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Science Snapshot

  • New PDA Team Seeks to Improve Operations Metrics

    by: Ramesh Tharuvai, Neurocrine Biosciences, Inc | Oct 01, 2018

    Operational metrics are critical for evaluating, sustaining and improving the performance of a manufacturing operation. Common examples of operational metrics include schedule adherence, cycle time, yield, reject rate and loss for each unit operation. The way metrics are chosen, defined and used varies greatly across the biopharmaceutical industry. PDA believes that the industry could benefit from suggestions related to the identification, definition and use of operational metrics. With this in mind, in late 2016, PDA’s Manufacturing Science and Operations Program (MSOPSM) established a small cross-industry operational metrics team to discuss how metrics can be used to improve operations on the shop floor, at the manufacturing site and across the globe.

    The operational metrics team includes members from Eli Lilly, Genentech/Roche, Merck, Neurocrine Biosciences and Sanofi, representing expertise in drug substance, drug product, device assembly, packaging, operational excellence, continuous improvement and supply chain. In 2017, the group conducted an all-day benchmarking workshop at Genentech/Roche that addressed such concerns as the definition of metrics, their use in driving improvement, and the pitfalls and benefits of using them—all in the context of real-world examples spanning segments of the biopharmaceutical the industry.

    The initial set of metrics targeted in the workshop consisted of overall equipment effectiveness (OEE), yield and cycle time. Key outputs from the benchmarking workshop include a compilation of best practices and approaches to using metrics to drive performance. Some examples of the insights from the workshop are: (1) OEE trending has been successful in driving benefits from better line uptime to better assay selection, and (2) using a balanced scorecard with “competing” metrics can help counteract behaviors that can otherwise result from focusing on a single key performance indicator. The group also reached a shared understanding of challenges in using metrics and how to overcome them, such as the visibility of metrics related to contract manufacturing, or the way yield indicators are defined in drug substance processes (either batch or perfusion) compared to drug product manufacturing.

    In 2018, the operational metrics team has continued to work under the guidance of the MSOPSM to address additional metrics such as schedule adherence, end-to-end cycle time, reliability and employee engagement. The 2018 action plan developed by the team includes a variety of outreach efforts to engage internally within PDA and across the industry as a whole through benchmarking. The ultimate intent is to share the outputs of the operational metrics team with PDA membership in ways that make them useful, relevant and practical. In the meantime, the operational metrics team is actively looking for additional participation from the PDA member community and is exploring ways to incorporate member feedback into its efforts.

  • Journal Top 10

    by: Rebecca Stauffer, PDA | Oct 01, 2018

    Below are the top ten articles from the PDA Journal of Pharmaceutical Science and Technology for the month of August.

    1. PDA Paper

      “PDA Points to Consider: Best Practices for Document/Data Management and Control and Preparing for Data Integrity Inspections”

    2. Review

      “Particulate Matter in Injectable Drug Products”

    3. PDA Paper

      “Industry Perspective on the Medical Risk of Visible Particles in Injectable Drug Products”

    4. Conference Proceeding

      “Role of Risk Assessments in Viral Safety: An FDA Perspective”

    5. Research

      “Vapor Phase Hydrogen Peroxide Decontamination or Sanitization of an Isolator for Aseptic Filling of Monoclonal Antibody Drug Product—Hydrogen Peroxide Uptake and Impact on Protein Quality”

    6. PQRI Special Section – Review

      “ The Product Quality Research Institute (PQRI) Leachables and Extractables Working Group Initiatives for Parenteral and Ophthalmic Drug Product (PODP)”

    7. PQRI Special Section – Research

      “Extractables Characterization for Five Materials of Construction Representative of Packaging Systems Used for Parenteral and Ophthalmic Drug Products"

    8. Research

      “Sealing Behaviour of Container Closure Systems under Frozen Storage Conditions: Nonlinear Finite Element Simulation of Serum Rubber Stoppers”

    9. Technology/Application

      “Ozone Generation during High-Voltage Leak Detection: Fiction or Reality?”

    10. Research

      “Determination of the Acceptable Ambient Light Exposure during Drug Product Manufacturing for Long-Term Stability of Monoclonal Antibodies”

  • Journal TOC

    by: Rebecca Stauffer, PDA | Aug 27, 2018

    All the Latest on Viral Clearance from the 2017 Viral Clearance Symposium

    The September/October edition of the PDA Journal of Pharmaceutical Science and Technology features summaries of presentations at the 2017 Viral Clearance Symposium. Topics covered include virus barrier filters, virus filtration and more!

    Editorial

    • Richard Levy, “Special Viral Clearance Issue and St Gallen PDA Collaboration Paper“
    • Franz Nothelfer, Stefan Hepbildikler, “Proceedings of the 2017 Viral Clearance Symposium – Introduction“

    Review

    • Glen Bolton, Dayue Chen, “Upstream Mitigation Part 1: Cell Bank and Bulk Harvest Testing“
    • Dayue Chen, Glen Bolton, “Session 1.1 Upstream Mitigation Part 2: Virus Barrier Filter and HTST“
    • Thomas Kreil, David Roush, “Proceedings of 2017 Viral Clearance Symposium Session 2.1: DSP Unit Operations – Virus Filtration/ Inactivation“
    • Thomas Kreil, David Roush, “Proceedings of 2017 Viral Clearance Symposium Session 2.2: DDSP Unit Operations – Purification Unit Operations“
    • Johannes Bluemel, Junfen Ma, “Proceedings of 2017 Viral Clearance Symposium Session 3: Resin Life Time“
    • Astrid Schwantes, Qi Chen, Rachel Specht, “Proceedings of 2017 Viral Clearance Symposium Session 4: Submission Strategies“
    • Junfen Ma, Thomas R. Kreill, “Proceedings of 2017 Viral Clearance Symposium Session 5: Facility Risk Mitigation“
    • Sarah Johnson, David Roush, “Proceedings of 2017 Viral Clearance Symposium Session 6: Ensuring Viral Safety in Continuous Processing“

    Editorial

    • Stefan Hepbildikler, Sarah Johnson, Johannes Bluemel, “Viral Clearance Symposium 2017 Conclusion“

    Research

    • Paul Buess, et al., “The Impact of Quality Culture on Operational Performance – An Empirical Study from the Pharmaceutical Industry“
  • Interest Group Schedule

    by: Rebecca Stauffer, PDA | Jul 09, 2018

    In addition to evening interest group meetings, some interest groups will convene during the lunch break at this year’s 2018 PDA/FDA Joint Regulatory Conference. Below is a schedule of meetings for interest groups focused on science and biotech topics.

    Monday, Sept. 24

    5:45 p.m.–6:45 p.m.

    • Environmental Monitoring/Microbiology Interest Group (joint meeting with Quality Risk Management Interest Group)
    • Facilities and Engineering Interest Group
    • Packaging Science and Visual Inspection Interest Groups (joint meeting)

    Tuesday, Sept. 25

    12:30 p.m.–1:30 p.m.

    • Vaccines Interest Group

    5:45 p.m.–6:45 p.m.

    • Cell and Gene Therapy Interest Group
  • Journal TOC

    by: Rebecca Stauffer, PDA | Jul 09, 2018

    Check Out the Latest in New Technology Advancements in the PDA Journal

    The July/August issue of the PDA Journal of Pharmaceutical Science and Technology features two articles spotlighting new technologies and applications. One looks at ozone generation during high-voltage leak detection and the other explores human factors for Ranibizumab 0.5 mg prefilled syringes.

    Research

    • Yuh-Fun Maa, et al., “Vapor Phase Hydrogen Peroxide Decontamination or Sanitization of an Isolator for Aseptic Filling of Monoclonal Antibody Drug Product—Hydrogen Peroxide Uptake and Impact on Protein Quality“
    • Alejandra Nieto, Holger Roehl, “Sealing Behaviour of Container Closure Systems under Frozen Storage Conditions: Nonlinear Finite Element Simulation of Serum Rubber Stoppers“
    • Alberto Chillon, et al., “Introducing the Alba® Primary Packaging Platform. Part 1: Particle Release Evaluation”
    • Alavattam Sreedhara, et al., “Determination of the Acceptable Ambient Light Exposure during Drug Product Manufacturing for Long-Term Stability of Monoclonal Antibodies“

    Technology/Application

    • Martin Becker, et al., “Ozone Generation during High-Voltage Leak Detection: Fiction or Reality?“
    • Andrew Antoszyk, et al., “Usability of the Ranibizumab 0.5 mg Prefilled Syringe: Human Factors Studies To Evaluate Critical Task Completion by Healthcare Professionals“

    Case Study

    • Yushi Uetera, et al., “The Role of Heat-Tolerant Endotoxin-Retentive Ultrafilters (UFs) for the Remediation of Reverse Osmosis (RO) Plants Employed for Surgical Hand Antisepsis Using Periodic Thermal Disinfection—A Ten Year Longitudinal Experience Study in the Operating Theater“

    Commentary

    • Kyle Zingaro, David Shaw, et al., “Implementation of Plate Imaging for Demonstration of Monoclonality in Biologics Manufacturing Development“

    Erratum

    • John Mattila, et al., “ERRATUM: Retrospective Evaluation of Low-pH Viral Inactivation and Viral Filtration Data from a Multiple Company Collaboration“
  • New Book Compiles Ten Years of Glass Research

    by: Rebecca Stauffer, PDA | Jul 03, 2018

    Are you aware of the latest glass research from the previous ten years? Do you want to learn more about new developments in glass composition? Are you still concerned about the effects of delamination?

    The recently published PDA Technical Series: Pharmaceutical Glass might prove valuable. This book collects 19 articles previously published in the PDA Journal of Pharmaceutical Science and Technology between 2007 and 2017. The articles are organized into four categories: Overview, Material Composition, Delamination and Quality Methods.

    Topics covered include vial breakage, chemical durability of Type I molded containers, effects of subzero temperature exposure, accelerated testing with different extraction media and more.

    Ten years ago, a series of product recalls due to glass particulates found in finished product sharpened the industry’s focus on pharmaceutical glass. PDA Technical Series: Pharmaceutical Glass addresses quality issues pertaining to glass and offers manufacturers a way to understand these issues in full. The publication of this book is part of an initiative PDA launched in 2017 to connect pharmaceutical manufacturers and glass suppliers to prepare for future developments. It can be purchased in the PDA Bookstore.

  • Journal Top 10

    by: Rebecca Stauffer, PDA | Jul 03, 2018

    Particulate Matter Still a Popular Topic in the PDA Journal

    Below are the top ten articles from the PDA Journal of Pharmaceutical Science and Technology for the month of April.

