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benetti > IC8 Sterile Products > Flashcards

IC8 Sterile Products Flashcards

1
Q

Define sterility (WHO guidelines)

A

Absence of viable microorganisms
Others: endotoxins within limits. No detectable particles

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2
Q

Explain why absolute sterility is almost impossible

A

Conditions that guarantee absolute sterility are usually too harsh for active ingredients

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3
Q

Define sterility assurance level

A

Indicates the probability of one viable microorganism in a certain number of drug products. It defines a safety level that is acceptable according to pharmacopeial standards

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4
Q

Define inactivation factor

A

Refers to the degree to which the viable organisms is reduced by the sterilisation treatment (method) applied

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5
Q

What kind of preparations need sterility as a general requirement?

A

1) Parenteral preparations

2) Eye preparations (ophthalmics)

3) Preparations for irrigation

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6
Q

Why is high bioburden critical?

A

1) Higher risk of contamination with viable microorganisms

2) Higher risk for contamination with pyrogens

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7
Q

What is the most common pyrogen?

A

Endotoxins, which are lipopolysaccharides (LPS) produced by Gram negative bacteria

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8
Q

Name a few non-endotoxin pyrogens

A

Other microbial substances, including those derived from Gram positive bacteria or viruses and pyrogens originating from yeasts and fungi

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9
Q

What are some Non-microbial pyrogenic substances?

A

rubber particles, microscopic plastic particles, or metal compounds in elastomers

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10
Q

Name the disadvantages of terminal sterilisation

A

1) Not for all materials (mostly meant for packaging and medical devices)

2) Affected by initial microbial load (lower the initial load, the more likely the process will succeed)

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11
Q

Name the disadvantages of aseptic production

A

1) Higher risk of contamination

2) More variables in the process and harder to control

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12
Q

Name the types of tests conducted to ensure SAL

A

1) Sterility tests
2) Endotoxin test
3) Bioburden test
4) Visible/non-visible particle test

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13
Q

Name 2 tests performed to validate sterility tests

A

1) Suitability test
2) Growth promotion test

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14
Q

Explain the rationale behind suitability test

A

To determine whether any inhibitory or antimicrobial properties in a product will prevent the sterility test from detecting the presence of viable microorganisms

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15
Q

What is the purpose of the postive control of suitability test?

A

shows how contaminated sample will look like

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16
Q

What will an acceptable sterility test method look like when suitability test is conducted?

A

Level of turbidity in the test sample that contains introduced microorganism is comparable to positive control AND no growth in negative control

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17
Q

What are the common growth mediums used in suitability tests?

A

Trypticase Soy Broth (TSB), Fluid Thioglycolate Medium (FTM)

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18
Q

What is/are the purpose(s) of Growth medium test?

A

The Growth Promotion Test is used to confirm that each lot of growth media used in the sterility test procedure will support the growth of less than 100 viable microorganisms. Ensures that negative result received from conducting sterility test is due to product being truly sterile rather than due to the growth media being unable to support growth of microorganism.

A portion of each media lot must be incubated and assessed for sterility according to the incubation parameters (time, temperature) established by the method. If the media is found to be non-sterile, then the test fails (positive result from sterility test might be due to the media not being sterile)

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19
Q

Name the growth mediums commonly used for sterility tests and name the microorganisms that are suitable to be grown on these mediums

A

1) Fluid thioglycolate medium (FTM) for anaerobic and some aerobic bacteria

2) Soybean casein digest medium (SCDM; same thing as TSB) for fungi and aerobic bacteria

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20
Q

State the incubation conditions for sterility tests and the rationale behind the conditions

A

14 days at 32.5 degC and 22.5 degC.

1) 14 days (to check for slow growing organisms)

2) Incubated at 2 different temperatures to determine if temperature can affect the process

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21
Q

What does the required sample size for sterility testing depend on?

A

1) Number of units in the batch (need a sample size that is representative)

2) Volume of liquid per container

3) Method of sterilization

4) Manufacturing requirements of the regulatory.

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22
Q

Name the 2 methods that can be used to test sterility of products

A

1) Membrane Filtration Sterility Test
2) Direct innoculation

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23
Q

What size filter is used in membrane filtration sterility test and why?

A

0.45 µm membrane filter.

Cannot use 0.22 µm filter as it is used for aseptic filtration. If bacteria present in test sample, will get filtered if use 0.22 µm, giving false negative

24
Q

What method is the preferred method for sterility test of filterable products?

A

Membrane Filtration Sterility Test

25
Q

Name 2 methods that can be used to estimate viable bacteria after sterility test has been conducted

A

Most probable number (MPN; less used), CFU counting

26
Q

Name the disadvantages of using direct inoculation method

A

1) Low sensitivity because of the small volumes of product drawn for testing compared to actual product size (microbes may be present just that volume drawn is too low to detect any)

2) Neutralization may be necessary if the product has antimicrobial properties

3) Cloudy sample may affect the reading of the microbial growth

27
Q

Suggest some ways to ensure sterility tests are more thorough for medical devices (those that are pipes/ have hollow space)

A

1) Consider use of rinsing solution containing growth media

2) Cutting the pipe into smaller pieces so that growth media can easily go through (if pipe is left as it is, air that is trapped in the pipes may prevent the growth medium from going through)

28
Q

Which is the most common endotoxin test?

A

Limulus Amoebocyte Lysate (LAL) Test

29
Q

Name some endotoxin tests

A

1) Limulus Amoebocyte Lysate (LAL) Test

2) Gel Clot

3) Turbidimetric or Chromogenic Method

30
Q

What is Endotoxin Limit Concentration (ELC)?

