LAB-075 Stability and Trial Testing Procedure for pharmaceuticals Products

1. Stability Programme Overview

1.1.  Stability is grouped into three (3) types:

a. Annual maintenance Stability

b. New product Stability

c. Special studies (Trials)

1.2. The general procedures and tasks for controlling the Stability programme are as follows:

1.2.1. Setting-up Stability

a. Batch for Stability testing is selected

b. Details entered into stability cards, Trial cards.

c. Samples put away in fridge/Stability room.

1.2.2. Testing

a. The Stability & Trials program is run monthly to identify the batches that require testing.

b. Cards are collected from the filing cabinet and distributed to the teams.

c. Teams perform testing in accordance with protocol.

d. Results written on cards and retained.

1.2.3. Reporting

a. Product not expired:

 – Cards filed away until next test point.

b. Product Expired / Trials completed:

– ‘Completed’ on Stability & Trials program.

– Complete stability/trial cards, sign and file.

– Discard remaining samples from Fridge/Stability room.

2. General Sampling

2.1. Sampling of products for Stability testing is initiated by the Laboratory staff.  Each week ,the Production Schedules are examined to determine which batches are required. The decision on which batches and which tests are required are based on Stability Programs.

2.2.  Samples must be set down within 30 calendar days from the date of packaging.

2.3. Sufficient samples for chemical, physical and microbiological testing plus an overage for repeat testing are to be set down.  The quantity of samples to be taken for Stability testing is given in SOP MAN-125.

2.4. All samples are to be stored at the temperatures specified in the Stability Protocol.

2.5. All products tested are to be stored in their usual containers, closures and packaging.

2.6. The frequency of testing points is recorded on the Stability & Trial cards.  Samples for testing are sourced from the Stability Rooms or refrigerators.

2.7.  Samples are stored in the fridge at 2-8°C and in the Stability rooms at the designated temperatures/humidity.
Ensure that all cartons are MARKED with BATCH NUMBER and EXPIRY DATE.

2.8. The temperature and humidity of the Stability rooms is monitored by the Plant Monitoring System.

2.9. When a batch is to be set down for Stability testing, the following details are filled in on the Stability/Trial card:

a. Product name and strength,

b. Container size and type

c. Product code

d. Batch number,

e. Date of manufacture

f. Storage temperature

g. Quantity required from production

h. Any relevant comments

The card is then sent to Production and warehouse office.

2.10. The Stability card then comes back to the Laboratory with the required samples.  The Laboratory Technician in charge of Stability then completes the card with the following:

a. The product Expiry date

b. The Team

c. Stability Specification no.(From Technical Service Master File, see SOP QMS-030)

d. Sequence

e. Tests to be performed

f. Relevant testing points

g. Container details (back of card)

h. Any other comments

i. Release results.

2.10.1. The Stability tests required are found by referring the Stability Specification folder.

2.10.2. Under “Sequence” indicate in which months testing is required.  Use this SOP to determine frequency of testing, and Stability Programs to determine which months and which testing sequence number.

2.10.3. When testing is complete, results are entered into the trial card.

3. General Requirements

3.1. Storage temperatures should be controlled to ±2°C and relative humidity at ±5%RH.  Excursions exceeding these ranges for more than 24 hours should be recorded.

3.2. Studies are carried out on closed primary packs, without secondary packaging except:

a. When secondary packaging affords additional protection.

b. When secondary packaging affords no additional protection but provides a convenient container for holding samples within the Stability rooms (e.g. box of tablet blister strips).

3.3. Primary packs selected for Stability should be representative of the entire batch.  This does not preclude taking all samples from a specific portion of the packaging run, if they are deemed to be representative.

3.4. Primary packs containing liquid should be stored in an orientation that is most stressful along with control samples stored in an upright position.

3.5. Time zero is taken from the date samples are placed in Stability rooms.

3.6. Analysis should be completed within 30 calendar days.

4. General Data Generation and Analysis

4.1. Validated control methods for testing must be followed.

4.2. Testing is to be done in singlicate for Stability where method precision allows.  If the test includes replicates, e.g. Dissolution, do a minimum number as required by the method.  Testing is performed in duplicate for Trials unless indicated otherwise by the protocol.

4.3.  Documented procedures shall be used to investigate OOS results and report any confirmed OOS to QA management.  See SOP LAB-055.

4.4. Record all results.  Normally this will only be one result, but if more than one determination was performed, compare each result with the specifications.

4.5. Trend analysis should be conducted annually.

4.6. Analytical results, which are numerical, are to be reported numerically not “complies” or “conforms” or “passes”.  This allows for data evaluation and analysis.

4.7. Testing dates are to be reported with each set of results.

5. Annual Maintenance Stability

5.1. Information regarding how many batches will be produced throughout the year is obtained from the preliminary master Production Schedules.

