Preservatives

Question 1

Preservation of pharmaceutical products

Answer 1

Sterile and non-sterile preparations
Parenteral, ophthalmic, oral, topical and otic (BP) preparations
Cosmetics

Question 2

Preservation- Background

Answer 2

Prevention of microbial spoilage of products and decreasing risk of infection when the preparation is administered.
Preservatives should prevent the proliferation of micro-organisms in non-sterile products.
Preservatives should kill micro-organisms in sterile products.

Question 3

Self sterilising products

Answer 3

Contain more than 15% alcohol (elixirs, spirits, tinctures)
High concentration of sugars ((>85%) syrups (exosmotic effect)
High concentration of sugar (>85%) and sufficient polyol (sorbitol, glycerin, propylene glycol)

Question 4

Ionizing radiations

Answer 4

Preservation of food (limited due to consumer’s concerns)

Question 5

High pressure

Answer 5

Preservation of food and drink (300-700 Mpa), doesn’t alter taste of food

Question 6

Favourable conditions for microbial growth

Answer 6

Water activity (tablets)
pH (acidic pH)
Temperature (low temperature)

Question 7

Sources of contamination

Answer 7

Raw materials
During manufacture- contaminated equipment, water, air operators, packaging materials
During use- re-use, multi-dose containers

Question 8

Spoilage can be caused by:

Answer 8

Low levels of acutely pathogenic micro-organisms
Higher level of opportunistic pathogens
Toxic metabolites can persist even after death of the original contaminants

Question 9

Physical changes due to microbial contamination

Answer 9

Microbial growth has initiated significant physical or chemical deterioration of the product:
Breakdown of emulsions, visible surface growth on solids, formation of slimes, pellicle or sediments in liquid
Changes can be accompanied by production of gas, odours or unwanted flavours

Question 10

Clinical implications

Answer 10

From local infections (wound infection) to systemic infections (parenteral products)
Septicaemia after infusion contaminated solution (gram-negative)
Ophthalmic infections (eye drops, eye cosmetics)
Degree of contamination is high- endotoxic shock

Question 11

Functional categories

Answer 11

Alcohol (ethanol)- disinfectant, preservative and solvent
Benzalkonium chloride- disinfectant, preservative, solubilising agent, wetting agent
Benzethonium chloride- preservative, wetting and solubilising agent
Benzyl alcohol- preservative, local anaesthetic (10% v/v), solubiliser (5% v/v)
Boric acid- preservative, buffering agent
Cetylpyridinium chloride- disinfectant, preservative, solubilising agent, wetting agent
Chlorobutanol- preservative, plasticizer

Question 12

Other ingredients labelled as antimicrobial preservatives

Answer 12

Butylene glycol, calcium acetate, propylene glycol

Question 13

Other ingredients not labelled as anti-microbial but have activity

Answer 13

Non-ionic surfactant, ionic surfactant, amphoteric compounds

Question 14

Testing for preservative efficacy

Answer 14

Test model offering manufacturers guidance, not intended for routine use, assess efficacy of preservative system during product development, reflect storage conditions (container, temperature and time), essential part of quality control

Question 15

Aims of testing for preservative efficacy

Answer 15

Measure products ability to resist microbial contamination
Predict long term preservative efficacy during use and storage
Assess the probability of recontamination

Question 16

Preservative efficacy test (PET): inoculum

Answer 16

Aspergillus niger
Candida albicans
Pseudomonas aeruginosa
Staphylococcus aureus

Question 17

Relevant industrial isolates

Answer 17

Preparation of inoculum well-described (media, temperature, time of incubation)
Harvesting inoculum (spores of A. niger)
Counting microbial concentration prior to test challenge

Question 18

PET test procedure

Answer 18

Inoculate a series of containers of the product with a suspensions of one of the test organisms
Volume of the suspension not to exceed 1% of the volume of the product
Incubation at 20-25c, protected from light
Sampling at zero hour and at appropriate intervals according to the type of the product
Determination of viable count: plate count, membrane filtration or most probable number

Question 19

Validation of PET

Answer 19

Verify its ability to demonstrate the required reduction in count of viable micro-organisms

Question 20

Criteria for acceptance of PET

Answer 20

Significant fall or no increase in the number of micro-organisms in the inoculated preparation after the times and at the temperatures prescribed
Different performance criteria are required depending upon the formaultion

Question 21

Limitations of PET and potential development

Answer 21

Laboratory evaluation instead of evaluation in situ
Stringency of the tests

Use of rapid detection technique
Real time monitoring

Question 22

Testing for preservative activity: regulatory aspect

Answer 22

Manufacturers must justify steps taken to assess and minimise the risk of microbial contamination and spoilage and demonstrate efficacy of the preservative system

Question 23

When preservatives are deemed necessary:

Answer 23

Preservative efficacy test to demonstrate adequate protection throughout life of product
Evidence of safety of preservative
Reasons for inclusion
Details of labelling and methods of control in the finished product

Question 24

What are the other tests for preservative efficacy?

Answer 24

Multiple challenge test (cosmetics)
Determination of D-value (decimal reduction time)
Test in loco (cosmetics)