Quality Assurance in Formulation Design and Development

QUALITY ASSURANCE IN FORMULATION DESIGN AND DEVELOPMENT

The risk of microbial infection and spoilage arising from microbial contamination during manufacture, storage and use could be eliminated by presenting all medicines in sterile, impervious, single-dosage units. However, the high cost of this strategy restricts its use to situations where there is a high risk of consequent infection from any contaminants. Where the risk is assessed as much lower, less efficient but less expensive strategies are adopted. The high risk of infection by contaminants in parenteral medicines, combined with concerns about the systemic toxicity of preservatives, almost always demands sterile single-dosage units. With eye drops for domestic use the risks are perceived to be lower, and sterile multidose products with preservatives to combat the anticipated in-use contamination are accepted; sterile single-dose units are more common in hospitals where there is an increased risk of infection. Oral and topical routes of administration are generally perceived to present relatively low risks of infection and the emphasis is more on the control of microbial content during manufacture and subsequent protection of the formulation from chemical and physico-chemical spoilage.

As part of the design process, it is necessary to include features in the formulation and delivery system that provide as much suitable protection as possible against microbial contamination and spoilage. Owing to potential toxicity and irritancy problems, antimicrobial preservatives should only be considered where there is clear evidence of positive benefit. Manipulation of physico-chemical parameters, such as A_w, the elimination of particularly susceptible ingredients (e.g. natural ingredients such as tragacanth powder, used as a thickening agent), the selection of a preservative or the choice of container may individually and collectively contribute significantly to overall medicine stability. For ‘dry’ dosage forms where their very low A_w provides protection against microbial attack, the moisture vapour properties of packaging materials require careful examination.

Preservatives are intended to offer further protection against environmental microbial contaminants. However, as they are relatively non-specific in their reactivity, it is difficult to calculate with any certainty what proportion of preservative added to all but the simplest medicine will be available for inactivating such contamination. Laboratory tests have been devised to challenge the product with an artificial bioburden. Such tests should form part of formulation development and stability trials to ensure that suitable activity is likely to remain throughout the life of the product. They are not normally used in routine manufacturing QC.

Some ‘preservative challenge tests’ (preservative efficacy tests) add relatively large inocula of various laboratory cultures to aliquots of the product and determine their rate of inactivation by viable counting methods (single challenge tests), while others reinoculate repeatedly at set intervals, monitoring the efficiency of inactivation until the system fails (multiple challenge test). This latter technique may give a better estimate of the preservative capacity of the system than the single challenge approach, but is both time-consuming and expensive. Problems arise when deciding whether the observed performance in such tests gives reliable predictions of real in-use efficacy. Although test organisms should bear some similarity in type and spoilage potential to those met in use, it is known that repeated cultivation on conventional microbiological media (nutrient agar, etc.) frequently results in reduced virulence of strains. Attempts to maintain spoilage activity by inclusion of formulation ingredients in culture media give varied results. Some manufacturers have been able to maintain active spoilage strains by cultivation in unpreserved, or diluted aliquots, of formulations.

The British Pharmacopoeia and the European Pharmacopoeia describe a single challenge preservative test that routinely uses four test organisms (two bacteria, a yeast and a mould), none of which has any significant history of spoilage potential and which are cultivated on conventional media. However, extension of the basic test is recommended in some situations, such as the inclusion of an osmotolerant yeast if it is thought such in-use spoilage might be a problem. Despite its accepted limitations and the cautious indications given as to what the tests might suggest about a formulation, the test does provide some basic, but useful indicators of likely in-use stability. UK product licence applications for preserved medicines must demonstrate that the formulation at least meets the preservative efficacy criteria of the British Pharmacopoeia or a similar test.

The concept of the D-value as used in sterilization technology  has been applied to the interpretation of challenge testing. Expression of the rate of microbial inactivation in a preserved system in terms of a D-value enables estimation of the nominal time to achieve a prescribed proportionate level of kill. Problems arise, however, when trying to predict the behaviour of very low levels of survivors, and the method has its critics as well as its advocates.