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Pharmaceutics > Sterilisation > Flashcards

Sterilisation Flashcards

1
Q

What are the two general sterilisation processes to produce a sterile medicinal/medical product?

A
  • produced under CLEAN conditions, but then terminally sterilised in the final container
  • produced under conditions completely FREE of MOs via aseptic processing (this method is more prone to error and more unreliable)
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2
Q

Where do contaminants of medical/medicinal products come from?

A
  • raw materials (synthetic/natural - intrinsic MOs)
  • water (a requirement for ALL MOs)
  • manufacturing environment (air, workers, equipment)
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3
Q

What types of organisms are found in the various contaminating environments?

A
  • RESIDENT organisms - live in these environments
    soil - gram positive, endospore forming, fungi
    water - gram negative, yeast, mould
    animals/humans - gram negative & positive, obligate anaerobes
    plants - yeast, mould
  • TRANSIENT organisms
    these are organisms that travel via water and air
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4
Q

Define “sterile”

A

an absolute term, which means that a product is free of all MOs

a product is either sterile or is not

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5
Q

Define “sterilisation”

A

the killing or removal of ALL viable MOs

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6
Q

What are the different sterilisation processes?

A

KILLING

  • Heat (moist heat using steam/ dry heat using an autoclave)
  • Chemical (Ethylene Oxide)
  • Radiation

REMOVAL
- Filtration

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7
Q

Who regulates the sterilisation standards?

A
  • EN
  • FDA

the standards vary slightly between the two, but if an American company wanted to sell their product in Europe, it would have to adhere to the EN standards

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8
Q

What are the sterilisation standards used for?

A
  • to control the number of MOs in a manufacturing environment
  • to VALIDATE sterilising agents and processes
  • to MONITOR sterilisation processes
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9
Q

What is inactivation kinetics?

A

measuring inactivation kinetics allows you to assess whether a process is delivering a sterile product

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10
Q

How do you produce a kill curve?

A

either

  • heat the culture at a certain temperature
  • add EtO at a certain conc to the culture
  • expose the culture to a certain dose of radiation

then take samples of the culture at regular intervals, dilute in order to culture and count colonies
- sample 0 is the sample before exposing to sterilisation
plot as the no. of survivors (no. of viable colonies) v time

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11
Q

What type of curve is a kill curve?

A

ASYMPTOTE curve

  • as long as you take samples at regular time intervals, the same proportion of cells will be killed as the last sample
  • the line will never reach 0, because the same proportion of cells are killed, which means that there is an infinite probability of survival
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12
Q

How do you produce a straight line relationship from the kill curve?

A
  • create a semi-logarithmic plot

log the number of survivors v time

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13
Q

What is the semi-logarithmic plot of the kill curve used for?

A

to take measurements:
GRADIENT =
- thermal death rate of the organism (how quickly the organism dies at that temperature)

OR how quickly the organism dies at a specific concentration of EtO or dose of radiation

you can then repeat at different temperatures/concentrations/doses OR organisms - inactivation kinetics are organism specific, vary between organisms depending on their intrinsic resistance

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14
Q

How many colony forming units do you need to have when taking a sample to produce the kill curve?

A

between 30 and 300 colonies

  • 30 is not statistically significant
  • 300 would be too difficult to count
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15
Q

What order of kinetics are inactivation kinetics?

A

FIRST ORDER

- reaction proceeds at a rate that depends on only one reactant (proportional to the heat/conc/dose)

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16
Q

What is the D Value?

A

is the time taken, at a fixed temperature, dose, concentration to reduce the MO population by 90%, or ONE FULL LOG CYCLE

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17
Q

How do you calculate the D Value?

A

on the semi-logarithmic plot of the kill curve:

  • choose a value on the log survivor’s axis
  • choose another value that is one full log cycle below the first value
  • extrapolate the time information of the two values
  • the difference of the two values gives the time

it doesn’t matter WHICH value you choose, as long as you go one full log cycle below, will always give you the same D value

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18
Q

What is a thermal resistance curve?

A

a log of D Values v Temperature

looks at the effect of temperature on the viability of the microorganism population

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19
Q

How do you produce a thermal resistance curve?

