For parametric release;
A) What is it?
B) What types of terminal sterilisation does it involve?
C) How to perform it?
D) Why is it performed instead of sterility testing?
A)
- Wherever possible, a process in which the product is sterilised in its final container (terminal sterilisation) is chosen
B)
- A fully validated terminal sterilisation method by steam, dry heat or ionising radiation
C)
- The release of a batch of sterilised items based on process data rather than on the basis of submitting a sample of the items to sterility testing
- May be carreid out subject to the approval of the competent authority
D)
- Sterility testing involves an aseptic procedure which is less reliable
> depends on the skill of the operator and environment
> picking a sample and not all the items
Why is process validation so crucial and why is it necessary? What happens if process validation doesn’t occur?
sterility is the absence of viable micro-organisms
The achievement of sterility for any one item in a population of items submitted to a sterilisation process can neither be guaranteed nor demonstrated.
- It is essential to study the effect of the chosen sterilisation procedure on the product (including its final container) to ensure its effectiveness and the integrity of the product –> validate the procedure before it is applied in practice
- Failure to follow meticulously a validated process introduces the risk of a nonsterile and/or deteriorated product
What are some examples of the principles of good manufacturing practice that will have been observed in the design of the process? Provide FIVE answers.
- qualified personnel with appropriate training,
- adequate premises,
- suitable production equipment, designed for easy cleaning and sterilisation,
- adequate precautions to minimise the bioburden prior to sterilisation,
- validated procedures for all critical production steps,
- environmental monitoring and in-process testing procedures
What are the TWO types of process data? Briefly explain what each type of process data constitutes.
Commissioning data
- Evidence that the equipment has been installed in accordance with specifications
- Equipment is safe to use
- Equipment functions within predetermined limits
Performance qualification data
- Evidence that equipment will produce a product with an acceptable assurance of sterility
- Physical performance qualification – evidence that the specified sterilisation conditions have been met throughout the sterilisation cycle
- Biological performance qualification – evidence that the specified sterilising conditions deliver the required microbiological lethality to the preparation/product
What does the validation of the sterilisation process include/not include? Provide THREE answers.
- Does not involve testing the products
- Tests of the process –> e.g. can oven reach 160Oc and stay there for 22 hours for dry heat sterilisation
- Keeping the variables within the validated limits; process is in control –> product will come out as expected = sterile
> If one or more variables is out of the limits, the process may fail thus product may not be sterile
What do process indicators do? How are they sorted?
Process indicators provide information on where went wrong
> Sorted according to the sterilisation method:
- Physical indicators
- Chemical indicators
- Biological indicators
What are SEVEN examples of physical indicators?
- Temperature (thermocouples) –> monitor temp for dry and moist heat sterilisation
- Time exposure
- Pressure variation (gauges or transducers) –> for moist heat sterilisation = remove air
- Gas concentration –> for ethylene oxide
- Relative humidity (hygrometers) –> ethylene oxide
- Steam purity –> any air involved in moist heat sterilisation
- Delivered dose (dosimeter) –> ionising radiation = monitor dose
For chemical indicators;
A) What do they vary depending on?
B Why are they unreliable in terms of meeting the BP requirement for sterility? Provide an example.
A)
- Vary depending on the sterilisation method
- They all change in physical or chemical nature in response to one or more parameters
B)
- Most process indicators demonstrate that an indicator has gone through a process but they do not guarantee that sterilisation was satisfactory
> Eg autoclave tape (single end-point indicator) reflects the conditions inside the chamber environment but is not able to demonstrate that an item has been sterilised –> will say the product has been heated but not for how LONG
What is a dry heat indicator (chemical indicator) strip used to monitor?
Monitor exposure to time and temperature in dry heat sterilisers.
- Verifies that the sterilant has penetrated to the point of placement in the pack and confirms that sufficient exposure conditions have been met
> 3M™ Comply™ Dry Heat Chemical Indicator has a wide block of chemical that turns from tan to black within 5 minutes at 340°F/170°C during exposure to dry heat and temperature. A black color reference standard is included as an interpretive match
How is exposure monitoring (indicator tapes) designed? What does it assure the operator?
Designed to seal packs and provide visual evidence that packs have been exposed to the steam sterilisation process
- Assures the operator handling the processed items that the pack has been exposed to the sterilisation process without the need to open the pack or check load control records
Explain how Thermalog S Integrator (chemical indicator ) is used for moist heat sterilisation testing.
Steam enters the permeable topside of the device – the chemical melts and migrates along the paper wick; the distance or extent of migration depends on exposure to steam, time, and temperature.
- The migration is visible through a window marked UNSAFE or SAFE. The color should enter the SAFE window. If it does not, then the critical parameters of the steam sterilisation process (time, temperature, and saturated steam) were not present
Explain how Thermalog EO Integrator (ethylene oxide) –> chemical indicator is used for testing for EO sterilisation.