5.2. The number of batches placed on Stability and the frequency of testing designed to confirm the product exhibits the same Stability profile that was demonstrated on the first three batches.  As suitable data is accumulated testing frequency can be reduced.

5.3. Examples of Stability Testing Schedule for Pharmaceuticals

5.4. Tests to be performed and result limits are assigned using the Stability Specification set for each product in the absence of a protocol. The Breakdown Products are also to be included on the stability card.

6. New Product Stability

6.1. The first three (3) routinely produced commercial scale batches with concentration and pack variants must be included in the programme.  For subsequent routine production a minimum of one batch per product per year must be included in the programme.

6.2. In markets where bracketing is permitted by the Regulatory authorities three batches of each concentration/pack variant combination may not be required.

6.3. See LAB-070 for information on protocol preparation and maintenance.

6.4. Stability studies on the first three/early three batches are run for a maximum of four years and cover Climatic Zones.

Examples of stability testing requirements for pharmaceuticals

6.5.  Where a lower temperature long term storage condition in necessary (product instability), the six month accelerated condition should be performed.

7. Special Studies Stability (Trials)

7.1. When a permanent change is made and approved by the authorities, e.g. Method of Manufacture, Manufacture off site, or primary packaging material, which may affect the Stability, the first three (3) batches produced after the change must be included in the programme.

7.2. If a single batch is subject to any significant deviation during production, e.g. concerning formula, method of manufacture, or primary packaging material and this change is likely to affect the product stability, this batch must be included in the programme to give further Stability data.

7.3. The following modifications are typical of situations, which may require additional Stability studies.

a. Changes in the manufacturing process of the bulk product

b. Changes in the manufacturing site of the bulk product

c. Changes in the formulation of the product

d. New composition addition of the product

e. Changes in the manufacturing process of the product

f. Changes in the manufacturing site of the product

g. Changes in the batch size of product

h. Changes to the closure/container system (e.g. materials, size, configuration)

i. Reprocessing of the drug product.

7.4. Special Studies Arising from Manufacturing Changes

7.4.1. The need for special studies, to support registration of specific manufacturing changes, shall be determined by a project team consisting of at least Technical, Regulatory, Production and Sourcing and Supply personnel.

7.4.2. An integrated Stability protocol or protocol is to be created.

7.4.3. The Project team will appoint a person responsible for responsible for coordinating all activities required to manufacture and pack the product and transport samples to the commercial Stability site.

7.4.4. The QA Manager of the site wishing to instigate a study shall agree the need for a study with other relevant sites (e.g. packaging or commercial Stability site).

8. Recording of Results on Stability Cards

8.1. Results MUST BE LEGIBLE.

8.2.  Assays MUST be initialled by the Laboratory Technician and dated so that the original results may be easily referred to at a future date.

8.3. Cards MUST be marked with Expiry Limits.

8.4. Note the relevant breakdown products on the card.

9. Interpretation of Results

9.1.  Check whether results are within Stability Specification Limits. For all non-annual maintenance Stability and Trials check that the result does NOT differ from the previous one by more than 2%.

If the result is outside the expiry limit see 9.4.  If the result varies by more than 2% from the previous result inform the Lab. Manager.  The significance of the results is reviewed against the Stability trend of previous batches and a decision made as to action to be taken.  This may result in forming a Project Team to evaluate the possible causes contributing to the variation and follow-up action to be taken.  This follow-up action, or the decision not to take action, must be recorded on the Stability card and initialled by the Lab. Manager.

9.2.  Known breakdown products and related substances are tested to the Control Methods.

9.3. If unknown breakdown products or related substances are found, attempt to identify and quantitated stating method used.

9.4. Out-of-Specification Results

9.4.1. An investigation should be initiated within one day of the OOS result.

9.4.2. If an investigation does not identify a reason for the OOS result, repeat testing in accordance with SOP LAB-055.

9.4.3. If the OOS result is confirmed, the Managers of the manufacturing, packaging and distribution sites are to be informed within 3 days.  The QA Managers will review the relevant records for the batch in question within one day of being informed of the OOS.

9.4.4. Adverse trends.  (A trend, when extrapolated, indicates a high probability of the study batch moving outside one of its registered limits.)

10. Conclusion of Testing Programme

10.1. The Laboratory staff enters the Stability data on to the stability card, including duplicate results, where applicable after testing.  When final testing is completed the Technical Department proof the Stability report against the Stability card.  The Stability report is to be signed by the Laboratory Manager.  The Technical Department is sent the original report, which is kept, in the Master Files.

10.2. The Stability results in the report are reviewed by the Laboratory Manager and Technical service Manager or delegate for Stability trends against previously reported batches.  Where it can be seen that there is a detrimental trend over a number of batches, which cannot be explained with respect to production, analytical, or processing anomalies, a Project Team is formed to analyse courses of action to be taken.

10.3. The Stability results are also included in the annual Product Review for each manufacturing process.

11. Summary of Changes