Contamination rates

The rate of contamination from the pump set is <10 molecule/(m -s) for molecular weights >44 (23). This is the maximum contamination rate for routine service for a weU-designed system that is used constantly and subject to automatic Hquid-nitrogen filling and routine maintenance. 

The primary disadvantage of fixed-bed adsorbers arises when contaminant rates are high. Because of the unsteady-state nature of the operation, a large portion of the in-process adsorbent inventory is saturated and, therefore, inactive. 

During a more controlled study carried out within an environment artificially contaminated with high levels of individual nebulized spores of Bacillus subtilis [2], a level of contamination within the environment was achieved which led to the contamination of broth-filled units. The results were extrapolated to suggest a contamination rate of 1 unit in 4 X 10 with a smrounding environmental contamination of 1 cfu/ml... 

The contamination rate of the area is stated as the number of viable microorganisms per 100 cm The area of a standard RODAC dish is 25 cm. ... 

The cross-contamination rate should meet the in-house criteria. Frequency... 

The probability of detection of nonsterility in a media fill = 1 - (1 - x)", where x = acceptable contamination rate and n = the number of vials filled, ft should be the same as a normal production run, but not less than 3000 units. 

The negative control contamination rate should be calculated and recorded. The results of negative product control tests facilitate the interpretation of sterility test results, particularly when used to declare a test invalid because of contamination in the negative product controls. 

A minimum of 4800 units will be filled and incubated. For multiple shift fills, at least 3000 vials/ampoules are to be filled per shift. Table 3 shows the acceptance criteria for initial performance qualification of an aseptic processing line. Table 4 shows the acceptance criteria for requalification of an aseptic processing line. Table 5 shows alert and action levels when a 0.1% contamination rate is attained for large numbers of media-filled units, i.e., when one elects to media-fill more than 3000 units. 

This alert level is based on selection of a 0.05% contamination rate. Contamination rate of >0.1% at a 95% confidence level. 

Unlike many dosage form specifications, the sterility specification is an absolute value. A product is either sterile or nonsterile. Historically, judgment of sterility has relied on an official compendial sterility test however, end-product sterility testing suffers from a myriad of limitations [1-4], The most obvious limitation is the nature of the sterility test. It is a destructive test thus, it depends on the statistical selection of a random sample of the whole lot. Uncertainty will always exist as to whether or not the sample unequivocally represents the whole. If it were known that one unit out of 1000 units was contaminated (i.e., contamination rate = 0.1%) and 20 units were randomly sampled out of those 1000 units, the probability of that one contaminated unit being included in those 20 samples is 0.02 [5], In other words, the chances are only 2% that the contaminated unit would be selected as part of the 20 representative samples of the whole 1000-unit lot. 

It is easily understood that if the aseptic operation is performed in a separated small space from which personnel have been completely excluded, the necessity for room classification based on particulate and environmental microbiological monitoring requirements may be significantly reduced. In other words, critical operations in an aseptic area should be performed in the smallest space, and intervention by personnel should be minimized by indirect means through the use of protective glove ports and/or half suits. Application of these methods can minimize the chance of contamination. Following are such systems currently in place to reduce the contamination rate in aseptic processing. 

Calculation of the surface contamination rate for a surface in different vacua... 

An empirical model was used by Opdyke and Loehr [17] to describe the contaminant rate of release (ROR) similar to what we observed a relatively rapid release of the chemical followed by a much slower release of the remaining chemical. The non-linear equation used to describe this biphasic behavior during desorption was given by... 

Anti-HBc IgM is the earliest immunological response of the body to HBV antigens. It is the most reliable marker, and once the disease is overcome, it can probably be demonstrated lifelong as anti-HBc IgG. In chronic hepatitis B carriers, low titre anti-HBc IgG may also be present. It is the most suitable marker for the HBV contamination rate of a population (more reliable than anti-HBs). The absence of HBsAg and anti-HBc IgM rules out acute HBV infection. In healthy patients who test positive for anti-HBc, latent viral replication is usually still to be found. This can be detected with the help of PCR. Active vaccination does not result in positive anti-HBc IgM. (s. p. 114)... 