A
  • calculate at least three different D Values (three different temperatures)
  • plot the LOG of the D Values v Temperature it was generated

produces a straight-line relationship graph

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20
Q

What is the Z Value?

A

the change in temperature needed to reduce the D Value by 90%, or ONE FULL LOG CYCLE

i.e. how much you have to change the temperature by to reduce the time taken to kill 90% of the MOs

  • this is a measure of thermal resistance
  • this is an indicator of efficiency
  • can be used to compare organisms (by their D and Z values)
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21
Q

How do you calculate the Z Value?

A

on the thermal resistance curve:

  • choose a value on the Log of D Values axis
  • choose a value that is one full log cycle below the first value on the same axis
  • extrapolate the temperature information of the two values
  • difference of the two temperature values gives you the change in temperature = Z Value
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22
Q

What are the reference organisms when comparing Z Values?

A

how does the organism you’re using compare to these, in the endospore form, most resistant (not vegetative):

Moist Heat Sterilisation:
- Bacillus stearothermophilus, Z Value = 10 degrees

Dry Heat Sterilisation:
- Bacillus subtilus, Z Value = 20 degrees

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23
Q

When is a product deemed sterile?

A

manufacturers have to reach the Sterility Assurance Level (SAL) of 10-6

this means that for every million products produced, only one will be contaminated

most manufacturers aim beyond this

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24
Q

How do you ensure the SAL 10-6?

A

calculate the time needed for a product to be processed (at a certain temperature, concentration or dose) to reach the 10-6 log of survivors (or 10 6 probability of survivors)

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25
Q

How do you calculate the time needed for processing to reach the SAL?

A
  • choose a value from the log of survivors axis, positive log value
  • work out how many log cycle reductions are needed to reach 10-6
  • if you know one log cycle reduction = the D Value, then multiple the number of log cycle reductions with the D Value

e.g. to go from 10 2 to 10 -6, 8 log cycle reductions, 8 x D value = the time needed for processing

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26
Q

What are D Values affected by?

A
  • bacterial species - different organisms have different intrinsic resistance
  • vegetative/spore form of species - vegetative form of the species will be more sensitive to the sterilisation
  • production method - how the product was produced
  • nutrient environment - that the organism is exposed to
  • treatment dose - of the sterilising agent
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27
Q

What is ‘bioburden’?

A

a population of viable MOs on or in a product/package

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28
Q

Why is estimating the bioburden important?

A

estimate the starting population associated with materials the makes up the product

important to know the initial numbers of MOs in order to specify sterilisation parameters and inactivation kinetics

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29
Q

What are the 8 steps of bioburden estimation?

A
  1. Sample Selection
  2. Collection of Items for Test
  3. Transfer to Test Laboratory
  4. Treatment (if required)
  5. Transfer to Culture Medium
  6. Incubation
  7. Enumeration and Characterisation
  8. Interpretation of Data
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30
Q

What does transfer to test laboratory involve when estimating bioburden?

A

there may not be a microbiology lab on the site of the production of the product, have to consider

  • cold temperatures - may get an UNDERESTIMATION of the bioburden as cells start dying
  • warm temperatures - may get an OVERESTIMATION of the bioburden as cells will multiply
  • time taken to transport, which would give a false representation of the bioburden
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31
Q

What does the treatment of the sample involve when estimating bioburden?

A

treatment may be needed to remove MOs from a product
DIRECT contact with the culture medium (e.g. agar plate)
- most ideal way, but not always possible

INDIRECT contact with the culture medium:

  1. first, contact of the product with an eluent to wash MOs from the product e.g. BUFFERED SALINE
    - don’t lyse/kill the cells by osmotic effects
    - could use a mild detergent to break covalent bonds between the MOs and the product, but some can be antibacterial
  2. then, physical treatment - which may be done in the presence of an eluent e.g. VORTEX, ULTRASOUND
    - ensure membranes aren’t perforated, which can happen if over-processed
    - could add glass beads to knock off the MOs from the product
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32
Q

What needs to be considered when selecting a removal technique when estimating bioburden?

