PB3318EN00_B_EM (1)

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PB3318EN00_B_EM (1)

  1. 1. Viral Safety: Protecting your process from start to finish
  2. 2. 2 Viral Safety: Protecting your process from start to finish As a drug manufacturer, you are required to ensure the viral safety of your biological therapeutic products. Regulatory guidance advocates virus control at various stages of the drug manufacturing process, directing that you: • Select and test source materials for the absence of virus • Test the capacity of the production process to remove or inactivate virus • Test the product at appropriate stages of production for detectable virus Partnering with a company that can assist you through all of these critical steps is an important factor. Regulatory Requirements To meet world wide regulatory guidelines, you may implement a combination of virus removal techniques, including: 1. Virus inactivation via chemical treatment such as low pH, chaotropes, or detergents 2. Chromatography 3. Filtration (size exclusion) United States, mid-1980s: HIV-contaminated Coagulation Factor VIII is sold to patients; 1996 settlement for $660 million Japan, mid-1980s: HIV-contaminated Coagulation Factor VIII is sold to patients; 1996 settlement for $900 million United States, 1994: Recall of Hepatitis C contaminated IgG United States, 1996: Recall of albumin by multiple companies following suspected contamination with TSE prions (Mad Cow Disease) Major Viral Contaminations of Drugs
  3. 3. 3 1 USA Food and Drug Administration, Points to Consider in the Manufacture and Testing of Monoclonal Anitbody Products for Human Use, FDA, Rockville, MD, USA (1997) United States, 2009: Production halted at major biotechnology manufacturing plant following discovery of Vesivirus 2117 in a bioreactor Other viral agents of concern include: Minute virus of mice, Cache Valley virus, circovirus, West Nile virus, SEN virus, Hepatitis G, Human Herpes virus 8, SARS, Influenza virus H1N1 Setting your strategy PREVENT introduction of adventitious agents into the bioreactor On the front end, raw materials, including cell lines, buffers, media and media components need to be screened for potential contamination. REMOVE any virus introduced into the process Downstream removal utilizes virus inactivation, adsorption, and filtration steps; each providing an additional level of safety assurance. TEST drug process material to ensure lack of contamination At least two complementary viral clearance methods are recommended by regulatory agencies1 , with at least one of these steps effective against non-enveloped viruses such as parvovirus. How can you assure viral safety of your drug product?
  4. 4. 4 Strategy: Choose the right materials Raw material qualification is a key factor in assuring the quality and safety of biopharmaceuticals. However, performing the necessary tests and compiling the required documentation all on your own is very costly and time-consuming. EMPROVE® bio: Ready-to-use documentation The EMPROVE® bio dossiers are specifically compiled to support material qualification for a safe biopharmaceutical process. EMPROVE® bio dossiers contain comprehensive information on manufacturing processes, testing procedures, and purity and are structured in conformance with international standards (Common Technical Document [CTD] or comparable format). EMPROVE® bio greatly reduces your workload and costs, considerably accelerating your qualification and registration processes. EMPROVE® bio: Raw Materials Our EMPROVE® bio raw materials for use in biopharmaceutical production offer specifications, as well as a Certificate of Analysis adjusted to your biopharmaceutical upstream and downstream processes. Selected EMPROVE® bio products comply with American Chemical Society standards. With EMPROVE® bio, you benefit from our proven expertise and reputation for uncompromising reliability and safety – so you can be certain that your documentation is comprehensive. With over 20 years’ experience working with drug manufacturers on viral safety solutions, we can support the decisions you must make in each phase of viral clearance implementation. Whether your questions are about government regulations, selecting the best filter, or process-scale implementation, we can help resolve even the most complex viral safety concerns. VIRUS BARRIER VIRUS CLEARANCE
