Filling trials

Media Filling Trials Media fills are intended to simulate the risk of contamination that may arise from the aseptic assembly of sterile product elements by substitution of a sterilized placebo for the dosage form. The placebo should be chosen to be of similar flow/filling performance characteristics to the sterilized dosage form to mimic accurately the normal conditions of the production process. 

Before conducting a trial for initial validation purposes, all aspects of every aseptic control system should have been verified as meeting their validation standard. Microbiological monitoring above and beyond that normally expected should be done in the filling room before and after the filling trial. 

For liquid filling trials the containers need only be filled with sufficient media to wet all of the interior surfaces in a manner that simulates exposure in normal production. In other words, it is not necessary to simulate the exact volume of liquid filled in routine production. Indeed, exact simulation could create a quite impossibly large demand for sterile media beyond the capacity of laboratory sterilizers. While suggesting this, it is important to recognize that every internal surface must come into contact with the medium. This may necessitate the incubation period being split into two halves, the first half with the containers incubated in their normal position, the second half with the containers incubated inverted. 

Each filling trial should consist of at least 3000 items (it is normal practice to exceed the minimum to account for breakages, etc.). The medium of choice is Soybean Casein Digest Broth VSP. Where necessary, for instance in antibiotic filling processes where, no matter how effective the cleaning, residues cannot be excluded, an inactivating agent (e.g., penicillinase) should be added to the medium at an appropriate concentration. 

What this equation means in relation to filling trials is that if a series of samples each comprising 3000 items were taken from a universe that actually contained contaminated items at a frequency of one in one thousand (0.1%). we would find one or more contaminated items in 95% of our samples. It effectively defines a miiumum sample size of 3000 (precisely 2996). because 95% confidence cannot be achieved with any smaller sample size. It also, by the inclusion of the expression determines the pass/fail criterion as accept... 

There are alternative interpretations of pass/fail criteria for filling trial results. 

In filling trials it is necessary (according to the FDA) to be 95% confident that P (the probability of contaminated units in the universe) is no greater than 0.001 (0.1%). Therefore 0.001 should be considered as the upper 95% confidence limit of Pgj(. 

Table 6 lists the upper 95% confidence limits of P when Pgjj is one, two or three contaminated items in a sample of 3000 items (AO. When Pgj, is 0.0003 (one contaminated item in three thousand), its upper 95% confidence limit is approximately 0.001 (0.1%). This interpretation therefore allows the pass/fail criterion for filling trials to be accept zero or one contaminated item, reject two or more contaminated items. The Table indicates the sample sizes that would be necessary to set the pass/fail criterion at two or less contaminated items (N = 5000) or three or less contaminated items (A/ = 7000). With three contaminated items in a sample of 3000 (Pg t = 0.001) the upper confidence limit indicates that we cannot be 95% sure that P (the actual frequency of occurrence of contaminated items in the universe) is any less than 0.2%. 

The third and least sophisticated approach to interpreting filling trial results is to regard the sample itself as the universe. This interpretation sets the pass/fail criterion at accept zero, one, two, or three contaminated items in three thousand, reject four or more. 

In practice all three of these theoretical interpretations can be allied to the level of reaction required in response to filling trials. 

No contaminated items in three thousand is the most favorable result that can be obtained from a filling trial. At initial validation of a new facility it should be interpreted as a cautious go-ahead signal as long as each and every... 

With revalidation filling trials, zero contaminated items is once again a cautious go-ahead, and one contaminated item in 3000 should demand an investigation and appropriate corrective action where necessary while allowing production to continue. Two or three contaminated items should require any product manufactured on the filling line since the date of the failed trial to be quarantined until an investigation and a successful repeat trial has been completed. 

Investigations should address the type of microorganisms isolated from the failed filling trial, their likely sources, their sensitivities to the antimicrobial characteristics of products that have been filled on the line, and most importantly their history of past occurrence. For instance, microorganisms that have been detected and represented as laboratory contamination in past Tests for Sterility should be considered as genuine product contaminants in those batches passed on retest. Batch withdrawal should be undertaken if they are also capable of surviving to any extent in the product. Identities should be at least to species level in failed filling trials. 

It is recommended that at least 3000 units of production be induded in each broth-fill trial. The target should be zero growth and anything above 0.1% of units contaminated should be considered unacceptable. Any contamination should be investigated. Broth fills should be repeated at regular intervals, and whenever a significant alteration in the product, premises, equipment, or process warrants revalidation. 

FIGURE 21.1 Selected composite results 20% fill trial (a) pressure (b) interior temperatures (c) exterior wall temperatures (d) mass (manually logged). (Source Roberts et al., 1995c)... 

The composite figures of pressure, mass, internal fluid, and external shell temperatures indicate no unusual characteristics in the recorded parameters such as were noted previously in the 20% fill trial. However, a detailed frame-by-frame analysis of the video record clearly shows that the fast fracture phase of vessel failure was preceded, at about 1 to 2 seconds (approximately 25 to 50 video frames), with the formation of a crack that permitted a vapor and then two-phase discharge to occur through the rupture. 

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