conditions as per regulatory / customer requirements and should be monitored at required intervals. Hence before subjecting an item/product to stability, required necessary information regarding stability storage condition, testing intervals, pack orientation if any, etc. should be collected and confirmed from the regulatory cell for regulatory products and R&D for local and general exports.
The quantity of sample/requirements shall be defined in the individual product-specific stability study protocol. A contingency sample (required for investigation purposes in case of OOS/OOT) shall also be collected as per the sampling plan. Samples are to be collected by the QA person and handed over to the QC person.
Contingency Stability samples quantity for Exhibit and commercial batches for each condition given as below:
For Exhibit Batches /Validation:
At real-time conditions (Long-term conditions) the sample quantity equivalent to two interval samples (2 times) for chemical analysis and one interval equivalent quantity (1 time) for microbiological analysis should be kept as a contingency sample for various purposes such as OOS / OOT evaluation, deficiency response, retesting because of analytical method revision, etc.
At accelerated conditions one interval equivalent quantity sample (1 time) for chemical and one interval equivalent quantity (1 time) for microbiology analysis for various purposes such as OOS / OOT evaluation, deficiency response, retesting because of analytical method revision, etc. This sample quantity shall be applicable only for 6 months’ stability station.
At Intermediate conditions, keep one interval equivalent quantity sample (1 time) for chemical and one interval equivalent quantity (1 time) for microbiology analysts.
For Commercial/Annual batches: At real-time conditions (Long-Term conditions) the sample quantity equivalent to two interval samples (2 times) for chemical analysis and one interval equivalent quantity (1 time) for microbiological analysis should be kept as a contingency sample for various purposes such as OOS / OOT evaluation/Market complaints, deficiency response, retesting because of analytical method revision, etc.
Note: Quantity shall be calculated in such a way that at every time interval intact sample bottles are available. This is not applicable for bulk packing e.g. if the Quantity required for analysis at a one-time interval is 90 tablets/capsules and the pack size is 60s then for twice the quantity 2 bottles should be available for that particular time interval.
Note: Stability samples should be packed in such a way so that for every time interval, intact samples are available for the intended purpose.
All the samples incubated should be properly labeled with condition and stability intervals for traceability. While withdrawing the sample from the incubator, withdraw required interval samples only, and other interval samples should not be withdrawn.
Wherever required placebo, it should also be incubated along with the sample to get information on the impact on ingredients other than the drug substance.
The pack incubated for stability should represent the market pack. Loose samples (e.g. blister strips) should not be subjected for stability. stability pack should not be enclosed in other closures (which may impact the study) for convenience.
The Incubator /walk-in chamber used for monitoring the stability study should be appropriately qualified and regularly calibrated for effective functioning.
The product monitored in the stability should have a defined protocol describing study intervals, conditions, orientations (where applicable) tests acceptance criteria, etc. and specifications should have detailed test procedures and acceptance criteria.
Withdrawal of samples from stability chamber /incubators should be carried out timely tested within in period specified for withdrawal and testing.
Any failure (OOS/OOT) observed during the analysis of the stability sample is to be investigated and documented as per the procedure defined in the SOP.
Whenever any batch is found failing in the stability study after the expiry interval then analysis of further intervals can be discontinued after confirming the same with Regulatory/ R&D.
The status of ongoing stability should be periodically reviewed (at least once a year). The stability program followed several batches, including the reason for monitoring, the condition of the stability incubator walk-in-chamber, any excursion or deviation of stability trend, and stability failure, which should be evaluated, and appropriate action if required should be initiated.
The Microbiological Examination of Non-Sterile Products / Microbial Contamination in Non-Sterile Products is to be monitored at initial, and terminal time points in case of failure at accelerated conditions, the monitoring should be done at the end of the intermediate.
In case the stability study of a batch is discontinued, follow the change control procedure. Indicate in the stability schedule by an asterisk mark from the interval at which the discontinuation comes in Document the details at the bottom of the schedule and intimate to R & D/RA/Production.
Storage conditions:
Following different temperature and humidity storage conditions for the long term. Accelerated and intermediate are to be applied based on the requirements.
| Long-Term Stability Condition | Accelerated stability Condition | Corresponding Intermediate Stability Condition | |||
| Temperature (OC) | Humidity (%RH) | Temperature (DC) | Humidity (%RH) | Temperature (DC) | Humidity (%RH) |
| 30±2 | 65±5 | 40±2 | 75±5 | – | – |
| 25±2 | 60±5 | 40±2 | 75±5 | 30±2 | 65±5 |
| – | – | 25±2 | 60±5 | – | |
| OR | |||||
| 30±2 | 65±5 | ||||
| OR | |||||
| 30±2 | 75±5 | ||||
| -20±5 | – | 5±3 | – | – | – |
| 25±2 | 40±5 ‘/I ‘C.- | 40±2 | NMT25 | 30±2 | 65±5 |
| 30±2 | 75±5 | 40±2 | 75±5 | – | – |
| 30±2 | 35±5 | 40±2 | NMT 25 | — | – |
The appropriate storage condition required for stability monitoring in the long term among the above-specified conditions is to be determined based on the climatic zone in which the active substance /pharmaceutical product is intended to be stored As per the long-term conditions, appropriate accelerated conditions are to be applied. In case of any specific customer requirement, perform the stability study at the conditions as per requirement.
