There are several broad areas to which contamination may be traced in the manufacture of all pharmaceutical preparations. Figure 4.3 shows a schematic representation of the sources of contamination in any nonsterile manufacturing facility. The main sources are:
• Incoming raw materials and ingredient water
• Facilities, services and cleaning materials
Environmental air Personnel
Raw materials are necessary and cannot be eliminated as sources of microbiological contamination. Pharmaceutical preparations should be formulated with raw materials that are unlikely to be sources of contamination. In principle, this means avoiding raw materials originating from plants or animal. Specifications for raw materials are generally defaulted to something in the order of 1000 cfu per gm or ml. It is often a difficult and contentious task to argue with vendors for the application of tighter microbiological specifications to raw materials used in critical applications.
Raw materials comprise the greater part of all topical formulation bases, thus, in terms of proportional contribution to microbiological contamination, they present the greatest threat.
Water is the base for lotions and creams, and so possibly the most significant source of contamination in any pharmaceutical preparation. It may be a source of contamination. It may be a vector for transmitting contamination. Its presence may encourage the proliferation of contaminants. Very significantly, water is the main habitat for Gram-negative types such as the pseudomonads, which are extremely metabolically versatile and potentially hazardous to topical preparations. Stringent microbiological controls are applied to ingredient water used in pharmaceutical manufacture.
The bases for gels are mainly cellulose derivatives, such as carboxymethyl-cellulose, prsenting only minor sources of microbiological contamination. For ointments, the base is generally something like petrolatum or white soft paraffin, very rarely sources or vectors of microbiological contamination. Although unlikely to be major sources of microbiological contaminants, it is essential they be sourced from suppliers who have given sound consideration to hygiene and microbiological control in the design of their manufacturing and distribution practices.
In addition to their bases, topical products also contain numerous excipients for emulsification, for maintaining suspensions, for absorbing water, for leaving protective films on the skin, and so forth. Some may be sources of microbiological contamination, for example, microcrystalline celullose, cetyl alcohol, stearyl alcohol, cetostearyl alcohol.
Water is the base and main raw material source of microbiological contamination to oral solutions and suspensions. In syrups the base may be sugar (sucrose), or in sugar-free syrups, sorbitol or hydroxypropoyl methyl cellulose. Sugar (sorbitol, hydroxypropyl methyl cellulose, etc.) may contribute to 60% or more by weight of the formulation. Sugar solutions up to about 65% by weight provide an excellent nutrient environment for molds, yeasts and other osmophilic microorganisms.
Microbiological specifications for sugar often contain special provision for limits on yeasts and molds, and may specify particular media for their detection. It is clearly impossible to apply the microbiological default specification of no more than 1000 cfu per g to sugar used at 60% concentration in a syrup with a finished product specification of (say) no more than 100 cfu per ml. A batch of sugar with contamination near the limit could be "passed" at incoming QC and then lead to "failure" of the finished pharmaceutical preparation after all other value has been added.
Tighter specifications must be applied, though it is often difficult to persuade suppliers to guarantee conformance to specification, particularly when pharmaceutical applications are only a small part of that supplier's output. Sometimes the willingness of a supplier to meet these demands is quite simply a cost function.
Emulsifying agents are essential to maintaining the stability of oral suspensions. They may be:
• Of natural origin (gelatin, casein, acacia, tragacanth, pectin, etc.)
• Finely divided solids (bentonite, aluminium hydroxide, magnesium trisilicate, etc.)
• Synthetic (sodium lauryl sulfate, benzalkonium chloride, etc.).
Those of natural origin are almost always microbiologically contaminated. Those of vegetable origin (such as acacia and tragacanth) often have large associated numbers of desiccation-resistant bacteria such as Bacillus. Other emulsifying agents rarely pose a microbiological problem.
Aqueous-based inhalations, may, according to the solubility of the active, be solutions or suspensions. All concerns regarding water in relation to other aqueous preparations apply equally to inhalations.
Microcrystalline cellulose is one of the agents most commonly used for maintaining insoluble actives in suspension. While microcrystalline cellulose is widely used in other pharmaceutical applications, tighter microbiological specifications may be required when it is used for inhalation preparations. This route of administration is thought to present a greater challenge to patient health than oral or topical routes. Thus the potential for particular microorganisms to be considered objectionable is greater.
Facilities are rarely intrinsic sources of microbiological contamination. Poorly designed facilities, poor materials of construction and poor operational practices can, however, have a significant influence on levels of contamination originating from other sources associated with the facility.
New facilities for manufacture of pharmaceutical preparations can be designed to minimize internal sources of microbiological contamination and to facilitate hygiene. Numerous other matters have to be considered in new-facility design. Therefore, prioritization is always necessary for the inevitable compromises to have pragmatic and sensible outputs. Existing facilities may present vulnerabilities to microbiological contamination not been previously addressed through design. Microbiological control of such facilities is often difficult to resolve.
It is unfortunate — but true — that facilities that are difficult to clean cannot be cleaned properly. Microorganisms will survive and most likely proliferate in any area where dirt is allowed to gather. Visibility is one major focus point for cleanliness in facility design; it is difficult to reconcile hygiene with visible dirt, so walls, floors and ceilings should have light-coloured, smooth, cleanable, finishes. Floor-to-wall junctions should be coved, piping should be boxed in, cupboards and storage areas should be kept to a minimum and drains should be controlled.
