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Pharmaceutics > Sterilisation > Flashcards

Sterilisation Flashcards

1
Q

What are the two general approaches to producing sterile products?

A
  1. produce in clean conditions, then terminally sterilise in final container (the better one, less error)
  2. produce and assemble in conditions free of micro-organisms (aseptic processing)
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2
Q

What are sources of microbial contamination in the manufacturing process?

A

Raw materials, water, the manufacturing environment

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3
Q

How can raw materials contaminate manufacturing processes?

A

Synthetic materials: low and not diverse microbial count, come from the process as don’t carry an intrinsic population
Natural materials: large and diverse microbial population, unique to that product

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4
Q

How can water contaminate the manufacturing process?

A

It’s the primary requirement for microbial growth - denying water prevents growth

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5
Q

How can the manufactuing environment contaminate processes?

A

Air, personnel, equipment and facilities

spores can survive and move sites, humans carry micro-organisms. any moving machinery parts can spread microbes, may have organisms associated

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6
Q

What are the resident organisms in soil?

A

gram positive

endospore forming

fungi

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7
Q

What are the resident organisms in water?

A

gram negative

yeasts & moulds

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8
Q

What are the resident organisms in humans and animals?

A

gram negative and positive

obligate anaerobes

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9
Q

What are the resident organisms in plants?

A

Yeasts & moulds

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10
Q

What are transient organisms?

A

spread from one source to another

carried by vectors (e.g. air and water, personnel)

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11
Q

Definition of sterile?

A

Free of viable micro-organisms

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12
Q

Defintion of sterilisation?

A

killing/removal of all viable micro-organisms

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13
Q

Methods of killing viable micro-organisms?

A

heating, chemical (ethylene oxide), radiation

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14
Q

Methods of removing viable micro-organisms?

A

filtration

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15
Q

What is a kill curve?

A

looks at numbers of surviving colonies over a period of time

take samples from a dilution at intervals and plot number of survivors

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16
Q

What shape is a kill curve?

A

asymptote

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17
Q

Why is a logarithmic kill curve used?

A

gives linear relationship (log survivors vs time)

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18
Q

What does the gradient mean on a logarithmic kill curve?

A

death rate

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19
Q

What does the aymptote shaped curve mean?

A

there is an infinite probability of survivors

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20
Q

What order are inactivation kinetics?

A

first

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21
Q

What is the D-value?

A

time taken (at a given temperature) to reduce the population by 90%

90% reduction in population is 1 log cycle

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22
Q

What is plotted on a thermal resistance curve?

A

Log D value vs temperature

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23
Q

What is the Z-value?

A

the temperature change required to produve a 90% reduction (1 log cycle) in D-value

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24
Q

What does the Z-value show?

A

a measure of thermal resistance of the organism

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25
Q

What are reference organisms?

A

something to compare other values to. usually the most resistant form to a given process

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26
Q

What is the Z-value of Bacillus stearothermophilus?

A

10 degrees

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27
Q

What is the Z-value of Bacillus subtilus?

A

20 degrees

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28
Q

What is the need for a sterility threshold?

A

Absolute zero is not possible

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29
Q

What is SAL?

A

Sterility assurance level

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30
Q

At what value can you guarantee a product is sterile?

A

10 ^-6

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31
Q

At what value does it become impossible to count the number of survivors?

A

10^0 (1) - must extrapolate from plots obtained

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32
Q

How can you use an extrapolated log kill curve to calculate the length of the process needed to reach SAL?

A

Calculate number of log cycles needed to reach 10-6 (from start count)

this many D cycles gives a duration of exposure required

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33
Q

What can affect how long an organism must be processed to reach SAL?

A

resistance the process, higher starting count, D-value

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34
Q

What are D-values influenced by?

A

the species, vegetative vs. spore form (vegetative more sensitive), production method, nutrient environment, treatment dose

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35
Q

What is the definition of bioburden?

A

The population of viable micro-organisms in a product/package

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36
Q

What is the importance of bioburden?

