Issue link: https://www.e-digitaleditions.com/i/988595
Pharmaceutical Technology BIOLOGICS AND STERILE DRUG MANUFACTURING 2018 5 The microbiological world is already extremely complex, and then there may be untold varia- tions within the same environment. Grow th- related met hods prov ide severely limited in- formation. Since t hey were f irst introduced, environmental monitoring programs have fix- ated on measuring at well below the level of de- tection for existing methods. Unrealistic expectations If an aseptic processing operator , when prop- erly gowned, sheds on the order of 1000 cfu/ hour (6), how cou ld reg u lator y expectations mandate less than 1 cfu on their gloves in an ISO 5 environment (2)? Products labeled sterile can be aseptically filled in the presence of microorganisms. Just because one cannot recover the microorganisms doesn't mean they are not present, and their absence isn't required for the preparation of safe medications. The pharmaceutical industry has made techno- logical improvements in aseptic processing over the past 30 years that have likely reduced the num- ber of microorganisms that can be recovered and detected by environmental monitoring equipment. But what other benefits have been made that actu- ally benefit the patient? Operating below the limit of detection, environmental monitoring is little more than a rote exercise of limited real value. As a result, current regulatory expectations are mis- guided. Further examples of their misinterpreta- tion of reality include the following: • "Air monitoring samples of critical areas should normally yield no microbiological contaminants" (1). • "When operators exceed established levels or show an adverse trend, an investigation should be conducted promptly" (1). • "In the absence of any adverse trend, a single result above an action level should trigger an evaluation and a determination about whether remedial measures may be appropriate" (1). • "A result at the action level should prompt a more thorough investigation" (1). • "If alert limits are exceeded, operating procedures should prescribe scrutiny and followup, which might include investigation and corrective action" (2). Clearly, FDA and the European Medicines Agency (EMA) believe in the accuracy, reproduc- ibilty, and utility of microbial monitoring. Reconciling expectations with science In fact, their conviction is so strong that they fre- quently expect increased monitoring to support safer aseptic processing when it may actually have the opposite effect. Reconciling regulatory expecta- tion with scientific reality is long overdue because: • Microorganisms have always been (and will continue to be) present during aseptic processing, and their presence has not had any impact on the safety of the materials produced. • Microbial monitoring could never be able to detect all of the microorganisms present in a given manufacturing environment. Operating below the limit of detection, environmental monitoring is little more than a rote exercise of limited real value.