    1. PDA Paper. Deborah M. Autor, et al., “PDA Points to Consider: Best Practices for Document/Data Management and Control and Preparing for Data Integrity Inspections,” Feb. 14, 2018 (accepted article)
    2. Review. Stephen E. Langille, “Particulate Matter in Injectable Drug Products,” May/June 2013
    3. PQRI Special Section – Research. Dennis Jenke, et al., “Extractables Characterization for Five Materials of Construction Representative of Packaging Systems Used for Parenteral and Ophthalmic Drug Products,” September/October 2013
    4. PDA Paper. Stan Bukofzer, et al., “Industry Perspective on the Medical Risk of Visible Particles in Injectable Drug Products,” January/February 2013
    5. PQRI Special Section – Review. Diane Paskiet, et al., “The Product Quality Research Institute (PQRI) Leachables and Extractables Working Group Initiatives for Parenteral and Ophthalmic Drug Product (PODP),” September/October 2013
    6. Review. Anil K. Rattan, “Data Integrity: History, Issues, and Remediation of Issues,” March/April 2018
    7. Technology/Application Bert Gunter, et al., “A Risk Index and Data Display for Process Performance in the Pharmaceutical Industry,” March/April 2018
    8. Research. Qingyu Zeng and Xia Zhao, “Time-Dependent Testing Evaluation and Modeling for Rubber Stopper Seal Performance,” March/April 2018
    9. Research. Benson Gikanga, Ada Hui and Yuh-Fun Maa, “Mechanistic Investigation on Grinding-Induced Subvisible Particle Formation during Mixing and Filling of Monoclonal Antibody Formulations,” March/April 2018
    10. Research. Ganapathy Gopalrathnam, et al., “Impact of Stainless Steel Exposure on the Oxidation of Polysorbate 80 in Histidine Placebo and Active Monoclonal Antibody Formulation,” March/April 2018
  • Freeze‑Drying IG to Meet before Annual Meeting

    by: Rebecca Stauffer, PDA | Apr 30, 2018

    Interested in learning about the latest developments in lyophilization? PDA’s Freeze‑Drying Interest Group will convene one day before the 3rd PDA Europe Annual Meeting, June 25, in Berlin. This all-day interest group meeting will explore the technical evolution of cooling equipment and state-of-the-art validation for freeze-dried products. Register Now.

    You do not need to be a member of the interest group to attend this meeting.

  • The Latest Sterile Filtration Research Available in the May/June PDA Journal

    by: Rebecca Stauffer, PDA | Apr 30, 2018

    Interested in the latest research on filtration? The May/June issue of the PDA Journal of Pharmaceutical Science and Technology features three research articles on filtration-related topics.

    Editorial

    • Govind Rao

    Research

    • Thomas Loewe, et al., “Benchmarking of Sterilizing-Grade Filter Membranes with Liposome Filtration”
    • Eric Vozzola, et al., “Life Cycle Assessment of Reusable and Disposable Cleanroom Coveralls”
    • Steven Novick, Perceval Sondag, Tim Schofield and Kenneth Mille, “A Novel Method for Qualification of a Potency Assay through Partial Computer Simulation”
    • Alexander Helling, et al., “Retention of Acholeplasma laidlawii by Sterile Filtration Membranes: Effect of Cultivation Medium and Filtration Temperature”
    • Stefanie Funke, et al., “Methods To Determine the Silicone Oil Layer Thickness in Sprayed-On Siliconized Syringes”
    • Roberto Menzel, et al., “Comparative Extractables Study of Autoclavable Polyethersulfone Filter Cartridges for Sterile Filtration”

    Technology/Application

    • Cleyton Lage Andrade, et al., “A Model of Risk Analysis in Analytical Methodology for Biopharmaceutical Quality Control”

    PDA Paper

    • Deborah Autor, et al., “PDA Points to Consider: Best Practices for Document/Data Management and Control and Preparing for Data Integrity Inspections”
    • Emma Ramnarine, Kevin O’Donnell, “Demonstrating PQS Effectiveness and Driving Continual Improvement: How to Get There Through Evidence-Based Risk Reduction: Part 1 – Conceptual Thinking”
  • PDA Task Force Meets Face-to-Face in Venice

    by: Jahanvi (Janie) Miller, PDA | Apr 02, 2018

    In January, Stevanato Group’s Paolo Golfetto,cochair of the joint PDA/Pharmaceutical Manufacturing Forum (PMF) task force on achieving zero defects for visible particles, welcomed the task force to a face-to-face meeting at Ca’ Foscari University in Venice.

    During the two-day meeting, the task force worked together to align on a common, harmonized rationale to support a practical industry-wide guidance, intended for use with existing compendial, regulatory and industry standards. This would then be used to better identify visible particulate matter. Multiple workgroups within the task force met to identify a visible particle-size threshold, review the gap analysis done for analytical methods (elastomer and glass components) and develop validation strategies. The full task force, comprised of pharmaceutical manufacturers and suppliers, agreed that providing a well-balanced perspective on best practices best served all parties involved.

    The task force has identified gaps in current risk assessments and methods used to detect and quantify visible particles. As a result, it has developed FMEAs for elastomer and glass components to help identify where the highest risk areas are for particulate contamination throughout the manufacturing process, and how to effectively control these risks. The task force will be seeking to validate their methods in the coming months to ensure that best practices are being applied, and that appropriate corrective actions to mitigate risks are being taken.

    PDA cordially thanks the Stevanato Group for hosting the full duration of this meeting, especially recognizing Golfetto, Mauro Stocchi and Gianmaurizio Fantozzi for organizing the tour of the OMPI, Optrel and SPAMI glass manufacturing facilities as a kickoff for Phase 2 of this ongoing initiative. PDA would also like to thank all the staff who made themselves available to support the 20+ task force members over those two days: Alessandro Zannini, Riccardo Stocco, Gaetano Baccinelli and Omar Pastrello from SPAMI; Alessandro Zannini and Gaetano Baccinelli from Optrel, and Alessandro Morandotti, Alessandro Faidutti and Barbara Lucato from OMPI.

  • Journal Top 10

    by: Rebecca Stauffer, PDA | Apr 02, 2018

    Particulate Matter, E&L Topics of Interest to Journal Readers

    Below are the top ten articles from the PDA Journal of Pharmaceutical Science and Technology for the month of February.

    1. Review. Stephen E. Langille, “Particulate Matter in Injectable Drug Products” May/June 2013
    2. PDA Paper. Stan Bukofzer, et al. “Industry Perspective on the Medical Risk of Visible Particles in Injectable Drug Products” January/February 2015
    3. Research – PQRI Special Section. Dennis Jenke, et al. “Extractables Characterization for Five Materials of Construction Representative of Packaging Systems Used for Parenteral and Ophthalmic Drug Products” September/October 2013
    4. Review – PQRI Special Section. Diane Paskiet, et al. “The Product Quality Research Institute (PQRI) Leachables and Extractables Working Group Initiatives for Parenteral and Ophthalmic Drug Product (PODP)” September/October 2013
    5. Review. Edward C. Tidswell and Tim Sandle, “Microbiological Test Data— Assuring Data Integrity” January/February 2018
    6. Review. Fran L. Degrazio, “Holistic Considerations in Optimizing a Sterile Product Package to Ensure Container Closure Integrity” January/February 2018
    7. Case Studies. Ana M. C. Santos, et al. “A QRM Discussion of Microbial Contamination of Non-sterile Drug Products, Using FDA and EMA Warning Letters Recorded between 2008 and 2016” January/ February 2018
    8. Research. Galen H. Shi, et al. “Impact of Drug Formulation Variables on Silicone Oil Structure and Functionality of Prefilled Syringe System” January/ February 2018
    9. Research. Dennis Jenke, et al. “Simulated Leaching (Migration) Study for a Model Container-Closure System Applicable to Parenteral and Ophthalmic Drug Products” March/April 2017
    10. Research. Jeffrey R. Vieregg, “Inhibiting Sterilization-Induced Oxidation of Large Molecule Therapeutics Packaged in Plastic Parenteral Vials” January/February 2018
  • New Survey Follows Up on 2013 Glass Survey Data

    by: Rebecca Stauffer, PDA | Feb 26, 2018

    At the 2018 PDA Glass Quality Conference, PDA President Richard Johnson offered a glimpse into PDA’s latest glass survey, currently scheduled for release sometime in Q1.

    Previously, PDA published surveys in 2011, 2012 and 2013 on the topic of glass. For these surveys, manufacturers spanning most segments of the pharma industry were queried about their experiences with glass products, including handling, breakage and relationships with suppliers. The latest survey uses the same questions from the 2013 survey, offering a look at any changes in the five years since the last survey.

    “PDA has conducted this survey a number of times and we did it again in preparation for this meeting,” Johnson said. “What we are trying to do is show you a comparison with the responses to the same questions back in 2013.”

    The 2018 survey will be available for purchase in the PDA Bookstore. The bookstore also offers a comparison of the 2012 and 2013 surveys in addition to proceedings of the 2013 PDA/FDA Glass Packaging Conference.

    Johnson also pointed to other PDA resources that cover glass packaging. These include a number of conferences such as the Parenteral Packaging meeting and the Universe of Pre-filled Syringes and Injection Devices; interest groups (Packaging Science, Prefilled Syringes and Visual Inspection); PDA Education courses and active task forces involved with glass handling and control of visual particulates. Information about many of these activities can be found on the PDA website.

  • Latest Issue of PDA Journal Looks at Particle Formation, Packaging and Vaccine Research Topics

    by: Rebecca Stauffer, PDA | Feb 26, 2018

    Subvisible particle formation, rubber stopper seal performance, and antigen adsorption are some of the latest research topics in the March/ April issue of the PDA Journal of Pharmaceutical Science and Technology.

