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  • Manual Aseptic Small-Scale Runs and Validation

    by: Cheryl Custard, Custard Consulting Group | Jul 09, 2018

    Are We Making Mountains Out of Molehills?

    When most of us think about manufacturing or aseptic processing, we envision large-scale bulk formulation or fills that take longer than 24 hours. But is this what a product looks like for everyone? After all, not every company focuses on large-scale bulk products, some specialize in small-scale products. Does this mean the regulations change if we go from large-scale to small-scale? In other words, are we scaling mountains to meet requirements that do not pertain to molehills?

    The goal of an aseptic operation is to prevent the contamination of materials intended to be sterile. This is where process verification testing becomes important. For large-scale automated operations with infrequent operator interventions, determining if the process can produce sterile products requires analyzing large-scale automated media fills that resemble normal production. Small-scale processes using all or partial manual procedures must also be evaluated by process verification testing.

    Manual operations present unique operational and evaluation challenges not generally encountered with automated operations. Manual aseptic processes rely heavily on the proficiency of the individual operator. Operations personnel and their activities are generally recognized as the greatest source of microbial contamination during any given process.

    Reproducible human performance cannot be assumed over time. In other words, unlike automated processes, humans cannot be “validated.” We can be qualified and tested, but we humans cannot provide the reproducibility of an automated system.

    In effect, what does this mean and how can we state that our drug products are safe, pure and effective if we cannot validate the manual or human aspect of our process? To achieve these key regulatory criteria, special attention to operator training and qualifications, as well as length of time away from/or absence from the process must be considered. Operator training should be extensive and include multiple challenges of all critical steps to a point of proficiency. Training must include qualifications not limited to gowning procedures, technique and media challenges. Documentation must include a list of all critical steps trained on, how many times an operator showed proficiency prior to final evaluation and length of time away from the process.

    This process takes into account a number of questions:

    • Is this product manufactured or processed daily, monthly or as needed by demand?
    • What if an operator is away from the manual process for any length of time?
    • What steps are needed to ensure the operators retained all critical steps during their time away from the process?
    • How is this process documented?

    The PDA Education course, “Recommended Practices for Manual Aseptic Processes,” addresses these and other challenges facing operators during smallscale runs. It not only covers the requirements of how to perform a manual aseptic process but also provides students with a hands-on laboratory media challenge. This course is designed for operations personnel who design, perform and evaluate manual aseptic processes—including personnel involved with compounding, filling, packaging and quality assurance operations, and is suitable for supervisors and managers as well as personnel engaged in manual processing operations.

    About the Author

    Cheryl CustardCheryl Custard is an independent pharmaceutical consultant and PDA Education instructor. She will teach the course, “Recommended Practices for Manual Aseptic Processes,” Sept. 26–28 at PDA's Training and Research Institute in Bethesda, Md.

  • Course Addresses Test Methods for Prefilled Syringes

    by: Rebecca Stauffer, PDA | Apr 30, 2018

    The prefilled syringe market has grown considerably over the past decade. A number of innovative prefilled syringe products are now available to patients. But, like any other parenteral container, these products must undergo compliance testing. Horst Koller, CEO, HK Packaging Consulting, and Roman Mathaes, PhD, Senior Group Leader, Lonza Drug Product Services, will present the course, “Test Methods for Pre-filled Syringe Systems,” that follows the 3rd PDA Europe Annual Meeting.

    The PDA Letter reached out to Koller who provided an overview of the course.

    What test methods will the course cover?

    The course looks at the combination of a syringe cartridge with a delivery device. The system functionality needs to be proven over the complete shelf life of the combined system. We will also cover the safety systems around prefilled syringe systems.

    What regulatory requirements will be addressed?

    We will address the regulatory requirements for three types of products:

    • empty prefilled syringes ready for filling
    • final filled product
    • combination products, such as autoinjectors

    If I have some years of experience, what can I get out of the course?

    It provides a good overview of the complete lifecycle of a prefilled syringe in general. From the basic idea of a syringe as a primary container to the functional, biological and regulatory performance of a prefilled syringe, including functions for delivery devices. This can be very complex. This is a chance for someone who works solely in manufacturing to understand the development of a prefilled syringe and vice versa.

    What materials will the course cover?

    It will cover glass and polymer containers.

    How will the course be structured?

    We will give an introduction and then go from there. Interaction between the attendees and instructors is very important for this course. In fact, we plan for it to be an interactive session for the complete two days. Students are welcome to ask questions as we work through the various topics.

    Learn more about the PDA Education course, Test Methods for Pre-filled Syringe Systems.