A
  • ensure the technique can actually remove any MO contamination from the product
  • ensure that the technique doesn’t have an affect on MO viability
  • consider the type and location of MO on the product
  • consider the nature of the product
  • consider the culture conditions
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33
Q

What will influence the type of MOs encountered when selecting the culture conditions when estimating bioburden?

A
  • nature of the product (natural materials will have a higher bioburden than synthetic)
  • method of manufacture (contamination due to the way the product has been handled)
  • potential sources of microbial contamination (operator/packaging/storage)
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34
Q

What influences the culture conditions when estimating bioburden?

A
  • there is no single growth medium that will grow all types of bacteria
  • conditions are decided after the technique has been validated (tested different cultures, for different lengths of time at different temperatures)
  • we then measure the number of Colony Forming Units (CFUs) there are, and how many different types of colonies

when you have a band new product, you go through the process multiple times to find the conditions - if you changed supplier of a raw material you would then have to repeat the process all over again

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35
Q

Which steps of the bioburden estimation have variability associated with them?

A
  • transfer of the samples to the test lab
  • treatment
  • transfer to the culture medium (direct/indirect)
  • incubation
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36
Q

Are there national standards for the bioburden of a product?

A

no, each manufacturer have their own in-house levels

the greater the bioburden, the greater the processing needed to sterilise the product

(BEFORE sterilisation, not like SAL, which is the number after sterilisation has occurred)

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37
Q

What is the process operation for sterilisation processing?

A
  • cycle development (conducted in test labs)
  • cycle validation (proof the process works)
  • cycle monitoring (every time you run the process, you get the same end result)
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38
Q

What is needed to prove cycle validation?

A

documentary evidence that the sterilisation process works

‘works’ - consistently makes a product that meets the pre-determined specification (the SAL level)

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39
Q

What are the two qualifications needed for cycle validation?

A
  • Instalment Qualification (prove that the equipment/facilities work)
  • Performance Qualification (does it produce results)
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40
Q

What are the two different types of performance qualification?

A

Physical Qualification

  • taking physical measurements of the process, e.g. monitoring the temperature of an autoclave
  • not subject to change
  • the better qualification for supporting performance qualification

Microbiological Qualification

  • using an organism that has defined, high resistance to the sterilisation process being used
  • used as a backup for physical qualification, or when physical qualification cannot be used (e.g. EtO has no means of physical qualification)
  • biological aspect makes this more prone to error
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41
Q

What is the definition of a biological indicator?

A

‘an inoculated carrier contained within its primary pack ready for use and providing a defined resistance to a specified sterilisation process’

‘provides a means of assessing directly the microbial lethality of a sterilisation process’

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42
Q

What is a biological indicator made of?

A

endospores (e.g. spore strips - with a defined number of endospores)

  • these are the most resistant form
  • killing the endospores means the process will kill all other forms
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43
Q

How do you use a biological indicator?

A

it is a standardised preparation of a specific organism with stable high resistance
- stable = always has the same D value

validation - for all processes
monitoring - only for EtO as there is no physical qualification for this

compare the number of organisms surviving the sterilisation process with the expected lethality of the process

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44
Q

What are the characteristics of a BI you receive from a supplier?

A
  • the strain of the organism on the test piece
  • reference to the culture collection
  • manufacturers name (who produced the test piece)
  • number of CFUs per test piece (10 6)
  • D Values at different temperatures
  • Z Values (for heat sterilisation)
  • recommended storage conditions
  • expiry date
  • disposal instructions
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45
Q

What are the factors that influences the choice of BI?

A
  • stability of the organism
  • resistance (high compared to the natural bioburden)
  • non-pathogenic
  • recoverable (able to recover and grow any surviving spores after testing sterilisation)
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46
Q

What is the recommended BI for filtration?

A

Brevundimonas dimunuta

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47
Q

What is the recommended BI for moist heat?

A

Bacillus stearothermophilus

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48
Q

What is the recommended BI for dry heat?

A

Bacillus subtilus

49
Q

What is the recommended BI for irradiation?

A

Bacillus pumilus

50
Q

What is the recommended BI for EtO?

A

Bacillus subtilus (different genotype to moist heat)

51
Q

What is the EMEA Decision Tree?

