Preservatives

Question 1

what are the consequences of microbial contamination of pharmaceutical products

Answer 1

• spoilage/ aesthetic effects/product changes
• toxic effects/health hazards

Question 2

give examples of spoilage, aesthetic effects and product changes that can occur

Answer 2

1. visible evidence of growth such as fungal colonies, turbidity or colour changes
2. organoleptic properties affected as a result of microbial growth or breakdown of product
3. audible effects- gas production, fizzing, explosions
4. degradation of active constituents/excipients
5. most ingredients are susceptible to microbial attack

Question 3

give examples of toxic effects and health hazards that can occur

Answer 3

1. production of toxins
   - gram - bacteria contain lipopolysaccharides in their outer cell membranes
2. infections in patients and end users
   - contamination by pathogens can result in infection
   - in hospitals, contamination of multi dose products can serve as vehicles for spread of disease

Question 4

what are the impacts of microbial contamination to the pharmaceutical industry

Answer 4

1. product recalls
2. loss of sales
3. financial loss
4. decreased customer confidence
5. damage to company’s reputation
6. legal proceedings

Question 5

what are sources of contamination of pharmaceutical products

Answer 5

1. raw materials
2. environmental contamination
3. manufacturing sources
4. while in use

Question 6

what are the different raw materials used

Answer 6

1. mains/raw water
2. purified water
3. water for injections
4. excipients and actives

Question 7

what should be noted when using mains/raw water

Answer 7

1. should be free from faecal coliforms
   - eg. E coli
2. other microorganisms may be present

Question 8

how is purified water achieved and what should be noted

Answer 8

1. distillation, reverse osmosis, ion exchange
2. Pharmacopoeias specific total viable counts
3. pseudomonas aeruginosa grow in purified water

Question 9

what is water for injections and what should be noted

Answer 9

1. purified water sterilised by autoclaving
2. water used as an ingredient of sterile medicines is often stored at temperatures greater than 80
   - to prevent bacteria multiplying and increasing endotoxin load

Question 10

give examples of genera of typical water borne bacteria

Answer 10

pseudomonas, klebsiella

Question 11

what should be noted with the use of excipients and actives as raw materials

Answer 11

1. synthetic compounds generally have low bioburdens
2. raw materials of natural origin are at a greater risk

Question 12

what is involved in environmental contamination

Answer 12

air and personnel

Question 13

explain how air is a source of environmental contamination

Answer 13

1. not a natural environment for microbial growth
2. but untreated air contains bacteria, moulds and yeasts
3. air contamination depends on the activity in the environment and the amount of dust which is disturbed
4. handling of contaminated materials during dispensing, blending and their addition to formulations
5. some packaging components contain moulds and bacteria, reflected in high counts around packaging machines

Question 14

give examples of bacteria commonly isolated from air samples

Answer 14

spore forming bacteria
- bacillus
staphylococcus

Question 15

give examples of sources of human contamination

Answer 15

1. skin scales
2. saliva
3. gut bacteria

Question 16

give an example of a manufacturing source of contamination

Answer 16

equipment
- biofilm formation is problematic

Question 17

what is meant by contamination while in use

Answer 17

during storage, in use by patient, consumer, nurse or doctor

Question 18

which pharmaceutical products offer higher contamination risk while in use

Answer 18

multiple use medicines offers higher risk of contamination

Question 19

define contamination

Answer 19

introduction of organisms into or onto the product

Question 20

define spoilage

Answer 20

result of subsequent microbial proliferation

Question 21

does contamination always lead to spoilage

Answer 21

no

Question 22

which pharmaceutical products are vulnerable to spoilage

Answer 22

1. products containing water
   - available to participate in chemical reactions and in quantities for growth to occur
2. dry products such as tablets, capsules and powders are not very susceptible to microbial spoilage

Question 23

what are the factors affecting risk of contamination and spoilage

Answer 23

1. types and size of microbial inoculum
2. nutritional factors, moisture content and water activity
3. storage temperature and pH
4. packaging design
5. protection of microbes within a product
6. mode of intended use
7. how long is the product likely to be used/stored

Question 24

what does a risk assessment for the preservation of pharmaceutical products involve

Answer 24

1. strategies to limit contamination and spoilage designed to deal with worse case scenarios
2. must assume that all microorganisms are infective for routes of administration where likelihood of infection from contamination is high
3. where risk is perceived to be lower, less expensive but also less effective measures are used to limit contamination

Question 25

what is the ultimate in use contamination control

Answer 25

to supply sterile, single dose, individually packaged applications

Question 26

what are the strategies available for the preservation of pharmaceutical products

Answer 26

1. low temperature storage 2. pH manipulation 3. water activity manipulation 4. use of specific chemical preservatives

Question 27

describe how low temperature storage can be used for the preservation of pharmaceutical products

Answer 27

1. some medicines stored at low temperatures to prevent spoilage 2. often used for short term storage of unpreserved or weakly preserved products 3. not suitable for most products

Question 28

Describe how pH manipulation can be used for the preservation of pharmaceutical products

Answer 28

1. useful for foods and other domestic products 2. less useful for pharmaceuticals 3. microbial spoilage is rare above pH 8 4. fungi spoilage is more likely between pH 3-4

Question 29

describe how water activity manipulation can be used for the preservation of pharmaceutical products

Answer 29

1. for spoilage to occur, microbes require water 2. no growth is expected below Aw 0.5 3. Aw is very low for tablets and other dry products 4. lower Aw of some aqueous formulations in order to inhibit microbial attack - may be achieved through addition of solutes such as sugar

Question 30

what is water activity Aw

Answer 30

the parameter that describes the amount of free water in a solution - has no units - scale from 1 (pure water) to 0

Question 31

what is the equation for calculating Aw

Answer 31

Aw= vapour pressure of solution/vapour pressure of pure water

Question 32

give examples of limiting values of Aw for microbial growth

Answer 32

- moisture soption isotherm - enzyme activity - mold growth - yeast - bacteria

Question 33

outline the limitations of Aw modulation for preservation

Answer 33

1. difficult to predict changes in Aw during storage 2. appropriate and more expensive packaging may be required to stabilise Aw over lifetime of the product 3. many fungi can grow at an Aw of 0.65 and it is difficult to lower Aw of aqueous solutions to this level

Question 34

describe how specific chemical preservatives can be used for the preservation of pharmaceutical products

Answer 34

1. to deal with possible contamination during storage, limit growth of contaminants and prevent spoilage 2. never should be added to deal with contamination or spoilage as a result of heavily contaminated raw materials or poor manufacturing process

Question 35

what are the properties of an ideal preservative

Answer 35

1. broad spectrum of antimicrobial activity and no vulnerability to resistance development - gram + and gram - bacteria, yeasts and moulds 2. rapid antimicrobial action/rate of kill 3. chemically stable, effective under all pH conditions 4. compatible with excipients and packaging materials 5. non volatile, odourless and tasteless 6. good solubility in water 7. low toxicity and cost effective

Question 36

how is a preservative selected

Answer 36

1. no single preservative satisfies all criteria 2. selection is a compromise determined by formulation characteristics and intended use of the product 3. range of preservatives greatest for topical drugs and more restricted for oral and parenteral products