Whenever stability is required 25± 2°c / 60±5 % RH or 30± 2°C / 65±5 % RH, study conducted at higher humidity like 30± 2°C / 75±5 % RH is also acceptable.
Long term 25± 2°c / 40±5 % RH or 30± 2°c / 35±5 % RH, and accelerated 40± 2°C / 20±5% RH condition is applicable for a pharmaceutical product packed in semi-permeable containers, e.g. Ophthalmic preparation /Inhalation solution packed in LOPE Bottles /repulse respectively.
Whenever 30± 2°c I 65±5 % RH or 30± 2°c / 75±5 % RH % RH or 30± 2°C / 35±5 % RH is a long-term condition there is no intermediate condition.
Additionally, if an alternative and parallel long-term study is required to be performed on one or more long-term conditions simultaneously as per the customer requirement the same can be done accordingly at 30± 2°c / 65±5 % RH or 30± 2°c /…7. 5±5 % RH or 25± 2°c / 60±5 % RH.
Stability studies for products stored in impermeable containers can be conducted under any controlled or ambient humidity condition.
Stability Specification
Prepare the stability study.
Stability specification should include testing of those attributes of the Pharmaceutical material/ product that are susceptible to change during storage and are likely to influence quality, safety, and/or efficacy.
The test selected for stability monitoring should be stability indicative.
The testing should cover as appropriate, the physical, chemical, biological, and microbiological attributes of preservative content (e.g. antioxidant, antibacterial preservative) and functional tests (e.g. for dose delivery system).
Synthetic impurities need not be monitored in drug product stability if these are monitored and controlled in the drug substance and are not degradation products.
Shelf life acceptance criteria should be derived from consideration of all available stability Information. It may be appropriate to have a justifiable difference between the shelf-life and release acceptance criteria based on the stability evaluation and the changes observed in storage.
Once the drug substance and drug product are released, shelf life specification becomes applicable for future evaluation and complaints, for a contract manufacturer if the batch-releasing body is a customer as per the agreement, the release limit will be applicable for analysis at the customer, hence in such case, time of delivery of goods manufactured, probable delay in transportation and time (Based on mode of transportation) within which customer will release the batch is to be defined. The impact on critical analytical parameters during analysis at both ends is to be evaluated before commitment.
In the case of Pharmacopoeia drug substance, and drug product, the criteria of release and stability specification will be as per monograph. In such cases, a tighter internal release limit needs to be retained to get drug substance and drug product within the criteria during the shelf-life.
Any differences between the release and shelf-life acceptance criteria for antimicrobial preservative content should be supported by a validated correlation of chemical content and preservative effectiveness demonstrated during drug development on the product in its final formulation (except for preservative concentration) intended for marketing. A single primary stability batch of the product should be tested for antimicrobial preservative effectiveness (in addition to preservative content) at the proposed shelf life for verification purposes, regardless of whether there is a difference between the release and shelf-life acceptance criteria for preservative content.
Whenever any analytical method is revised or monograph is updated, or acceptance criteria are revised, based on the evaluation of the change and if samples are not available in the warehouse, extra stability samples preserved may be analyzed and evaluated for further decisions. The evaluation form is to be filled (wherever required) and necessary decisions are to be documented.
Whenever specification is updated for any reason like a change in analytical method, acceptance criteria, Test inclusion/deletion, etc. update the associated stability protocol for the required changes. Indicate the changes e.g. Specification No., Acceptance criteria, etc. in the Stability Testing Form.
Stability specification (Page of ‘Standards for stability study’) need not be made obsolete wherever new and old batches are monitored with different sets of specifications.
Stability Protocol:
Prepare the stability protocol as follows
Allocate the protocol number.
Maintain a list of all the stability protocols prepared In the laboratory.
Prepare the stability protocol as per the specified format.
In case of tests that are not performed during all intervals, g. Microbiological Examination of Non Sterile Products, Sterility, etc., details of the frequency of these tests for testing are to be specified in the individual stability protocol.
In the case of ANDA or any other regulatory, prepare a ‘Pre-approval stability protocol ‘for registration purposes and a ‘Post-approval stability protocol ‘for commercial requirements.
