Application of an Industrial Aseptic Process Simulation Methodology to the Preparation of Chemotherapy Drugs in Hospitals

Introduction
The preparation of chemotherapy drugs in hospitals complies with the requirements of the 2023 Good Preparation Practices, which mandate the performance of Media Fill Tests to validate the aseptic process and qualify operators. Aseptic Process Simulations (APS), governed by Good Manufacturing Practices 2024, introduce the concept of microbiological contamination risk analysis (RCM) based on a “worst-case scenario” approach.
Given the increase in activity, the diversity of operating procedures (OPs), and the coexistence of preparation processes in our unit: manual preparation (MP) and robotic preparation (RP) the objective of this study is to develop a tool to identify the OPs with the highest MCR in each process, in order to establish an APS protocol based on industrial methodology.

Materials and Methods
A multidisciplinary working group (WG) developed a rating grid for the RCM of preparation processes. The active pharmaceutical ingredients (APIs) and associated preparation systems were extracted from the CHIMIO^® software for analysis to define the scoring criteria (SC). The SC, grouped into three categories (active ingredient, diluent, and final packaging), covered all stages of preparation. An RCM scoring scale was defined for evaluating all active pharmaceutical ingredients, ranging from 1 to 4 (from lowest to highest RCM) or from 1 to 2 based on the operation of the automated system. An overall score (OS), expressed as a percentage, was calculated by summing each CC to rank the OMs based on their RCMs. Critical steps and interventions not related to the OM were identified for inclusion in the APS protocols.

Results
The working group consisted of four members: a laboratory technician, a resident, a pharmacist, and a qualification engineer. Two rating scales were created: one for the PM and one for the PR. The PM scale included 19 CCs rated on a scale of 1 to 4; the PR scale included 14 CCs, of which 12 were rated on a scale of 1 to 4 and 2 on a scale of 1 to 2. The data extraction included 395 drug products for the PM, excluding clinical trials, and 44 for the PR. In the PM, compliance rates ranged from 5.2% to 64.5%; the highest rates were achieved by two drug products: “Melphalan in 3% NaCl solution” and “Blinatumomab cassette.” The average SG was 42.6 ± 8.7 (%) and the median was 40.8%. For the PR, SG values ranged from 53.8 to 80.8%, with the maximum reached by the “Cyclophosphamide” MO, which had an average SG of 63.4 ± 7.3 (%) and a median of 60.6%. Thirteen high-risk situations were identified for PM and 9 for PR, such as: “remaining airlock connection” for PM or “airflow disruption related to the need for the control unit” for PR.

Discussion/Conclusion
This study enabled the development of an objective tool for assessing RCM risk to draft APS protocols that incorporate the MO and the situations posing the highest RCM risk, thereby defining the scenarios. This methodology makes it possible to demonstrate its relevance without having to develop multiple preliminary studies, despite the diversity of operating modes and systems used. Ultimately, this methodology could be extended to other aseptic preparation processes and automated systems.