Creams & Ointments

Question 1

What is your opinion on the risks associated with creams manufacture?

Answer 1

Micro-contamination, multi-use, separation of water and oil phase

Question 2

What are the typical constituents of a cream? What are they there for?

Answer 2

Cream - 50 oil phase:50 water phase both heated separately then mixed together along with the emulsifier
4 main ingredients: Oil, Water, emulsifier (dispersing agent helps oil disperse in water), thickening agent
80:20 - ointment.

Question 3

How would you validate a cream manufacturing process?

Answer 3

Treat like a water system where possible e.g. sanitary fittings, appropriate materials on construction, closed systems where possible with appropriately graded background etc. Understand the CPPs and CQAs of the product / process and consistently manufacture a defined number of batches of suitable quality

Question 4

What can go wrong?

Answer 4

Micro and particulate contamination - from water, environment, raw materials, equipment, overmix. Underheating - wax will not melt and will not be homogenous. Cooling too slow - impact crystal formation. Air removal - if vacuum fails can impact viscosity, fill volume and may cause oxidation in product. Under mixing oil and water discernment, homogeneity.

Question 5

What should be in the water phase?

Answer 5

Preservative - used to control micro contamination. Humectant - used to prevent the loss of water - Hydrolytic and salicylic acid. Chelating agent - protect ingredients from oxidation / improves the efficacy of preservatives and antioxidants

Question 6

What should be in the oil phase?

Answer 6

Active. Emulsifiers - to disperse in water. Anti-oxidants - are used to protect oils and / or butters against rancidity

Question 7

How do you look for the preservative?

Answer 7

Assay. EP method for typical preservatives e.g. Hydroxy benzoate, Sodium Benzoate

Question 8

What else? … what is PET? What does it mean?

Answer 8

Preservative efficacy test to see is preservative effective inoculate / spike cream with each of the challenge organisms (103 to 106) and take measurements over a period of time (7, 14, 21 days and possibly sample periodically throughout the shelf life depending on risk assessment) - Yeast, Mould, Gram neg, Gram Positive and a Aspergillus brasiliensis - mould, Staph Aureus - people skin Gram positive, Pseudomonas aeruginosa - water Gram negative, Candida Albicans - yeast, E. Coli objectionable from the gut

Question 9

When is the preservative added and why?

Answer 9

Preservatives are added at the end of the manufacturing process to protect the product over its self-life, if it is put in too early it can mask problems present in the formulation from the manufacturing process itself and this is not its purpose

Question 10

What are your thoughts as a QP about this test? Is it meaningful?

Answer 10

Irrelevant for release as have a specification and preservative are not relied upon to support OOS. It tells you for a multi-use cream gives confidence the presentative effective in your cream. Cannot control with patient

Question 11

Which layer would the preservative be in?

Answer 11

aqueous layer, where water activity is at its highest

Question 12

What key characteristic of a preservative is important?

Answer 12

soluble in right phase, efficacious, safe and stable, non-reactive with packaging

Question 13

Pseudomonas in a cream what is the problem?

Answer 13

water system contamination, high water activity and substrate for growth on product. Objectionable for topical

Question 14

What is an acceptable level of micro contamination in a cream?

Answer 14

Topical - 20 yeasts and moulds 200 bacterial, rectal and oral are higher

Question 15

What is a humectant and why is it used in creams and ointments?

Answer 15

A substance that draws water into the skin, hair, or nails. In the skin, this may come from the deeper layers, or from the air if it is humid enough. Humectants are useful for adding hydration without feeling heavy or oily.

Question 16

What are preservatives present for in creams? Are they important to the shelf life? How would you test for this?

