2011 Technical Report No. 22 (Revised 2011) Process Simulation for Aseptically Filled Products Process Simulation for Aseptically Filled Products PDA Task Force James Agalloco, Agalloco it is not intended to establish any mandatory or implied standard. The reader must recognize that there may be additional requirements imposed because of new or localized regulatory expectations that are not included in this document. This technical report does not provide a universally appropriate template for the execution of process simulation studies. Each company must determine the appropriate rationale and approaches applicable to their unique operations. A recurring theme in this report is the consideration of risk to product sterility and patient safety as criteria for the design of the aseptic process simulation studies. Regulatory authorities have issued recommendations for aseptic process study design and companies should be aware of these recommendations when planning their studies. However, the use of relative risk and scientific evaluation as a means to provide information used to make decisions on study design may be of benefit because it should result in better understanding of the aseptic process and its capabilities. The use of risk assessments and related information may result in studies which go beyond the recommendations of regulatory authorities. It may also result in studies which differ from those recommendations. However, it should not result in studies which are less effective than those recommended by regulatory authorities. 1.1 Scope This technical report addresses process capability assessment for aseptic processing. Such assessments consist of one or more aseptic process simulations (APS) during pharmaceutical and biopharmaceutical formulation and filling activities (referred to as secondary manufacturing in many parts of the world). Aseptic operations required in the preparation of sterile bulk materials and biotechnology inoculums, and feed materials are not a part of this document; refer to PDA Technical Report No. 28: Process Simulation Testing for Sterile Bulk Pharmaceutical Chemicals (1). While the focus of this document is on aseptic processing in the pharmaceutical and biopharmaceutical industry, application of the concepts and principles to the preparation of sterile medical devices and diagnostics may be appropriate. 1.2 Previous PDA Publications PDA has published previous reports on the aseptic filling process: Technical Monograph No. 2: Validation of Aseptic Filling for Solution Drug Products; Technical Report No. 6: Validation of Aseptic Drug Powder Filling Processes, and the 1996 edition of this report, Technical Report No. 22: Process Simulation Testing for Aseptically Filled Products (2,3,4). 1.0 Introduction 2 2011 Parenteral Drug Association, Inc. Technical Report No. 22 (Revised 2011) 1.3 Reason for Revision Since the above reports were issued, there have been continued advances in facility and equipment design, such as the use of barrier, isolation and blow-fill-seal technologies. The understanding and philosophies of aseptic process qualification, validation and control have evolved as well. In addition, global regulatory and standards authorities have revised their own guidances on aseptic processing (5,6,7,8). The 2011 version of Technical Report No. 22 features the following new or revised information. Risk Management: This report frequently references the use of quality risk management concepts in the design of APS programs Concepts and Principles: There have been clarifications and enhancements of Section 3.0, in keeping with current scientific knowledge, experience and regulatory expectations Lyophilized Products: The section on “Lyophilization of Dilute Medium” has been removed as this APS approach is generally not considered appropriate. Freezing of Media: For similar reasons references to freezing of media have been removed. Powder Filling: Certain APS approaches for powder filling have been removed, including: On-line powder fill followed by off-line liquid fill Non-aseptic liquid fill, sterilized, and followed by on-line powder fill Off-line liquid fill followed by on-line powder fill Isolators, restricted access barrier systems (RABS), blow-fill-seal (BFS): Updated information include in Section 4.8 Elements of APS: Enhanced information is included for: filling speed, interventions, and duration and number of units filled Interventions: This report differentiates aseptic process interventions as either “inherent” or “corrective,” a distinction that is helpful in understanding their relationship to microbial contamination and the design of the APS program. Acceptance Criteria: Section 10 includes background, current recommendations and good practices in setting acceptance criteria for the APS On-going Process Evaluation: Formerly referred to as Validation Maintenance, this section has been updated to reflect that the state of control