A

the initial numbers are required to determine sterilisation parameters and inactivation kinetics

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37
Q

Process of bioburden estimation?

A
  • sample selection
  • collection of items for test
  • transfer to lab
  • treatment if required
  • transfer to culture medium
  • incubation
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38
Q

At which stage does the greateset variability occur in bioburden estimation?

A

treatment - it’s very product specific

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39
Q

stages in direct methods for bioburden estimation?

A

product –> contact with culture medium –> incubation

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40
Q

stages in indirect methods for bioburden estimation?

A

product –> contact with eluent –> physical treatment –> transfer to culture medium –> incubation

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41
Q

What eluents can be used in estimating bioburden ?

A

the correct one for expected organisms.

mild detergent can help remove from surfaces, but have mild antibiotic properties so some bacteria are sensitive

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42
Q

What are examples of physical treatments that might be required for bioburden estimation?

A

swabs, ultrasound

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43
Q

What considerations are necessary when selecting a removal technique for bioburden estimation?

A
  • ability to remove microbial contamination
  • effect of removal method on microbial viability
  • types and location of organisms
  • nature of product
  • culture conditions
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44
Q

What are the types of micro-organisms likely to be encountered dependent on?

A

nature of the product, method of manufacture, potential sources of contamination

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45
Q

Why is selection of culture conditions so important?

A

there is no universal medium - no medium will support the growth of every single micro-organism

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46
Q

What are CFUs?

A

Colony forming units (aka microbial count)

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47
Q

What types of organisms can grow in Saraboud?

A

Yeast and fungi

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48
Q

What is cycle development in sterilisation processing?

A

Determining bioburden to define the process

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49
Q

What is cycle validation in sterilisation processing?

A

establishment of documentary evidence that provides a high degree of assurance that a specific process will consistently produce a product meeting its pre-determined specifications

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50
Q

Pooled raw milk at the processing plant has bacterial population of 4x10exp5/mL. It is to be processed at 79°C for 21 seconds. The average D value at 65°C for the mixed population is 7 min. The Z value is 7°C. How many organisms will be left after pasteurization? What time would be required at 65°C to accomplish the same degree of lethality?

A

At 79°C, the D value has been reduced by two log cycles from that at 65°C since the Z value is 7°C. Hence it is now 0.07 min. The milk is processed for 21/60=0.35 min, so that would accomplish 5 log cycle reductions to 4 organisms/mL. At 65°C, you would need 35 minutes to accomplish a 5D reduction.

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51
Q

What is performance qualification in process validation?

A

measure of ability to produce a sterile product

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52
Q

What are the two types of performance qualification in process validation?

A

phyisical and microbial qualification

physical is preferable, it is far more reliable. microbial qualification is a confirmation of your physical measure, or used if there are no physical parameters

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53
Q

Definition of a biological indicator?

A

An innoculated carrier contained within its primary pack ready for use, and providing a defined resistance to the specified sterilisation process

i.e. we already know their D values, so can test the effectiveness of a method using the theoretical conditions

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54
Q

What processes are biological indicators used for?

A

Validation of steam, dry heat, radiation and EtO

Monitoring of EtO

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55
Q

What are biological indicators characterised by?

A
  • strain of organism
  • reference to culture collection
  • manufacture details
  • number (10^6) CFUs per piece
  • D and Z values
  • recommended storage conditions
  • xpiry date
  • disposal instructions
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56
Q

What factors determine choice of biological indicator?

A
  • stability
  • resistance to method (should be high compared to product bioburden)
  • non-pathogenic (safety)
  • recoverability
57
Q

What biological indicator is recommended for filtration?

A

Brevundimonas diminute (the smallest)

58
Q

What biological indicator is recommended for moist heat?

A

Bacillus stearothermophilus

59
Q

What biological indicator is recommended for dry heat?

A

Bacillus subtilus

60
Q

What biological indicator is recommended for irradiation?

A

Bacillus pumilus

61
Q

What biological indicator is recommended for EtO?