Answer 16

A preservative is essential to help prevent microbes (bacteria, mould, and yeast) growing which helps to preserve the product. Preservatives stop growth by acting on spores when they germinate and killing cells (usually by disrupting cell membranes) or by making the product hostile to growth. Preservative efficacy test to prove the efficacy of the chosen preservative against a number of challenge organisms. The product is spiked with each of the challenge organisms at a concentration of 103 to 106. Measurements are taken over a period of time - 7, 14, 21 and 28 days, possibly sample periodically throughout the shelf life depending on risk assessment. Challenge organisms include Yeast, Mould, Gram neg, Gram Positive and a Aspergillus brasiliensis - mould, Staph Aureus - people skin Gram positive, Pseudomonas aeruginosa - water Gram negative, Candida Albicans - yeast, E. Coli objectionable Gram negative gut organism. Looking for a minimum of a 3 log reduction at 14 days and no regrowth

Question 17

Can preservatives migrate? How?

Answer 17

Some preservatives such as Parabens are very oil soluble so tend to migrate to the oil phase, where their activity is greatly diminished. For preservative to stay in the aqueous phase a water soluble preservative should be chosen

Question 18

What is the difference between a cream and an ointment?

Answer 18

Creams. Due to their high water content, creams are easily absorbed, so they can cover large areas of skin. Their oil content also means they stay on your skin’s surface to help protect against moisture loss, which makes them ideal for treating dry skin, rashes, or skin lesions. Ointments. Of all skin products, ointments contain the most oil. They stay on top of your skin rather than being absorbed right away, which offers more protection against moisture loss and the elements, like cold or dry air. Common ingredients found in ointments include mineral oil and petroleum.

Question 19

Manufacturing process for a cream

Answer 19

Preparation of the oil phase. Flake/powder ingredients, sometimes dry blended in advance, are dispersed into mineral oil or silicone oil. …
Hydration of aqueous phase ingredients. …
Forming the Emulsion. …
Dispersion of the Active Ingredient.

Question 20

CPPs for a cream

Answer 20

Drug substance addition
Mixing temp
Mixing time
Mixing speed
Heat and cool rate
Hold time
Droplet size distribution
Vacuum pressure

Question 21

CQAs for a cream

Answer 21

Emulsion stability
appearance
Homogeneity
Viscosity
Sterility (for ophthalmic or for severely injured skin applications)

Question 22

Example emulsifiers

Answer 22

Nin-ionic (PEG esters, Tween 80)
Anionic (SLS)
Cationic (Cetrimide)

Question 23

Example humectants

Answer 23

Propylene glycol
Glycerol
Sorbitol

Question 24

Example preservatives

Answer 24

Parabenzoates
Phenoxyethanol
N=Benzoic acid

Question 25

Example antioxidants

Answer 25

BHT (butylated Hydroxytoluene)

Question 26

Example chelating agent

Answer 26

EDTA

Question 27

What is found in the eater phase of a cream?

Answer 27

Preservative, Humectant, chelating agent

Question 28

What is found in the oil phase of a cream?

Answer 28

Active, emulsifiers, antioxidant

Question 29

What is important about the heating temperature of a cream?

Answer 29

It should be heated to a few degrees above the highest melting point of the way (60-80oC)

Question 30

What is important about the cooling rate of a cream?

Answer 30

It should be cooled quick to avoid ice crystals forming - viscosity

Question 31

You have a cream product that has failed TYMC (yeasts and moulds). You have retested and it passes, you therefore have one passing result and one failing result

What would you investigate?

Answer 31

What was the rationale for re-testing?
TYMC testing is generally a destructive test so the repeat would have been performed on a different sample. Micro contamination is not uniform so this would not negate the initial result.
Could the preservative ‘cleaned up’ the sample - if so its there to protect in use not to clean up poor product

If you get a second batch with the same issue: Now know its not a batch specific issue – it is likely to be a process or environmental issue.
Stop production until the point of cause / root cause has been determined
Pause release and quarantine any batches within your control, determination of stock location

Question 32

What is the preservative efficacy test? What organisms would you use? How long would it last?

Answer 32

Testing performed on the finished product – product is spiked with known organisms and you are looking to observe a log reduction in these organisms over time.

Pseudomonas aeruginosia
Stapylococcus aureus
Candida Albicans
Aspergillus Brasiliensis

28 days