Update the ‘Pre-approval and Post-approval’ stability protocol based on the impact of the changes on the stability protocols, g. whenever deficiencies are received during registration for which testing parameters get affected and have an impact on the sample quantity calculated earlier or if a test is added or deleted from the existing tests available etc.
In case of any specific customer requirements, prepare the protocol accordingly. In such cases allot protocol numbers as per the procedure specified above but include the name of the customer in brackets to identify and differentiate customer requirements.
In case of any changes in the existing stability protocol, the same should be done through a change control procedure and based on the nature of changes, evaluation of R & D, RA or CQC may be required. An addendum to the protocol can be prepared based on the nature of the change. During the revision of the protocol content of the addendum (if any) shall be incorporated in the Protocol.
The protocol is to be prepared by QC, reviewed by the stability Section Head, verified by the Head of Quality control and Quality Assurance, and approved by the Head of QA and Regulatory Head.
Selection of Batches and monitoring of Stability study
Drug substances (API):
Select the batches of the drug substance to be studied as per the table given below:
| Category | Selection of batches | Frequency of Testing (Months) | ||
| Accelerated | Long Term | Intermediate | ||
| New Drug substance/ drug substance manufactured by major process change | First Three Batches | 0,3 and 6 Months | 0,3,6,9,12,18,24,36, 48 and 60 Months | 0,3,6,9 and 12 Months |
| Annual Stability | One batch every year (if the product is manufactured) | 0, 12, 24, 36,48 and 60 months | ||
| Change in the source of the vendor of starting material (After Validation). | One Batch | 0,3 and 6 Months | 0,3,6,9,12,18,24,36, 48 and 60 Months | |
| Drug substance with primary pack change | First Three Batches | 0,3 and 6 Months | 3,6,9,12,18, 24.36, 48 and 60 Months | 0,3,6,9 and 12 Months |
| Drug substances with secondary pack change | One Batch | 0,3 and 6 Months | 3,6,9,12,18, 24,36, 48 and 60 Months | 0,3,6,9 and12 Months |
| Change in batch size beyond a factor of 10 times the batch size of the masterbatch | One Batch | 3 and 6 Months | 3,6,9,12,24,36,48 and 60 months | – |
| Changes within the single facility where the same or similar equipment, SOP, environmental condition, and control are common to both manufacturing sites is used no changes are made to PDS (pharmaceutical development services) except for administrative information and the location of the facility | One Batch | – | 3,6,9,12,24,36,48 and 60 months | – |
| Consist of change of site within a contiguous campus or between facilities in an adjacent city block, where the same/ similar equipment, SOP, environment condition, and control are used. No changes are made to PDS Except for the administrative information and the location of the facility. a | First Three Batches | 0,3 and 6 Months | 3,6,9,12,18, 24,36, 48 and 60 Months | 0,3,6,9 and 12 Months |
| Reworked Batches | Concerned Batches | 0,3 and 6 Months | 3,6,9,12,18, 24,36, 48 and 60 Months | 0,3,6,9 and 12 Months |
| Reprocessed Drug Substance | Concerned Batches | 0,3 and 6 Months | 3,6,9,12,18, 24,36, 48 and 60 Months | 0,3,6,9 and 12 Months |
| If approved batches are blended based on customer requirements. | One Batch | – | 3,6,9,12,18, 24,36, 48 and 60 Months | – |
Note:
1. In case of revision in the frequency of testing intervals as per the table above, implement the same only after revising the stability protocol.
2. Consider a Minimum of 30 days for 1 month 90 days for 3 months and 180 days for 6 Months and for the subsequent station also.
If any regulatory/ party or customer demands to monitor stability for any other reason or at other conditions with different time points than specified above or with a different number of batches, the same can be carried out as per requirement and fulfilled.
Batches manufactured for registration should be incubated in stability preferably within a month from the date of manufacturing.
The batches incubated in the stability within a month after release are not to be tested again. In this case, data derived at the time of release is to be considered as initial data, and data of further stability should be evaluated against the same.
If the batch is incubated in the stability after a month from the date of initial release and within six months from the date of manufacturing, then the analysis is to be performed as per stability specification before incubation and to be Incubated immediately (within one month). The data derived is to be considered as initial data and further stability data should be evaluated against the the same.
The stability is to be monitored till 60 months from the date of manufacturing i.e. 60-month interval to be calculated from the date of manufacturing and not from the date of incubation e.g. If a drug substance batch is manufactured in March 2023 and incubated in stability in August 2023, stability should be continued till March 2028 (Pull out date 1st March 2028) i.e. 60 months from the date of manufacturing and it should not be counted from August 2023 which will result up to August 2028 which will result in 65 months.
