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PY365 Quality Of Sterile Medicines > Preservative efficacy testing > Flashcards

Preservative efficacy testing Flashcards

1
Q

why are preservatives used

A
  • to protect non sterile pharmaceutical products from microbiological growth
  • to protect sterile products packaged in multi dose containers
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2
Q

name the classification of common preservatives

A
  1. acids and esters
  2. alcohols
  3. biguanides
  4. heavy metals
  5. phenols
  6. quaternary ammonium compounds
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3
Q

what are the properties of acids and esters as preservatives

A

active against bacteria and fungi

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4
Q

give an example of an acid and ester used as a preservative

A

methylparabens, sodium benzoate

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5
Q

what are the properties of alcohols used as a preservative

A

broad spectrum, poor penetration of organic matter, volatile

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6
Q

give an example of an alcohol used as a preservative

A

benzyl alcohol

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7
Q

what are the properties of biguanides used as a preservative

A

active against gram + bacteria
- inactivated by organic matter
- limited antifungal activity
- water insoluble

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8
Q

give an example of a biguanide used as a preservative

A

chlorhexidine

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9
Q

what are the properties of heavy metals used as a preservative

A

broad spectrum of antibacterial activity
- low capacity to organic matter
- toxicity issues

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10
Q

give an example of heavy metals used as a preservative

A

phenylmercurate salts

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11
Q

what are the properties of phenols used as a preservative

A
  • cheap
  • activity against fungi and gram + bacteria
  • low water solubility
  • absorbed by rubber
  • volatile
  • irritant
  • pH dependent
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12
Q

give an example of phenols used as a preservative

A

dichlorophene

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13
Q

what are the properties of quaternary ammonium compounds used as a preservative

A
  • activity against gram + bacteria
  • organic matter affects activity
  • pH dependent
  • non toxic
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14
Q

give an example of quaternary ammonium compounds used as a preservative

A

benzalkonium chloride

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15
Q

give examples of common oral preservatives

A

methylparabens, sodium benzoate, benzoic acid

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16
Q

give examples of common parenteral preservatives

A

benzyl alcohol, chlorbutanol, methylparabens

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17
Q

give examples of common topical preservatives

A

benzalkonium chloride, benzoic acid, methylparabens

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18
Q

give examples of common ophthalmic preservatives

A

QACs such as benzalkonium chloride
benzoic acid

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19
Q

what is discouraged in oral and topical products

A

the use of phenols and organo mercurial

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20
Q

describe the mechanism of action of preservatives

A
  1. limited protection against viral contamination
  2. bactericides and fungicides target several cell targets
  3. cytotoxicity may also affect mammalian cells
  4. target cell wall, cell membrane or cytoplasm
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21
Q

explain how preservatives target the cell wall

A

cell wall activity may involve:
1. lysis due to enzyme inhibition
2. irreversible cross linking at cell wall

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22
Q

explain how preservatives target the cell membrane

A
  1. changes to membrane potential, enzymatic function and permeability
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23
Q

what does cetrimide, chlorhexidine, paragons and phenols affect

A

affect membrane permeability leading to leaking of cell constituents and cell death

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24
Q

what is the effect of sorbic acid targeting cell membrane

A

inhibits transport mechanisms across the membrane

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25
Q

what is the effect of chlorhexidine on targeting cell membranes

A

inhibits membrane ATPase

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26
Q

what is the effect of chelators such as EDTA on targeting cell membranes

A

compromise membrane integrity by chelating Ca2+ and Mg2+

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27
Q

what is the effect of QACs on targeting cell membranes

A

bind strongly to the cytoplasmic membrane leading to damage and leakage

28
Q

explain how preservatives target the cytoplasm

A
  1. uncoupling of oxidative and phosphorylation processes or interference with active transport mechanisms
  2. other preservatives inhibit electron transport chains
29
Q

what is the effect of benzoic acid and parabens on targeting cytoplasm

A

inhibit folic acid synthesis

30
Q

what is the effect of bronopol and organomercurials on targeting cytoplasm

A

target thiol enzymes

31
Q

what is the effect of imidurea on targeting cytoplasm

A

acts on the carboxylic and amino enzymes

32
Q

what is the effect of phenols and alcohols on targeting cytoplasm

A

cause protein denaturation

33
Q

what are the requirements of a preservative

A
  1. must exert a wide spectrum of antimicrobial activity at low concentration
  2. remain essentially in the aqueous phase in multiphase products
  3. maintain activity throughout product manufacture, shelf life and usage
  4. not compromise the quality or performance of the product, pack or delivery system
  5. not adversely affect patient safety or tolerance of the product
34
Q

give examples of combinations of preservatives

A
  1. benzalkonium chloride is ineffective against some strains of pseudomonas aeruginosa, but can be combined with EDTA or benzyl alcohol
  2. parabens activity increases with increased alkyl chain length, so often used in combination
35
Q

outline the safety and side effects of preservatives

A
  1. alcohols are generally considered to be safe, but benzyl alcohol is not recommended for parenteral products
  2. carboxylic acids (benzoic acid) can be gastro-irritant and mildly irritant to skin, eye and mucous membranes
  3. parabens are considered unsuitable for parenteral and ophthalmic use due to irritancy
36
Q

what are the factors affecting the efficacy of preservatives

A
  1. preservative concentration
  2. temperature
  3. degradation of preservatives
  4. factors affecting availability of preservatives
37
Q

describe how preservative concentration can affect the efficacy of preservatives

A
  1. the higher the concentration of the biocide, the greater the rate of killing
  2. exponential relationship between potency and concentration
38
Q

what is the parameter used to assess preservative concentration

A

concentration exponent (n)