    About the Expert

    Prior to becoming a consultant, Horst Koller worked for Abbott Diagnostic and SCHOTT Pharmaceutical Packaging with a total of more than 20 years of industry experience. His consulting company focuses on technical, regulatory and quality metrics support around primary and secondary packaging systems, including medical devices.

  • Course Sheds Light on Prefilled Manufacturing

    by: Rebecca Stauffer, PDA | Oct 03, 2017

    Interaction between drug delivery system and drug product. Quality Control. Stability. These are some of the extra concerns that pharmaceutical manufacturers face when producing prefilled syringes. Sterile products have always presented challenges but prefilled syringes amplify these challenges.

    Egmont Semmler

    In light of this, PDA Europe is offering a new, two-day course on prefilled syringe manufacturing following the Universe of Pre-filled Syringes and Injection Devices. The PDA Letter spoke with instructor Egmont Semmler, PhD, Director R&D Pharmaceutical Fill and Finish, Groninger, about the new course.

    What spurred the development of this new course?

    The course, “Development and Manufacturing of Pre-filled Syringes,”covers the latest trends in prefilled syringes, aseptic manufacturing and drug delivery. We have been working on this course with several partners to deliver a complete picture of the manufacturing process from forming to nested objects, testing and visual inspection, container closure, regulatory aspects and, finally, insertion into drug delivery devices. We especially focused on practical, hands-on applications so that students will have the opportunity to perform and understand key aspects (particles, siliconization, elastomers for closures, plunger testing, filling) around prefilled syringes.

    Will the course address some of the newer, more flexible technologies available for prefilled syringe manufacturing, such as robotic filling lines, compartmentalized isolators, etc.?

    Yes, the course will also address these emerging technologies and their benefits to the manufacturing process for prefilled nested components. Where applicable, we will go in depth and discuss the risks and benefits.

    How will the course address manufacturing in an aseptic environment?

    It will address aseptic manufacturing throughout the entire prefilled syringe product lifecycle, starting with the glass forming/injection molding process for a glass/plastic syringe and the requirements to control particle load and microbial ingress, continuing to aseptic processing in filling to insertion into drug delivery devices. The most important aseptic concepts, e.g., RABS and isolators, will be discussed with a focus on prefilled syringe production.

    What technologies and equipment will students be using in the handson sessions?

    The students be able to turn lecture contents directly into practical experience using our trial equipment. We will have equipment for siliconization, filling, stoppering, qualitative function testing and quantitative particle/siliconization testing. Furthermore, we will have a number of samples of prefilled syringes from different manufacturing steps, from raw materials to a fully integrated device, so the students can experience the look and feel to enhance their understanding.

    Who would benefit from this course?

    This course would be of value to pharmacists, engineers and anyone dealing with prefilled syringes on a daily basis who wants to understand them more in depth and how they differ from traditional parenteral products.

    I also welcome professionals from adjacent fields who want to broaden their perspective on prefilled syringe manufacturing.

    As an instructor, what is your main goal for this course? What do you want students to take away from it?

    I sincerely hope that students will enhance their understanding of prefilled syringes as a primary container for their drug and drug delivery systems. Students should be able to evaluate and determine root causes of potential failures around prefilled syringes. Additionally, they will have the tools to prevent these issues by choosing the right delivery system and closure upfront along with awareness of the detailed interactions between prefilled syringes and drugs.

    Learn more about the course "Development and Manufacturing of Pre-filled Syringes."

  • Instructor Sees Future for QbD in Biopharmaceuticals

    by: Rebecca Stauffer, PDA | May 01, 2017

    The biopharmaceutical space is facing a sea of change as new therapies enter the market, necessitating more flexible forms of manufacturing. From advanced therapy medicinal products (ATMPs) to biosimilars, this transformation brings both opportunities and challenges to the industry.

    John Geigert

    Can Quality by Design (QbD) play a role in addressing these challenges as innovative therapies come out of biopharma? PDA Education instructor John Geigert, PhD, President, BioPharmaceutical Quality Solutions, thinks so. He took some time to explain to the PDA Letter how his upcoming course, “Quality by Design (QbD) for Biopharmaceuticals,” scheduled before the 2nd PDA Europe Annual Meeting, addresses the ways QbD can help biopharmaceutical manufacturers in an era of change.

     

    What is QbD and is it still relevant?

    QbD is a systematic risk- and science- based approach to developing an effective control strategy. It was described almost a decade ago in the ICH Q8–Q11 guidances. It is still an optional strategic approach even today, yet with the challenging processes biopharmaceutical manufacturers encounter, it can be tremendously rewarding, if not a necessity. Through risk prioritization tools, limited resources focus on the areas of control with the greatest impact on product safety and quality. By relying on sound science, we gain an improved understanding of complex manufacturing processes, which should result in fewer manufacturing deviations and batch failures.