If a batch is to be monitored for stability after six months from the date of manufacturing, the batch should be subjected to long-term stability only an accelerated stability study should not be performed in such case. Perform analysis before incubation as per stability specification. The time interval of exposure that occurred after manufacturing should be reported and should not be considered as initial data e.g. if a batch has been incubated in the 8th month from the date of manufacturing, data of analysis generated should be labeled as pre-incubation data. The analytical data obtained at this stage and further stability interval should be compared with initial data obtained at the time of release of batch, for stability.
Drug product (Packed finished product):
Minor Change: The changes that don’t have impact on quality of the product.
Major Change: The changes that have impact on quality of the product
— Not applicable
Note:
After Completion of 6M Accelerated condition stability studies, remaining samples of ACC condition shall be stored at storage condition mention on label till ANDA Approval (This samples are kept for any ANDA query response purpose, and reconciliation of these sample shall be done.
Note: If any changes in time interval is required or recommended same can be included /excluded and control through respective stability protocol.
Note: Consider Minimum 30 days for 1 month 90 days for 3 months and 180 days for 6 Months and for the subsequent station also.
In case of revision in the frequency of testing intervals as per table above, implement the same only after revising the stability protocol.
Frequency of testing: Stability study is to be conducted at the interval of every 6 months after 12 months for new product. In case of the new product, the stability is to be conducted till Shelf life plus 1 year e.g. if a new product is having shelf life of 24 months, study to be extended for 30,and 36, months.
Note: Frequency shall be govern through stability study protocol of that particular product.
Based on the stability data of initial three batches the expiry of the product is to be established and extended if required. For further any new batch to be monitored for 1 stability, perform the stability only up to the expiry interval.
e.g. If the Initial expiry of the product was assigned as 24 months, and based on the stability data, the expiry of the product was revised to 36 months, then any further batch to be kept for stability, monitor the same only up to 36 months.
Till the establishment of the expiry based on the initial data monitor the stability for any subsequent batches as define in respective protocol. Once the establishment of the expiry is confirmed, the remaining intervals of the subsequent batches should be discontinued based on the established expiry.
For split up batches from same mother batch if the primary packaging material is same, only one child batch to be kept for stability.
If any regulatory / party or customer demands monitoring of stability for any other reason or at other conditions with different time points, different number of batches etc. than specified above, the same can be carried out as per requirement.
In case of change in storage condition of finished product, need for subjecting the batch to stability study should be evaluated by Unit QA and to be informed to QC for the change.
For formulations where MOC (Material of construction) of closure is different than the MOC of container e.g. injections, nasal sprays, liquid orals, ophthalmic solutions etc., stability study can be monitored by placing the bottle inverted which Will provide worst scenario as product will come in contact with closure: In such case, number of batches can be reduced.
Instead of keeping all the batches in both orientations, one batch (preferably first) .Can be monitored in both the orientations and remaining can be monitored in upright orientations.
If another batch has been reprocessed / reworked by the same process and is monitored in stability, further batches need not be studied for stability. Any drug product reprocessed or atypical batch is identified; it should be monitored for long term as routine. Stability of normal batch do not support atypical batch for its validity within shelf life. In case of any
excursion before shelf life, recall can be initiated.
Whenever the drug product becomes established, further subsequent batches should be monitored as per procedure of established product as specified above. (If any process is revised, it should not be considered as subsequent batch, procedure of revised process specified above to be followed.). In case of products for regulatory authorities like US, UK, Brazil
etc. the testing intervals of 12 and 24 months should be mentioned in the post approval stability protocol and should be implemented only after the approval from the respective authority.
Wherever there is requirement for specific API source (OMF grade) to be used in manufacturing of drug product e.g. regulatory/country/party requirements stability study to be initiated in case of change of source. In such cases, the study should also be initiated for significant change in synthetic route of manufacturing of API which may impact physical
characteristic and /-or impurity profile of API.
Change of primary pack container closure system needs to be evaluated for stability as it will impact on product quality. Changes in primary pack may involve different scenarios like.
Change in MOC of pack e.g. glass bottles to PET or plastic bottles, Blister pack to Alu-Alu pack etc. which needs stability evaluation.
Changes in closure system like CRC to non-CRC HOPE bottle pack, change of valves for aerosol, nasal spray etc. need stability evaluation.
Change in pack size with same MOC and container closure system e.g. 50 ml pack to 100 ml glass bottle pack, 100 counts to 500 counts tablets in HOPE CRC bottle pack etc. needs proper evaluation before subjecting to stability.
In case where container capacity and volume of contents are proportionate generating same headspace volume, stability need not be repeated. In above e.g. if 50 ml was filled in 75 cc glass bottle and if 100 ml is filled in 150 cc glass bottle, stability for anyone will be acceptable.
