Process Design and Mode of Operation

Many process-related aspects of manufacture of pharmaceutical preparations contribute to contamination, or conversely, to contamination control. These are generally product-specific, but some have intrinsic similarities amongst groups of products.

Figure 4.4 shows a process flow diagram for creams manufacture, given as an example for creams, lotions, gels and ointments. The major items of equipment are the fats vessel, the manufacturing vessel and the holding vessel. These three vessel types are general to all topicals manufacturing processes. Creams and lotions are at greater risk from microbiological contamination and proliferation than ointments and gels for formulation-related reasons.

Closed fats and manufacturing vessels are best from a microbiological standpoint because they are amenable to application of Clean-in-Place (CIP) systems. These usually afford opportunities for higher temperature cleaning than do manual systems.

They are now commonly used, although the reason for this may have as much to do with facilitating the process, as to preventing microbiological contamination. Where open vessels are used and have to be cleaned out by hosing, there are significant risks of spreading and aerosolizing contamination throughout the area.

Materials are heated in both the fats and the manufacturing vessels to temperatures likely to inactivate most Gram-negative microorganisms, even if initially present in large numbers. Gram-positive spore-forming bacteria generally withstand these temperatures. These heating processes are pretty effective at minimizing the numbers of microorganisms introduced with ingredient water, raw materials and environmental air.

The drainage from the fats and manufacturing vessels may contribute to general microbiological contamination of topicals manufacturing areas. Control of this is not solely associated with leaving air breaks between floor and vessel drains to avoid backflow of polluted water into the vessels. It is also connected with the potential for drains to be blocked with solidified fats. Large volumes of water, which only have to comply with the microbiological limits for potability, may have to be used for the first stages of cleaning these vessels. If drains are not adequately provided with fat traps to ensure that the waste water is taken away fast enough, they may block and overflow. This results in the consequent spread of contaminants on floors and via the feet of personnel working in the area.

Most microbiological contamination in topicals manufacture arises from drains and wash-bays. The most significant vectors are personnel. Whereever possible personnel who work in wash-bays and with water should be required to wear dedicated footwear in these areas and rubber aprons to prevent their working garments becoming wet and contaminated. There is a significant risk of these personnel carrying contaminants to creams, gels, lotions and ointments during their transfer to the holding vessels, when the product has been cooled to temperatures at which microorganisms are likely to survive. Even products such as ointments and gels that are intrinsically unlikely to support microbial growth, have been known to become contaminated in holding vessels. There is evidence (in the public domain) of pseudomonads grown on films of condensed water lying on the surface of ointments and creams in holding vessels. Covering product surfaces in holding vessels with plastic "skins" is one means of minimizing this possibility.

Figure 4.5 shows a process flow diagram for syrup manufacture, as an example for solutions, suspensions and syrup. Again there are three types of vessel — ancillary, manufacturing and holding. As with topicals manufacture, the heating stages in manufacture are quite effective at minimizing microbial contaminants coming from ingredient water and raw materials.

Again, as with topicals, process-related sources of contamination are mainly from potable water used for cleaning and foul water from drains. Personnel and water are the most potent vectors of contamination. When possible, CIP systems provide better control of microorganisms than manual cleaning. It is an interesting and curious anomaly that vessels in which oral suspensions have been manufactured are most difficult to clean from a chemical cross-contamination standpoint, but vessels and pipework in which syrups have been manufactured are most difficult to clean from a microbiological standpoint. Validation criteria based on suspensions being the worst case (most difficult to clean), may not effectively address the risk of microbiological contamination after syrup manufacture.

If syrup residues are not cleaned from valves, pipework, filters, etc., they may create opportunities for environmental microorganisms to survive, proliferate, and create further problems. Screw-thread pipework connections must be avoided. There are frequently permanent hard-piped systems several metres long. They take oral liquids from manufacture to filling. Dead-legs and other foci for microbial proliferation in these pipework systems must be avoided. Such systems should preferably be designed as "demountable" for cleaning.