    Review

    Anil K. Rattan, “Data Integrity: History, Issues, and Remediation of Issues“

    Research

    Yuh-Fun Maa, et al., “Mechanistic Investigation on Grinding- Induced Subvisible Particle Formation during Mixing and Filling of Monoclonal Antibody Formulations“

    Qingyu Zeng, Xia Zhao, “Time-Dependent Testing Evaluation and Modeling for Rubber Stopper Seal Performance“

    Patrick L. Ahl, et al., “Quantitative Analysis of Vaccine Antigen Adsorption to Aluminum Adjuvant Using an Automated High- Throughput Method“

    Ganapathy Gopalrathnam, et al., “Impact of Stainless Steel Exposure on the Oxidation of Polysorbate 80 in Histidine Placebo and Active Monoclonal Antibody Formulation“

    Case Studies

    Laurent Siret, et al., “Development of a Premium Quality Plasma-derived IVIg (IQYMUNE®) Utilizing the Principles of Quality by Design—A Worked through Case Study“

    Technology/Application

    Daniel Coleman, et al., “A Risk Index and Data Display for Process Performance in the Pharmaceutical Industry“

    Tony Cundell, David Jones, “Method Verification Requirements for an Advanced Imaging System for Microbial Plate Count Enumeration“

    Commentary

    Derek Willison-Parry, et al., “Microbiological Control for Affinity Capture Chromatography Processing: An Industry Perspective“

  • New Format for PDA Interest Group Meetings at This Year’s Annual Meeting

    by: Rebecca Stauffer, PDA | Jan 29, 2018

    Change is in the air for PDA interest group meetings at this year’s Annual Meeting! Instead of occurring after the final session of the first two days of the meeting, interest group meetings will be held concurrent with breakout sessions, starting the second day of the conference. This will give attendees more sessions from which to choose during the day and free up time in the evenings. The new schedule for interest groups falling under the Science and Biopharmaceutical Advisory Boards is as follows:

    Tuesday, March 20

    • 10:45 a.m. – 12:15 p.m.
    • Process Validation Interest Group
    • Filtration Interest Group
    • 1:45 p.m. – 3:15 p.m.
    • Biopharmaceutical Manufacturing Interest Group (replacement for Biotechnology Interest Group)
    • 4 :00 p.m.– 5:30 p.m.
    • Cell and Gene Therapy Interest Group (new interest group!)
    • Facilities and Engineering Interest Group

    Wednesday, March 21

    • 10:45 a.m. – 12:15 p.m.
    • Visual Inspection of Parenterals Interest Group
    • Combination Products Interest Group

    The schedule for the Regulatory Affairs and Quality Advisory Board interest group meeting can be found here. For more information about interest group meetings, visit the Annual Meeting website.

  • Interest Group Tours Prefilled Exhibition Hall

    by: Derek Duncan, PhD, Lighthouse Instruments, EU Packacing Science Interest Group Leader | Jan 29, 2018

    During the Universe of Pre-filled Syringes and Injection Devices conference and exhibition in Vienna, the EU Packaging Science Interest Group met for a guided tour through the exhibition area before the start of the second day of the conference on Nov. 8. Starting in the Innovation Gallery, a new addition where key exhibitors could showcase innovative technologies, the group was given an interactive presentation and demo from Smart Skin Technologies on their novel pressure-sensitive skin technology. A lively discussion followed about the applications for monitoring and troubleshooting points in packaging and filling lines where containers experience excessive contact or pressure points using this solution.

    The group was then hosted by representatives from Groninger who invited the group to view a demonstration of a new technique for decontaminating packaging components and transferring them into the sterile area. The next visit was to the poster area where experts from Oval Medical Technologies led a discussion about autoinjector design. Here, discussions covered the use of polymers for better user-centric device designs as well as the ability to handle administration of challenging formulations. The tour ended with a stop at the Atec Sterile Technology booth where representatives from the company provided a demonstration of a stopper processing system.

    The purpose of the Packaging Science Interest Group is to bring packaging experts together to openly discuss current packaging topics. Thanks to all the people and companies who made the meeting in Vienna a success! The next meeting of the group will be the afternoon of Feb. 26 before PDA’s Parenteral Packaging conference in Rome. Don’t miss this opportunity!

  • PDA Welcomes New Standards Manager

    by: Christine Alston-Roberts, PDA | Jan 02, 2018

    PDA is pleased to welcome Christine Alston-Roberts who joins PDA as its Senior Standards Manager. Christine will manage various workgroups to develop consensus standards and oversee the American National Standards Institute (ANSI) standards process. PDA was approved by ANSI as a standards development organization (SDO) in 2016.

    Christine comes to PDA after spending 15 years at the American Type Culture Collection (ATCC) where she worked as a Standards Specialist. There, she was responsible for ensuring the effective operation of the ATCC SDO and any standards or certification initiatives undertaken by ATCC. Her responsibilities included coordinating workgroups, performing administrative, operational and compliance functions of the company’s standard program, communicating as required with the Steering Committee, the membership, standard development workgroups and ANSI, ensuring that records of the ATCC SDO were maintained in compliance with ANSI requirements and serving as the content administrator for the SDO website.

    In addition to the SDO duties, she effectively maintained the ATCC Proficiency Standard program and product line, led cross-functional project plans and teams that involved planning, production, and launch of company certified reference materials (CRM) to satisfy ISO Guide 34 requirements and ensured that information was accurate on the company’s Web-based Standards Resource site.

    Christine graduated with a bachelor’s degree from Virginia Tech. She is excited to join the Scientific and Regulatory Affairs department at PDA.

  • Pharmaceutical Microbiology Analyzed in Three Papers

    by: Rebecca Stauffer, PDA | Jan 02, 2018

    Journal Preview

    This edition of the PDA Journal of Pharmaceutical Science and Technology offers three papers on pharma microbiologys: Tidswell & Sandle on Micro Data Integrity; Menezes, et al, on QRM and micro contamination for non-sterile drug products; and Jimenez, et al, on real-time PCR for low-level contamination.

    Review

    • Edward C. Tidswell, Tim Sandle, “Microbiological Test Data – Assuring Data Integrity“
    • Fran L. DeGrazio, “Holistic considerations in optimizing a sterile product package to ensure container closure integrity“

    Research

    • Matthew V. Tirrell, et al., “Inhibiting sterilization-induced oxidation of large molecule therapeutics packaged in plastic parenteral vials“
    • Bruna Filipa Ribeiro Berardo, Ana Teresa Machado Reis, Rui Loureiro, “Quality of medicines in Portugal: a retrospective review of medicine recalls (2000–2015)“
    • Natarajan Rajagopalan, et al., “Impact of Drug Formulation Variables on Silicone Oil Structure and Functionality of Prefilled Syringe System“

    Case Study

    • José C. Menezes, et al., “A QRM Discussion of Microbial Contamination of Non-Sterile Drug Products, using FDA’s and EMA’s Warning-Letters Recorded Between 2008 and 2016“

    Technology/Application

    • Luis Jimenez, et al., “Real-Time PCR Detection of Burkholderia cepacia in Pharmaceutical Products Contaminated with Low Levels of Bacterial Contamination“

    Commentary

    • Derek Willison-Parry, et al., “Elastomer Change Out—Justification for Minimizing the Removal of Elastomers to Prevent Cross-Contamination in a Multiproduct Facility“
    • Derek Willison-Parry, et al., “Guidelines for Risk-Based Changeover of Biopharma Multi-Product Facilities“

    Letter/Erratum

    • John Mattila, et al., “Erratum to “Retrospective Evaluation of Low-pH Viral Inactivation and Viral Filtration Data from a Multiple Company Collaboration” “
  • Journal Preview

    by: Rebecca Stauffer, PDA | Nov 06, 2017

    Latest Research on Packaging, Validation and Microbiology Available in PDA Journal

    The Nov./Dec. issue of the PDA Journal of Pharmaceutical Science and Technology includes the latest research around a myriad of topics, including packaging, validation of a system and pharmaceutical microbiology. Make sure you don’t miss an issue and sign up for eTOC alerts.

    Letter

    John Mattila, et al., “Erratum to ‘Retrospective Evaluation of Low-pH Viral Inactivation and Viral Filtration Data from a Multiple Company Collaboration’”

    Research

    Ken G. Victor, et al., “Method Development for Container Closure Integrity Evaluation via Headspace Gas Ingress by Using Frequency Modulation Spectroscopy”

    Alberto Leyva, et al., “Demonstration of the Maintaining of the Validated State of a System Used to Generate Water for Injection by Thermocompression Distillation”

    Lloyd Waxman, Vinod D. Vilivalam, “A Comparison of Protein Stability in Prefillable Syringes Made of Glass and Plastic“

    Masakazu Tsuchiya, “Factors Affecting Reduction of Reference Endotoxin Standard Activity Caused by Chelating Agent/Detergent Matrices: Kinetic Analysis of Low Endotoxin Recovery“

    Technology/Application

    Annalaura Carducci, et al., “Development of Methods for Recovering Endotoxins from Surfaces and from Air in Production Environment of Injectable Drugs“

    Robert A. Schaut, et al., “Enhancing patient safety through the use of a pharmaceutical glass designed to prevent cracked containers”

  • Potency Assays, Aging Facilities Prove Twin Challenges for Vaccine Manufacturers

    by: Rebecca Stauffer, PDA | Nov 06, 2017

    The challenge of using the right potency assays and the regulatory issues of aging facilities served as focal points of discussion at the Vaccines Interest Group meeting, Sept. 11, at the 2017 PDA/FDA Joint Regulatory Conference.

    Interest group meeting leaders, Jane Halpern, PhD, Health Specialist, Vaccine Translational Research Branch, Vaccine Research Program, DAIDS, NIAID, U.S. National Institutes of Health, and Sara Gagneten, PhD, Associate Director for Regulatory Policy, Division of Viral Products, CBER, U.S. FDA, headed off the discussion on potency assays. A common challenge for all animal-based vaccines is variability. This often becomes apparent during the transition from in vivo to in vitro testing. Sometimes manufacturers accumulate data from clinical studies conducted for different purposes; this additional data may be used to correlate animal tests with human tests.

    While Gagneten conceded that FDA continues to conduct research tests on potency assays, she cautioned that the Agency does not view itself as being able to impose specific potency tests.

    Following the discussion on potency assays. Michael Schwartz, Director, Global Regulatory Affairs, GSK Vaccines, and Linda Kramer, Director, Global Regulatory Affairs, Establishments, GSK Vaccines, gave a short presentation on regulatory and compliance issues facing aging facilities. The main concerns, according to Kramer, are the potential for contamination, inspection issues, potential for drug shortages and the impact of modernization (recapitalization, time, product holds and process validation).

    Vaccine manufacturers faced with an aging facility will have to make some hard decisions regarding modernization, Kramer further explained. If a manufacturer decides to outsource some or all of the process to a CMO, quality agreements come into play. If the manufacturer chooses to modernize the facility, the process may even need to be changed. And if the manufacturer chooses to build a new site filled with modern equipment, “that’s going to take time, money and validation.”

    Naturally, any modernization plan will require involvement with FDA. Kramer recommends going to FDA with a well-thought-out modernization plan outlining defined expectations for the discussion.

    Anyone interested in getting involved with the Vaccines Interest Group is encouraged to contact PDA.

  • Journal Top 10

    by: Rebecca Stauffer, PDA | Oct 03, 2017

    PDA Papers on Particulates and PACs and PQRI Papers on Extractables Popular Reads

    Below are the top ten articles from the PDA Journal of Pharmaceutical Science and Technology for the month of August.

