Stability Testing – An Overview

Introduction

In Stability Testing – An Overview we look at stability testing requirements – chamber choice , validations requirements, IQOQPQ & IPV considerations.

To prove the shelf life of a drug in a certain market, the manufacturer must store it at a relevant temperature and humidity for a specified time. This is done in a stability chamber also known as a stability cabinet.

Each market’s regulatory authority e.g., the FDA in America, the HPRA in Ireland, specify what temperature and humidity conditions should be used and how long the samples are to be stored, e.g., 6 to 12 months minimum. During this period the samples are tested and their potency and degradation measured and recorded. This is called stability testing.

The most common conditions are 25°C/60%RH. For a new product accelerated conditions may be 40°C/75%RH. Other conditions include 30°C/65%RH, 30°C/35%RH and 25°C/40%RH.

Another condition is 5°C ±3°C for products intended to be stored in a refrigerator. For products intended for storage in a freezer the test conditions are -20°C ±5° C.

ICH

ICH, International Conference on Harmonisation of Technical Requirements for the Registration of Pharmaceuticals for Human Use, sets the rules by which stability testing is run. 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 a lot of paperwork. 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.

It may be necessary to enlist the assistance of a Service Engineer if no obvious explanation is available. 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.

Photostability testing

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. ICH Q1B stipulates that temperature should be controlled to prevent local hot spots.

Monitoring and 21 CFR Part 11

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.

Chamber Qualification

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.

You might also find our Chamber Mapping & Qualification blog of interest, click here.

Chamber Choice Considerations

The following factors need to be considered:

• 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

References:

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

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

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/part-11-electronic-records-electronic-signatures-scope-and-application#iiic

A Glossary of Terms Used in the Field of Stability Testing.
Term	Definition
Stability Chamber	A machine, similar to an oven, in which the temperature & humidity are controlled at a particular pair of set points.
I.P. or Transmitter.	An Independent Probe is a combined temperature and humidity probe used to monitor the chambers operating conditions independently of the control system. It is connected to a box of electronics that may have a display. It is called a transmitter and will be connected to a recorder, a BMS or some other software system.
ICH	Stands for “International Conference on Harmonisation of Technical Requirements for the Registration of Pharmaceuticals for Human use”. See – http://www.ich.org/products/guidelines/quality/article/quality-guidelines.html
Data Logger	Refers to a data recording system comprising a meter with multiple temperature & humidity probes which is capable of recording a measurement of all probes over a period of time at set measurement intervals. The data is imported into a PC system used to calculate the average, maximum and minimum values recorded during the measurement time. Where a channel number is referenced this is the input channel number on the data logger.
Pt 100 Probe	This is a high accuracy temperature measurement probe. There should be a number of these probes used during this qualification and they are attached to the data logger.
Humidity Probe	This is the % humidity measurement probe. There are a number of these probe types used during qualification and they are attached to the data logger.
Spatial Fluctuation	This is the variation in the temperature or humidity values throughout the usable volume of the climatic chamber.
Temporal Fluctuation	This is the variation in the temperature or humidity values of the climatic chamber over time.
% RH	Percentage Relative Humidity. The ratio of water in the air relative to the maximum amount of water the air can hold at a particular temperature.
cGMP	Current Good Manufacturing Practice. Guidelines for best manufacturing practice. A set of rules that govern data protection in the field of stability testing. See:https://www.fda.gov/drugs/pharmaceutical-quality-resources/current-good-manufacturing-practice-cgmp-regulations
IQOQPQ	Installation Qualification, Operation Qualification, Performance Qualification. A documented series of tests and certification on a new stability chamber prior to use.
IPV	Instrument Performance Validation. A documented series of tests similar to a PQ, performed on a stability chamber in use.
BMS	Building Management System. A computerised system for gathering analogue and digital data.

IQOQPQs on Stability Chambers

Introduction

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 hand written 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 siting
• That any monitoring probes are installed correctly
• That it initialises correctly

We have seen check lists of internal components however many see this as unnecessary.

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 particular 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.

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

Instrument Performance Validation (IPV) for Stability Chambers

Introduction

In the Pharmaceutical Industry it is normal that an annual IPV is performed on each stability Chamber. An IPV is a series of calibrations with traceably calibrated standards, well documented with printed data.

The first few pages will record the Customer name & address, chamber details and standards to be used details. A full description of how the tests will be performed and specifications for the tested will be listed.

Accuracy Record

The chamber will require an accuracy check and possibly an adjustment before the IPV proper 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, temporal run 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. Their system should be 21 CFR Part 11 compliant.

Performance Validation

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 is normally done on the loaded chamber. If the chamber is overloaded it may fail. Again, all readings are compared to spec and noted as pass or fail.

1. A final cert is filled out noting any deviations from spec.
2. A deviations log may be included.
3. A document history is recommended.
4. All data runs, signed off, and standard certs are appended along with a copy of the PO and the Engineers training cert.
5. The document will be reviewed and signed off by the Customer.
6. It is advisable to get and file a copy once signed off.

More Information

If you would like to discuss any of the points made in ‘Stability Testing – An Overview’ please do get in touch, we are very happy to share our knowledge – Contact us.

You might also find the following blogs of interest:

What is Qualification in the Pharmaceutical Industry

Calibration Equipment. What to Use and How to get Them Calibrated.

CO₂ Refrigeration Technology: The Future of Cooling

 

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IQOQ, IPV’s, Calibration and Validation

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Installations

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