But in second example if 100 counts of tablets are packed in 250 cc HOPE bottle and if 500 counts tablets are packed in 750 cc HOPE bottle, both with CRC caps then based on case to case, stability needs to. be considered. e.g. if 100 counts stability is already monitored and 500 counts is a new pack stability need not be monitored but in reverse case, i.e. 500
counts is monitored and 100 count is new pack, stability will be required.
Change in characteristic of pack but MOC and container closure is same, e.g. colored bottles to clear transparent bottles, plain strip to amber colored strip etc., rationale as above to be applied i.e. if clear pack is monitored and found stable, amber colored pack need not be monitored but in reverse case, it will require stability study.
Bracketing can be applied for change of volume where MOC and container closure system of pack is same e.g. 2.5 ml, 5 ml and 10 ml filled in 10 ml glass bottle pack. ~ere stability for 2.5 ml and 10 ml to be monitored and stability for 5 ml can .be skipped.
In case stability is not monitored based on scientific rationale, the same to be justified and documented in stability protocol with valid reason.
In case where study is required on different packs to establish suitable pack, or if regulatory / party demands stability on all the packs, in such case stability to be monitored for all the packs.
Change of secondary pack which may impact product quality needs to be evaluated for stability. e.g. if a semi permeable primary pack (e.g. FFS) which was stored in carton is changed to pouch. Change such as carton of combi-pack to unit pack or vice versa or carton to catch cover etc. which does not have impact on product quality need not be evaluated.
In case of products which do not have a shelf life of more than 36 months, the number of intervals can be reduced after discussion with R&D and Regulatory Affairs (wherever applicable). e.g. In case of injectable which have a maximum shelf life of 36 months, stability study can be performed only up to 36 months after confirmation on the same with R&D.
In case of Established product, for pharmacopeia grade change with no change in formulation. (E.g. In-house to IP, USP), perform the stability of one batch as per the protocol.
If drug products from drum pack are packed again at Customer end in different packing configuration and stability of that finished pack (market pack) is monitored at Customer end, then monitor stability of the drum pack for subsequent batches as per Customer’s requirement. Subsequent batches need not be monitored if approval is obtained from concerned
Customer.
Batches should be incubated for stability within six months from the date of manufacturing or within the bulk hold time period established for the product, whichever is earlier.
Batches manufactured for registration should be incubated for stability preferably within a month of manufacturing.
The batches incubated in stability within a month after release are not to be tested again. In this case, data derived at the time of release to be considered as initial data and data of further stability should be evaluated against the same.
In case of tests like preservative efficacy test, Microbiological Examination of Non-Sterile Products /Microbial Contamination in Non-Sterile Products or Sterility batch can be incubated in stability before completion of these tests, provided chemical testing is completed (any test result awaited from the external testing laboratory, Head QA/Designee should specify the reason for delay on the COA/TDS and samples can be charged on stability) and does meet requirement of specification. Such test results to be ensured before initiation of first interval.
If packing is done after a month from date of initial release and within six months from date of manufacturing, then analysis to be performed on packs as per stability specification and batches to be incubated immediately (within one month).
The data derived to be considered as preincubation data and further stability data should be evaluated against the same. If bulk hold time study is available for same product having same manufacturing formula and if data are satisfactory, analysis before incubation in stability need not be performed till the time period for which data is available e.g. if bulk hold period is available up to 3 months and if a batch is packed at~ months from the date of manufacturing, testing before incubation is not required and data derived during release of the batch to be considered as initial data for stability evaluation.
Products which are filled in primary pack immediately after manufacturing like metered dose inhalers (MOl’s), parenteral preparations, liquid orals etc., if packed (I.e. labelling and packing in carton) after a month but within three months from the date of manufacturing, testing need not be performed before incubation of sample for stability. Data generated at the time of release should be considered as initial data for stability evaluation.
Such products if packed after 3 months but within 6 months from the date of manufacturing, analysis to be performed as per stability specification.
The data derived to be considered as initial data and further stability data should be evaluated against the same. Testing for other products like tablets, capsules etc., is required if batch is incubated after a month of packing as these are retained in bulk pack and not in primary pack hence exposure may impact the characteristic of product if bulk hold period is not
available.
The shelf life intervals and intervals after expiry are to be calculated from the date of manufacturing and not from the date of incubation. e.g. If a product bears shelf life of 24 months and if a batch is manufactured in March 2023 and is packed in April 2023, shelf life stability interval should be March 2025 (1St March 2025 pull out date) i.e. 24 months and 1 year
after expiry interval should be March 2026 and it should not be counted from April 2023 which will result in shelf life interval up to April 2025 which will result in 25 months.