    1. Review

    Stephen E. Langille “Particulate Matter in Injectable Drug Products” May/June 2013

    2. PQRI Special Section – Research

    Dennis Jenke, et al. “Extractables Characterization for Five Materials of Construction Representative of Packaging Systems Used for Parenteral and Ophthalmic Drug Products” September/ October 2013

    3. PDA Paper

    Stan Bukofzer, et al. “Industry Perspective on the Medical Risk of Visible Particles in Injectable Drug Products” January/February 2015

    4. PDA Paper

    Emma Ramnarine, et al. “PDA Points to Consider: Technical Product Lifecycle Management. Pharmaceutical Quality System Effectiveness for Managing Postapproval Changes” May/June 2017

    5. PQRI Special Section – Review

    Diane Paskiet, et al. “The Product Quality Research Institute (PQRI) Leachables and Extractables Working Group Initiatives for Parenteral and Ophthalmic Drug Product (PODP)” September/October 2013

    6. Review

    James Agalloco “Increasing Patient Safety by Closing the Sterile Production Gap—Part 1. Introduction” July/August 2017

    7. Review

    Robert A. Schaut and W. Porter Weeks “Historical Review of Glasses Used for Parenteral Packaging” July/August 2017

    8. Review

    James Agalloco “Increasing Patient Safety by Closing the Sterile Production Gap—Part 2. Implementation” July/August 2017

    9. Review

    James Agalloco “Increasing Patient Safety by Closing the Sterile Production Gap—Part 3—Moist Heat Resistance of Bioburden” July/August 2017

    10. Research

    Dennis Jenke, et al. “Simulated Leaching (Migration) Study for a Model Container- Closure System Applicable to Parenteral and Ophthalmic Drug Products” March/ April 2017

  • A Handy Guide to Preventing Contamination

    by: Andrew Dick, Johnson & Johnson, and Marilyn Foster, PDA | Oct 03, 2017

    The prevention of microbiological contamination in the nonsterile manufacture of drugs and consumer products is paramount to maintaining a robust supply chain and ensuring consumer safety. Consequently, the importance of understanding, practicing and maintaining control of sanitation in a manufacturing plant cannot be emphasized enough.

    For these reasons, the upcoming PDA book, Handbook on Contamination Prevention for Nonsterile Pharmaceutical Manufacturing, will provide solutions to ongoing contamination events. Chapters will cover:

    • Facility Layout
    • Equipment Design, Components, and Maintenance
    • Cleaning and Sanitization Practices
    • Purified Water System and Microbiological Controls
    • Hygienic Manufacturing Practices (Raw Materials and Sampling)
    • Personnel
    • Plant Microbiological Risk Assessment and Qualification Checklist

    Handbook on Contamination Prevention for Nonsterile Pharmaceutical Manufacturing will be available shortly for purchase in the PDA Bookstore.

  • New PDA Task Force Hopes to See Zero Defects for Visible Particles

    by: Jahanvi (Janie) Miller, PDA | Aug 29, 2017

    Visible particulate matter has long been a popular topic for PDA members. In fact, the PDA Paper, “Industry Perspective on the Medical Risk of Visible Particles in Injectable Drug Products,” has been viewed over 9000 times on the PDA Journal of Pharmaceutical Science and Technology website (1). Ideally, both industry and regulators seek a clearly defined, risk-based particle specification (e.g., size, type and quantity). While such specificity is desirable, the lack of relevant clinical trials limits the ability to establish specifications typically done for other “impurities.” Therefore, sterile manufacturers have relied on a large body of anecdotal information to guide understanding of clinical risk. While this is useful, it does not offer an exact limit for setting acceptance criteria for injectable products and the primary packaging used in their preparation. This, coupled with the normal variability of human visual inspection, has led to a wide range of practices and limits applied to particles in injectable drug products and their packaging materials. Due to PDA members’ involvement in providing consensus-based guidance to the industry, the Pharmaceutical Manufacturing Forum (PMF) has tasked PDA members with diving deeper into developing particle specifications.

    A new task force has formed to align on a common, harmonized rationale across the industry and develop a practical guide intended for use along with existing compendial, regulatory and industry standards. The Zero Defects for Visible Particles in Injectables Task Force plans to identify gaps in current risk assessments and methods used to detect and quantify visible particles in order to develop a series of best practice documents. The purpose of these documents would be to potentially reduce defects related to particles. Within this group, subgroups will work on separate workstreams, each working to identify a visible particle size threshold, analytical method gap analysis (for elastomer and glass components) and validation strategies. Volunteers working within these subgroups will consist of representatives from both manufacturers and suppliers to ensure a well-balanced perspective for resulting documents.

    PDA intends to expand the resources relating to visible particulates to support continuous improvement and development of new best practices for the industry and its members. In fact, the 2017 PDA Visual Inspection Forum in October will offer opportunities to learn more about the latest practices in this area and discuss some of the task force’s developments.

    Reference

    1. Bukofzer, S. “Industry Perspective on the Medical Risk of Visible Particles in Injectable Drug Products.” PDA Journal of Pharmaceutical Science and Technology 69 (2015): 123-139.
  • September/October Issue Includes QRM Survey Results

    by: Rebecca Stauffer, PDA | Aug 29, 2017

    Where does the industry stand when it comes to quality risk management (QRM)? PDA members Kelly Waldron, Emma Ramnarine and Jeffrey Hartman provide results from the 2015/2016 Quality Risk Management Benchmarking Survey in the PDA Journal of Pharmaceutical Science and Technology.

    Review

    Kelly Waldron, Emma Ramnarine, Jeff Hartman, “2015/2016 Quality Risk Management Benchmarking Survey“

    Research

    Dennis Jenke, “Extractables Screening of Polypropylene Resins used in Pharmaceutical Packaging for Safety Hazards“

    Ruojia Li, Weiguo Cai, Marcel Zocher, “A Novel Lack-of-Fit Assessment as a System Suitability Test for Potency Assays“

    Technology/Application

    Christopher L. Timmons, Chi Yuen Liu, Stefan Merkle, “Particulate Generation Mechanisms during Bulk Filling and Mitigation via New Glass Vial“

    Neil McLeod, M. Clifford, J.M. Sutton, “Evaluation of novel process indicators for rapid monitoring of hydrogen peroxide decontamination processes“

    Jay Bolden, Kelly Smith, “Application of recombinant Factor C reagent for the detection of bacterial endotoxins in pharmaceutical products“

    Commentary

    Derek Willison-Parry, et al., “Mold Control and Detection in Biological Drug Substance Manufacturing Facilities: An Industry Perspective“

  • July/August Issue of PDA Journal Includes Part III of the Sterile Production Gap Series

    by: Rebecca Stauffer, PDA | Jul 10, 2017

    The latest issue of the PDA Journal of Pharmaceutical Science and Technology looks at bioburden moist heat resistance in Part III of James Agalloco’s series on the sterile production gap.

    Review

    James P. Agalloco, “Increasing Patient Safety by Closing the Sterile Production Gap—Part 1. Introduction”

    James P. Agalloco, “Increasing Patient Safety by Closing the Sterile Production Gap—Part 2. Implementation”

    James P. Agalloco, “Increasing Patient Safety by Closing the Sterile Production Gap—Part 3. Moist Heat Resistance of Bioburden“

    Robert A. Schaut, Wendell Porter Weeks, “Historical Review of Glasses Used for Parenteral Packaging“

    Binbing Yu, Harry Yang, “Evaluation of Different Estimation Methods for Accuracy and Precision in Biological Assay Validation“

    Research

    Alberto Biavati, et al., “Complexing Agents and pH Influence on Chemical Durability of Type I Molded Glass Containers“

    Technology/Application

    Christopher M. Weikart, Carlo G. Pantano, Jeff R. Shallenberger, “Performance Stability of Silicone Oxide Coated Plastic Parenteral Vials"

  • PDA/FDA JRC Interest Group Meeting Schedule

    by: Rebecca Stauffer, PDA | Jul 10, 2017

    To supplement regular sessions, a number of PDA Interest Groups will convene at the 2017 PDA/FDA Joint Regulatory Conference. Below is a schedule of interest group sessions falling under the Science and Biotechnology Advisory Boards.

    Monday, Sept. 11

    5:30 p.m. – 6:45 p.m.

    • Vaccines Interest Group
    • Visual Inspection of Parenterals and Packaging Science Interest Groups (combined meeting)

    Tuesday, Sept. 12

    5:30 p.m. – 6:30 p.m.

    • Lyophilization and Sterile Processing/Parenteral Drug Manufacturing (combined meeting)
    • Facilities and Engineering Interest Group
  • Call for Volunteers

    by: Rebecca Stauffer, PDA | Jul 10, 2017

    Revision of Technical Report No. 45: Filtration of Liquids Using Cellulose-Based Depth Filters

    A variety of our technical reports are becoming aged and require revision, including Technical Report No. 45: Filtration of Liquids Using Cellulose-Based Depth Filters. The current report no longer meets the standards of technological advancements in this area and PDA is forming a revision task force. Ideally, the revision will also broaden the scope of this technical report to include non-cellulose-based filter types, meaning all common forms of liquid prefilters.

    To commence work, PDA is looking for volunteers to form a revision task force and present a formal proposal outlining the scope and major points of focus of the revised technical report. To volunteer, please send an e-mail with your contact details to Maik Jornitz and note whether you are able to be a coleader of the task force.

    Thank you in advance!

  • Packaging-related Research Tops List of April Most Read Journal Articles

    by: Rebecca Stauffer, PDA | May 30, 2017

    Below are the top ten articles from the PDA Journal of Pharmaceutical Science and Technology for the month of April.

    1. PQRI Special Section – Research

    Dennis Jenke, et al., “Extractables Characterization for Five Materials of Construction Representative of Packaging Systems Used for Parenteral and Ophthalmic Drug Products” September/October 2013

    2. Research

    Dennis Jenke, et al., “Simulated Leaching (Migration) Study for a Model ContainerClosure System Applicable to Parenteral and Ophthalmic Drug Products” March/April 2017

    3. PDA Paper

    Stan Bukofzer, et al., “Industry Perspective on the Medical Risk of Visible Particles in Injectable Drug Products” January/February 2015

    4. PQRI Special Section – Review

    Diane Paskiet, et al., “The Product Quality Research Institute (PQRI) Leachables and Extractables Working Group Initiatives for Parenteral and Ophthalmic Drug Product (PODP)” September/October 2013

    5. PDA Paper

    Emma Ramnarine, et al., “PDA Points To Consider: Technical Product Lifecycle Management: Communication and Knowledge Exchange between Marketing Authorization Holders and Health Authorities” March/ April 2017

    6. Review

    Stephen E. Langille, “Particulate Matter in Injectable Drug Products” May/June 2013

    7. Research

    Paul Flaya, James D. Stamey, and John W. Seaman, Jr., “A Bayesian Approach to Determination of F, D, and Z Values Used in Steam Sterilization Validation” March/April 2017

    8. Research

    Julie Wang, et al., “Mycoplasma Clearance and Risk Analysis in a Model Bioprocess” March/April 2017

    9. Conference Proceeding

    George Miesegaes, “Viral Clearance by Traditional Operations with Significant Knowledge Gaps (Session II): Cation Exchange Chromatography (CEX) and Detergent Inactivation” January/February 2014

    10. Technology/Application

    Eric C. Hilario, et al., “An Improved Method of Predicting Extinction Coefficients for the Determination of Protein Concentration” March/April 2017

  • Packaging-related TR Continues to Draw Discussion

    by: Jahanvi (Janie) Miller, PDA | May 30, 2017

    Whenever I hear industry experts citing a PDA technical report, it provides insight into the value of these documents that can be shared with technical report teams, other volunteers, and staff. At the Parenteral Packaging conference in March, amid discussions about regulatory updates, inspection findings, primary packaging challenges, and container closure integrity issues, speakers often referenced Technical Report No. 76: Identification and Classification of Nonconformities in Elastomeric Closures and Aluminum Seals for Parenteral Packaging. Apparently, organizations are using this document to better classify their nonconformities. This technical report was published in October, and six months later it’s still gaining traction as a topic of discussion.

