A few weeks ago, SmithKline Beecham’s Worthing West Sussex, U.K., site received an FDA warning letter related to, primarily, alleged failure to ensure microbiological contamination of products manufactured there. The site was inspected last March, and in April the Agency said that GSK's response to initial concerns lacked sufficient corrective actions.
The key issues cited in the warning letter seem a bit unique, even picky, so we contacted aseptic processing expert James Akers, president of Akers Kennedy & Associates, to get his take. Indeed, Akers says that some of the Agency's points are puzzling. "The only issue cited by FDA that is a real concern to me from a product safety point of view is the media fill with two positive units," he says. "I can't say though that the warning letter wasn't justified; that would depend upon whether or not the media fill failure was an isolated incident and also upon their facility monitoring data over time."
Following are FDA’s main criticisms, and Akers' responses to them:
FDA: Your disinfectant qualification for (b)(4) and (b)(4) bi-spore disinfectants documented that the log reduction criteria (Bacteria = 4, Fungi = 3) was not met when challenged with multiple organisms in a variety of surfaces. After disinfection, you recovered Micrococcus luteus on vinyl, (b)(4), stainless steel, glass, and wall laminate and Enterobacter cloacae, Rhodococcus sp, Burkholderia cepacia, Pseudomonas aeruginosa, Methylobacterium mesophilicum and, Acinetobacter lwoffi on glass. However, your procedures for routine cleaning of the aseptic manufacturing area continue to require the use of unqualified disinfectants during days (b)(4) through (b)(4) of your disinfectant program.
Akers: The statement that the firm’s qualification for Bi-spore was not met for bacteria or mold is puzzling—perhaps this statement is incomplete in some respects. Bi-spore is a Chlorine dioxide based sporicide and would quickly inactivate all of the organisms listed in the second sentence of this quote from the warning letter.
In my opinion the importance of the substrate effect on disinfectant efficacy is somewhat to tremendously overstated. In fact, the emphasis on spore log reduction in these cases results in very difficult to conduct studies. Drying 10E3 or 10E4 spores on a surface results in considerable biofilm which may be difficult to penetrate. It requires one to disinfect a dirty surface in an effort to judge sporicide efficacy.
There can be little doubt regarding the efficacy of Chlorine dioxide at the concentrations used in Bi-spore; there is ample published work in refereed journals to establish this efficacy. It is impossible for the organisms listed to survive Bi-spore treatment if done correctly. I don't know what FDA means by "unqualified" disinfectant, but in my scientific opinion if there is a body of published data regarding the use of a disinfectant (and with all of the routinely used disinfectants in industry of which I am aware this is certainly the case), these disinfectants are qualified for use because they are generally recognized as effective. In most cases that effectiveness has been proven over years of use in the pharmaceutical industry, other industries and in general healthcare practice.
FDA: A media fill conducted during January 2011 resulted in two contaminated units. Your firm attributed the failures to stopper bags left inside the class 100 area for a long period of time (throughout a shutdown that took place prior to the media fill in January 2011 shutdown). There is inadequate information available to support your conclusion, including information regarding the microorganisms recovered from the stopper bags and the sterility test conducted, along with an evaluation of your sampling procedure and environmental monitoring program.
Akers: I find it rather unlikely that the stored stopper bags were the root cause of the media fill positives. First, if the bags were fully integral and the sterilization process for the stoppers was sufficient, the stoppers had to remain sterile. Second, the statement notes that the stoppers were stored in a "class 100" area which with reasonably well controlled human activity should be very low contamination risk.
Realistically, most any gowned operator intervention is a greater source of risk than the stopper bags. If the allegation that the exterior surfaces of the bags were contaminated, then the route of contamination would logically be stoppers contacting the outer surface of the bag, which presumably would have been contaminated from sitting during storage. Even in the unlikely event this were true, microorganisms would have had to retain viability in the absence of nutrients or moisture and would have had to be transferred by contact onto stoppers or made airborne by the movement of the bags. Transfer of organisms from surfaces is a relatively inefficient mechanism and the likelihood of organisms proliferating on the stopper bags is near zero.
FDA: The inspection documented that your firm conducts personnel monitoring on a (b)(4) basis and upon (b)(4) the classified manufacturing rooms by only sampling the hood, goggles, and sleeves. We are concerned about your current gowning monitoring approach as operators may perform substantial interventions into the Restricted Access Barriers (RABs), where sterile product is exposed, several times per week. In addition, the investigators noticed during the inspection one of the operators sanitizing his hands with (b)(4) immediately prior to conducting his own personnel monitoring sampling. Your personnel monitoring program should include appropriate sampling and practices to reflect whether personnel maintain asepsis during sterile drug manufacture.
Akers: Sampling of the gloves, sleeves and goggles should be adequate to determine the adequacy of the firm's gowning and aseptic operational practices. More intensive sampling of a larger number or sites does not equate to better risk identification. I do not normally find that other glove locations are more likely to result in contamination recovery than are these three. One can best determine whether the personnel-related contamination control during aseptic operations is adequate by looking at personnel monitoring rates of contamination recovery over time. If the recovery rate is sufficiently and consistently low, and I saw evidence of good aseptic technique in observing operations, I would not be concerned. Also, the use of RABs, even if open RABS, should reduce the frequency of direct human intervention and therefore mitigate contamination risk significantly.
The use of disinfectants on gloves in aseptic processing is frequent and generally encouraged by companies, and it can be overdone. Certainly disinfection immediately prior to glove sampling will reduce the likelihood of microbial recovery. I think this practice should be discouraged. However, I would want to know if the practice reported in the warning letter is a common practice rather than an employee error or simply a misunderstanding. My reaction to this would be far different if this is a very common occurrence as opposed to something that happens infrequently.
FDA: In addition, the (b)(4) “Dynamic Airflow Visualization” video provided in your firm’s response shows an operator spraying his hands with (b)(4)(b)(4)(b)(4)% directly over the air viable microbial plate. This practice is unacceptable because the environmental monitoring results from plates sprayed with (b)(4) may be inaccurate and may not reflect the actual microbiological environment of the Class 100 (ISO 5) room.
Akers: As mentioned above operators disinfecting their hands can become something of a compulsive action in aseptic processing environments because of natural concerns about contamination control. It is often overdone.
Quite frankly I'm not sure at all that doing this kind of activity near a settle plate or active air sampling point wouldn't increase the likelihood of microbial recovery rather than diminish it. Studies have indicated consistently that movement during work correlates to increased microbial release and the disinfection of gloves is often accompanied by intensive hand and arm movement. If this were an effort to bias outcome it would be a poorly chosen one. Firms are encouraged to take samples in areas of operational activity and in this case it seems to me that the firm did just that. Perhaps the sample location should be reconsidered, but I do not find this an issue that is of sufficient import to be mentioned in a warning letter.