SPOILAGE
Introduction
The process of deterioration of pharmaceutical products by the contaminant microbes is known as microbial spoilage. A stable and effective medicine may get contaminated and damaged due to microbial growth. These microbes can enter the product either during manufacturing or use by the patient or medical staff. Such spoilage either results in immediate product loss or increased lactic acid litigation cost that whether the spoilage will harm the user, thus leading to financial problems to the manufacturer.
Based on its proposed use, a pharmaceutical product is considered to be microbiologically spoiled due to:
1) Presence of low levels of acutely pathogenic microbes or higher levels of opportunist pathogens,
2) Presence of toxic microbial metabolites even after death or removal of initially present microorganisms, and
3) Occurrence of detectable physical or chemical changes in the product.
Formulating an economic product of desirable efficiency, stability, and patient acceptability requires the incorporation of various ingredients in a complex physical balance. This potentially increases the risk of microbial attack and even microbial growth in the product. Since the demand of sterile or self-sterilising products is increasing, the formulators should establish a system having low levels of microbial contamination, or even if it occurs the microbes either fail to multiply or multiply minimally during the product life.
Types of Spoilage
Spoilage may be of the following types:
1) Oral medications have a variety of microorganisms, few of which are infective. However, tablets or capsules of yeast. thyroid, pancreatin, and carmine are
con With Salmonella species, thus causing infections. The antacid suspensions (mainly those flavored with peppermint water) often get con with Pseudomonads and causes bowel infections.
High levels of infection-causing Pseudomonads are often present in dilute antiseptic and disinfectant solutions of quaternary ammonium type. These pathogenic agents either cause food spoilage infection or serve as reservoirs of contamination. Such preparations become readily inactive during use and have poor activity towards these microorganisms. which thus survive and start multiplying in them.
The available regulatory restrictions of recent years have failed to reduce the incidence of drug-induced infections. At the current time, the main concerns are the high occurrence of in-use contamination of infusion and Total Parenteral Nutrition (TPN) fluids; and the antiseptics and aqueous oral mixtures (contaminated with gram-negative bacteria) which cause harmful infections to a large number of patients receiving immunosuppressive therapy.
Microbial toxins present in pharmaceutical products are the pyrogens (microbial lipopolysaccharides) liberated by gram-negative bacteria and blue-green algae (cyanobacteria), and pyrogenic substances liberated by fungi. Pyrogens present in infusion fluids may cause acute febrile shock. Pyrogenic reactions resulting from contaminated hemodialysis fluids have been recorded.
Also, there is some evidence that pharmaceutical products contain bacterial toxins causing food poisoning spoilage bacteria; although pharmaceutical products are detected with toxigenic fungi including aflatoxin-producing Aspergilli. The irritant products of degradation (such as salicylic acid) produced by microbial hydrolysis of aspirin or of the allergenicity of high levels of microorganisms cause a potential problem.
2) Chemical and Physicochemical Deterioration of Pharmaceutical Products: The degradation frequency of microorganisms is such that all organic matter is subjected to chemical modifications under conditions milder than those for reactions performed by non-biological processes. Biological half-lives of materials released into the environment range from hours (phenol) to months (surfactants) to years (halogenated pesticides).
Biodegradable material accumulating in the environment is the result of localized adverse conditions or the absence of particular microorganisms. For example. lignans accumulate as peat and persistence of oil slicks in seawater. However, this discussion is restricted only to the fate of ingredients within the specialized microenvironments of various types of pharmaceutical formulation, rather than their subsequent fate when released into the biosphere.
The degradation rate of ingredients depends on their chemical structure, the
Physicochemical properties of the product. and the microbial contamination level
Present. 'The liability to attack ingredients and the physical characteristics of some Pharmaceuticals lead to microbial growth from metabolites, thus the degradation rates of recalcitrant components are enhanced along with the rapid onset of formulation destruction. The initial attack by a group of spoilage organisms makes the product Vulnerable to the second group of organisms, thus causing more damage.