39
Q

what is the concentration exponent

A

measure of the effect of changes in preservative concentration on cell death rate

40
Q

how is the concentration exponent measured

A

determined by measuring the time necessary to produce a comparable level of killing in a bacterial suspension (T1, T2) at 2 different concentrations of antimicrobial agent (C1, C2)

41
Q

give the equation that can be used to calculate concentration exponent

A

(C1/C2)n = T2/T1

42
Q

what does it mean if a preservative such as formaldehyde has a concentration exponent of 1

A

n=1, it will need 2^1 times more time to achieve the same killing result

43
Q

what does it mean if a preservative such as phenol has a concentration exponent of 6

A

it will need 2^6 times more time to achieve same killing result

44
Q

how does dilution affect agents with high n values

A

marked increase in time needed for comparable killing effect

45
Q

how does dilution affect agents with low n values

A

less influenced

46
Q

describe how temperature can affect the efficacy of preservatives

A
  1. activity of a preservative usually increases when the temperature increases
  2. the effect of temperature may be expressed by temperature coefficient
47
Q

what is the equation used to calculate temperature coefficient

A

Q10= time to kill at T1/ time to kill at T2

48
Q

what factors influence the stability of preservatives and lead to their degradation

A
  1. temperatures reached during processing
  2. inappropriate pH
  3. exposure to light
  4. interaction with other ingredients
49
Q

what does preservative degradation lead to

A

lowers concentration and may also lead to toxicity

50
Q

name the factors affecting the availability of preservatives

A
  1. effect of pH
    2.effect of organic load
    3.partitioning
51
Q

describe how formulation pH can affect preservative availability

A
  1. changes in preservative molecule
  2. changes to the bacterial cell surface
52
Q

describe the effect of organic load on availability of preservatives

A
  1. organic matter that contaminates a product can influence preservative availability
    - serum, blood
  2. interference of organic matter may reduce preservative concentration
  3. organic matter may also protect microbes from lethal effects of preservative
53
Q

what are the 2 types of partitioning

A
  1. multiphase systems- partitioning between phases
  2. adsorptive loss of preservative- partitioning with packaging
54
Q

describe the effect of partitioning using multiphase systems on availability of preservatives

A
  1. in multiphase formulas, such as oil-water emulsion, preservatives distribute among the aqueous phase and:
    - oil phase
    - the surfactant micelles by solubilisation
    - polymeric suspending agents and other solutes
    - particulate and container surfaces by adsorption
    - any microorganism present
  2. generally, preservative availability is related to the small proportion left in the aqueous phase
55
Q

describe the effect of partitioning using adsorptive loss of preservative on availability of preservatives

A
  1. phenol used as a preservative and vials are sealed with a rubber closure
  2. portioning of biocide occurs between rubber and aqueous solution
56
Q

what is the impact of changes in preservative availability on efficacy

A

the concentration of the preservative available to control the growth of the microorganism will be reduced in the pharmaceutical product

57
Q

describe the microbial resistance to preservatives

A
  1. different microorganisms show varying sensitivity to preservatives
  2. some organisms are intrinsically resistant or may acquire resistance
58
Q

what do pharmacopoeial preservative efficacy tests involve

A
  1. challenging a product with a defined number of CFUs of a variety of test microorganisms
  2. enumeration at time zero and then monitoring kill/survival rate at defined time intervals up to 28 days
  3. it is also a requirement to assess the preservative efficacy of a product at the end of the products proposed shelf life
59
Q

what are the sources of variability which must be standardised in PET

A
  1. choice of test organism and strain to use
  2. inclusion of supplementary strains not listed in the pharmacopoeia
  3. culture maintenance and storage
  4. preparation of inocula
  5. methods employed for microorganism enumeration
  6. assay time and incubation temperature
  7. incorporation of organic load into the test
60
Q

what is the impact of origin of the test organism in PET

A
  1. different strains of a same species may exhibit variations in their properties
  2. control strains may be obtained from culture collections
61
Q

give examples of the test organisms recommended by most pharmacopoeias for use in PET

A

staphylococcus aureus, pseudomonas aeruginosa

62
Q

describe how the inoculum concentration and physiological state affects PET

A
  1. large inoculum levels result in reduced activity of antimicrobials
    - drug adsorption on to the cell surface and absorption into the interior of the cell
    - some organisms can synthesise inactivating enzymes
  2. the manner in which the inoculum has been grown and prepared influence its susceptibility
63
Q

describe how the composition and pH of the culture medium affect PET

A
  1. media may contain substances that antagonise the action of the test compound
  2. organic matter in media may have a protective effect on the test organisms
  3. the microbial growth rate is influenced by pH
  4. many preservatives are weak acids or bases, which are more lipid soluble in the unionised form
  5. pH affects degree of ionisation, and therefore lipid solubility, and so their antimicrobial effect
64
Q

describe how the exposure and incubation conditions affect PET

A
  1. temperature, duration and redox conditions of exposure to the preservative may all have a significant effect on its measured activity
  2. effect of temperature may be assed by the Q10 value
  3. organisms may adapt and become resistant to the presence of preservatives
65
Q

describe the interpretation of results in PET

A
  1. acceptance criteria require satisfactory reduction for each challenge organism
  2. killing required for use in parenteral or ophthalmic products is greater than that required in topical products
  3. 2 alternative performance criteria
    - A: recommended efficacy to be achieved
    - B: where criteria A cannot be attained

PY365 Quality Of Sterile Medicines (19 decks)

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