Whenever any batch is incubated after one month and within six months, in such case if the preceding interval of shelf life is within 1 month then that interval is to be skipped and shelf life interval analysis is to be performed. e.g. If a product bears shelf life of 24 months and a batch is manufactured in May 2023, packed and incubated on 24th Oct 2023, i.e. 5
months after manufacturing, in such case, shelf life stability interval should be May 2025. (1st May 2023 pull out date) and 18-month Interval should be 24 April 2025.in such case shelf-life 18-month analysis need not to be performed.
If packing is done after six months from the date of manufacturing, and is required to be monitored in stability, deviation should be filled for the same and the batch should be monitored only to evaluate the Confidence of the batch ‘and not Product Stability. In such case, following procedure to be followed.
Batch should be subjected to long term stability of 25°C / 60 % RH or at warehouse (WIP) product storage condition only. Accelerated stability study should not be performed in such case. Perform analysis before incubation as per stability specification and report as pre-incubation data.
The time interval of exposure that occurred after manufacturing should be considered and should not be accounted as initial data, e.g. if a batch is manufactured in March 2023 and incubated in October 2023 at 25°C / 60 % RH, then 9 months interval should be calculated as December 2023, 12 months interval should be March 2024, similarly 24 months interval should be in March 2025 The analytical data obtained at this stage and further stability interval should be compared with initial data obtained at the time of release of the batch, for stability evaluation.
In case of stability requirement not equivalent to warehouse condition like 30°C/ 65 % RH or 30°C /75 % RH, such batches delayed for packing for more than 6 months should not be incubated at long term condition. New batches which are packed within 6 months to be incubated for such stability for proper evaluation.
In case of new product where first three batches are monitored for stability, such batches should be incubated for stability preferably within a month of manufacturing (since accelerated study is compulsory for first three batches of new product).
The time intervals of stability in such case (stability incubated equivalent to warehouse condition e.g. 25°C / 60 % RH) should be calculated from the date of manufacturing e.g. if a batch is analyzed and released in January 2016 and is re-analyzed in September 2023, data of September should be labelled as 8 months’ pre-incubation and further interval of 12 months will fall in January 2024.
If time interval at the stage of incubation is within a month from scheduled interval, do not perform testing for that interval and monitor further intervals e.g. in above case, 9 month testing in October 2023 should not be performed and directly 12 months testing to be performed and continued.
In case of the product transfer from one site to the other site, before performing the stability study, perform the verification of the stability data available at the transferring site with the help of the ‘Product transfer stability study evaluation checklist.
Section Head should perform the verification, Head Quality Control should review and Head QA should approve the verification of the stability data available at the transferring unit.
If the stability data available at the transferring site is complying with the checklist requirement, incubate only one batch for the stability study at the verification site. If it does not comply to the checkpoints of the verification checklist, incubate three batches for the stability study as described above.
Stability Schedule
Prepare a schedule Monthly and Yearly for the batches kept under stability. Indicate the batch details and reason in the stability schedule with predetermined interval and the category under which the sample is kept for stability (e.g. first batch of the year, first registration batch, formula changed reprocessed batch etc.).
Annual stability schedule shall be prepared in January month for preceding Year samples. Addendum to Annual stability schedule shall be prepared during charging of new sample and same shall be included in Annual Stability schedule in subsequent year.
Receipt/ Sampling/ Labelling and incubation of stability samples
Receive intimation from Production /QA for batches to be monitored for stability study.
Section Head should allocate the work for sampling. In case of drug substance, perform sampling as per site Sampling SOP In case of finished product collect the required finished packed samples over a time span, which covers the entire packaging of the batch during pack line inspection as per procedure specified in site SOP.
Samples collected for stability study shall maintain and are to be stored in suitable area as per drug substance / drug product storage condition prior to their incubation. Record the ‘stability sample inward’ in stability chamber.
Affix a label .The label is to be affixed to the entire consignment (shippers) for different type stability study use colour of label.
Note: If other than above storage conditions any specific conditions required for monitoring of stability of the product, black and white label shall be used with applicable storage conditions and same shall be updated in protocol.
In case of drug substance, / drug product having storage condition like 2°C to 8°C store the samples in chambers having corresponding storage conditions in dedicated tray allocated for storage of such samples.
In case of drug substance, / drug product with storage conditions like ‘Below 25°C’, store the samples in chambers having corresponding storage conditions in dedicated tray allocated for storage of such samples.
Sub-divide samples required for stability study into quantities required for each interval of testing as per the stability testing protocol.
In case of drug products packed in HOPE / LOPE containers e.g. Tablets capsules, syrups in HOPE containers, Ophthalmic solution, inhalation solution in LOPE containers etc. Stability study for leachability test and other specific test required shall be carried out product specific protocol (whenever required).
The contingency sample quantity to be kept can be reduced in case of costly items / product.