3) Ingredients Subject to Microbial Attack: The ingredients easily attacked by microbes are:
i) Cationic Surfactants: The surfactants used as antiseptics and disinfectants in pharmacy are resistant, although there are reports of the microbial attack at both
'use' concentrations and diluted. as occurring in sewage. Gram-negative bacteria grow extensively in these solutions at the expense of other ingredients, e.g., using ammonium acetate buffer as a vehicle.
ii) Anionic Surfactants: Alkali-metal and amine soaps of fatty acids are readily degraded in sewage but are normally stable in their slightly alkaline formulations. Alkyl, alkylbenzene sulfates, and sulphonates undergo metabolism when the terminal methyl group is attacked with sequential oxidation of the alkyl chain and cleavage of sulfate from the fruits and vegetable molecule after aromatic ring fission. The ease of degradation decreases with an increase in length and complexity of alkyl chain branching. Alkyl sulfates and alkyl ether sulfates undergo oxidation readily compared to the recalcitrant polypropylene alkyl benzene sulphonates. The released sulfate reduces to hydrogen sulfide by the sulfate-reducing anaerobic bacteria in shampoos; thus, indicating the generation of very low oxygen tensions in viscous formulations.
iii) Non-Ionic Surfactants: Alkylpolyoxyethylene alcohol emulsifiers readily undergo metabolism by various microorganisms. ease of degradation again decreases with an increase in length and complexity of alkyl chain branching. Alkylphenol polyoxymethylene alcohols are attacked in the same way but are more resistant. After the lipolytic release of fatty acids from Sorbian esters, polysorbates, and sucrose esters, the cyclic nuclei degrade to produce nutrients for microbial growth.
iv) Ampholytic Surfactants: Phosphatides and some betaine derivatives readily undergo degradation. Accumulation of the early, recalcitrant, anionic detergents in the biosphere results in the designing of such anionic and non-ionic surfactants which readily metabolize, and thus cause nutritional hazards to pharmaceuticals formulated with them.
v) Organic Polymers: Various thickening and suspending pharmaceutical agents result in nutritive fragments and monomers when subjected to microbial depolymerization by extracellular enzymes, e.g., amylases (starches), pectinases (pectin), celluloses (carboxymethylcellulose), urbanites (tragacanth and acacia). dextranases (dextran), and proteases (proteins); the enzyme names are mentioned along with their substrates in parenthesis.
Agar is used as an inert support for culture media because even if agar degrading microorganisms are present, agar rarely undergoes depolymerization. Polyethylene glycols readily undergo degradation by sequential oxidation of hydrocarbon chains, except for the very high molecular weight congeners. Recalcitrant polymers are used in plastic packaging; however, cellophane is an exception subjected to cellulolytic attack in some cases.
vi) Humectants: High concentrations of glycerol and sorbitol used in pharmaceutical formulations support microbial growth.
vii) Fats and Oils: These hydrophobic materials are attacked by microbes when dispersed in aqueous formulations; although fungal growth is observed in condensed moisture films on the surface of bulk oils or when the bulk phase is contaminated during storage by water droplets.
The lipolytic rupture of triglycerides releases glycerol and fatty acids: in the latter, ß-oxidation of the alkyl chain occurs producing odorous ketones
Microbial metabolism of hydrocarbon oils poses a problem in engineering and
technology When water also acts as a contaminant: although only limited evidence of this case has been reported in pharmaceuticals. Cladosporium retinae cause the metabolism of food products of aviation kerosene. thus, inducing corrosion in aircraft. resulting in the build-up of acid products.
viii)sweetening. Flavoring, and Colouring Agents: Sugars and other sweetening agents used in pharmaceutical preparations act as substrates for microbial attack. concentrated stock solutions of sugars (syrups) having low water activities are resistant to microbial attack. although evidence of their spoilage by the growth of osmophilic yeasts has been reported and therefore preservatives are added. Aqueous stock solutions of flavoring agents (e.g... peppermint water and chloroform water) and coloring agents (e.g., amaranth or tartrazine) support the growth of bacteria and yeasts; while simple stock solutions of savoring agents are no longer used, and of coloring agents are still commonly used for dispensing.
ix) Potent Therapeutic Agents: It has been demonstrated by laboratory experimental reports that many drugs undergo gross degradation by various microbes. which spoilage is the process either destroys or changes the therapeutic efficiency. Materials like alkaloids (e.g., morphine, strychnine, atropine. etc.). analgesics (e.g., aspirin. paracetamol, etc.). thalidomide. barbiturates. steroid esters. or mandala acid can undergo metabolism and serve as substrates for microbial growth.
