Ben Forbes - All IPM COPY Flashcards
what are the standards for sterile products
- Sterility test
- Pyrogens test
- Particle-free
- Preservative Efficacy Test
what is a serial dilution? what is it based on, and what are the pros.
its a form of viable counting. Based on most probable number (MPN). It is a statically based assay
- A series of dilutions are made and each dilution is inoculated into several tubes of broth
- Incubate 30 - 35°C for 5 days , then observe for growth OR no growth.
- Reference to tables -> to estimate MPN
- Good method if # of microbes is unknown
- Good for a wide range of microbes
what mechanisms affect drugs staying on eyes?
- Tear flow = washes away drugs
- Blink frequency = eyelids wash away the fluid coating surface of the eye
- Drug properties: If Irritant = this leads to increased tear flow, and an increased blink frequency ∴ this reduces retention time
Why do we have preservatives
Protection against:
- Residual contamination not removed by GMP in non-sterile product
- Contamination introduced during use
e.g. creams, eye drops
Name examples of preservative and what pH they are effective at
Benzoic and Scorbic acid as a pka of 4.2-5, and are active at lower pH’s
Phenolics are only affective above pH 9
Cationic preservatives are inactive below pH 4-5 e.g Chlorhexidine
advantages and disadvantages of light blockage method
Pros:
- Rapid
- Accurate
Cons:
- Affected by shape and transparency
- If particle is transparent then the result is biased
- Variation b/w commercially available instruments
what ingredient can dilate the pupil? what constricts?
Mydriatics dilate (e.g atropine) and miotics constrict (e.g pilocarpine)
Explain this equation
equation showing Effect of dilution on preservative
- t1 and t2 = time required to reduce a viable population to the same extent using the preservative at different concentration; C1 and C2
- indicates reduction in preservative activity due to dilution
- e.g. Phenol activity = 6, when diluted 4-foldà activity reduces by 46 = 4096 times
How does rabbit testing work
inject rabit with formulations and see if temperature rises. If 3 rabbits have a combined increase of temperature > 2.65oC, then product fails.
Advantages
The febrile response of the rabbits are similar to human (so humans have the same reactions)
Disadvantages
- Expensive
- Time consuming
- It’s NOT easy to measure the temperature of a rabbit
- Ethics lol
Explain how the light blockage method works
A high intensity light source is used shone on the particle as it passes through the detection chamber. The particle passes through the light source (typically a laser or halogen light) and scatters the light which is detected by a photo detector.
Detects
Particles > 2um:
Particles > 5um:
what is special about water for injection B.P
water for injection BP is a specialist product that is sterile and pyrogen free- the water is distilled in specialist distillation equipment that prevents any carry over of water droplets. Heat to 80oC to prevent any recontamination and use within 4 hrs
Explain the visual inspection pros and cons, and state the GMP guidelines here, if any
Advantages
- Detects large contamination + incompatibilities in admixtures e.g. CaCl2, K2PO4
- No need to destroy product
Disadvantages
- Only LARGE particles are detected by human eye
- Subjective
GMP requires each container of a batch to be examined by trained personnel
e.g. look through polarised light
what do we pyrogen test?
Tests are applied to ALL injections > 15 ml and powders for reconstitution, especially infusions that are large volume, direct IV and in seriously ill patients
what are particulates, and what is the issue with defining them?
Particles -> mobile undissolved substances unintentionally present in parenteral solutions. Particles can be living and non-living. It must be removed to produce a sterile product
There is no single standard of particle to match against
Only a certain type of product needs Preservative efficacy testing name two types
Oral mixtures (to check for absence of E.Coli) and high in sugar products, to check for absence of Saccharomyces
physical properties of pyrogens
They are non-living (so you cannot use preservatives to kill them; no antibiotic; chemical strategies can be used)
They are thermostable- can survive in temperature of up 250 OC; so they cannot be destroyed via heat.
They are water soluble ∴ during filtration, passes through the filter paper easily
They are non-volatile -> use this as a target
Limitations of Preservative Efficacy Testing
The 4 organisms (or the organisms) inoculated with sample are not representative of all possible contaminants Lab strains of bacteria have different patterns of resistance to the wild stains contaminating the product during use or manufacture.
28 days cannot be extrapolated to an expected shelf life of 2-3 years (which is the shelf life of API) so will the preservative function for this long time period? Sample of 1 ml will be unable to detect <1 organism/ml
What are pyrogens?
Pyrogens are not removed by filtration. They are
- Defined by their action: They are fever-inducing substances (so anything you inject that will induce a fever )
- They do NOT have a chemical structure
- Most potent ones are from Gram -VE bacteria
- They have a high MW
- They are lipids but their potency is enhanced by protein/polysaccharide
What tool do we use to define the paramateters of microbial contamination?
In-house guideleines for hospitals and industry, and the BP:
Pharmacopeia
>states the regulatory controls
- Works within limits
- Total viable counts changes for FORM of meds
- Oral, inhalation
- Herbal meds have higher limits than synthetic meds
- Absence of specific organism
- S. auerus and pseudomonas affects inhalation products
- If microbe present = product fails
how do we label eye drops for expiry purposes?
- Theatre (minims = SINGLE use) - 24hrs à discard after use
- Hospital- 1 week (due to risk of Hospital acquired infection once the eye drop bottle is opened)
- Community – 28 days
- > Label for EACH eye, esp. in infections
How to detect specific organisms