A

helps guide the choice of which sterilisation process to use

  • moist heat sterilisation
  • modified moist heat sterilisation
  • filter
52
Q

What is the general guidance when selecting a sterilisation process?

A
  • sterilisation in the final container is preferred over aseptic processing
  • sterilising agent needs to get into contact with the whole product
  • all variables of the process need to be controlled and monitored
  • process doesn’t have any hazards to operators/environment
  • process doesn’t leave any toxic residues in the product
53
Q

What is the definition of filtration?

A

“the passage of a fluid (liquid or gas) over a filter, removing any contaminating solutes)

54
Q

How does filtration work?

A

the pore size of the filter is SMALLER than the solute you want to remove (solutes larger than the pore will not pass through, be trapped and therefore filtered out)

55
Q

Which four processes of filtration result in particles smaller than the pore size being removed and filtered?

A
  1. Irregular Shape
    angles of the particles arriving at the pore, e.g. when a rod bacterium is lengthways
  2. Simultaneous Arrival
    particles that arrive at the pore at the same time, then don’t fit through the pore
  3. Blocked Pore
    larger particles that have been filtered may block the passage of smaller particles
  4. Surface Interactions
    most bacteria are negatively charged, so a positively charged filter will interact
56
Q

What is filter voidage?

A

filters don’t have straight holes through them, they are convoluted, meaning that there is no direct path through the filter

open spaces in the filter is called voidage, and this is where particles accumulate

when there is an accumulation of particles on top of the filter, this means that the voidage in the filter is full

57
Q

What does filter voidage indicate?

A

indicates the capacity of the filter

e.g. capacity could be 10 7 of 0.5cm particles in size

58
Q

What are the two different types of filter?

A

Depth

Screen (Absolute Filters)

59
Q

What are the characteristics of a depth filter?

A
  • non-fixed pore size
  • inertial impaction (relies on the particle colliding into the filter matrix)
  • high retentive capacity, don’t become blocked easily
  • robust
  • cheap
  • no sterility - CANNOT guarantee a sterile product
60
Q

What are the characteristics of a screen filter?

A
  • uniform pore size (smaller the pore size, easier it becomes blocked)
  • direct interception (the particle is usually larger than the pore)
  • easily blocked
  • fragile
  • expensive
  • sterility is GUARANTEED with a pore size of 0.22um (EU standards, FDA standards are 0.45, but this matches the size of the smallest vegetative cell)
61
Q

What are the validation tests for filtration?

A
  • Bubble Point Pressure Test

- Challenge Filter With Brevundimonas diminuta

62
Q

What does the bubble point pressure test involve?

A
  • increase the amount of air being pushed through the filter (pressure)
  • this creates bubbles in the wet area above the filter
  • creates a steady stream of bubbles - which is the direct relationship between pressure applied and the porosity of the filter
63
Q

What does the test with Brevundimonas diminuta involve?

A

challenge the filter with the most resistant form, which is the smallest form (Brevundimonas diminuta = 0.4um)

minimum requirement of a filter is to retain 107/cm2 of cells (working capacity is higher than this)

  • take a defined number of the BI
  • pass the culture over a filter
  • check that the number of cells retained matches the requirement
64
Q

What are the two different types of heat sterilisation?

A

Moist Heat - where the steam is in excess of 100 degrees

  • death by protein coagulation and hydrolysis
  • used for aqueous products, devices, dressings

Dry Heat - slower than moist heat

  • death by oxidative processes
  • used for dry powders, oil preparations, glassware, instruments
65
Q

What is the different equipment used for dry heat sterilisation?

A
  • Dry Heat Oven for BATCH processing

- Sterilising Tunnel for CONTINUOUS processing

66
Q

What is the mechanism of heat transfer in dry heat sterilisation (the sterilising agent)?

A
  • conduction
  • convection
  • radiation
67
Q

What factors influence the dry heat sterilisation process?

A

product size
- smaller products have a larger volume to surface area ratio, meaning they will heat quicker

loading pattern
- there needs to be free circulation of air all around the product

air circulation
- the air within the whole equipment needs to have the same temperature or you would have warm air at the top, and cooler air at the bottom

68
Q

What are the stages of the dry heat sterilisation cycle?

