Recommended Practices for Manual Aseptic Processes PDA Technical Report 62 Authors:
H: Sterile Processing By: Carol Lampe Recommended Practices for Manual Aseptic Processes PDA Technical Report 62 Recommended Practices for Manual Aseptic Processing © 2012 Parenteral Drug Association Authors: Olivia A. Henderson, Ph.D., Biogen Idec (co-Chair) Carol Lampe, J.M. Hansen & Associates, Inc. (co-Chair) James Agalloco, Agalloco and Associates, Inc. Edward A. Fitzgerald, Fitzgerald Consulting Thomas Genova, Ph.D., Johnson & Johnson John W. Levchuk, Food and Drug Administration (retired) John M. Lindsay, Aseptic Solutions, Inc. Jeanne E. Moldenhauer, Excellent Pharma Consulting Robert J. Nolly, University of Tennessee, Pharmaceutical Sciences Laura A. Thoma, Pharm. D., University of Tennessee, Pharmaceutical Sciences Contributors: Mark Birse, Medicines and Healthcare Products Regulatory Agency Mark Ellison, Medicines and Healthcare Products Regulatory Agency Andrew Hopkins, Medicines and Healthcare Products Regulatory Agency Ian Jackson, Medicines and Healthcare Products Regulatory Agency Terry E. Munson, PAREXEL Consultants Michelle Rowson, Medicines and Healthcare Products Regulatory Agency Recommended Practices for Manual Aseptic Processing © 2012 Parenteral Drug Association 2 1 H: Sterile Processing By: Carol Lampe Technical Report Purpose Outline methods and approaches for control and evaluation of aseptic processing operations for drug products/medicinal products which use all or partial manual procedures. Image courtesy of pharm.lancasterlabs.com Recommended Practices for Manual Aseptic Processing © 2012 Parenteral Drug Association 3 Technical Report Scope Build upon & supplement, published guidance which is generally more focused on automated large-scale operations. Recommended Practices for Manual Aseptic Processing © 2012 Parenteral Drug Association 4 2 H: Sterile Processing By: Carol Lampe Technical Report Scope The guidance provided in this report may be applicable to operations including: Vaccine preparation Cell culture Gene therapy Investigational New Drug/IMP manufacturing Clinical and commercial manufacturing Pharmacy formulation and dispensing Recommended Practices for Manual Aseptic Processing © 2012 Parenteral Drug Association 5 Out of Scope Human intervention into an otherwise automated filling process. Examples include: • Reach-ins to remove a toppled vial from the filling line or to obtain a container for quality testing • Aseptic connection made during set-up • Corrective activities during line stoppages Recommended Practices for Manual Aseptic Processing © 2012 Parenteral Drug Association 6 3 H: Sterile Processing By: Carol Lampe Blanket Statement • When manual aseptic processing of sterile dosage forms is required, special consideration must be given to sterility and verification of processing accuracy: – Training of Personnel involved in Sterile Preparation Processes – Environmental Control and Monitoring Requirements – Specifications for Sterile and non-Sterile Ingredients and Components – Release Criteria for Sterility and Pyrogen Testing. Note: Refer to the following documents 2004 FDA Guidance on Aseptic Processing, EU GMP – Annex 1, Ph Eur 5.01.01 “Methods of Preparation of Sterile Products”, and USP Chapters “Pharmaceutical Compounding – Sterile Preparations– Sterile Preparations” and “Radiopharmaceuticals for Positron Emission Tomography – Compounding” Recommended Practices for Manual Aseptic Processing © 2012 Parenteral Drug Association 7 Table of Contents 1. 2. 3. 4. 5. 6. 7. 8. Introduction Glossary of Terms Buildings and Facilities Operational Personnel Training and Qualifications Equipment, Components and Container/Closure Process Time Limitations Design of Manual Aseptic Processes Evaluation of Manual Aseptic Processing – Process Simulation 9. Conclusion 10. References 11. Additional Reading Recommended Practices for Manual Aseptic Processing © 2012 Parenteral Drug Association 8 4 H: Sterile Processing By: Carol Lampe Definition: Aseptic Processing Handling sterile materials in a controlled environment, in which the air supply, facility, materials, equipment and personnel are regulated to control microbial and particulate contamination to acceptable levels. Recommended Practices for Manual Aseptic Processing © 2012 Parenteral Drug Association 9 What makes MAP special? (1) • Manual aseptic processing (MAP) operations differ from automated operations • These differences pose unique operational and evaluation challenges Image courtesy of inventionmachine.com • These challenges must be considered thoroughly when designing the evaluation procedure or protocol for the MAP operation Recommended Practices for Manual Aseptic Processing © 2012 Parenteral Drug Association 10 5 H: Sterile Processing By: Carol Lampe What makes MAP special? (2) MAP involves a human operator performing, at a minimum, the container and/or closure movements MAP relies heavily on individual operators’ basic understanding of microbiology proficiency Personnel must be individually qualified Recommended Practices for Manual Aseptic Processing © 2012 Parenteral Drug Association 11 People - the Usual Suspects! Human performance deviations or failures are linked to: • Complex aseptic processing tasks • The continuous span of time during which an operator carries out repetitive aseptic activities • The expected rate of activity • Change in personnel Recommended Practices for Manual Aseptic Processing © 2012 Parenteral Drug Association 12 6 H: Sterile Processing By: Carol Lampe Goal of Aseptic Processing Evaluation Prevent the contamination of sterile materials during their processing • Demonstrate that aseptic processing can be achieved and maintained successfully under