A

ELC Dictates the maximum concentration of endotoxins acceptable in the product (should be as low as possible)

31
Q

How is Endotoxin Limit Concentration calculated?

A

ELC = K/M

K = threshold pyrogenic dose (constant; usually 5 EU/kg for IV or IM; above this dose rabbit get fever)

M = dose of drug (dose/kg/hr)

32
Q

Explain what is Maximum Valid Dilution

A

Maximum allowable dilution of a specimen at which the endotoxin limit can be determined (i.e how much you can dilute the sample before you cannot determine if the number of endotoxin units is high or low enough).

Depends on method sensitivity and method used

33
Q

How to calculate maximum valid dilution?

A

MVD = ELC/method sensitivity

34
Q

Define bioburden

A

the concentration of microorganisms in a material

35
Q

What is the bioburden limit as defined by EMA?

A

≤ 10 CFU/100mL

36
Q

Name some potential strategies to reduce bioburden (7 in total)

A

1) Reduce microbial load prior to and on sterile filter; remove bioburden with pre-filters (pre-filter before aseptic filtration or put more filters in series)

2) Limit hold times and room temperature storage

3) Implement aseptic handling techniques where appropriate

4) Select and validate sterile filter membranes with high microbial retention capabilities (≥ 10^6 CFU/cm 2)

5) Increase effective filter surface area by using larger single filter or multiple filters in series

6) Limit batch volume to be sterile filtered (smaller sample, smaller bioburden; but final product may not be enough)

7) Test integrity of sterilising filters pre and post use

37
Q

How to calculate bioburden?

A

t = D*(LogN0 – LogSAL)

Combination of D value equations and LogN equations

38
Q

What does D value represent?

A

Decimal reduction value = the time of exposure from a sterilisation process required to reduce microbial population by 90%

39
Q

What is/are not considered as particulate contamination?

A

Gas bubbles

40
Q

Name some possible extrinsic and intrinsic sources of particulate contamination

A

Extrinsic: e.g. environmental contamination, like manufacturing equipment, primary packaging (stainless steel, hair, fibers, glass, rubber)

Intrinsic: e.g. formulation, e.g. API, proteinaceous, excipients unintentionally present in the solutions

41
Q

What are the tests for visible/sub-visible particles?

A

Light obscuration particle count test, Microscopic Particle Count Test

42
Q

State how the following are tested for sub-visible/visible particles using Light Obscuration:
a) Large volume parenterals
b) Small volume parenterals (< 25mL in volume)
c) Powders for parenteral use

A

a) single units are tested

b) contents of 10 or more units are combined in a cleaned container to obtain a volume of not less than 25 ml

c) reconstituted with particle free water or with an appropriate solvent without contamination of particles when particle free water is not suitable

43
Q

State the criteria for which the preparation complies with the light obscuration particle count test.

A

Average number of particles of particle size ≥ 10 µm present in the units tested is less than 6000 per container

AND

Average number of particles of particle size ≥ 25 µm does not exceed 600 per container.

44
Q

State the criteria for which the preparation complies with the microscopic particle count test.

A

Sub-visible particles
* Average number of particles of particle size ≥ 10 µm present in the units tested is less than 6000 per container AND
* Average number of particles of particle size ≥ 25 µm does not exceed 600 per container

Visible particles
* Free of visible particles

45
Q

Define sterile preparation

A

The process of ensuring that there’s no microbial contamination on anyone or anything involved with healthcare practices, like surgeries and drug manufacturing.

46
Q

List the parameters for sterile preparations

A

1) Safety (free from adverse toxicological concerns

2) Sterility (free from microbiological contamination)

3) Nonpyrogenic (free from pyrogenic endotoxin contamination)

4) Particle free (free from visible particle)

5) Stability (chemical, physical, microbiological)

6) Compatibility (compatible with formulation, package, other diluents)

7) Tonicity (isotonic with biological fluids)

47
Q

What size filter is used for aseptic filtration?

A

0.22 µm

48
Q

State the limitation(s) of aseptic filtration

A

Can remove bacteria and moulds, but not all viruses or mycoplasmas or ions (Additional heat treatment needed for mycoplasma)

49
Q

State the 3 seperate and interdependent processes in lyophillisation and what happens during these 3 processes.

A

1) Freezing (lower T at constant pressure)
- Freezing the solution by placing the partially stoppered containers on cooled shelves in a freeze-drying chamber or pre freezing in another chamber

2) Primary Drying (Sublimation; drying under vacuum/aqueous vapour removal; end point = temperature rising indicates that almost all water removed)

3) Secondary Drying (Desorption of water stuck to particles under vacuum; end point = water content < 1%)

50
Q

What may affect the final lyophilised product in the freezing step?

A

Crystal size may affect final product (change crystallinity, change product behaviour)

51
Q

What are some alternatives to lyophilisation?

A

Sterile recrystallisation, Spray drying

52
Q

Describe what is meant by aseptic process simulation

A

A method used to validate a planned aseptic process by running the process using a microbiological growth medium (instead of product) under conditions that closely approximate those being used during the product production process.

53
Q

Is aseptic process simulation a form of quality asssurance?

A

No

54
Q

What is the typical SAL for parenteral products

A

1 x 10^6

55
Q

What is the typical SAL for low sterilisation

A

1 x 10^3

56
Q

What is the typical SAL for high sterilisation

A

1 x 10^4

benetti (7 decks)

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