Design of premisses and contamination

Describe how can Product spoilage creates hazards to the product

Breakdown of the active

o Alkaloids, morphine, penicillin's (drugs from natural sources) can easily degrade

o might not be an obvious change in taste or looks

• Breakdown of the formulation

o Tablets, capsules are resistant to microbes, but ointments, creams, suspensions etc can easily get contaminated

o Bacteria use suspending agents, thickening agents and surfactants as a nutrient source, this starts to affect the product

o Bacteria can ferment the sugars, which leave acid behind giving bad taste

• Reduced acceptability

o Metabolic waste products of bacteria(hydrogen sulphides, amines, alcohols,

fatty acids) give horrible taste or cause discolouration

o E.g. tablets have black spots

• Degradation of preservative

o Direct effect of microbial action, which initiates product spoilage

o Bacteria can be resistant to some preservatives e.g. Pseudomonas can degrade phenol

Describe how product spoilage creates a hazard to health

Type of organism

o Some bacteria are benign vs others are pathogenic - primary (Salmonella) and

opportunistic ( Pseudomonas,

Staphylococcus Aureus )

• Health of patient

o Old patients, severe chronic disease, poor immune system e.g. chemotherapy,

corticosteroids, so more susceptible to hazards from contamination

• Number of organisms

o Probability of infection increases with the number of organisms

• Route of administration

o E.g. if administering to the eye, there is a higher chance of infection, bc. eye is

moist, warm and has nutrients

o Oral administration has the most protection from microorganisms, bc. we have

various barriers, acids and enzymes, which can kill them

o Injections are the riskiest route

What organisms should not be present in inhaler and oral products

inhaled product or a topical product should have an absence of

Staphylococcus aureus and Pseudomonas aeruginosa, because they are

the opportunistic pathogens via that route i.e infect in those body areas

for oral products it's Salmonella and E. coli

For which products does GMP require the highest level of sterilisation

1) Aseptically prepared (take ingredients that are already sterile, seal it into a sterile

container and not add any contamination while preparing, risker to produce)

2) Terminally Sterilised (preferred choice, product is in its final sealed container and

sterilised via autoclave, heat sterilisation or irritation)

a. Filter is not terminal sterilisation and is the 2nd preferred choice, as it can remove the

microorganisms, but putting the seal on can introduce contamination

3) Microbiologically vulnerable non-sterile products (creams, solutions, suspensions etc)

4) All other products (tablets, capsules etc)

What formulation factors affect microbial content

water content

o if you add solute into the water, vapour pressure reduces (most organisms grow

well in dilute solutions i.e. high water activity)

o water activity > 0.98 -> microbes grow well

o adding glucose reduces water activity e.g. this is used in syrups

• Nutritional value

o More nutrition value more contamination

o E.g. Pseudomonas can even grow in simple salt solutions

• pH

o bacteria can live in pH 4-8, making the product acidic can kill microbes

o fungi and yeast can also grow in low pH 3-5

• Osmotic pressure

dilute water has lower osmotic pressure, where bacteria grow better

• Surface tension

o Lower surface tension-gram negative bacteria growth (reduced growth of gram+)

• Oxygen tension

o If product is O2 free only anaerobic bacteria will grow

• Storage

o Packaging in self-sealing rubber wads for injections, screw-capped tubes for

creams

o strip foils need to be of water-vapour proof material)

What are pyrogens

pyrogens are fever inducing substances, which are water soluble, thermostable, non-volatile, high Mw, liposaccharides

What are the sources of pyrogens

•solvents

• medicament

• excipients

• manufacturing apparatus

What are the hazards of pyrogens

•reddening of injection site

• pain in legs and trunk

• high temperature

• multiple organ failure

DEATH

How can we detect pyrogens

Rabbit test: fluid is injected into 3 rabbits, and if their combined T increase in more than 2.65 product fails

+ febrile response of rabbits is similar to humans

- expensive, difficult to quantify, some injections like insulin can alter body T

LAL test: in vitro test, where the fluid is added to LAL, and if coagulation is observed, then product fails. LAL is based on American Horshoe Crab primitive clotting mechanism.

+ in vitro, cheap, fast, quantifiable

- pH, cations, can affect results

What are the sources of particulate matter

Raw Ingredients. Drug, solvent, material not filtered out at the clarification stage of manufacture prior to filling

The final container. Material not removed during rinsing prior to filling

Environmental. Material falling into the final container during filling eg, cellulose, fibres, dust, hair, dandruff, flakes of skin

Container and closure (during storage and use).

a) Deposition of closure components during sterilisation,

eg Zn oxide, clay (coat with lacquer, but ® flaking)

b) Reaction of formulation with container,

eg flaking of glass ® care with choice of container

c) Rubber fragments due to coring by needles

d) Glass fragments on opening of ampoules

What are the hazards of particulate matter

Vascular occlusion.

Directly by particles > 7.2 µm could block arterioles / capillaries indirectly through formation of emboli

Inflammatory response.

Neoplastic response.

Antigenic response i.e. allergic response

What are the methods of detection of particulate matter

Visual inspection.

optical microscopy

electrical sensing zone method

light blockage method

What factors do the hazards depend on

.Size of particles.

Large particles > 590 µm block the needle

Particles > 8 µm lodge in the lung

Particles 3-5 µm taken up the spleen and liver

Particles < 3 µm may agglomerate

Site of occlusion.

Shape, surface characteristics of the particle.

Affects adherence

Nature of the particle.

Host response

What are the advantages and disadvantages of visual inspection

Disadvantages

only larger particles are detected by human eye

subjective

Advantages

detects gross contamination and incompatibilities in admixtures,

e.g., CaCl2 and K2PO4

non destructive

What are the advantages and disadvantages of optical microscopy method

Disadvantages

labour intensive, training required

special facilities required

difficulties with oily and viscous solutions

small sample

Advantages

Identification of particles

What are the advantages and disadvantages of electrical sensing method

Advantages

not dependant on operator technique

readily detects particles of relevant size

reliable and reproducible

Disdvantages

non-conducting solutions require addition of NaCl

bubbles can contribute false counts

destructive

small samples

no indication of the nature of the particle

What are the advantages and disadvantages of light blockage method

Advantages

rapid

accurate

Disadvantages

affected by the shape and transparency

variation between commercially available instruments