Facility-related microorganisms may originate from cleaning materials (water), drains (foul water), services (cooling water, compressed gas). Most of these are water-related, again reflecting the importance of water as a source of contamination.
The cleaning process is intended to improve the cleanliness of the treated object. Sometimes it is ineffective. Many cleaning processes in pharmaceutical manufacture have been validated to avoid cross-contamination, with a focus therefore, on chemical cleanliness. It is quite possible that microbiological cleanliness may not be achieved on an object that is satisfactorily chemically clean. It is also possible that equipment and materials (e.g., water) used to obtain chemical cleanliness could leave the object in a poorer state of microbiological cleanliness than it initially was. This is not to say that there should be any greater stress on microbiological cleaning validation, perhaps only that there should be more emphasis on the microbiological validation of cleaning equipment and materials.
The main source of microbiological contaminants from cleaning is water. Water is typically the cleaning agent of choice. All cleaning water in facilities for the manufacture of pharmaceutical preparations must be of good microbiological quality. The degree to which cleaning water must be microbiologically controlled is a function of where it is to be used, what products and equipment it is being used in association with, and of the volumes to be used.
Potable water (generally to a microbiological specification of no more than 500 cfu per ml and absence of Enterobacteriaceae) is generally good enough for cleaning walls and floors in nonsterile manufacturing facilities. In some areas the municipal supply may easily meet these standards, but in others it is common to rechlorinate municipal or well supplies to ensure consistency, and to keep the distribution system in good order. Cleaning agents and disinfectants for walls and floors should be chosen carefully, even for these purposes. On occasions, personnel may become confused as to what is a cleaning agent, a disinfectant, and what is a proprietary cleaning agent-disinfectant combination. The author has experienced a facility in which product contamination with pseudomonads was traced to daily floor mopping with a cleaning agent thought to be a disinfectant but turned out to be something else.
Washing of product contact equipment and any product contact packaging components requires more attention to microbiological control than walls and floors. Solution residues may be easy to remove. Residues from suspensions (lotions and oral emulsions), syrups and semisolids (creams, ointments, gels) are difficult to remove. In the first instance the product residues must be removed to meet criteria for gross chemical cleanliness, along with materials that encourage the growth of microorganisms (e.g., sugar). Hot potable water would be the water quality of first choice, but it may be necessary to include the use of surfactants or cleaning agents. Residues of these surfactants may not be left on equipment and therefore the final rinses must be with water complying with the requirements of purified water (USP or PhEur). The microbiological limit applying to purified water is normally in the region of no more than 100 cfu per ml.
The most heavily contaminated water in pharmaceutical manufacturing facilities is in drains, the main habitat for Gram-negative microorganisms. These contaminants would be transmitted to other areas if there were a backflow, and on the feet and garments of operators who work close to drains (e.g., wash-bay operators). Drain locations should be minimized and facility design should ensure that drains are able to cope with expected volumes of water. Unused drains should be capped.
Cooling water is often of extremely poor microbiological quality (chlorination is often avoided to reduce the water's corrosion potential). Great care must be taken to ensure that it does not contaminate product through pin-hole or larger leakage in heat exchangers or jackets. Sometimes water of poor microbiological quality is used to cool glands on stirrers. Again, great care must be taken to ensure that O-rings and other seals are intact, in place and correctly specified. The author has experience of syrups rejected as a result of a pseudomonad contamination arising from a damaged seal in a water-cooled gland on a base-mounted stirrer in a manufacturing vessel.
Compressed gases are potentially potent sources of microbiological contamination in sterile facilities. This is because gas leakage, unlike water leakage, is not immediately visible. Gases are less likely to be major sources of contamination in nonsterile manufacturing facilities; nonetheless they may possibly lead to contamination, usually from Gram-positive desiccation-resistant species.
Environmental air is an unavoidable source and vector for microbiological contamination. It is not a medium for proliferation, and many microorganisms find it inimical. Most airborne contaminants are desiccation resistant, Gram-positive bacilli and cocci carried and protected on fragments of dust, saliva proteins, etc.
Control of airborne contaminants is often one of the greatest perceived concerns in new-facility design. For most nonsterile pharmaceuticals, however, the risk of significant problems arising from airborne microorganisms is insignificant when compared to the risks from water.
Filtration, pressure differentials and air flows are used to control the contamination potential from environmental air. The degree to which these are necessary is a function of risk to product.
Personnel are not only a source of microbiological contamination, they are also a vector for contaminants. People are mobile and unpredictable. They have their own microflora that can vary from person to person and occasion to occasion.
Even the healthiest, most hygienic person carries significant microflora — mainly staphylococci, micrococci and coryneform bacteria. Street clothing may carry a distinctly different microflora. Generally these microorganisms are harmless to the person and often to pharmaceutical preparations as well. The principles of containment apply to both the person (protective garments) and the process (line covers, laminar flow protection, etc.).
Illness changes the types of microorganisms originating from personnel, and increases their numbers. Pathogens like Staphylococcus aureus, Streptococcus spp., Enterobacteriaceae, etc. may be disseminated from open wounds, coughing, sneezing, skin-flaking, diarrhoea, etc.
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