A

Bacillus subtilus

62
Q

What is the first choice according to the EMEA decision tree?

A

autoclave (moist heat) - 121 degrees for 15 mins

63
Q

What is the second choice according to the EMEA decision tree?

A

moist heat with sufficient lethality >8 mins

64
Q

What is the third choice according to the EMEA decision tree?

A

Filtration and aseptic processing

65
Q

What is the final choice according to the EMEA decision tree?

A

Pre-sterilised individual components and asecptic filling

66
Q

What factors determine choice of biological indicator?

A
  • stability
  • resistance to method (should be high compared to product bioburden)
  • non-pathogenic (safety)
  • recoverability
67
Q

What biological indicator is recommended for filtration?

A

Brevundimonas diminute (the smallest)

68
Q

What biological indicator is recommended for moist heat?

A

Bacillus stearothermophilus

69
Q

What is filter voidage?

A

The empty space inside the filter. Actually a network of tunnels, not straight through pores, which allows for more trapping of microbes

70
Q

What biological indicator is recommended for irradiation?

A

Bacillus pumilus

71
Q

What biological indicator is recommended for EtO?

A

Bacillus subtilus

72
Q

What is the first choice according to the EMEA decision tree?

A

autoclave (moist heat) - 121 degrees for 15 mins

73
Q

What is common procedure for filtration sterilisation?

A

depth filter first to remove large particles, then screen filter to sterilise

74
Q

What is the third choice according to the EMEA decision tree?

A

Filtration and aseptic processing

75
Q

What is the final choice according to the EMEA decision tree?

A

Pre-sterilised individual components and asecptic filling

76
Q

Important considerations when it comes to selection of a sterilisation process

A
  • terminal sterilisation is preferred to asecptic processing
  • agent must be in contact w all parts of product
  • process variables must be controlled and monitored
  • process must not present hazard to operators or environment
  • cannot leave toxic residues on product
77
Q

Definition of filtration?

A

“Passage of a fluid (liquid or gas) across a filter, removing any contaminating solutes”

78
Q

Mechanisms through which filters remove bacteria?

A

irregular shapes, simultaneous arrival at a pore, blocking pores, surface interactions (most bacteria are negatively charged)

79
Q

What is filter voidage?

A

The empty space inside the filter. Actually a network of tunnels, not straight through pores, which allows for more trapping of microbes

80
Q

What are the two types of filters?

A

depth and screen

81
Q

What are depth filters?

A

e.g. filter paper - variable pore size, intertial impaction, high retentive capacity, robust, cheap, no sterility

82
Q

What are screen filters?

A

uniform pore size (fixed), direct interception, easily blocked, fragile, expensive, pore size less than 0.22 microns gives sterile product

83
Q

What are the critical aspects of dry heat sterilisation?

A

Loading patterns, air circulation, product size

84
Q

What are the two types of filters?

A

depth and screen

85
Q

What are depth filters?

A

e.g. filter paper - variable pore size, intertial impaction, high retentive capacity, robust, cheap, no sterility

86
Q

What are screen filters?

A

uniform pore size (fixed), direct interception, easily blocked, fragile, expensive, pore size less than 0.22 microns gives sterile product

87
Q

What is common procedure for filtration sterilisation?

A

depth filter first to remove large particles, then screen filter to sterilise

88
Q

What is the bubble point pressure test?

A

place filter in a closed system with water on top, apply pressure underneath. relationship between when bubbles appear and the porosity of the filter

89
Q

What type of qualification measure is the bubble point pressure test?

A

physical

90
Q

What is a method of microbial qualification of filters?

A

challenge filter with its biological indicator, minimum requirement of 10^7 / sqcm removal. working capacity should be 10^9-10^10

91
Q

How does moist heat kill microbes?

A

protein coagulation and hydrolysis

92
Q

What products is moist heat used for?

A

aq. products, dressings, swabs, devices

93
Q

How does dry heat kill microbes?

A

oxidative processes

94
Q

What products is dry heat used for?

