What is stability testing?

Stability testing protocols for listed and complementary medicines are developed in Australia by the Therapeutic Goods Administration (TGA) for all medicines to be used within Australia. It applies to complementary medicines and sunscreens. Stability testing is used to test the long-term stability and quality of a therapeutic product under various temperature, humidity and light conditions. Theses tests are best performed in stability cabinets and photostability cabinets (chambers) such as those manufactured by Weisstechnik and distributed in Australia and New Zealand by Simultech.

Stability studies need to be performed in accordance with a predetermined protocol, which is in line with ICH Guidelines for stability testing. Stability testing is ongoing to ensure that the product remains stable over its shelf life.

Stability studies need to examine relevant physical, chemical, and microbiological characteristics of the product.

Stability testing in real time at the storage conditions specified on the product label. Common test points are:

• 40C ± 2°C and 75 ± 5% relative humidity 
• 30 ± 2°C and 65 ± 5% relative humidity
• 25 ± 2°C and 60% ± 5% relative humidity
• 5 ± 2°C

To prove shelf life under ambient lighting conditions the samples may be subjected to precise doses of UV and visible light in a specially designed chamber such as the PharmaEvent Photostability Chamber.  ICH Q1B stipulates that temperature should be controlled to prevent local hot spots.

The Australian Government’s Department of Health Therapeutic Goods Administration bases its stability testing protocols around the ICH, International Conference on Harmonisation of Technical Requirements for the Registration of Pharmaceuticals for Human Use guidelines. ICH Q1A stipulates that during a stability test the conditions shall stay constant ±2°C and ± 5%RH. Also, if these conditions are not met for more than 24 hours the test may have to be lengthened, incurring significant administration work.

While many stability chambers manufacturers may claim they meet these performance requirements often this is not the case and they may simply be quoting the accuracy of the individual sensor used for the measurement in ideal conditions. The measurement and control of relative humidity is very sensitive to temperature and all hygrometers (relative humidity sensors) have a degree of temperature dependence. Typically, a +/- 1 deg C temperature uncertainty will introduce a +/- 6% uncertainty in relative humidity. As such, Weisstechnik has spent considerable time and expense developing stability chambers which achieve the highest level of accuracy for temperature and relative humidity both in time and also in homogeneity in the test space.

If the conditions stray outside ±2°C/±5%RH, even for a short time it should be explained. It may be due to a door opening, to “pull” a sample. Events like that are normally recorded in a chamber log. If the chamber fails, a rapid response from the supplier is required and although he is expected to stock the main spare parts, auditors like the site to stock some as well. It is also advisable to have redundancy i.e. another chamber on site as back up. This chamber must be fully validated and ready for use.

Independent monitoring of the conditions within the chamber should be carried out. This typically entails a temperature and humidity transmitter connected to a recording system. In a Photostability chamber temperature, UV and visible light intensities will be recorded.  This system must conform to the American 21 CFR part 11 regulation, whether it is a paper recorder or a computer system. 21 CFR part 11 stipulates that all associated data collection and storage systems must be designed to prevent falsification, corruption, untraceable alteration, or loss of data. In the case of a computer system it should be formally tested (IQOQ-Installation Qualification, Operation Qualification) to prove compliance. Weisstechnik’s S!MPATI Pharma Software satisfies these requirements.

Likewise, a new chamber must be formally tested (IQOQ and PQ-Performance Qualification). During its life it should be maintained regularly (typically an annual preventative maintenance service with a calibration check) and ideally mapped with multiple probes annually (IPV-Instrument Performance Validation). PQ and IPV usually entail at least one 24 hour monitoring run, empty, loaded or both. During that run the conditions must be shown to remain at the set points  ±2°C, ±5%RH. The test equipment for these tests must be traceably calibrated, at least annually, and be IQOQ’d as 21 CFR P11 compliant.

The following factors should be considered when considering the purchase of a stability cabinet or photostability cabinet or chamber:

• Reliability; is the make known, used and trusted?
• The temperature and humidity should have low fluctuations
• Capacity; plan for future requirements as well as current needs
• Footprint; floor space may be limited
• Is local service available with fast response, spare parts stock and refrigeration repair certification?
• The chamber should have integrated control including a temperature limiter and error message recording
• Automatic water replenishment should be available
• Low user maintenance
• Few if any consumables needed
• Sterile humidity generation.  Micro-organisms must not be injected into the chamber
• It should be possible to lock the keyboard
• There should be an output in case of an error that can be monitored by a Building Management System
• It should be designed in accordance with GAMP; Good Automated Manufacturing Practice
• IQOQ, PMs and IPVs with traceably calibrated, 21 CFR Part 11 compliant, standards should be available from the supplier
  
   

IQ/OQ/PQs on Stability Chambers

When a new stability chamber is installed an IQOQPQ must be performed. This stands for Installation Qualification, Operation Qualification and Performance Qualification. Typically, this will be bought as a package with the chamber and will include a documentation cost as well as performance cost. The PQ tests to be performed will be agreed beforehand and will be reflected in the cost. The documentation will be discussed and amended if necessary. Usually the amendments are small but if they are extensive and time consuming an extra charge may be agreed. Once complete the documentation will be approved by the Customer.