A
  1. Drying (drying any moisture)
  2. Heating (to the specified temperature)
  3. Exposure/Holding (when the sterilisation takes place)
  4. Cooling - the longest part of the cycle, may add sterile air to speed up this process

total 16 hours to complete

69
Q

What is the recommended pharmacopeial cycle for dry heat sterilisation?

A

this only provides information on how long the HOLDING period is, you would have to account for the other stages

their suggestions should guarantee a sterile product

  • 170 degrees for 60 minutes is the most common
70
Q

What is the different equipment used for moist heat sterilisation?

A

Autoclave

  • self-boiling
  • mains steam
71
Q

What is the mechanism of heat transfer in moist heat sterilisation?

A
  • latent heat of vaporisation
    steam condenses around an object, where the heat is then transferred to the object, and a vacuum pulls in more steam
    this process continues until there is equilibrium (the object is at the same temperature as the steam)

moisture is created during the process, so the product needs to be able to withstand heat and moisture to use this sterilisation method

72
Q

What factors influence the moist heat sterilisation process?

A
  • air removal - all air needs to be removed from the chamber or you will not get temperatures exceeding 160 degrees
  • saturated steam - the steam needs to be dry, saturated , with the defined, correct moisture content
  • steam under pressure - the steam needs to be generated under pressure or you will not reach the temperatures required
73
Q

What type of steam is needed for moist heat sterilisation?

A

DRY, SATURATED
- wet steam WOULD sterilise the product, but would make the product soggy

  • supersaturated steam has LOW moisture content, and you move towards oxidative killing, which is slower and you wouldn’t reach the SAL level in the time given (it’ll take longer than usual, meaning that there would be MOs remaining)
74
Q

What are the other critical lethal parameters for moist heat sterilisation?

A
  • temperatures are maintained within +/- 5 Kelvin of the limit
  • time of contact is sufficient to reach minimum SAL 10-6
75
Q

What are the stages of moist heat sterilisation?

A
  1. Air Removal - either by:
    downward displacement (steam from the top pushing the air out of the bottom) OR/AND
    evacuation (using a vacuum)
  2. Heating
  3. Holding
  4. Cooling (actively by pumping in sterile cool air, or a natural decay)
  5. Drying (MOIST heat sterilisation)
76
Q

What is the recommended pharmacopeial cycle for moist heat sterilisation?

A

the cycles are all based on PRESSURE (autoclaves = like pressure cookers)
- 121 degrees, 15 mins, 15 psi

77
Q

What are the different types of cycle for moist heat sterilisation?

A
  1. Fluid Cycle - for AQUEOUS FLUIDS, takes 2 hours
  2. Porous Load Cycle - for FABRICS/DRESSINGS, takes 30 mins (fabrics trap air, so air removal is key before doing the process)
  3. Air Ballasted Cycle
78
Q

What are the different cycle validations for heat sterilisation?

A

MASTER TEMP RECORD

  • test load to check the cycles work
  • thermocouples (minimum of 12 probes), and check whether all probes meet the right temperature

TEMPERATURE RECORD CHART
- thermocouple probe in the drain, as the drain is the coolest part - so once this probe has reached the correct set temperature, then the whole chamber should in theory be at the correct temperature too

79
Q

What is important to note about master temperature records?

A

they are SPECIFIC to ONE type of load

  • if you want to change the product, e.g. make it larger, this will influence the loading pattern and therefore heating of the chamber
  • if you want to add a syringe to the product, this will also influence the loading pattern
80
Q

What is a compendial cycle?

A

a standard set of conditions for a cycle from the British Pharmacopeia to achieve SAL levels

it just states the requirements for the HOLDING period of the heat cycles

81
Q

What is compendial lethality?

A

looking at the lethality associated with the WHOLE kill curve, rather than just the holding period (BP states that at 121 degrees, for 15 mins you may get an SAL of 10-15)

bacteria will also die during the heating and cooling processes

82
Q

What are the issues with gross overkill/over-processing?

A
  • problems of product degradation

- economically wasteful and expensive

83
Q

What is the F0 value?