A

dry powders, oil preparations, glassware and instruments

95
Q

What are the two types of machinery used for dry heat sterilisation?

A

dry heat ovens and sterilising tunnels

batch vs continuous processing

96
Q

When are sterilising tunnels used?

A

In industry, easier at scale. move at a set speed to expose product for long enough

97
Q

What are the critical aspects of dry heat sterilisation?

A

Loading patterns, air circulation, product size

98
Q

What are the four stages of a dry heat cycle?

A

drying, heating, exposure, cooling

99
Q

what are the holding times accoring to pharmacopoeia?

A

480 mins at 120 degrees
120 mins at 160 degrees
60 mins at 170 degrees
30 mins at 180 degrees

100
Q

what is used for moist heat sterilisation?

A

autoclave (essentially a pressure cooker)

101
Q

What heat transfer mechanism occurs in moist heat sterilisation?

A

latent heat of vapourisation

102
Q

What does the high pressure inside an autoclave enable?

A

temperatures to reach higher than 100 degrees

103
Q

why must all air be removed from an autoclave?

A

this is the only way temperatures will reach higher than 100 degrees

104
Q

How does steam cause the product to heat in moist heat sterilisation?

A

When heat transfers from steam to product, a slight vacuum forms around the product. this draws in more heat

105
Q

What are the critical lethal parameters for moist heat sterilisation?

A
  • steam (must be dry steam, not wet or superheated)
  • temperature (maintain within 5k of limit)
  • time of contact (sufficient to reach SAL)
  • bioburden level (nature, number and location of microbes)
106
Q

what are the conditions for moist heat cycles according to pharmacopoeia?

A

115-118 degrees - 30 min - 10psi
121-124 degrees - 15 min - 15psi
126-129 degrees - 10 min - 20psi
134-138 degrees - 3 min - 30psi

(psi = steam pressure unit)

107
Q

What are the stages in an autoclave cycle?

A
  1. air removal (by downward displacement or evacuation)
  2. heating
  3. sterilisation/holding period
  4. cooling
  5. drying
108
Q

whats the difference between downward displacement and evacuation of air in moist heat sterilisation?

A

displacement - steam enters in top and forces air out the bottom
evacuation - air is suctioned out. used for products that may retain air e.g. porous dressings

109
Q

what are the three types of cycle used in an autoclave, and what types of product are they used for?

A
  1. fluid cycle - used for most products e.g. saline, containers, glass, heat stable aq products
  2. porous load cycle - used for fabrics/dressings etc. introduce steam and actively withdraw a few times to ensure all air is removed. higher temp (134)
  3. air ballasted cycle - used for sealed containers that would explode in a regular cycle
110
Q

How are moist heat cycles monitored and validated?

A

Master temp record (uses a test load and thermocouples to profile the temperatures reached) - validation

Temp records throughout the cycle - monitor. drain should always have the lowest temperature

111
Q

What is the minimum number of thermocouples to use in master temp records for moist heat sterilisation?

A

12

112
Q

What is the problem with compendial cycles in moist heat sterilising?

A

achieve 10^-15 ish, gross overkill past SAL

risks of product degradation, economical waste etc

113
Q

How does the gross overkill from compendial cycles arise?

A

Uses only the holding period lethality, where in reality death of organisms will start to occur from 50 degrees. need to determine total lethality

114
Q

What is the F0 value?

A

The lethality expressed in terms of the equivalent time in minutes at a temperature of 121oC delivered by the process to the product in its final container with reference to microorganisms possessing a z-value of 10.

provides an alternative to compendial cycles, and allows lethalities to be compared, can choose lower temperatures

115
Q

What is the minimum F0?

A

8 (i.e. 8 minutes at 121 degrees)

116
Q

What is the relationship between F and D values using biological data?

A

F = D (logN0 - Log N)

N0 = initial bioburden
N = number of organisms surviving the process
117
Q

What is the relationship between F and D values using thermal data for moist heat sterilisation?