In case of drug substance, make individual aluminum packs / sample packets using polythene bags taking necessary precautions for light sensitive and hygroscopic’ materials or heat seal the polythene bags as per sample storage requirement. Affix the appropriate label on each of the packets. Enclose the labelled packets in outer packet and in turn in a miniature fiber board drum or stainless steel container in a manner that simulates the final packing in which it will be marketed. Labelled outer container with the appropriate label.
In case of drug product, collect required samples for the analysis of each interval and affix appropriate label on each of these samples. Enclose these samples in containers (like cartons) in which they are marketed, wherever applicable. Following precautions to be taken.
Pack incubated for stability study should represent market pack. Loose samples (e.g. blister strips, bottles) should not be subjected for study as market pack has outer carton.
Do not collect and pack samples of individual interval in other outer pack like polyethene bag or boxes / cartons or make bundles by affixing cellophane tape to bottles I cartons for convenience of withdrawal. Use thread/ fastener to tie sample packs required for individual intervals.
In case of bigger packs for multiple intervals (e .g. container pack of 1000 tablets), affix outer carton / container label to the container / pack and mention total number of intervals. In case of stability monitoring for regulatory product or registration purpose, preferably incubate individual container for individual study intervals.
Do not affix cellophane tape or labels over HOPE / LOPE / PET / Plastic containers or semi-permeable packs to avoid leaching of labels adhesive photo-initiator in products generating undesired impurity peaks during impurity determination. ln ‘such cases, affix label on cardboard and tie the same to container pack’.
Do not affix cellophane tape over carton opening which will block the pack and impact stability results.
In case of dummy pack of same MOC used (e.g. registration study pack), use carton/pack of appropriate gauge simulating pack used for commercial / market applications.
Do not affix label on the overprinted matter and product name. Do not incubate loose packs; enclose the packs in dummy carton simulating market pack.
Whenever a bigger pack common for multiple intervals is used (e.g. container pack of 1000 tablets), Stability study shall be performed on simulated pack.
Store the samples under the conditions. up to the storage periods mentioned in the relevant stability protocol. Prepare a sample location chart for easy retrieval of the sample.
Testing
List out the samples due for the analysis in the upcoming month in the last week of previous month e.g. List shall be prepared in the 4th Week of September 2023 for the sample due for analysis in the Month of October 2023.
Withdraw the samples from stability chamber/ incubator as per the time point, window for sample pull-out as given below
| Time point windows | Within days after schedule days |
| Up to 6 Months | 3 working days |
| More than 6 Months and up to 24 Months | 7 working days |
| More than 24 months | 15 working days |
While withdrawing the samples of accelerated stability conditions also withdraw samples of intermediate stability condition (if applicable)
Record the pull-out activity in the ‘stability sample inward, pull-out and reconciliation log’
If the samples are not being planned for analysis on the same day, transfer the samples to designated area in reserve sample room or suitable controlled temperature area as per the product requirements.
Section Head should collect the issued blank TDS from the respective file should allocate the work for analysis of these samples and should handover the suitable specification, issued blank TDS and sample to the concerned analyst.
After withdrawing samples from their storage places, allow the samples to attain ambient temperature before proceeding for the testing. For the samples store at 2 to 8 °C the same temperature shall be maintain to store the sample during analysis period.
In case of drug products, prepare composite sample of individual interval samples before proceeding for analysis. e.g. In case of analysis of 10 strips of tablets containing10 tablets each, all the tablets are to be removed from the 10 strips and transferred in bigger container/ bottle. All the tablets are to be mixed by carefully rotating the bottle.
Section Head should ensure that the analysis is initiated and completed within 30 working days after pull out the samples, except for the tests like preservative efficacy and testing performed at outside testing laboratory or if the test requires more than 30 working days of testing time.
In case tests like preservative efficacy and testing performed at outside testing laboratory or if the test requires more than 21 days of testing time for the initiation or completion of analysis, Head Quality Control should specify reason of delay in the Test Data Sheet against the respective test with date and sign. The same should be verified by QA Head with sign
and date.
Carry out the tests specified in the relevant stability testing protocol, following the stability study specification and/ or additional test as per requirement.
If any significant change observed, follow the procedure given below under Significant Change.
If no significant change is observed during accelerated stability study, then discard the samples of intermediate stability study.
In case of any results found Out of Specification /Out of Trend, follow OOS/OOT test procedure for investigation . if OOS is confirmed intimate to Quality Assurance,
Regulatory and product development cell (R & D) for necessary action.
Whenever the stability samples are to be pulled out for different purposes like OOS /OOT investigation, evaluation of new test method, verification of compliance to regulatory deficiency etc., Section Head should raise the request for the withdrawal contingency sample which should be reviewed by Head Quality Control/Designee and approved by Head QA/Designee. Document this pull out details in the stability sample pull out log.
At the end of the stability study, if extra samples are not utilized, destroy the same.