    An annex to TR-76 is currently under development. The annex will focus entirely on identifying nonconformities specific to prefilled syringes and will complement some of the existing information in Technical Report No. 73: Prefilled Syringe User Requirements for Biotechnology Applications. As far as other packaging-related technical reports, a team is looking to revise or, potentially add an Annex to Technical Report No. 27: Pharmaceutical Package Integrity—a document last published in 1998! The team working on this revision expects to send a draft out for peer review toward the end of this year. Interestingly, the team has already expanded part of the document in response to the revision of USP General Chapter <1207> Sterile Product Packaging–Integrity Evaluation. In addition, the document will address new technologies and the application of risk-based approaches.

    As you can see, we continue to add to our library of technical reports on packaging topics. If you’re interested in working on a technical report team for such a document in the future, I recommend getting involved with our Packaging Science Interest Group. The leadership team supporting this group is very high energy with a wide range of expertise across multiple areas of packaging science. Derek Duncan, the EU head of the interest group, facilitated an in-depth discussion on the latest in packaging at the group’s first meeting of 2017, held during the Packaging Conference. Based on this, and the group’s dynamic leadership team, we anticipate more lively interaction and member support from this interest group.

    If you would like to take part in future discussions, please visit the interest group’s PDA ConnectSM page.

  • PDA: Enabling Pharmaceutical Manufacturing Today

    by: Rich Levy, PDA, Debbie Goldstein, PDA | May 01, 2017

    PDA has a long tradition of providing the scientific foundation to facilitate the technological developments that advance pharmaceutical and biotechnological manufacturing and, in so doing, benefit the public health.

    The vocations of many of our members reflect manufacturing-related activities, such as supply chain, cleaning and disinfection, glass handling and packaging, aseptic processing and pharmaceutical microbiology, as well as biotechnological areas, such as sterile filtration, ultrafiltration, and chromatography.

    For more than 70 years, PDA has been providing high-quality, expert manufacturing resources to meet the needs of our members and other industry professionals involved in these aspects of bio/pharmaceutical manufacturing. These resources include:

    • Peer-reviewed technical reports offering guidance on a variety of manufacturing-related topics, such as aseptic processing, validation of dry and moist heat sterilization, steam-in-place, validation of tangential flow filtration, sterilizing filtration, virus filtration, parametric release, validation of column-based chromatography, pharmaceutical package integrity, process simulation of aseptic processing, process validation, technology transfer, single-use systems, reprocessing, and identification and classification of nonconformities in glass vials and in elastomeric closures, to name a few.
    • Conferences and workshops focused specifically on trends in manufacturing, such as Quality Risk Management (QRM) for manufacturing systems, aging facilities, analytical methods, continuous manufacturing, glass quality and handling, single-use systems, lyophilization, pharmaceutical packaging, and prefilled syringes and injection devices.
    • Lecture and lab-based education courses providing in-depth training and practical solutions to manufacturing challenges, including aseptic processing, bioburden and biofilm management, cleaning and disinfection, container closure and integrity testing, contamination control and environmental monitoring, cleanroom and isolator technology, facility design and operation, filtration, GMPs, moist heat sterilization, single-use systems, technology transfer, visual inspection, and multiple courses on the validation of manufacturing processes.
    • Subject matter expert-generated content on the latest manufacturing science covered in the PDA Journal of Pharmaceutical Science and Technology and PDA Letter magazine.

    Further, we monitor and support the global regulatory interests of our members. We have frequent interactions with global regulatory authorities related to GMPs. We do this by cosponsoring meetings with regulators (FDA, EMA,PIC/S, ICH, ANVISA), and through our commenting teams, who respond to health authorities with PDA’s official thoughts on proposed regulations and guidances. By doing this, we promote science-based regulations.

    PDA recognizes that to better serve patients we must improve manufacturing processes and efficiencies and build quality into our products, rather than inspect after. We are committed to helping to advance technological enhancements by identifying improvement and facilitating dialogue with regulators to encourage adoption.

    To that end, PDA has established a formal steering team to guide PDA’s future manufacturing efforts through the Manufacturing Science and Operations ProgramSM.

    PDA’s Manufacturing Science and Operations Program (MSOPSM) — Enabling Pharmaceutical Manufacturing’s Future

    In an effort to continue PDA’s leadership position at the forefront of advances in bio/pharmaceutical manufacturing, PDA has established the Manufacturing Science and Operations ProgramSM, the goal of which is to:

    • Highlight the ongoing focus PDA has on pharmaceutical and biopharmaceutical manufacturing
    • Strengthen and build practical solutions by filling known gaps in current manufacturing science as well as gaps that will become apparent based on ongoing developments and analyses
    • Identify and encourage use of new manufacturing technology and methods

    The steering team has identified several areas of interest which we are beginning to explore, which include the following:

    • Leveraging Technology — Leveraging technology is about delivering existing technology faster and more efficiently, this will enable suppliers to provide one best solution even if it’s less expensive and deliver new technology faster
    • Manufacturing Organization, Culture and Process Understanding — Improving these three areas will lead to operational/technical improvements
    • Data on the Shop Floor — Using manufacturing data in real time on the shop floor will deliver better decisions and reduce variability
    • Aseptic Processing/Technology/Real-Time Release — Implementing technology advances in aseptic processing as well as real-time release will lead to improvements in pharmaceutical and biotech manufacturing as well as the quality of drug products and delivery devices

    To learn more about how PDA is promoting progress in bio/pharmaceutical manufacturing, how you can benefit from the expert tools and resources available and how you can become involved in this initiative to advance bio/pharmaceutical manufacturing, please visit the PDA website.

  • May/June Issue of Journal Looks at Sterile Production Gap

    by: Rebecca Stauffer, PDA | May 01, 2017

    James Agalloco looks at the latest research in how the sterile production gap impacts patient safety in the May/June issue of the PDA Journal of Pharmaceutical Science and Technology.

    Review

    James P. Agalloco, “Increasing Patient Safety by Closing the Sterile Production Gap – Part 1 - Introduction“

    James P. Agalloco, “Increasing Patient Safety by Closing the Sterile Production Gap – Part 2 - Implementation“

    Research

    Yuh-Fun Maa, et al., “Processing Impact on Monoclonal Antibody Drug Products: Protein Subvisible Particulate Formation Induced by Grinding Stress“

    Fernando A. Garcia, Michael W. Vandiver, “Throughput Optimization of Continuous Biopharmaceutical Manufacturing Facilities“

    Marcel Goverde, Oliver Gordon, Alexandra Staerk, David Roesti, “Validation of Milliflex® Quantum for Bioburden Testing of Pharmaceutical Products“

    Technology/Application

    Ildikó Ziegler, et al., “Revision of Viable Environmental Monitoring in a Development Pilot Plant based on Quality Risk Assessment: A Case Study"

    Commentary

    Mostafa Essam Eissa, “Quantitative Microbial Risk Assessment of Pharmaceutical Product”

    PDA Paper

    Emma Ramnarine, et al., “PDA Points to Consider: Technical Product Lifecycle Management: Pharmaceutical Quality System Effectiveness For Managing Post-Approval Changes“

  • ATMPs Offer Promise But Also Challenges

    by: Josh Eaton, PDA | Apr 04, 2017

    Advancements in gene- and cell-based therapies now link the emerging field of advanced therapy medicinal products (ATMPs) to all aspects of the pharma industry. Yet traditional GMP approaches to these products face a multitude of challenges, such as short shelf-lives, specific temperature requirements, facility usage, control strategies, and more. Manufacturers, regulators, and suppliers are all responsible for overcoming these challenges.

    In the United States, the US FDA is inundated with data regarding the production of these nascent technologies, although presentation of the data in common terms and conversion of it into knowledge and understanding of the products and processes is lagging. The process for using data to rationalize decisions needs to be integrated with the Quality Risk Management (QRM) process.

    The Bioassay Methods Group of the US National Institute of Standards and Technology’s Biosystems and Biomaterials Division is working with industry on one specific aspect of this issue: off-target genome editing. Off-target genome editing occurs when a gene therapy modifies genes other than those causing the disease-state of the patient; in other words, genes that are not the “target” of the therapy. Naturally, this introduces the potential for a negative impact, the results of which can be unpredictable. For example, the mistakenly altered genes could result in another ailment, such as dysfunctional enzymes, overreactive hormones, or even cancerous growth of cells. In other cases, the unintended modification may have no repercussions at all. The Bioassay Methods Group is focused on determining the degree of on-target vs. off-target modifications and the subsequent identification, characterization, and evaluation of off-target genome edits and their potential consequences.

    Manufacturing operations for advanced therapies can be approached in various ways. Some manufacturers, particularly new companies, may purpose-build a production facility for convenience or out of necessity, while established companies must determine how to reconfigure existing facilities to adapt to these unique products. For instance, a production site may need upgrades to meet particular requirements of a biological product, or a physical plant, while adequate, may operate below capacity due to a decreased volume of production. To compensate, several companies have employed single-use systems alongside, or in place, of conventional stainless steel equipment, a strategy that requires evaluating the possible interactions of the therapeutic product and the raw materials with the disposable equipment— sometimes across several vendors. For autologous therapies, where the starting material is often extremely limited, careful monitoring of materials and processes is crucial, creating a need for increased scrutiny of raw materials and incorporation of process analytical technology to monitor production via inline testing and sampling. Given that many therapies have a limited useful lifetime once produced, the timing of production and the facility’s distance from the recipient of the final material are also key factors. Some companies locate their production facilities geographically to account for these concerns; this may require a significant outlay for facility construction and maintenance. Others rely on contract manufacturing organizations (CMOs) for their operations, which brings its own concerns: not all CMOs are equal, so each must be evaluated individually. Depending on the biological product and processes involved—if a specialized technology/skill is required or if any of the materials are toxic or infectious—there may be few viable CMO options.

