Manufacturing Of Sterile Pharmaceutical Products Flashcards
Sterile pharmaceutical products must be free of…
Living microorganism e.g. bacteria, fungi, viruses
- patient at risk of infection
- risk of degradation of therapeutic agent/formulation
*Particles - can block capillaries
*Pyrogens - substances that raise body temperature causing fever
- can withstand sterilisation
- mainly lipopolysaccharide (endotoxin from the outerwall of gram-negative bacteria)
What medicinal products must be sterile?
Injectable formulation
Ophthalmic preparation
Solutions for nebulisation
Solutions for wound/bladder injection
Dressings, sutures, implants
Surgical materials
Techniques of sterile production
Terminal sterilisation
Aseptic sterilisation
Terminal sterilisation
Product is manufactured, sealed in final container + sterilised
- low risk of microbiological contamination
- used for sterilisation of raw materials + surfaces
- not always possible ( if drug is thermosensitive)
Aseptic technique
Medicine, container + closure are sterilised separately then combined in sterile environment e.g. Sodium Cromoglicate Eye Drops BP
- high risk of microbiological contamination in final product
- sterility assurance + control are crucial
Sterilisation processes accepted by BP
Moist heat (steam)
Dry heat
Ionising radiation
Gaseous sterilisation
Filtration
Which sterilisation processes are terminal?
Terminal = Biocidal processes (micro-organisms are killed)
- Moist heat (steam)
- Dry heat
- Ionising radiations
- Gaseous sterilisation
Which sterilisation processes are aseptic?
Aseptic = micro-organisms (and particles!) are physically removed from the product
- Filtration
What is Moist Heat (steam) process?
Sterilisation by saturated steam under pressure in an autoclave
- 121 degrees for 15 min or 134 degrees for 3 min
- efficient - organisms are killed by denaturation/hydrolysis of essential cell constituents
- used to sterilise bottled aqueous solutions, containers, dressings, instrumenta
- items must be packed to allow steam penetration + post sterilisation protection
What is the Dry Heat process?
Sterilisation in a hot air oven
- 160-180 degrees for 2 hours
- less efficient than steam (kill microorganisms due to oxidative processes)
- used to sterilise glass bottles + metal surgical instruments
- Advantage = destruction of pyrogens (250 degrees)
- Items must be packed to allow contact with heat and post-sterilisation protection
What is the Ionising Radiation process?
Sterilisation using accelerated electrons/gamma rays
- damage DNA of microorganism (biocidal)
- used for heat-sensitive products (can accelerate degradation of plastics or aqueous drug solutions)
- used for sterilisation of ointments, instruments, sutures etc.
- BUT…UV radiation is not suitable for the sterilisation of pharmaceutical products (not as efficient at killing micro-organisms as ionising radiations)
What is the Gaseous Methods process?
Sterilisation using toxic gas e.g. ethylene oxide/ formaldehyde
- biocidal activity due to chemical modifications of proteins + nucleus acids
- used to sterilise powders + instruments
- sterility assurance is lower than with heat processes
- the toxic gases are mutagenic + carcinogenic = protection of staff
What is the Filtration of solutions process?
Sterilise heat sensitive injectable or opthalmic solutions
- pore diameter of filters: 0.22 micro moles
- removal of particles (can’t use for suspension formulations)
- different types of filter depending on solution properties
- Requires working in laminal flow cabinet which provides a sterile environment
What is a Laminar airflow cabinet?
Provides continuous, unidirectional flow of clean filtered air
How to sterilise aqueous pharmaceutical product?
How to sterilise non-aqueous pharmaceutical products?
How to ensure product sterility?
Sterility control
Sterility assurance
What is Sterility control?
Incubation of the whole or portion of the product with a nutrient medium to verify abscence of contamination
- Legally required
Limitations of sterility tests
- Product is destroyed
- Few samples of each batch are tested
- Not reliable
- Do not detect presence of viruses
Unsuitable for personalised medicines produced for individual patients
Offer no guarantee of sterility for all products of a batch
What is Sterility Assurance?
Working in a clean environment
Follow GMP/GWP rules
Use contamination free-starting materials
Suitable packaging + storage
Validation + in-process control of sterilisation
Crucial to guarantee sterility and patient safety
Cleaning procedures
-
Regular cleaning/disinfection
- floor + horizontal surfaces cleaned + disinfected everyday
- ceiling + walls cleaned + disinfected @ once a month
-
Design of premises
- smooth surfaces + rounded coving to prevent accumulation of dust + easy cleaning + disinfection
- separation of storage + prep areas from aseptic production areas
- different routes for staff + materials
- unidirectional flow of sterile products
- supply of filtered air @ positive pressure
-
Suitable clothing
- sterile trouser suit, hat enclosing hair, facemask, gloves, overboots
- non-shedding materials
- non-reusable
-
Strict changing procedures
- passage from outside to clean area via dividing step over sill
- outer garments removed in the ‘black area’
- hands washed in a sink with elbow/foot operated taps
Disinfectants
Remove microorganism from objects/surfaces
Antiseptic
Active against microorganism on living tissue
Preservatives
Added to pharmaceutical, cosmetic, food products to avoid microbial spoilage
In-process control of procedures
Biological indicators
Chemical indicators
Physical indicators
Biological indicators
Heat sterilisation - Ampoules containing spores of a heat resistant bacteria placed in autoclave/oven
Aseptic filtration - Filtration of culture of a non-pathogenic bacteria of 0.3 mM through 0.22 mM pore size filter
Incubation to verify absence of bacterial growth in the medium
Limitations: incubation time!
Chemical indicators
Chemical indicators - Melt when the T° is reached or change colour when irradiated
- Highlight a failure in the process but do not confirm this has been completed successfully
Physical Indicators
Heat sterilisation: temperature record (+ time T° was maintained for autoclaving)
Aseptic filtration: integrity of the filter
- Bubble point pressure test for membrane filters
- Retention of particles of known dimensions for HEPA filters