Considering the number of permutations of container, closure system, and other product attributes that must be encompassed in a process simulation program, it should be evident that only in the simplest of situations would a single set of media fills be adequate to provide coverage of all aseptic processes performed. Where multiple lines are present in the facility, each should be considered independently. Process simulation results of one line are not predictive of results on another because the contamination rate is primarily dependent upon human performance. Even identical equipment in two clean rooms designed to the same standard will not give uniform results unless the aseptic technique of the operators is at the same level of performance. 

Additional publications which have provided acceptance criteria for aseptic processing validation have been prepared by both CEN and PIC. " These have attempted to reconcile the differences between the ISO document and the PDA guidance. The essence of these documents is the following. Ideally the contamination rate should be zero. However, currently the accepted contamination rate should be less than 0.1% with a 95% confidence level. This appears to be an effort to have it both ways, and it is unclear whether the two perspectives can really be reconciled so easily. 

Test methodology should be sensitive enough to confirm a low process simulation test contamination rate, and the selected limit must be routinely achievable. 

Process simulation test contamination rates approaching zero should be achievable using automated production lines in well-designed aseptic processing facilities, blow-fill- seal and form-fill-seal and in isolator-based systems. 

Processes conducted in older facilities or employing considerable product handling or manual operation may not be capable of achieving near-zero contamination rates. Nevertheless, such processes must be capable of a process simulation test contamination rate not exceeding one in 1000 when 3000 units are filled. 

This raises a second question of how much confidence must one have to claim sterility The answer to this question, for terminally sterilized products, is that there must be no more than one chance in a million that viable contaminants survive in any one unit. This is called a sterility assurance level (SAL) of 10 . The answer for aseptically filled products is that the SAL must be as close to 10 as is technically possible, with the proviso that thedegree of protection given to the process must afford no more than one chance in a thousand of any one unit becoming contaminated. This is called a contamination rate of 10 , and unlike the SAL it relates only to the protection given to the process and not to the potential for contaminants surviving or proliferating in actual products. ... 

Table 12.1 summarizes some data on direct photolysis rates and quantum yields for some organic contaminants. Rates of direct photochemical reactions of aqueous species, S, as measured in thin-layer samples, correspond to rates that would occur in the top few centimeters of a water column. Corrections have to be considered for mixed water columns at greater depths (see Zahriou, 1973, and Haag and Hoign, 1986). 

Figure 1. The shaded area represents the 95% confidence interval for true contamination rate, assuming random distribution of contaminated samples and given a constant 0% detected contamination rate (adapted from ref. 1). The upper boundary of the curve represents the upper 95% confidence limit for true contamination rate. Thus, if ten samples were analyzed with no contamination detected, the true contamination rate 95% confidence interval would be between 0% and 30.8%.

Fig. 4.18. The different contamination rates of Bi2212 (a) before and (b) after plasma eleaning. Notiee that the amorphous edge of the B12212 at B and C in (a) has nearly disappeared after plasma cleaning in (b).

Simulation trials (media fills) do not validate SALs for asepiieally filled products. The frequently encountered regulatory requirement for aseptic filling processes to be validated by simulation versus a standard of no more than 1 contaminated item in 1,000 items is not intended to imply that an SAL of 10 is satisfactory for these products. The SAL is a complex function of contamination rate and probability of survival the simulation trial measures only the first of these factors. SALs for aseptically filled products are in all likelihood much better than 10, only they are nonmeasureabie, and there is no basis or generally accepted theory to support extrapolation. 

The PDA Technical Monograph on aseptic filling [19] quotes the following equation to describe the probability of finding one or more contaminated items in a sample of size S taken from a universe with a contamination rate of 0.1% ... 

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