    Not only do manufacturers need to innovate in this area, suppliers will need to adapt. Materials and equipment suppliers, for example, play a critical role in the development of revolutionary treatments for injuries like damaged spinal cords or knee cartilage, and for diseases like Parkinson’s and multiple sclerosis. Cell-free manufacturing systems employing GMP-compliant processes are being developed to avoid potential endogenous viral contamination and meet regulatory guidelines. Some innovative suppliers are offering microsized bioreactors capable of producing a single autologous cell therapy dose to avoid cross-contamination and drastically reduce the footprint needed to produce the treatment. Others are envisioning a dehydrated, portable “cell factory” with all components included for ondemand biomolecular manufacturing.

    In the rapidly evolving arena of gene and cell therapies, there are many moving pieces and, as part of its mission, PDA intends to aid its members in navigating this ever-changing landscape. Volunteer groups are currently working to revise Technical Report No. 42: Process Validation for Protein Manufacturing to reflect the advent of ATMPs and are drafting a new technical report focused on control strategies for producing autologous cell therapies. Both are scheduled for peer review soon.

    PDA is sponsoring several events in 2017 that will focus on gene and cell therapies: a workshop following the 2017 PDA Annual Meeting in April; the annual PDA Europe Advanced Therapy Medicinal Products conference in June; and a US-based meeting on ATMPs in December, PDA’s first US conference on the topic. PDA has designed these conferences and technical reports to help ATMP manufacturers, regulators, and suppliers address the challenges of these innovative products.

  • Journal Top Ten

    by: Rebecca Stauffer, PDA | Apr 04, 2017

    The Latest Industry Research Comprises Half of the Most Popular Journal Articles for February

    Below are the top ten articles from the PDA Journal of Pharmaceutical Science and Technology for the month of February.

      .
    1. PQRI Special Section – Research: Dennis Jenke, et al., “Extractables Characterization for Five Materials of Construction Representative of Packaging Systems Used for Parenteral and Ophthalmic Drug Products” September/October 2013
    2. PDA Paper: Stan Bukofzer, et al., “Industry Perspective on the Medical Risk of Visible Particles in Injectable Drug Products” January/February 2015
    3. PQRI Special Section – Review: Diane Paskiet, et al., “The Product Quality Research Institute (PQRI) Leachables and Extractables Working Group Initiatives for Parenteral and Ophthalmic Drug Product (PODP)” September/October 2013
    4. Research: Marcel Goverde, Julian Willrodt, and Alexandra Staerk, “Evaluation of the Recovery Rate of Different Swabs for Microbial Environmental Monitoring” January/February 2017
    5. Research: Roland Guinet, et al., “Multicenter Study on Incubation Conditions for Environmental Monitoring and Aseptic Process Simulation” January/February 2017
    6. Review: Stephen E. Langille, “Particulate Matter in Injectable Drug Products” May/June 2013
    7. Research: Steven J. Novick, Wei Zhao, and Harry Yang, “Setting Alert and Action Limits in the Presence of Significant Amount of Censoring in Data” January/February 2017
    8. Research: Tobias Werk, et al., “A Method To Determine the Kinetics of Solute Mixing in Liquid/Liquid Formulation Dual-Chamber Syringes” January/February 2017
    9. Research: Bryan Lei Yu, et al., “Kinetic Modeling of the Release of Ethylene Oxide from Sterilized Plastic Containers and its Interaction with Monoclonal Antibodies” January/February 2017
    10. Technology/Application: Kiyoshi Fujimori, Hans Lee, Joseph Phillips, and Yasser Nashed-Samuel, “Development of Conductivity Method as an Alternative to Titration for Hydrolytic Resistance Testing Used for Evaluation of Glass Vials Used in Pharmaceutical Industry” January/February 2017
  • PDA Points to Consider on Post-Approval Changes Available in March/April Issue of PDA Journal

    by: Rebecca Stauffer, PDA | Mar 06, 2017

    The March/April issue of the PDA Journal of Pharmaceutical Science and Technology features a PDA Points to Consider paper from members of the Post-Approval Change: Innovation for Availability of Medicines (PAC iAM) technical report team.

    Research

    Alberto Biavati, Michele Poncini, Arianna Ferrarini, “Complexing Agents and pH Influence on Chemical Durability of Type I Molded Glass Containers”

    Dennis Jenke, et al., “Simulated Leaching (Migration) Study for a Model Container-Closure System Applicable to Parenteral and Ophthalmic Drug Products”

    Paul Faya, James D. Stamey, John W. Seaman Jr., “A Bayesian Approach to Determination of F, D, and Z Values Used in Steam Sterilization Validation”

    Kurt Brorson, et al., “Mycoplasma Clearance and Risk Analysis in a Model Bioprocess”

    Technology/Application

    Harry Yang, et al., “Characterizing the Overall Derivatization of Conjugated Oligomeric Proteins”

    Eric Hilario, et al., “An Improved Method of Predicting Extinction Coefficients for the Determination of Protein Concentration”

    Commentary

    Raja Mazumder, Vahan Simonyan, Jeremy Goecks, “Biocompute Objects—A Step towards Evaluation and Validation of Biomedical Scientific Computations“

    Klaus Wuchner, et al., “Container Closure Integrity Testing—Practical Aspects and Approaches in the Pharmaceutical Industry“

    PDA Paper

    Emma Ramnarine, et al., “PDA Points To Consider: Technical Product Lifecycle Management: Communication and Knowledge Exchange between Marketing Authorization Holders and Health Authorities“

  • Annual Meeting Interest Group Meeting Schedule

    by: Rebecca Stauffer, PDA | Mar 06, 2017

    As always, relevant interest groups will meet in the afternoon for the first two days of the 2017 PDA Annual Meeting. Below is a schedule of interest group meetings that fall under the Science and Biopharmaceutical Advisory Board umbrellas. Note: All interest group meetings are open to meeting registrants.

    Monday, April 3

    4:15 – 5:30 p.m.

    • Advanced Virus Detection Technologies Interest Group
    • Facilities and Engineering Interest Group
    • Filtration Interest Group
    • Microbiology/Environmental Monitoring Interest Group
    • Packaging Science Interest Group

    Tuesday, April 4

    4 p.m. – 5:15 p.m.

    • Process Validation Interest Group
    • Sterile Processing Interest Group
    • Visual Inspection of Parenterals and Lyophilization Interest Groups (joint meeting)
    • Pre-filled Syringes Interest Group
  • New Year, New Name, New Activities for BioAB

    by: John Geigert, PhD, BioPharmaceutical Quality Solutions, BioAB Chair | Mar 06, 2017

    PDA’s Biotechnology Advisory Board is now officially the Biopharmaceutical Advisory Board (BioAB). This new name better represents the scientific and technical information this advisory board provides to PDA’s board of directors and its membership regarding biopharmaceutical manufacturing, quality and regulations.

    But BioAB is more than an advising group. Its members actively participate and take leadership roles in numerous PDA events. And 2017 is proving to be an active year with BioAB members involved in three major upcoming events:

    2017 PDA Annual Meeting

    Michael De Felippis, PhD, Senior Research Fellow, Bioproduct R&D, Eli Lilly & Company and Vice-Chair of BioAB, and Morten Munk, Senior Technology Partner, Global Business Development, NNE Pharmaplan, are co-chairing this signature PDA event in April, assisted by Laurie Graham, Acting Director, OPQ, US FDA, and a number of other PDA volunteer members from across the bio/pharmaceutical industry on the conference planning committee.

    2017 PDA Cell and Gene Therapy Workshop

    Due to the increasing importance of cell and gene therapy products, BioAB has designated this area of biopharma as a major initiative for the advisory board, led by volunteers Vijay Chiruvolu, PhD, Senior Director, Product Sciences, Kite Pharma, Michael Blackton, Vice President, QA CMC, Adaptimmune, and Karen Walker, Global Head, Quality, Cell and Gene Therapy Units, Novartis. All three have been heavily involved in developing this workshop on these “next wave” biopharmaceutical products. It is scheduled to follow the Annual Meeting in April.

    2017 PDA Biosimilars Conference

    Vince Anicetti, Executive Director, Quality, Coherus Bioscience, and Stephan Krause, PhD, Director, QA Technology, AstraZeneca Biologics, are co-chairing this year’s biosimilars conference in June, assisted by Michael VanDerWerf, Director, Regulatory Affairs, Teva, Laurie Graham, and Jens Schletter, PhD, Head, Regulatory CMC Group Biopharmaceuticals, Sandoz. BioAB has been heavily involved in this area as biosimilars are already market-approved in both Europe and the United States, with many more in various stages of clinical development or under active regulatory authority market approval review.

    PDA’s BioAB members continue to work hard to cover emerging developments and technology in biopharma. The advisory board hopes these three PDA events offer members a chance to learn more about the latest biopharmaceutical trends and challenges as well as debate these topics with other members.

  • Jan/Feb Issue of PDA Journal Includes Disinfectant Testing Commentary

    by: Rebecca Stauffer, PDA | Jan 30, 2017

    David Shields, Carol Bartnett, and James N. Polarine, Jr., offer their perspective on the challenges of testing disinfectant effectiveness in the latest issue of the PDA Journal of Pharmaceutical Science and Technology.

    Research

    Alberto Biavati, et al., “Complexing Agents and pH Influence on Chemical Durability of Type I Molded Glass Containers”

    Tobias Werk, et al., “A Method To Determine the Kinetics of Solute Mixing in Liquid/Liquid Formulation Dual-Chamber Syringes”

    Bryan L. Yu, et al., “Kinetic Modeling of the Release of Ethylene Oxide from Sterilized Plastic Containers and Its Interaction with Monoclonal Antibodies”

    Steven J. Novick, Wei Zhao, Harry Yang, “Setting Alert and Action Limits in the Presence of Significant Amounts of Censoring in Data“

    Marcel Goverde, Julian Willrodt, Alexandra Staerk, “Evaluation of the Recovery Rate of Different Swabs for Microbial Environmental Monitoring”

    Peter Stärtzel, “The Application of Amino Acids in Freeze-Dried Protein Formulations“

    Roland Guinet, et al., “Multicenter Study on Incubation Conditions for Environmental Monitoring and Aseptic Process Simulation“

    Technology/Application

    Yasser Nashed-Samuel, et al., “Development of Conductivity Method as an Alternative to Titration for Hydrolytic Resistance Testing used for Evaluation of Glass Vials Used in Pharmaceutical Industry“

    Commentary

    David J. Shields, Carol Bartnett, James N. Polarine, Jr., “Disinfectant Effectiveness Testing Challenges“

  • IG Gets Hot and Heavy with “Speed Dating” Exercise

    by: Shelley Preslar, Azzur Group | Jan 03, 2017

    On Sept. 13, PDA’s Facilities and Engineering Interest Group convened on the second day of the 2016 PDA/FDA Joint Regulatory Conference. Following a review of interest group business, group members came together in a large circle to participate in the interest group’s first speed dating session. Originally developed for the Inspection Trends Interest Group, this exercise involves participants spending five to ten minutes on “dates” with topics of interest in the industry. During these “dates,” participants discuss the topic and make recommendations until it is time to rotate to a new topic.