A

F0 = ( Log-1 (T-121)/10) ) x dt

118
Q

What is the relationship between F and D values using thermal data for dry heat sterilisation?

A

F0 = ( Log-1 (T-170)/20) ) x dt

119
Q

What are the benefits of radiation sterilisation?

A
  • ‘cold’ so suitable for thermolabile products
  • continuous or batch
  • safe, reliable, reproducible
  • single parameter (dose)
  • ease of dose measurement
  • ease of process control
120
Q

What types of products is radiation sterilisation used for?

A

single use medical devices, surgical devices, containers, wrappers etc - DRY products

121
Q

How does radiation sterilisation work?

A

expose product to high energy radiation to inactivate any present micro-organisms
induces a chemical change in vital components of the microbial cell
induced chemical changes in the product must be at an acceptable level and not affect integrity

122
Q

What is ionising radiation?

A

contains sufficient energy to eject one or more orbital electrons

Important characteristic is the localized release of large amounts of energy. The energy per ionizing event is 33eV, which is more than enough to break a chemical bond. For example, the energy associated with a C=C bond is 4.9eV.

123
Q

What are the units for radiation dose?

A

Gray (Gy)

1 Gy = absorption of 1J/kg off irradiated material or = 6.242 x10^15 eV/g)

124
Q

What is a dosimeter?

A

Device having reproducible measurable response to
radiation used to measure absorbed dose in a give
material.

125
Q

How is the radiation dose determined for a product?

A

based on the innate population’s resistance

minimum dose 25Gy

126
Q

What source is used for ionising radiation

A

Cobalt 60

127
Q

What types of devices is EtO used for?

A

Disposable, approx 50% of medical devices

128
Q

By what mechanism does EtO kill bacteria?

A

alkylation of sulphhydryl, amino, hyroxyl and carboxyl groups on Protein and nucleic acids

129
Q

Disadvantages of EtO sterilisation?

A
  • lethality is not uniform, affected by conc, temp and RH
  • not same degree of sterility assurance
  • explosive
  • toxic residues (can be carcinogenic)
  • must be over processed to ensure each part of the product is sterile, higher risk to operators
130
Q

What are the critical lethal parameters for EtO sterilisation?

A
  • time (1-24 hours)
  • temperature (25-65 degrees)
  • humidity (40-85%)
  • EtO concentration (250-1200mg/L)
131
Q

Which organisms are used for validation and monitoring of EtO sterilisation?

A

B. subtilus for both

132
Q

What are the three stages of EtO sterilisation?

A
  1. pre-conditioning
  2. sterliser
  3. aeration (expose to sterile air to remove residuals)
133
Q

what are the 7 stages within the sterilisation cycle?

A
  1. evacuation
  2. vacuum hold (leak test)
  3. conditioning
  4. sterilant injection
  5. exposure
  6. sterilant removal
  7. flushing

stages 1-3 done at low pressure, increases for sterilant injection
flushing involves cycling pressure to flush product with sterile air

134
Q

how long does the aeration phase last?

A

12 hours to 7 days depending on product

135
Q

How is sterilant removed from the chamber?

A

catalyst

136
Q

How is choice of sterilising method determined?

A

initial product research and development

  • microbiocidal effectiveness should be demonstrated (e.g. enzyme kinetics, environmental parameters)
  • product compatibility should be demonstrated
  • safety and environment
137
Q

What are some examples of new/emerging sterilising technologies?

A
  • X-ray irradiation (low power, expensive)
  • Pulsed light (short pulses broad spectrum white light, UV output, used for in-line sterilisation and intravascular medicines development)
  • microwaves (intense heating for short cycles, used for solutions in vials, contact lenses etc)
  • gas plasma (mix of ions, free radicals, electrons/neutrons, alternative to EtO)
138
Q

Problems with new and emerging sterilisation techniques?

A

unknown lethal effects, kill kinetics are different to existing processes, validation compliance, monitoring, no established regulatory requirements

Pharmaceutics (5 decks)

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