A

‘the lethality expressed in terms of the equivalent time minutes at a temp of 121 degrees by the process to the product in its final container with reference to microorganisms possessing a Z Value of 10’

e.g. a F0 value of 3 - means that for the conditions you’ve calculated the lethality to be the same as when you have the conditions set at 121 degrees for 3 minutes

84
Q

What is the minimum F0 value?

A

8 (8 minutes at 121 degrees)

85
Q

What does the F0 calculation allow you to do?

A
  • alternative to compendial cycles (can change the time/temperature of the set conditions of the BP)
  • allows the lethality’s to be compared
  • can be used for heat labile products
  • offers greater flexibility for heat sterilisation
86
Q

What are the two different F0 calculations?

A
  • biological data (the relationship between F0 and D values)
  • thermal data (calculate lethality’s across the graph to get a cumulative F0)
87
Q

What is the biological F0 calculation?

A

(F = D (Log N0 - Log N))

  • D is the D Value at a given temperature (need to be able to calculate this)
  • N0 is the initial number of microorganisms, the bioburden
  • N is the number of survivors (or in this case the SAL 10-6)
88
Q

What is the thermal data F0 calculation?

A
  • where you subdivide the graph into minute intervals
  • calculate the F0 at each interval
  • add all of the calculations together to give you a measure of the TOTAL process lethality

F0 = (Log-1 (T-121/Z)) x dt

  • Z is 10 from the F0 definition
  • T is the temperature for that 1 minute (take an average if its heating/cooling)
  • dt is the time of heating

so calculate the brackets, then take an antilog, then multiply by the time

89
Q

How can you manipulate the F0 calculation to customise the compendial cycles?

A
  • rearrange to get the time needed at a specific temperature that may be lower than the standard (e.g. if your product is heat labile and is only stable at a lower temperature)
  • rearrange to get the temperature needed to have the sterilisation done in a certain amount of time (e.g. if you want the process done quicker)
90
Q

What is the Fh value?

A

the same as the F0 value but in reference to the dry heat sterilisation process

91
Q

What are the references for the Fh calculation?

A

related to the Bacillus subtilus

  • temperature of 170 degrees
  • Z value of 20
92
Q

What is ethylene oxide sterilisation used for?

A
  • disposable items

- medical devices (major use)

93
Q

What is the MOA of ethylene oxide for sterilisation?

A

causes blockage of the reactive sites in MOs (alkylation of various groups and molecules)

  • this means that it is also toxic to humans, toxic residues need to be removed from products
  • it is also explosive in air, so considerations for operator safety need to be made
94
Q

What are the factors that affect the ethylene oxide sterilisation process?

A
  • concentration of the EtO
  • temperature
  • relative humidity (MOs are more sensitive to EtO when there is a higher humidity)
95
Q

How do you measure the cycle validity and monitoring of ethylene oxide sterilisation?

A
  • not able to measure the SAL accurately
  • no physical qualification available as you cannot measure the concentration of EtO
  • can only use BIs, so biological qualification
  • use Bacillus subtilus (different to that of dry heat) for validation AND monitoring
96
Q

What are the process parameters for ethylene oxide sterilisation?

A
  • time anywhere from 1 - 24 hours
  • 25 - 65 degrees to boost the relative humidity
  • 40 - 85% humidity (high) to enhance the effects of EtO
  • concentration of EtO from 250-1200mg/L

even though we know the concentration, there are distribution and penetration issues within the chamber which makes it difficult to measure the concentration for validation and monitoring

97
Q

What are the three main stages of ethylene oxide sterilisation and where are they performed?

A
  • preconditioning (room/chamber)
  • steriliser
  • aeration (room/chamber)
98
Q

What are the stages of the steriliser cycle process for ethylene oxide sterilisation?

A
  1. Evacuation - of all air as EtO is explosive
  2. Vacuum Hold - to check there isn’t a leak of air into the chamber
  3. Conditioning - boost humidity levels and start to heat
  4. Sterilant Injection - EtO is injected and vaporises at 10 degrees
  5. Exposure - additional EtO if necessary
  6. Sterilant Removal - catalytic converters turn EtO into Co2 and H2o
  7. Flushing - sterile air mixed with nitrogen
99
Q

What does the aeration process involve of the ethylene oxide sterilisation process?