    Stephen Roenninger, Director, International Quality External Affairs, Amgen, led the group discussion on health-based limits for dedicated facilities. Speed daters discussed the EMA’s recent guideline on this topic. Overall, speed daters felt that the values behind the cleaning limits for these facilities should be risk-based and draw from normal production experiences.

    Speed daters also met with Christopher Smalley, PhD, to discuss the Quality Risk Management (QRM) process for aging facilities. What is the key to QRM success? The group consensus is that it is critical to understand the process through an assessment, and then evaluate if the cost of the replacement overrides the cost benefit. Ultimately, the overall ROI needs to be evaluated.

    Ravi Samavedam, General Manager, Azzur Group, led the group conversation on implementation of phase-appropriate GMPs. Here, discussions explored different requirements for Phase I products, ICH Q7: Good Manufacturing Practice for Active Pharmaceutical Ingredients, Quality Control, and audits of raw material vendors, to name a few.

    In the final group, Laurie Norwood from the U.S. FDA covered Agency-related topics. Here, daters came to the consensus that while change can be hard, with many initial drawbacks (temporary slowdowns, “if it ain’t broke, don’t fix it” attitude, etc.), it is necessary. Daters left this round understanding that open communication with FDA about facility upgrades and improvements can only help as the Agency really does want the industry to improve.

    While speed-daters may not have found a “perfect match” in their dates, all in all, the discussions during the exercise showed that interest group members remain committed to finding solutions to the issues affecting manufacturing facilities.

  • PDA Maintains a Productive Publishing Year

    by: Walter Morris, PDA | Jan 03, 2017

    PDA’s Board of Directors, advisory boards, technical report teams and Science and Regulatory staff produced four technical reports, a Points to Consider document, and three PDA surveys in 2016—continuing a streak of highly productive publishing years. This batch of varied and interesting publications included:

    • Technical Report No. 56 (Revised 2016): Application of Phase- Appropriate Quality System and cGMP to the Development of Therapeutic Protein Drug Substance (API or Biological Active Substance)
    • Technical Report No. 74: Reprocessing of Biopharmaceuticals
    • Technical Report No. 75: Consensus Method for Rating 0.1μ Mycoplasma Reduction Filters
    • Technical Report No. 76: Identification and Classification of Visible Nonconformities in Elastomeric Components and Aluminum Seals for Parenteral Packaging
    • Points to Consider for Aseptic Processing, Part 2
    • PDA Survey: 2015 Aging Facilities
    • PDA Survey: 2015 Particulate Matter in Difficult to Inspect Parenterals
    • PDA Survey: 2015 Particulate Matter in Oral Dosage Forms

    PDA technical reports go through the PDA peer review process, which includes a global review by subject matter experts, advisory board ballot, and Board of Directors (BOD) ballot. Both the advisory board ballot and BOD ballot can result in rejection of the document or changes to it. Surveys are produced as part of the development of a future document (usually a technical report)] but do not go through the peer review process. All PDA technical document projects are sanctioned, or approved, first by an advisory board (i.e., the Science, Biotechnology, or Regulatory Affairs and Quality Advisory Board). PDA also published two “PDA Papers” in the PDA Journal of Pharmaceutical Science and Technology. These are official position papers approved through the PDA peer review process.

    Members can expect more of the same in 2017. The first technical report out this year will cover blow/fill/seal technology and will publish in January. Members can also look forward to other several other TRs covering important topics like glass handling, autologous cell therapy control strategies, and validation of protein manufacturing, along with more “PDA Papers” and surveys.

  • New Interest Group Offers Data Analysis Insights

    by: Mike Long, Concordia ValSource | Nov 07, 2016

    Statistics doesn’t have to be scary! Proper data analysis techniques throughout the product lifecycle are critical in assuring robust product and processes. Applied statistics is a supporting element within the product lifecycle and essential to applying ICH Q9: Quality Risk Management and risk-based thinking. PDA created the Applied Statistics Interest Group (ASIG) to help provide guidance on the application of good data analysis techniques to manufacturing statistics.

    One of ASIG’s goals is to work with other PDA interest groups to provide informative webinars. Recently, ASIG held two webinars in conjunction with the Process Validation IG and the Quality Risk Management IG on the application of good statistical techniques and analysis to the process validation lifecycle. The leaders of these interest groups intend to repeat the webinar this fall for those members outside the United States.

    The ASIG held a well-attended meeting at the 2016 PDA/FDA Joint Regulatory Conference in September that featured great talks by J. Patrick Donohue, Senior Associate Scientist, Janssen, and the U.S. FDA’s Karthik Iyer. Donohue spoke about sample size justification when analyzing a large molecule drug product, while Iyer offered the FDA perspective on using statistics to analyze the stages of the process validation lifecycle.

    A number of questions were raised during the webinars and at the interest group meeting:

    • How are CQAs defined?
    • Are normality tests overused?
    • What is the importance of graphing data prior to any other analysis?
    • What is the rationale for the Use of Tolerance intervals?
    • Why are some statistical tools used for Process Performance Qualification (PPQ) and not others?
    • What is the rationale for an objective criteria for sample size selection for drug product PPQ?
    • How do we assure the integrity of our data? After all, data is coming out of the system into statistical packages then presented in reports.
    • How do we rightsize our data analysis not just for PPQ but for other quality system elements?

    To discuss these questions, visit the Applied Statistics Interest Group Forum on PDA ConnectSM and continue the conversation!

    Future projects include technical reports on continuous process verification and PPQ data analysis techniques and a joint meeting with the Process Validation IG at the 2017 PDA Annual Meeting. The group also plans to continue working with other IGs on areas of mutual interest.

  • Journal TOC: Virus Commentary from One of PDA’s Newest Interest Groups in Latest Issue of PDA Journal

    by: | Nov 07, 2016

    The Advanced Virus Detection Technologies Interest Group (AVDTIG) is one of PDA’s newest interest groups. In the November/December issue of the PDA Journal of Pharmaceutical Science and Technology, read their commentary on high-throughput sequencing for virus detection.

    Commentary

    Arifa s. Khan, Dominick A. Vacante, et al., “Advanced Virus Detection Technologies Interest Group (AVDTIG): Efforts for High Throughput Sequencing (HTS) for Virus Detection”

    David Bain, et al., “Risk Management in Biologics Technology Transfer”

    Research

    Michael Washabaugh, Patricia Cash, et al., “Qualification of a Quantitative Method for Monitoring Aspartate Isomerization of a Monoclonal Antibody by Focused Peptide Mapping”

    Tobias Werk, et al., “The Effect of Formulation, Process, and Method Variables on the Reconstitution Time in Dual Chamber Syringes”

    Patrick J. Faustino, et al., “Dose Uniformity of Scored and Unscored Tablets: Application of the FDA Tablet Scoring Guidance for Industry”

    Ankit Patel, et al., “A Small-scale Model To Assess the Risk of Leachables from Single-use Bioprocess Containers through Protein Quality Characterization”

    Harry Yang, Steven Novick, Richard K. Burdick, “On Statistical Approaches for Demonstrating Analytical Similarity in the Presence of Correlation”

    Technology/Application

    Bernhard Hladik, Uwe Rothaar, Michaela Klause, “Comparative Delamination Study to Demonstrate the Impact of Container Quality and Nature of Buffer System”

    Frank Günther, et al., “Sterility Testing of Injectable Products: Evaluation of the Growth-based BacT/ALERT® 3D™ Dual T Culture System”

    Case Studies

    Sal Giglia, et al., “Air-Water Binary Gas Integrity Test for Sterilizing and Virus Filters”

  • PDA BioAB Members Keep Busy in First Half of 2016

    by: John Geigert, BioPharmaceutical Quality Solutions | Oct 03, 2016

    PDA’s Biotechnology Advisory Board (BioAB) hit the ground running in the first half of 2016 and its activities continue to gain momentum. BioAB members help PDA establish its strategic direction and provide oversight for the Association’s biopharmaceutical scientific and technical activities. The following are a few highlights of BioAB members’ activities from the first part of the year.

    In June, Vince Anicetti, Senior Vice President, Quality and Compliance, Coherus Bioscience, and Stephan Krause, PhD, Director, QA Technology, AstraZeneca Biologics, co-chaired the 2016 PDA Biosimilars Conference in Baltimore. Michael VanDerWerf, Director, Regulatory Affairs, Teva, and Laurie Graham, PhD, Acting Director, Division of Internal Policies and Programs, OPQ, U.S. FDA, helped moderate the sessions. Over 120 attended the conference, representing a number of international companies actively pursuing manufacturing of biosimilars, leaving with a better appreciation of FDA’s analytical comparability approach and its similarities and differences with EMA’s approach. Following the conference, Stephan Krause and John Geigert, PhD, President, BioPharmaceutical Quality Solutions, taught two new biosimilar courses they had developed for the PDA Education program.

    Also in June, Karen Walker, Global Head, Quality, Cell and Gene Therapies Unit, Novartis, covered how to manage raw material risks for cell and gene therapies at the Advanced Therapy Medicinal Products conference in Berlin. Here, attendees expressed the need for further PDA guidance to help better understand the challenges of taking one’s product from development to the clinical stage. John Geigert also taught another PDA Education course in conjunction with this meeting. This was a new course on practical GMPs for ATMPs, adapted from GMP principles on proteins described in PDA Technical Report No. 56: Application of Phase-Appropriate Quality Systems and CGMP to the Development of Therapeutic Protein Drug Substance.

    On the regulatory side, Vijay Chiruvolu, Senior Director, Kite Pharma, is now serving as team lead for PDA’s review of the FDA draft guidance on Comparability Protocols. Nadine Ritter, President, Global Biotech Experts, is also serving as team lead of the PDA commenting team for the FDA draft guidance on analytical methods validation for immunological methods.

    BioAB members also reviewed and recommended for publication Technical Report No. 74: Reprocessing of Biopharmaceuticals and Technical Report No. 75: Consensus Method for Rating 0.1μm Mycoplasma Reduction Filters. Both were published this summer.