The manufacture of inhalation products requires more attention to microbiology than manufacture of topicals or oral liquids. This is because inhalation products couple a severe risk to patient health from the route of administration with a

Ingredient: Water


Manufacturing vessel with heating to 70-90°C and subsequent cooling to <40oC

Holding vessel

Wash bay

Holding vessel

Wash bay


Figure 4.5. Generalized process flow diagram for syrup manufacture.

manufacturing process that does not necessarily incorporate any antimicrobial stages.

Manufacture of inhalations does not necessitate special manufacturing or filling equipment. It is possible, but quite unusual, for heating to be required for dissolution or suspension of the active ingredients. If manufacturing vessels are jacketed, it is to support high-temperature cleaning and sanitization. They are jacketed to support microbiological (rather than chemical or pharmacological) properties of the product.

Potable water is of insufficiently high microbiological quality for use in cleaning equipment during inhalations manufacture. Water complying with the microbiological limits for purified water must be used, even in the initial stages of cleaning product-contact parts and equipment. The concentration on cleanliness extends beyond the manufacturing process, to the control of the containers into which inhalations are filled, and to the applicators through which the products are administered to the patient.

4.3 Formulation-Related Microbiological Control

The problem of water content affecting the probability of microbial proliferation in pharmaceutical preparations has been discussed. Additionally, other formulation-

related factors can influence microbial proliferation. Generally these are the inclusion of antimicrobial agents in formulations.

Gels and lotions frequently contain large concentrations of alcohols (e.g., iso-propanol) for therapeutic reasons, such as rapidity of evaporation and provision of a "cooling" effect on the skin. More frequently, antimicrobial agents are included specifically for their preservative effects.

There is often some confusion as to exactly why preservatives are included in pharmaceutical preparations. They are included in multidose presentations to ensure that microorganisms — which inevitably contaminate preparations after they are first opened by the patient — do not proliferate to unacceptable levels before the patient finishes the course of treatment. The confusion arises because the same antimicrobial action providing "bathroom shelf" protection, can (a) prevent microorganisms multiplying over the unopened shelf life of the product, and (b) may also inactivate any microorganisms that contaminated the preparation in manufacture. However true this may be, and however effective the preservative system may be in particular preparations, it is totally unacceptable for preservation to be used as an excuse for poor microbial control in manufacture.

The measure of the effectiveness of preservative systems in pharmaceutical preparations is defined by the antimicrobial effectiveness tests described in detail in the pharmacopoeias.

The details of antimicrobial effectiveness tests differ between USP and PhEur. Nonetheless they follow very similar principles. A sample of product is inoculated with a specific culture. Subsamples are withdrawn at time zero and at intervals thereafter, and the number of viable microorganisms surviving is counted. According to the number of numerical logarithmic reductions at particular time intervals, the preparation passes or fails the test. This test must be done individually against a specified array of microorganims intended to represent the types of contaminant found in the bathroom-shelf environment. Some manufacturers support the inclusion of microorganisms from the local manufacturing environment in this array. It is unclear how these species can be considered relevant to the purpose intended for the inclusion of preservatives in formulations.

The advantage of performing a microbiological test of preservative activity over a chemical assay is that it takes account of any binding or inactivation of the preservative within the formulation that may impair its biological activity, but might not be detected by chemical assay. The antimicrobial effectiveness test must be done in new-product development and initially for determining product stability. Once the biological effectiveness has been established during new-product development, routine quality control may confine itself to chemical assay of preservative content.

In performing this test, it is preferable to inoculate product within its market container. It is mandatory that the volume that contains the inoculum is minimized in relation to the volume of product inoculated. This in itself may present serious technical difficulties. Good mixing is essential. This is often difficult to do in an ointment tube. Poor mixing may result in erratic results in the antimicrobial effectiveness test.

It should not be assumed that all aqueous-based nonsterile pharmaceutical preparations are preserved. There are pressures — regulatory and otherwise — to move to more nonpreserved nonsterile dosage forms. Although there are some containment systems allegedly designed to prevent ingress of microorganisms after delivering the dose, nonpreserved preparations are not generally suited to multidose presentations because they have no bathroom-shelf protection. They tend to be filled into single-dose presentations, such as nasal drops or sprays in plastic nebules. Soft gel capsules could be another route, but would require formulation in nonaqueous bases.

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