A

products are exposed to nitrogen for 12 hours - 7 days in order to remove any toxic residues of EtO

100
Q

What are the issues with the newer sterilising technologies?

A
  • unsure lethal effects (unsure as to how the MO cells are killed)
  • different kill kinetics
  • validation compliance
  • unsure as to what monitoring techniques to adopt (biological or physical means)
  • no established regulatory requirements (because they are so new)
101
Q

What are the newer sterilising technologies?

A
  • X Ray Irradiation
  • Pulsed Light
  • Microwaves
  • Gas Plasma
102
Q

X Ray Irradiation

A
  • ionising
  • expensive
  • low penetrating power
103
Q

Pulsing Light

A
  • short bursts of white light

- used for in line sterilisation for catheters and tubing

104
Q

Microwaves

A
  • short bursts of intense heating (seconds)

- used for small, batch processing

105
Q

Gas Plasma

A
  • used as an alternative to EtO

- used for medical devices

106
Q

What is involved with Quality Control and Quality Assurance?

A
  • bioburden estimation
  • test OF sterility
  • test FOR sterility
  • pyrogen testing (LAL test)
107
Q

What is the purpose for the test OF sterility?

A
  • performed on products exposed to only a fraction of the sterilisation process
  • part of the validation procedures
  • similar procedure to the bioburden estimation procedure, by doing direct/indirect counts of MOs

PURPOSE: validation of the sterilisation process

108
Q

FALSE POSITIVES (test of sterility)

A
  • record the frequency of false positives to see if you can link it to a particular operator or part of the process
  • perform similar test on the actual ‘sterile’ samples as a control (if you then get growth you know its down to an operator or process)
109
Q

How do you minimise false positives?

A
  • use an environmentally controlled area/room
  • use aseptic techniques
  • avoid introducing contamination
  • decontaminate test surfaces
  • sterilise test equipment and materials
  • minimise manipulations
  • monitor and control incubator environment
  • minimise aerosol production
  • train personnel
110
Q

FALSE NEGATIVES (test of sterility)

A

may be due to

  • inadequate culture conditions
  • presence of a bacterio cidal/static substance
  • delayed time between treatment and testing for MOs
111
Q

What is the purpose of test FOR sterility?

A

testing for a NEGATIVE/ABSENCE of MOs at the end of production of a batch of products

  • take a sample which is representative of the batch
  • statistical test involving frequency of contamination and number of tests to calculate the probability of rejection\
  • therefore it is imprecise and extremely limited
  • the only test for sterility available
  • destructive test - the sample will not be used for treatment
112
Q

What is the number of tests allowed for the test for sterility?

A
  • 2 re-tests after an initial positive
  • on the 2nd test
    if the MO is the SAME - then you reject the batch
    if the MO is DIFFERENT - then re-test again
113
Q

What is the conclusion that can be drawn for the test FOR sterility?

A

the batch passes the test for sterility, not that the batch is sterile

114
Q

What is a pyrogen?

A

an endotoxin that is produced by the LipoPolySaccharide (LPS) of GRAM NEGATIVE bacteria

115
Q

What is the structure of a LPS?

A
  • Lipid A - the ENDOTOXIN
  • Core
  • O - Antigen

gram negative bacteria naturally shed the LPS whilst growing and multiplying

116
Q

What is the test for pyrogens?

A

LAL - Limilus Amoebocyte Lysate Test

  • equal amounts of the lysate and the test solution in a tube
  • incubate at 37 degrees for 1 hour
  • invert the tube

ANY solid clot that withstands the inversion of the tube constitutes a positive test for the pyrogen

117
Q

What are the other forms of LAL testing?

A
  • Gel Clot
  • Turbidimetric (measure the rate of clotting)
  • Colorimetric (add a chromagen to the LAL, increase in colour with presence of pyrogens)
118
Q

What are the procedures for depyrogenation?

A
  • always better to prevent pyrogens entering the product rather than trying to remove them
  • rinsing/dilution
  • pyrogens in glass/vials can be destroyed by dry heat sterilisation at high temperatures (250 degrees for 45 mins)
  • pyrogens removed from water for injections by distillation

Pharmaceutics (6 decks)

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