the specified operational configuration, activities, and conditions • Same goals for manual or automated aseptic operations and for small-scale or large scale operations Recommended Practices for Manual Aseptic Processing © 2012 Parenteral Drug Association 13 Other Points • Personnel performing the manual processes are located in the surrounding clean area • Appropriate gowning facilities are required (consistent with the background environment requirements) • Execution of the MAP is usually supported by sterilization equipment and processes for materials • Overall flow of MAP facility, personnel and equipment is consistent with large scale environments Recommended Practices for Manual Aseptic Processing © 2012 Parenteral Drug Association 14 7 H: Sterile Processing By: Carol Lampe Elements of Training Requirements Microbiological Principles Sterility Assurance Aseptic Practices Gowning Practices Sterilization Recommended Practices for Manual Aseptic Processing © 2012 Parenteral Drug Association 15 Risk Management MAP frequently involves greater risks than automated aseptic processes. A risk-based quality management system is necessary. “Quality risk management can be an effective method of identifying and reducing aseptic processing risk, thus improving the assurance of sterility, endotoxin control, and subsequent patient safety.” (PDA Technical Report 44) Recommended Practices for Manual Aseptic Processing © 2012 Parenteral Drug Association 16 8 H: Sterile Processing By: Carol Lampe APS • Requires operators to perform aseptic interventions during the simulation that are typically conducted during manufacturing • Operators will assemble the sterilized equipment prior to the media fill MAP are more susceptible to Importance of APS human contamination than automated aseptic processing Interventions during MAP are frequent; may be complicated by suboptimal equipment design. Note: Aseptic processing simulations are understood to be synonymous with media fills, simulated product fills, broth trials, broth fills, etc. Recommended Practices for Manual Aseptic Processing © 2012 Parenteral Drug Association 17 Manual Aseptic Interventions • Frequent and may be complicated • Individuals must demonstrate proficiency in rigorous MAP requirements regardless of technology used − Various challenge tests where operator directly handles sterile equipment and materials − Representative of the actual process steps Intervention: An aseptic manipulation or activity that occurs within the critical area. This technical report regards interventions as either corrective or inherent. Recommended Practices for Manual Aseptic Processing © 2012 Parenteral Drug Association 18 9 H: Sterile Processing By: Carol Lampe Equipment, Components & Container/Closure MAP is similar to automated lines, but on a smaller scale: Sealed package is supplied to the APA after depyrogenation/ sterilization Requires validated depyrogenation/ sterilization methods Prep methods prior to depyrogenation/ sterilization similar to automated AP, but smaller scale If sterilization/ depyrogenation processes cannot be used on non-product contact surfaces, validated sanitization process must be performed When sterile containers/closures are purchased from a commercial source, procedures should be in place and implemented to ensure the sterility of these items are maintained when introduced into an aseptic environment and used in production. Recommended Practices for Manual Aseptic Processing © 2012 Parenteral Drug Association 19 Process Time Limitations MAP time limitations more critical than for Automated AP Short/non-repetitive processes time may be of little relevance “Worst case” fatigue evaluation = APS ≥ duration of longest period of uninterrupted task performance APS at the end of a normal day’s production can evaluate the effect of fatigue on the operator’s aseptic technique Repetitive tasks for long periods fatigue must be considered in both routine operation and the APS. The operator’s aseptic technique may deteriorate with the passage of time. Recommended Practices for Manual Aseptic Processing © 2012 Parenteral Drug Association 20 10 H: Sterile Processing By: Carol Lampe Design of Manual Aseptic Processes • Sterility assurance to mitigate contamination requires a holistic approach that encompasses the following: – – – – – Facility Equipment Process design Aseptic practices/validation Risk Assessment • Manual Aseptic Processes should be designed to minimize the impact of personnel – Process design reduces contamination risk Aseptic Filling: The part of aseptic processing where a pre-sterilized product is filled and/or packaged into sterile containers and closed Recommended Practices for Manual Aseptic Processing © 2012 Parenteral Drug Association 21 MAP Design Principles: Unidirectional Air Flow Hood (1-7) • Adequate space to perform the work • Exposed product and product-contact components remain in First Air • Aseptic manipulations made in First Air • Decontaminate or change gloves on a frequent basis • Use sterile tools and utensdils First Air (First Work Location): The work location first in the path of HEPA filtered air Recommended Practices for Manual Aseptic Processing © 2012 Parenteral Drug Association 22 11 H: Sterile Processing By: Carol Lampe MAP Design Principles: Restricted Access Barrier systems (RABs) • Variable design • Items introduced via rapid transfer port (RTP) OR • May resemble manned clean rooms in design and operation; similar to Unidirectional Air Flow Hoods Image courtesy of Bayer Healthcare • Aseptic, not sterile, process enclosures • Aseptic technique must be followed consistent with the design of the system (enclosure) Restricted Access Barrier System (RABs): Aseptic processing