Lecture 10 - Industrial Production of Antibiotics Flashcards
What are antibiotics?
compounds that kill bacteria or prevent the growth of bacteria
What is propolis?
a construction and repair material, sealant to fill gaps, smooth out internal wall
a natural product from the beehive
What is propolis used in?
creams, lotions, tinctures, toothpastes, sprays, mouthwashes
What properties did propolis have?
antibacterial, antifungal, antiviral effects
What was the first penicillin discovered?
benzylpenicillin
by Alexander Fleming (1928)
What can bacteria produce?
beta lactamases that will degrade beta lactam antibiotics
What is the 4 membered ring in beta lactams?
the active core of the molecule, but also its weakness
What does clavulanic acid too?
binds to the enzymes allowing the antibiotics to work effectively
Structure of clavulanic acid?
has the beta lactam ring, but no left side chain and does not posses any microbial activity on its own
How is clavulanic acid used?
with a penicillin to be active
What is augmentin?
amoxicillin (broad spectrum) + clavulanic acid
How is augmentin produced?
via fermentation, enzymation, extraction and isolation
How is benzylpenicillin produced?
by fermentation of penicillium
How is amoxicillin produced?
after additional enzymation and extraction
How is clavulanic acid produced?
by fermentation followed by solvent extraction and chemical salt conversion
How is augmentin then formed?
by isolation of each pure compound
What type of penicillin is amoxicillin classed as?
semi synthetic
What is clavulanic acid made from?
streptomyces clavuligerus
What is a monoculture?
we only want to keep the desired organism growing
How much broth is made for clavulanic acid?
100,000L of broth every 12 hours
What is a key challenge of fermentation of beta lactams?
the process is aqueous and the beta lactam structure is prone to hydrolysis
What can improve the stability?
chilling batches and modifying the pH
Why does stability need to be improved?
to mitigate losses
What is benzylpenicillin made from?
penicillium chrysogenum (fungus)
Steps of fermentation?
spore preparation
seed fermentation
production fermentation
harvest
What is benzylpenicillin converted to?
6-APA (aminopenicillanic acid) by enzymatic cleavage of the amide side chain
How can amoxicillin be made?
either synthetic or enzymatic processes can be used to add alternative side chains to th 6-APA core molecule
After fermentation, what is the ‘broth’?
a dilute mixture containing large molecules, trace salts, proteins, dissolved materials
What is membrane technology used to do?
filter through fine membranes and then reverse osmosis to concentrate the volume down to a manageable amount
What does resin treatment do?
absorbs proteins that would precipitate in solvent mixtures downstream
What is post initial clean up?
material is fed into a continuous solvent extraction loop
What do delays in extraction cause?
degradation and efficiency losses
pH and temperature are important in managing stability challenges
Steps of extraction?
ultrafiltration
reverse osmosis
resin
forwrd extraction
carbon treatment
What does carbon treatment do?
treatment to remove coloured impurities
adsorbs coloured impurities associated with any degradation prior to isolation
What is critical when extracting from aqueous into solvent?
the ratios, pH and temperature
ensures effective extraction with minimal degradation losses of the unstable material at low pH
What are the steps of isolation?
back extraction
intermediate isolation
K salt conversion
pre-mix blend
What does isolation do?
isolates the product that we are interested in
What is back extraction?
the material is back extracted into an aqueous solution, the pH adjusted to control byproduct impurities that carry through the extraction processes and then crystallised to solvent
What do washing and drying do?
ensure product quality not just at the point of manufacture but throughout the product shelf life
What does increased moisture during storage lead to?
degradation
What is potassium clavulanate isolated as?
not pure active pharmaceutical ingredient but is blended with inert excipients prior to being formulated into a drug
What do pharmaceutical industries need to ensure?
that the processes involved in developing, producing, testing and distributing their drug products do not negatively affect the quality and efficacy nor patient safety
What is vital?
that product quality is built into all stages of industrial production and this involves applying a product lifecycle management approach
What are the 3 stages of the PLM?
stage 1 - process design
stage 2 - process qualification
stage 3 = continued process verification
What is root cause analysis?
identifying the problem and fixing exactly what it is
What is technical risk assessment?
to predict technical and operational risks based on knowledge and process understanding, implementing mitigation actions to prevent issues from occuring
What is vital to ensure product quality?
understanding the link between critical parameters and critical atrributes