    Why was the course developed?

    QbD has been embraced by both global regulators and the larger biopharmaceutical companies. But many biopharmaceutical companies either have not yet visualized, or have misunderstandings about, the true value of QbD. This course was developed to address these shortcomings, and to present a practical six-step approach to implementing the core principles of QbD.

    Has this course evolved over time to reflect changes in technology, particularly the growth in biosimilars and advanced therapies?

    The core principles of QbD—quality target product profile (QTPP), critical quality attributes (CQAs), critical process parameters (CPPs), and control strategy (CS)—are applicable to all biopharmaceutical manufacturing processes. Those involved in recombinant protein and monoclonal antibody manufacturing have well embraced QbD, as evidenced by a quick look at the public summaries of these products being approved for the marketplace today.

    Biosimilar manufacturers also fully under- stand the importance of QbD, especially with the need to rapidly reverse-engineer the manufacturing process of the innovator, and to adjust the CPPs to yield the desired product-related substance and product-related impurity CQA values for the required analytical comparative studies. Even those involved in advanced therapies (i.e., gene and cell therapy manufacturers) are beginning to realize the value of QbD, as judged by the number of publications on this topic, as well as by recent market-approved genetically engineered viruses and genetically engineered cells that have incorporated QbD’s core principles.

    What is one thing you hope students will take away from this course?

    My hope is that students leave with an increased appreciation of QbD for all bio- pharmaceutical manufacturing processes. Yes, the investment in QbD takes place during clinical development when the product is at significant risk of not passing the threshold of the different clinical stages, but investment in sound science pays off in a fuller understanding of the manufacturing process and its proper control. I trust that the students will go back to their respective companies with this message.

    Learn more about the PDA Education course, "Quality by Design for Biopharmaceuticals."

  • Container Closure Integrity Critical for New Biologics

    by: Lei Li, PhD, Eli Lilly and Company | Mar 06, 2017

    Drug product package systems, such as vials and prefilled syringes, must provide a barrier that protects drug product stability and sterility throughout the entire shelf life. Manufacturers are required to demonstrate that systems are capable of maintaining microbial barrier integrity. When it comes to biologics, these products may even require that package systems maintain integrity in stringent environmental conditions (such as frozen or cryogenic environments).

    The recent industry trend toward combination product development and patient-centered drug delivery has driven increasingly innovative package design using a wide selection of new packaging materials—all this has implications for testing the integrity of microbial barriers. In addition, more package systems are fully integrated with delivery devices. The package systems not only have to meet the traditional requirements of protecting drug product but also need to enable other system requirements such as proper device functionality. These new requirements lead to customized package design with increased system complexity and, in many cases, present a high level of technical risk for maintaining container closure integrity (CCI). Therefore, CCI testing plays an increasingly important role in informing material selection, derisking of system design and verifying CCI performance.

    Upon product filling and sealing, package systems experience downstream processes, ranging from device assembling, packaging, storage, and distribution, all the way to patient use. These processes may introduce additional mechanical stresses and expose the containers to unfavorable environmental conditions that may affect CCI. For example, additional mechanical stress that occurs on a sealing component during device assembly may affect its seal quality. Frozen or cryogenic temperatures during transportation and storage may critically affect sealing capability of elastomer components. These processrelated risks to CCI must be assessed and the potential impact on product sterility and stability considered. Appropriate CCI testing should be integrated into process development studies to detect and control the risk of temporary or permanent loss of integrity.

    In response to increasing regulatory expectations and industry needs, the pharmaceutical industry has witnessed significant technical advancements in CCI testing technologies. Advanced technologies, such as high voltage leak detection (HVLD) and vacuum decay, have demonstrated improved detection capabilities compared to conventional dye and microbial ingress methods. Many of the technologies have been used for on-line inspection and/or drug product stability testing. Even these advanced technologies, however, have limitations; there is no “one-size-fits-all” solution that can be applied to all product– package configurations and meet all process development CCI testing needs. The recently revised USP <1207> Package Integrity Evaluation—Sterile Products promotes a risk- and science- based approach and uses the package integrity profile database as a tool to ensure CCI throughout the package design and development, validation and routine manufacturing phases. Under this framework, pharmaceutical and packaging industries are experimenting with best practices to de-risk packaging design and verify continued package integrity throughout the product lifecycle.

