Media Fills Purposes

Media fills, broth fills, simulation trials and so on, are all synonymous names for an exercise undertaken as part of the validation of a new aseptic process, and as a frequent validation review thereafter. Regulatory pressure to repeat media fills at six- and even three-month intervals, is gradually merging media fills into routine environmental monitoring programs.

The purpose of the media fill is to provide a measure of the likelihood of microbiological contamination arising in particular aseptic processes. A placebo is substituted for the product, and is processed in an identical manner identical to the processed product.

In its simplest form, an aqueous liquid microbiological growth medium is substituted for an aqueous liquid product. The medium is incubated, the number of contaminated versus uncontaminated units are scored, and decisions made based on the number or proportion of contaminated units, and from the identities of the contaminating microorganisms.

It should initially be emphasized that media fill results do not provide an index of the probability of nonsterile product units in product populations. In other words, they do not represent a measure of the Sterility Assurance Level (SAL) achieved for any particular aseptically filled product. This conceptual difference between the proportion contaminated in a media fill and the SAL of sterile products is generally poorly understood.

In properly conducted media fills the aseptic process is simulated exactly as it would be carried out routinely. The only difference is the use of a placebo to replace a pharmaceutical product. An aqueous placebo is used to simulate aqueous liquid dosage forms, a solid placebo to simulate sterile solid dosage forms, and something with similar rheological characteristics to an ointment to simulate ointments.

Table 3.1 compares the composition of the placebo most commonly used for aqueous liquid media fills, Tryptone Soy Broth (TSB), with the formulation of a typical aqueous injection. There is no coincidence. TSB is widely used as a placebo for media fills as a general-purpose microbiological growth medium, in which a broad spectrum of types of microorganisms is expected to survive and multiply.

Table 3.1 Comparison of TSB with an Aqueous Injection

Aqueous Injection (g/l)

Drug substance Casein

Soy bean meal

Dextrose

Phenol

NaCl

K2HPO4

KH2PO4

Na2HPO4

The injection described in Table 3.1 has been formulated for completely different purposes, most significantly containing a preservative (0.5% phenol) for the express purpose of inhibiting the survival and growth of microorganisms. The proportion of contaminated units found in media fills is based on the process in which this product is filled. This is arguably the worst SAL for this aqueous injection, or any other aqueous injection filled in the same process. Frankly, however, this is unlikely to bear a major resemblance to the real probability of finding a nonsterile unit in a manufactured population, batch or lot.

Another example to emphasize the same point — that media fills simulate process contamination and not SALs — is evident when different dosage forms with different formulations, drug substances, preserved and nonpreserved, etc. are manufactured in the same filling process. It is not feasible that they should all produce the same SALs, because of the effects of their formulations on contaminant survival. But it is only usual to perform one set of media fills for each process and to obtain only one index of the probability of contamination in the process.

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