    BioAB members continue to work hard for PDA. Please give them a round of thanks for their continuing service to you.

  • Journal Preview: September–October Issue of PDA Journal Covers 2015 Viral Clearance Symposium

    by: | Oct 03, 2016

    In October 2015, industry and regulatory experts gathered to discuss critical viral clearance concerns in Cambridge, Mass. at the 4th Viral Clearance Symposium. The latest issue of the Journal features proceedings from this important meeting.

    Conference Proceeding

    • Glen Bolton, Rich Levy, “Introduction: Proceedings of the 2015 Viral Clearance Symposium“
    • Junfen Ma, David Roush, “Session 1.1: Viral clearance using traditional, well-understood unit operations: Low pH and Detergent“
    • David Roush, Junfen Ma, “Viral clearance using traditional, wellunderstood unit operations“, “Session 1.2: Virus Retentive Filtration“
    • Johannes Blümel, Kurt Brorson, “Session 2: Company specific data on cycled resin testing“
    • Chris Gallo, Dayue Chen, “Session 3.1: Protein A, Hydroxyapatite, and Mixed Mode Chromatography“
    • Dayue Chen, Chris Gallo, “Session 3.2: Viral Clearance of Emerging Unit Operations:“
    • Rachel Specht, Meisam Bakhshayeshi, “Rachel Specht, Meisam Bakhshayeshi“
    • Meisam Bakhshayeshi, Rachel Specht, “Session 4.2: Viral Spiking, Viral Preparation, and Upstream Risk Mitigation Strategies“
    • Glen Bolton, Johannes Blümel, “Session 5: Conference Summary: Key Discussion and Outcomes, Pending“

    PDA Paper

    • Bob Buhlmann, Madlene Dole, Zena Kaufmann, “PDA Points to Consider: Fundamental Concepts in Data Integrity“
  • PDA’s LER Task Force Holds its First Workshop

    by: Dayue Chen, Eli Lilly and Co., Friedrich von Wintzingerode, Roche Diagnostics GmbH, Josh Eaton, PDA, Patricia Hughes, U.S. | Aug 29, 2016

    Since it was first reported by Chen and Vinther in 2013 (1), the phenomenon known as low endotoxin recovery (LER) has been broadly observed in certain matrices commonly used for biologic formulations and certain therapeutic proteins. These observations have generated concerns that a pharmaceutical product contaminated with endotoxin may go undetected by the compendial USP <85>/EP 2.6.14./JP 4.01 bacterial endotoxin test (BET). In response to these reports, the U.S. FDA’s Center for Drug Evaluation and Research (CDER) recently began asking companies to conduct endotoxin spike/hold recovery studies to determine whether a given biological product is affected by LER (2–4). As a result, numerous spike/hold recovery studies have been carried out by many individual firms hoping to ameliorate FDA’s concern. These studies, however, have often produced confounding and sometimes contradictory results with regard to the cause, biochemical mechanism, and biological relevance of the LER phenomenon, likely due to variations in study designs, experimental procedures, and/or type of endotoxin used. Clearly, there is a mutual interest and desire for the industry and FDA to work together to develop a science-based and data-driven strategy in dealing with the LER phenomenon.

    Recognizing the significance and complex nature of the LER issue, PDA’s Biotechnology Advisory Board (BioAB) sanctioned the LER Task Force in early 2015.This Task Force is composed of subject matter experts from academia, FDA, the biopharmaceutical industry, and reagent-supplier/testing companies. Many of the firms that have submitted LER data to the FDA are represented on the PDA LER Task Force, ensuring broad representation. The Task Force, however, will continue to reach out to maximize industrial participation.

    The task force has three specific goals:

    1. Investigate the root cause of LER
    2. Standardize the experimental protocols for spike/hold recovery studies
    3. Identify the potential safety impact of the LER phenomenon

    As part of the effort to achieve these goals, the Task Force sponsored the first workshop exclusively dedicated to LER in March 2016 in San Antonio, coinciding with the 2016 PDA Annual Meeting. To facilitate the discussion, a questionnaire was sent out prior to the workshop to individual participating firms to collect specific information relevant to the LER phenomenon and spike/hold recovery studies. This approach proved to be highly valuable and effective since such details/specifics were usually not included or shared in conventional meetings.

    Once at the two-and-one-half day workshop, attendees heard 11 presentations on endotoxin spike/hold recovery studies. Approximately two hours were allocated for each speaker, divided roughly between a 45 minute oral presentation and in-depth Q&A discussion. Highlights extracted from the workshop are summarized below.

    Lack of Standardized LER Protocol Complicates BLA Review

    Due to the lack of a standardized protocol, individual companies perform spike/hold recovery studies differently as reflected by the information provided to the FDA. This sometimes complicates the BLA review process by the agency and highlights the urgent need to establish a harmonized procedure for spike/hold recovery studies.

    Although there was extensive discussion of how spike/hold recovery studies should be executed with regard to temperatures in the context of GMP manufacturing conditions, the issue remains unresolved at this time. It has been observed that different compendial bacterial endotoxin testing (BET) methods—kinetic turbidimetric assay (KTA), kinetic chromogenic assay (KCA), and gel clot assay (GCA)—may have different susceptibility to LER. FDA will accept change to another compendial method that does not show LER, provided that the results are consistent and reproducible. Change to a noncompendial method will even be accepted if adequate method validation data and relevant information are provided.

    Several firms presented data from spike/hold recovery studies using both purified lipopolysaccharide (LPS) and in-house prepared natural occurring endotoxin (NOE). In some studies, LER was observed only when LPS was the spiking analyte, but not with NOE. In other studies, no difference was seen between LPS and NOE with regard to LER. In one study, it was shown that NOE prepared from different bacterial species exhibited a great degree of variability in recovery when spiked into a drug product formulated in a phosphate and PS80 matrix. The same study also reported that reference standard endotoxin had substantially slower rate of activity loss than control standard endotoxin in the drug product matrix. The exact bases for such confounding and even contradictory results remain unknown and the debate of using LPS versus NOE in spike/hold recovery studies is likely to continue for the foreseeable future.

    Different Strokes for Different LERs

    Data shared at the workshop showed that LER could be triggered by very different factors. Multiple companies reported that therapeutic products themselves could potentially cause LER. Although the combination of chelator/PS80 often leads to LER, it is not always the case, suggesting the involvement of other unknown elements or synergistic effects of individual components.

    Participants also discussed that the role of surfactants (e.g., PS80) in LER is significantly less profound than chelators (e.g., citrate). One participant reported that LER observed in a DP formulated with citrate and PS80 could be overcome by the addition of divalent Mg++ prior to testing, suggesting that LER is readily reversible. A similar approach, however, did not result in successful rescue of recovery in other companies. The data and experimental details of these studies will be collected and analyzed in order to better understand the cause for the apparent discrepancy.

    In addition, the Task Force learned that LER could be overcome by a “de-masking” process using proprietary reagents. However, the effectiveness of de-masking appears to be product/formulation dependent.

    Finally, it was shown that LPS recovery can also be influenced by sampling scheme and vortex time (5).

    Recommendations

    Based on the data and experience shared at the workshop, the group has proposed several recommendations with the objective of ensuring the relevance of the spike/hold recovery studies and harmonizing the experimental procedure as much as possible:

    1. If there is no LER observed in the final DP, it is not essential to perform the spike/hold recovery studies with the prior process intermediates such as drug substance (DS)
    2. Spike/hold and recovery studies should be carried out in a manner representative of the corresponding QC BET testing with regard to materials, containers, and experimental procedures
    3. LER is defined as the endotoxin activity falling below 50% of the spiked amount at two consecutive time points; and
    4. Sampling repeatedly from a single spiked container should be avoided. Instead, reverse assay (spiking independently on different days and testing all the spiked samples on the same day) or multiple-aliquot approach (dispensing the spiked material into individual containers and testing individual containers on different days) is strongly recommended

    Workshop Moves Debate Forward

    The LER phenomenon has generated much discussion and debate in almost every microbiology conference and workshop during the last three years. Experimental results and data presented at this workshop indicate that while considerable progress has been made during this period, fundamental questions concerning the LER phenomenon remain unanswered.

    All individual members of the PDA LER Task Force are committed to work together to advance our understanding of the LER phenomenon.

    The LER Task Force currently has four subgroups with each working on a different aspect of the LER phenomenon. Subgroup 1 is focused on providing a clear guidance for spike/hold recovery studies. Subgroup 2 is working on understanding the underlying mechanism of the LER phenomenon and evaluating whether it is possible to develop a procedure/method to produce an endotoxin standard for spike/hold recovery studies. Subgroup 3 is concentrating on assessing the potential safety risk of the LER phenomenon by careful evaluation of the available data. And finally, Subgroup 4 is devoting all its efforts to providing clear definitions for terms relevant to the LER phenomenon using the USP Pharmacopeial Forum (PF) as a starting point.

    There is no doubt that more research and investigation are needed in order to better understand the LER phenomenon, elucidate its underlying mechanism, and determine its potential clinical significance. The LER Task Force is confident, however, that the group’s specific goals will be achieved by working together as a team and adhering to data-driven/ science-based principles.

    [Editor’s Note: Learn more about the Task Force’s workshop in session “A2: Challenges in Endotoxin Recovery,” Oct. 24, 1:30 p.m. at PDA’s pharmaceutical microbiology conference.”]

    The task force acknowledges the following individuals for sharing their information and data at the workshop: Mazukazu Tsuchiya, Charles River; John Dubczak, Charles River; Jay Bolden, Eli Lilly; Stefan Ishak, Sandoz; Johannes Reich, Hyglos; Phil Villari, Merck Sharp & Dohme; Cheryl Platco, Merck; Anders Thorn, Novo Nordisk; Chris Knutsen, BMS; Ned Mozier, Pfizer; and Karen McCullough; MMI Associates.

    References

    1. Chen, J., and Vinther, A. “Low Endotoxin Recovery in Common Biologics Products.” Presented at the 2013 PDA Annual Meeting, Orlando, FL. April 2013.
    2. Guidance for Industry Pyrogen and Endotoxins Testing: Questions and Answers, U.S. Food and Drug Administration, June 2012
    3. Hughes, P. “Endotoxin – A FDA Perspective.” Presented at the PDA 10th Annual Global Conference on Pharmaceutical Microbiology, Bethesda, MD, October 2015.
    4. Hughes, P., et al. “Low endotoxin recovery: An FDA perspective.” BioPharma Asia 4 (2015): 14–25
    5. Bolden, J. et al., “Endotoxin recovery using Limulus amoebocyte lysate (LAL) assay.” Biologicals. 16 (2016): S1045– 1056.