Significant change
For drug substance
At long term /intermediate and accelerated condition: Failure to meet the specification is considered as significant change.
For drug product
At long term and intermediate condition: Failure to meet the specification is considered as significant change.
At accelerated condition: Following changes are considered as significant change.
A 5% change in assay from its initial value or failure to meet the acceptance criteria for potency when using biological or immunological procedure, for vitamins and for testing procedure using a measuring device (e.g. Metered Dose Inhalers, Nasal Spray etc.)
Any degradation product exceeding its acceptance criterion.
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· (e.g. softening of suppositories, melting of creams, disfiguration of capsules) may be expected under accelerated conditions
and not to be considered as a “significant change”.
As appropriate for the dosage form Failure to meet the acceptance criteria for pH; or Failure to meet the acceptance criteria for dissolution for 12 dosage units.
If “significant change” occurs at any time during 6 months testing at the accelerated storage condition, and if long-term studies are conducted, conduct additional testing at the intermediate storage condition up to 12 months wherever applicable and evaluate against significant change criteria.
A significant change in water loss (for semi permeable packs) alone at the accelerated storage condition does not necessitate testing at intermediate storage condition. However data should be provided to demonstrate that the drug product would not have significant water loss throughout the proposed shelf life at long term condition.
A 5% loss in water from its initial value is considered a significant change for a product packaged in a semi permeable container after an equivalent of three months’ storage at 40 ± 2°c / 20 ± 5 % RH. However, for small containers (1 ml or less) or unit dose products, a water loss of 5% or more after an equivalent of three months storage at 40 ± 2°C / 20 ± 5 % RH may
be appropriate, if justified.
Where significant change occurs at the intermediate condition, the proposed retest period or shelf life should not exceed the period covered by long-term data. In addition, a retest period or shelf life shorter than the period covered by long-term data.
Reporting
After completion of all the tests, generate the Stability Test Report. Ensure that the figures for quantitative tests are rounded to the number of decimal places indicated in the standards given in the individual stability specification.
Report the stability test results of all intervals in the Stability study results as and when the analysis of the sample of a particular interval is completed and reviewed.
The content of the format may be modified as per customer or party requirement for any addition or omission of any information.
Compare the analytical results with initial/ previous intervals and make comments under the column ‘Remarks’ Make. the remark as ‘Product is stable’ or ‘significant change observed’. Specific comments may also be stated as “Significant change observed for Description test” etc.
Attach the Test Data Sheets and instrumental raw data to the Stability Test Report.
Submit the completed Stability Test Report along with all raw data and updated Stability Testing Form to the Reviewer for review. Reviewer should review the report and Stability Testing Form obtained from analyst.
Head Quality Control/ Designee should counter check the report and Stability Testing Form reviewed by the Reviewer and should approve the same with sign and date.
Update the stability schedule to indicate the completion of testing.
Section Head should submit the approved report to QA and QA should verify the report.
After verification, QA should hand over the Stability Testing Form to Head QA /Designee for final approval.
Stability Report Summary
Prepare stability summary report for each drug product / drug substance at the end of completion of stability study or whenever required
Wherever required trend for critical parameters shall be prepared. Critical parameters to be selected based on product nature.
Utilize the stability data obtained for evaluation of container closure system adequacy of labelling and confirmation of the shelf life / retest period.
Stability walk-in-chambers/ incubators
Walk-in-chamber or incubator used for the incubation of the stability samples should be adequately qualified. Incubators or chambers should be installed in appropriate area where temperature and humidity is maintained such that excursion of surrounding area will not impact on temperature / humidity controlling system of incubators / chambers.
Mean kinetic temperature of the storage area of stability samples shall be determined as and when required as per site specific procedure.
Extrapolation:
Statistical analysis is useful in supporting the extrapolation of retest periods or shelf life. An extrapolation of stability data (minimum three-time point data is required) assumes that the same change pattern will continue to apply beyond the period covered by long term data.
A step-wise approach to stability data evaluation, when and how much extrapolation can be considered for a proposed retest period or shelf life, when and how statistical analysis is to be used in supporting the extrapolation of retest periods or shelf lives is depicted in the Decision Tree given in Workflow.
Stability Data Evaluation for Retest Period or Shelf Life Revision shall performed.
Extrapolation of retest date can be up to twice but should not be more than 12 months from the already established retest period.
Field alert:
In case, if any stability failure is observed during stability studies of the commercialized products / materials Field alert report shall be issued to regulatory department for necessary action within 3 business day.
Stability study for Injection and Ophtl:lalmic containers:
Stability study sample shall be charged at inverted and upright position for Injection and ophthalmic containers .
Inverted position sample shall be marked with symbol.
Upright position sample shall be marked with symbol.
Analysis shall be performed as per respective stability protocol (if applicable).