Ethylene oxide (EO) and moisture enter the unsealed side of the integrator and turn the strip at that point from yellow to blue. The distance or rate of migration of the blue color is influenced by all the critical parameters of EO sterilisation (i.e., EO concentration, relative humidity, time and temperature)
- The blue color migration is visible through windows marked UNSAFE or SAFE. For a SAFE result, the strip inside the integrator will turn blue and enter the SAFE window.
- If the blue color has not migrated into the SAFE window then the critical parameters of the EO sterilisation process were not present
What is the Bowie-Dick Test? What does it monitor?
clue: air removal
Monitor the effective removal of air in autoclaves with a pre-vacuum cycle
- Based upon an observed colour change in autoclave tape inserted in the centre of a test pack of cotton towels, following sterilisation
- Required to be used in the first cycle of the day as an equipment-function test
How are Browne’s tubes used to measure sterilisation? Why is it a more reliable chemical indicator for sterility compared to the previous examples?
Glass tubes containing red liquid that changes to green after successful sterilisation
> Available in two ranges:
- the black tubes stop changing color after 20 minutes at 121°C and the green tubes stops changing colour after 60 minutes at 160°C
A more reliable indicator of sterility than simple indicators such as tapes, as it shows both temperature and time are sufficient for sterility, whereas tape merely indicates a heat was achieved.
For biological indicators;
A) they are standardised preparations of selected micro-ogranisms used to assess ….?
B) Which is the chosen challenge organism?
C) What do they consist of?
A)
- Used to assess the effectiveness of a sterilisation procedure
B)
- The chosen challenge organism is usually the most resistant to a particular process
C)
- Consist of a population of bacterial spores placed on an inert carrier, for example a strip of filter paper, a glass slide or a plastic tube
What are the different ways that biological presenters are presented?
Test pieces = something like the load physically and of the same sort of material, mostly for research
- Gauze –> contaminated gauze
- Syringe –> contaminated syringe
Spore strips absorbent paper carries the organism
- Filter paper, aluminium
For Biological Indicators;
A) What occurs after exposure to the sterilisation process?
B) What does the terms positive control and negative control mean?
C) What does it mean if no growth occurs?
A)
- Indicators are removed aseptically and incubated in suitable media to detect the presence of surviving microorganisms
B)
- Positive control: see positive growth without heating spore strips
- Negative control: media by itself, the media has to be sterilised before conducting the test.
C)
- Sterilisation process is said to have had sufficient lethality
Provide THREE reasons why sterility tests (direct test on the product) is unreliable.
Rely on statistical probability: Not a powerful test
- Not testing all of the product –> only selecting a few number of products for testing
- The probability of detecting micro-organisms by the test for sterility increases with their number present in the sample tested and varies according to the readiness of growth of micro-organism present
- The probability of detecting very low levels of contamination even when it is homogenous throughout the batch is very low
Destructive test
- Open ampoule and test content
- The interpretation of the results of the test for sterility rests on the assumption that the contents of every container in the batch, had they been tested, would have given the same result
- Since it is manifest that every container cannot be tested, an appropriate sampling plan should be adopted
Pass or fail
- Does not tell you where went wrong
What is an example of an integrity test? When is integrity important?
Bubble point test –> before and after sterilisation
- integrity important for sterilisation by filtration
Provide two definitions of parametric release
- A system of release that gives the assurance that the product is of the intended quality based on information collected during the manufacturing process and on the compliance with specific GMP requirements related to Parametric Release
- It is recognised that a comprehensive set of inprocess tests and controls may provide greater assurance of the finished product meeting specification than finished product testing
What is the basis of when the elimination of the sterility test is valid?
Only valid on the basis of successful demonstration that predetermined, validated sterilising conditions have been achieved
- A sterility test only provides an opportunity to detect a major failure of the sterility assurance system due to statistical limitations of the method
When can parametric release be authorised?
Parametric release can be authorised if the data demonstrating correct processing of the batch provides sufficient assurance, on its own, that the process designed and validated to ensure the sterility of the product has been delivered
What are THREE conditions that have to happen in order to carry out a parametric release?
- Only for products terminally sterilised in their final container.
- Sterilisation methods using steam, dry heat and ionising radiation may be considered for parametric release
- Process data –> successfully demonstrate that the sterilisation condition has been achieved –> if the parameter is within an acceptable window, the parametric release can be carried out.
SA questions;
A) When does a batch of products qualify for parametric release?
B) Give an example of a physical, chemical, and biological indicator
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Sterilisation by membrane filtration23
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Sterility Testing19
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Colligative Properties 1+255
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Formulation of eye drops27
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Cold sterilisation26
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Parametric Release24
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CDR and TPN36
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DDS: Pulmonary23
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DDS: Implant18
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DDS: Nasal24
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DDS: Intraocular26
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Protein and Insulin38
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DDS: Transdermal37
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Drug targeting and nanotechnology 129
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Drug targeting and nanotechnology 2 + 336
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Recombinant Pharmaceuticals 1 and 238