systems (ISO 5) intended to substantially reduce human borne contamination within the aseptic environment where sterile product, containers, closures and equipment are exposed by the use of separative devices and defined mechanical features and operating procedures Recommended Practices for Manual Aseptic Processing © 2012 Parenteral Drug Association 23 MAP Design Principles: Isolators • Sealed or supplied with air through a microbial retentive filtration system (HEPA minimum) and may be reproducibly decontaminated Image courtesy of Amercare, Ltd. − Closed: Uses only decontaminated (where necessary) interfaces or Rapid Transfer Ports (RTPs) for materials transfer − Open: Allows for the ingress and/or egress of materials through defined openings (“mouseholes”) that have been designed and validated to preclude the transfer of contamination. • Isolators can be used for aseptic processing activities, containment of potent compounds, or simultaneously for both asepsis and containment Validation: Establishing documented evidence that provides a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality attributes. Recommended Practices for Manual Aseptic Processing © 2012 Parenteral Drug Association 24 12 H: Sterile Processing By: Carol Lampe MAP Design Principles: Isolators and RABs (1-4) Decontaminate enclosure according validated procedure Fresh sterile gloves prior to entering enclosure gloves Use sterile tools and utensils rather than direct contact with the enclosure gloves Introduce items and equipment into enclosure via validated decontamination / sterilization methods and/or RTPs Perform as much of the process as possible inside the enclosure to minimize removal & re-entry of sterile items Recommended Practices for Manual Aseptic Processing © 2012 Parenteral Drug Association 25 Evaluation of MAP: Process Simulation • Process Simulation Design • Media Sterilization* • Frequency and Number of APS Runs • Observation of the Process Simulation* • Media Fill Volume* • Anaerobes / Inert Gassing* • Environmental Monitoring • Execution of the Simulation • Pre-Incubation Inspection* • Incubation Time / Temperature* • Post-Incubation Inspection* • Growth Promotion* • Interpretation of Test Results *Similar to automated processes Recommended Practices for Manual Aseptic Processing © 2012 Parenteral Drug Association 26 13 H: Sterile Processing By: Carol Lampe Process Simulation Design • Supporting Rationale – Media fill design must simulate routine manufacturing – Define adaptations to the production process • Failure Investigations – Maintaining the sample contamination point fill sequence can aid in determining – Include definition of sample points in the rationale • Keep Current – Update the simulation rationale with changes to process, products, components, or equipment that could impact acceptability – Changes will require rationale and support of qualification (3x) or requalification (1x) Recommended Practices for Manual Aseptic Processing © 2012 Parenteral Drug Association 27 Frequency & Number of APS Runs Operator Qualification • Semi-annually or in accordance with the applicable regulatory requirements • Initial qualification is typically three replicate APS studies • More frequent studies may be required for infrequent manufacturing operations Duration of Runs • Should meet or slightly exceed the expected maximum duration of a single working session by a single operator Size of Runs • Dictated by the time period that a single operator performs the same activity • Actual numbers of units produced in that time period should meet or exceed the normal production quantity Recommended Practices for Manual Aseptic Processing © 2012 Parenteral Drug Association 28 14 H: Sterile Processing Interpretation of Test Results By: Carol Lampe (1) • MAP Production lots are typically smaller standard minimum simulation size of 5,000 units – MAP simulations in support of container filling must have a contamination frequency of zero (0) filled units – In compositing or formulation simulations, the simulated bulk material container(s) should be sterile Recommended Practices for Manual Aseptic Processing 29 © 2012 Parenteral Drug Association Interpretation of Test Results (2) Technical hurdles in achieving this goal • Media and simulated product do not match real product processing characteristics • Media simulation differences in solubility, pH, filtration rates, filterability and viscosity • Reconstituting powdered simulation materials or adding extra equipment or manipulation increases contamination risk • Microbiological medium is designed to support / stimulate microorganism growth versus processed product hostile anti-microbial characteristics Recommended Practices for Manual Aseptic Processing © 2012 Parenteral Drug Association 30 15 H: Sterile Processing By: Carol Lampe Conclusion • This technical report is one of the first attempts to address the subject of manual aseptic processing • Manufacturers that use manual aseptic processing to produce products used in patients must be aware of the uncertainties associated with a manufacturing process so heavily reliant on personnel performance • In new installations, it is strongly encouraged to use isolation technology to minimize the risk of microbial contamination from personnel involved in the manufacturing operations Recommended Practices for Manual Aseptic Processing © 2012 Parenteral Drug Association 31 Future Updates • MAP of non-aqueous drug products • Additional information on “process time limitations” • Additional information on “equipment, components and container/closures” Recommended Practices for Manual Aseptic Processing © 2012 Parenteral Drug Association 32 16
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