    The upcoming new PDA course, “Container Closure Systems and Integrity Testing,” scheduled to follow the 2017 PDA Annual Meeting, aims to better equip the industry with information about advanced CCI testing technologies as well as practical business approaches to effectively detect, mitigate and control package integrity. First, the course features lectures by industry experts, on-site instrument demonstrations, and hands-on exercises for advanced CCI testing techniques. The combination provides participants with a unique opportunity to not only learn the working principles but also personally experiment with these relatively new technologies and instruments, including tracer gas detection (e.g., helium leak detection), electrical conductivity and capacitance, vacuum decay leak detection, laser-based gas headspace analysis, mass extraction leak testing.

    Furthermore, the course introduces a practical and meaningful risk-based methodology to construct a package integrity profile database using appropriate CCI testing methods. Such an approach starts with a thorough understanding of the construction of package materials, system design and manufacturing processes. The CCI failure modes and effects associated with each aspect are identified based on which type of CCI study is needed. In most cases, a series of CCI tests must be applied in concert with product development, including initial design confirmation, machinability studies and product stability testing, to ensure CCI is achieved and well maintained. The comprehensive results from these studies establish the package integrity profile database and inform CCI control strategy development.

    Finally, the course uses case studies and group discussions to promote active participation among students, instructors and industry experts. These open-ended discussions should provide insight into the fast-evolving regulatory landscape and novel applications of CCI testing technologies.

    Upon completing the course, participants will be able to compare and contrast various CCI testing technologies and understand their applicability, advantages and limitations. Through case studies, participants will become familiar with establishing a package integrity profile database using appropriate test methods in support of new product marketing approval and commercial CCI control strategy development. Furthermore, the best practices for CCI method development and validation will be discussed.

    About the Author

    Lei Li currently serves as an engineer advisor at Delivery and Device R&D, Eli Lilly and Company. He has nine years of experience in the pharmaceutical and medical device industry, with a focus on developing API and drug product packaging in support of clinical development and product commercialization, and establishing cold chain distribution for biologic products.

    Learn more about this and other PDA Education courses following the 2017 PDA Annual Meeting.

  • PDA Education Offers Intro to Working World to Intern

    by: Ryan Morris, University of Maryland | Nov 07, 2016

    When I first started my internship at PDA’s Training and Research Institute (TRI) this summer, I was not sure what to expect. I’ll be honest; I felt some trepidation as I entered the building on my first day. After all, my father, Walter Morris, also works at PDA, overseeing the very magazine you are reading right now. Working in the same building as my dad was a scary prospect at first. Plus, I had just graduated from high school and only had my experiences in school to draw from, so I truly did not know what to expect.

    Fortunately, once I got settled in at TRI, I felt right at home, thanks to the TRI staff. I worked on many projects that became very informative learning experiences, and gave me knowledge to use in college and beyond. First, I helped David Talmage start a new online inventory system that simplifies how TRI organizes its stock. To fulfill this task, I had to inventory much of TRI’s supplies, input this data into the new system, and organize it into easy-to-use groupings.

    In addition, I had an opportunity to work in the TRI labs. My favorite responsibility there involved using the autoclave. I learned a lot about this remarkable machine—how it works, why autoclaving is important, and how to prepare items for the autoclave process. The autoclave is a very important tool for a lab because it sterilizes the equipment before it enters the lab. First the materials are packaged into autoclave-safe bags, which will not melt or catch on fire. The bags are then loaded into the autoclave which blasts extremely hot steam at temperatures upward of 250˚F onto the bags until the equipment is properly sterilized.

    Ryan Morris
    Ryan Morris poses in the gowning area at PDA TRI in Bethesda, Md.

    Finally, I helped the PDA Education staff prepare for the renovation of the original TRI office and lecture room spaces into new laboratory spaces. While it was overwhelming at first, surrounded by boxes and stacks of papers, I took the initiative and lent a hand filing old papers and scanning others into a computer. Hopefully, this means there will be less stacks of paper for the next round of renovations!
    While my work was beneficial to TRI and the PDA Education staff, I believe it was equally helpful for me as I learned so much from the experience. My biggest takeaway? Working is a lot different than going to school. Until this internship, I’d never known what it was like to work in an office. I found I needed more independent thinking to complete my tasks successfully as the requirements were not as straight-forward as they would be for say, a class project. I also honed my time management skills, learning to use the time allotted to me effectively and efficiently.

    I also discovered work is not always monotonous. Many parts of my internship were quite enjoyable and engaging. I want to thank PDA, and more specifically, Craig Elliott and the PDA Education staff for not only giving me this opportunity, but for making it a memorable experience that will benefit me going forward in my academic and professional life. I enjoyed this internship and would certainly do it again.

    PDA Who’s Who

    Craig Elliott, Senior Vice President, Education, PDA

    Walter Morris, Senior Director, Publishing, PDA

    David Talmage, Director, PDA Education