Formation Of irritant salicylic acid from aspirin or of inactive products from penicillin (by ß-lactamase) or chloramphenicol (by chloramphenicol acetylase) or certain other antibiotics are examples of such spoilage. Microbial transformations yeasts and bacteria of steroid molecules form the basis of a valuable biotechnology tool used in the production of potent drugs from inert steroids.
Other drugs such as Ms danophone are highly recalcitrant; however, such attacks on pharmaceutical formulations meat and poultry have been rarely reported. Loss of potency of some alkaloids (e.g., atropine in eye drops and in an oral medication) and degradation Of aspirin and paracetamol in aqueous formulations have been recorded. Penicillin injections have been found to be inactivated by ß-lactamase-forming bacteria. Localized transformation of steroids occurs around fungal colonies developing on the steroid tablet surfaces and in steroidal creams.
x) Preservatives and Disinfectants: Most of the organic preservatives and disinfectants undergo metabolism by various bacteria and fungi; and even sometimes act as growth substrates at concentrations below the 'use' levels, as in sewage and effluent with the exception of quaternary ammonium antimicrobial agents.
Halogenation or nitration increases recalcitrance up to a considerable level. Rapid microbial conversion of organomercurial preservatives is of the main concern. These preservatives are used and released in industrial effluent in large quantities that spoil food infect humans via an ascending food chain. Microbial degradation at 'use' levels of these antimicrobial agents is rarely reported but includes a few metabolisms including that of chlorhexidine, cetrimide, phenolics, phenylethyl alcohol, and benzoic acid acetic acid .
It has been reported that benzalkonium chloride is utilized at a concentration below the 'use' levels, but rapid utilization of-hydroxybenzoate esters (
concentrations previously recommended for preservation of eye ropes another aqueous pharmaceutical mixture) occurs by various food preservation Pseudomonads and related bacteria, including Pseudomonas aeruginosa, often using them as substrates for growth.
4) Observable Effects of Microbial Attack in Pharmaceutical Products: In a pharmaceutical product, microbial spoilage becomes visible if there is a very high contaminant level or extensive multiplication. However, bacterial growth is observed on a surface moisture film (and not in the bulk of the product) or is indicated by the production of odoriferous products.
Aqueous products and water in the early stages of microbial attack develop earthy tastes. Microbial spoilage results in unpleasant tastes and odors; for example, sour-tasting fatty acids and ketones; fishy odor of amines, spoilage including 1-12S, and ammonia; or metabolites with bitter, sickly, or alcoholic tastes and odors. Apart from the colored microbial colonies or sediments, the formulations may also become green, pink, brown, black, or yellow-colored due to the diffusible microbial pigments.
Depolymerisation of thickening and suspending agents reduces the viscosity and sedimentation of suspended materials. The sugary products and concentrated shampoos are reported to develop polymeric, slimy strands. Spoiled creams become lumpy or gritty to feel. The product pH varies due to the build-up of metabolites. Yeast attack of some acidic products raises the pH to a clostridium perfringens extent allowing microbial attack, which was formerly inhabited. Bubbles of gaseous metabolites accumulate in viscous formulations and also cause ballooning of flexible plastic packages.
The o/w (oil-in-water) emulsions and creams serve as rich substrates for microbial attack and undergo gross deterioration in their physicochemical structure. Surfactant degradation and pH reduction by lipase attack of triglycerides induce progressive coalescence of lipid droplets, ultimately leading to preservation methods cracking (i.e., complete separation of the two phases) and forming an intermediary, unstable, w/o emulsion state. Most of the surfactants lose their surface activity at a very early stage due to metabolism. Plastics (e.g., polyethylene) may undergo a pink discoloration after limited fungal colonies are formed.
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