During the life of the chamber a similar validation may be performed. This is called an IPV or Instrument Performance Validation.  This usually involves an accuracy test, spatial mapping and a 24 hour run. As before what this entails will be agreed and the documentation approved.

Installation Qualification:

After some front pages there may be a system description, site requirements, standards listing with cert numbers and some details on how the documented procedure should be executed. Any page that requires handwritten entries of data should have a signature box for the test Engineer and approving Customer to fill in. The chamber model & serial number should be written in at the page top.

The IQ proper will include checks of:

• Shipping damage, if any
• Completeness of order including delivery of accessories and manuals
• Ambient conditions suitability
• Suitability of the services: power, water, drain
• Suitability of sitting
• That any monitoring probes are installed correctly
• That it initialises correctly

Finally, there will be a sign off page in the form of an IQ certificate. On some sites the IQ must be fully signed off before the OQ can be started.

Operation Qualification:

The OQ tests the functioning of the chamber with focus on:

• Correct functioning of limiter/protection devices
• Recording of errors
• Retention of set points after a power cut
• Resumption of control after a power cut

Finally, there will be a sign off page in the form of an OQ certificate. On some sites the IQ must be fully signed off before the next part can be started.

Accuracy Record:

The chamber will require an accuracy check and possibly an adjustment before the PQ is performed.

In this section the conditions inside the chamber and any monitoring system are compared to the standards. Typically, a 21 CFR P11 compliant logger system with temperature and humidity probes will be used. The position and serial numbers of each standard probe are listed. All “as found” readings are recorded and if any adjustment is made the readings are recorded after that adjustment. The specifications for this section may be more stringent than later tests. This gives a margin of comfort in later sections. The final, loaded chamber specification will be the ICH Guidelines specs of ±2° C, ±5%RH (relative humidity) but an accuracy of; for example, ±1.9°C and ±4.9%RH would mean that any natural fluctuation of conditions inside the chamber could easily exceed the ICH specs.

It depends on the quality of the chamber build but we use approximately ¼ ICH, i.e. ±0.5°C and ±1.25 %RH. Obviously, the standards used must show a high degree of accuracy on their calibration certs. The standards should also be calibrated at conditions to fully bracket the set points. Ideally at the “4 corners” of a temperature/humidity graph i.e. low temp with high humidity, low temp with high humidity, high temp with low humidity and high temp with high humidity. Calibrating a standard at 23° C with low and high humidity does not certify it at 40° C and any humidity.

Performance Qualification:

The standards will be in place and the conditions settled from the accuracy test.

Here the spatial spread throughout the chamber is listed. Typically 9 points are used; the top 4 corners, the centre and the bottom 4 corners. In the case of a walk in chamber up to 15 positions may be chosen. No probe should be closed than 100 mm from any wall, floor, ceiling or door as the air flow along these surfaces are unpredictable.

The specifications for this test will be listed and will depend on any manufacturers spec and on whether the chamber is loaded or not. Each probe will be recorded and compared to the spec. The average of the temp probes will constitute the overall temp value inside the chamber. The same will be true for the humidity probes used.

An accuracy test cert page may be included here to compare the set points, the chamber actual values display, the average of the standards and the monitoring system readings.

Finally, a 24 hour (or longer) run will usually be performed to show that no probe strays outside spec during that period. It may be done on an empty chamber or a dummy load may be used. Both may be done. Again, all readings are compared to spec and noted as pass or fail.

Other optional tests:

Power failure test: In this test the power is turned off and the standards are left recording. It is recorded when the first probe goes out of spec. It is not a pass/fail test. In this test it will take longer for a probe to go out of spec in a chamber set to 25 ° C/ 60 %RH than in a chamber set to 40 ° C/ 75 %RH. This is due to the fact that 40 ° C/ 75 %RH is further from ambient conditions.

 Open door test:  In this test the door is opened for an agreed time, such as 1 minute, while the standards are left recording. After the door is closed the conditions start to recover towards the set points. The length of time it takes each probe to come back and stay within spec. is recorded. This is not a pass/fail test. If the chamber’s fan stops or is stopped when the door is open the chamber will recover quicker.

• Final certs are filled out noting any deviations from spec
• There may be a deviations log included
• A training log is required here for the Customers trained
• A document history is recommended
• All data runs, signed off, and standard certs are appended along with a copy of the PO and the Engineers training cert
• The document will be reviewed and signed off by the Customer
• It is advisable to get and file a copy once signed off

Watch the video for more on the Weisstechnik Stability Test Chambers
 

Authors note: Special thanks to Dactec Ltd, Weisstechnik’s Irish distributor for creation of the original article.

References:

https://www.dactecltd.com/products/stability-climate-chambers/stability-chambers/

https://www.tga.gov.au/publication/ongoing-stability-testing-listed-and-complementary-medicines

https://www.npl.co.uk/special-pages/guides/a-guide-to-the-measure-of-humidity-gpg103

http://www.ich.org/products/guidelines/quality/article/quality-guidelines.html

http://www.ispe.org/good-automated-manufacturing-practice-gamp-resources

http://www.21cfrpart11.com/files/library/government/21cfrpart11_final_rule.pdf