  5. 5. 5 Strategy: Inactivate virus in your process There are a variety of methods that can reduce virus, including treatments that use dry heat, steam or low pH. For virus inactivation in proteins, such as Factor VIII or van Willebrand factor, a solvent/detergent treatment is the method of choice to inactivate lipid-coat enveloped viruses. With other proteins, such as albumin, pasteurization is the preferred option. Chemicals that are used for virus inactivation must meet the same quality standards as the other raw materials in your process. All of our products are manufactured or purified according to GMP standards from high purity raw materials. What’s more, they bear the EMPROVE® trademark and come with comprehensive regulatory documentation that contributes to the quality of your registration dossier. The result: greater productivity and lower costs. EMPROVE® high-quality products for virus inactivation Solvent and detergent treatment: • Tri-n-Butyl phosphate EMPROVE® bio Ph Eur • Tween® 80 (Polysorbate) EMPROVE® exp Ph Eur, JP, NF • Triton® X-100 EMPROVE® bio Ph Eur, NF Protein stabilizers for pasteurization: • Sodium caprylate EMPROVE® exp Ph Eur, NF • Caprylic acid (Octanoic acid) Ph Eur • N-acetyl-DL-tryptophan EMPROVE® bio Ph Eur, BP Reagents for low pH treatment: • Acetic acid (glacial) 100% EMPROVE® bio Ph Eur, BP, JP, USP, ACS • Caprylic acid (Octanoic acid) Ph Eur • Sodium acetate trihydrate EMPROVE® bio Ph Eur, BP, JP, USP • Sodium acetate anhydrous EMPROVE® bio USP STERILE FILTRATION FINAL FILL
  6. 6. 6 Strategy: Virus adsorption using chromatography Chromatography is a widely accepted approach for removing viruses, irrespective of their size and morphology. Depending on the parameters of your process, you have the option of implementing a viral adsorption strategy utilizing our innovative bead-based technologies and prepacked chromatography columns at different steps in your process. VIRUS BARRIER VIRUS CLEARANCE
  7. 7. 7Eshmuno® A Protein A Chromatography resin A rigid, high capacity, acid and alkaline resistant Protein A affinity chromatography resin for the purification of Fc-containing proteins, including but not limited to monoclonal antibodies. Eshmuno® A resin can make an important contribution to help reach your process virus reduction targets. The ProSep® family of resins This family of protein-A based affinity chromatography media is designed for large-scale, cost-effective purification of high titer therapeutic antibodies. An optimized pore size selection and ligand immobilization results in a significant increase in dynamic capacity. Its rigid controlled pore glass (CPG) base matrix allows for predictable scale-up and greater flexibility, enabling you to reduce your equipment footprint and purify larger volumes of feedstock. The Eshmuno® IEX family of resins A unique family of ion exchangers designed for highly productive downstream purification of diverse biomolecules. Its strong anion exchange resin, Eshmuno® Q, combines a tentacle structure with an innovative hydrophilic polyvinyl ether base matrix for more effective binding of the target molecules, offering you outstanding virus removal capabilities. The Fractogel® family of resins A synthetic polymer media, with efficient tentacle technology, offers a number of advantages over con- ventional resins: Long linear polymer chains (tentacles) increase the functional groups’ accessibility for biomol- ecules, ensuring a tighter binding of target molecules and sharp elution profiles. The result: high throughput and high selectivity with excellent purity and yield. STERILE FILTRATION FINAL FILL
  8. 8. VIRUS BARRIER VIRUS CLEARANCE 8 Strategy: Remove viruses through nanofiltration Viresolve® Pro Solution Our Viresolve® Pro Solution is unlike any other virus filter on the market today. The innovative, dual layer patented asymmetric PES membrane and device were designed to simultaneously deliver high parvovirus LRV (log reduction value), capacity and flux. Viresolve® Pro Devices are easy to scale and implement and the single-use flow path eliminates the need for cleaning validation. Produced using a patented membrane manufacturing process, our Devices have the lowest variability compared to traditional filters and are less affected by process interruptions; providing unparalleled product consistency and value. The addition of a Viresolve® Pro Shield enhances capacity of the Viresolve® Pro Device while delivering high parvovirus removal, capacity and flux. Our 5-tier approach ensuring virus retention and integrity Based on decades of virus filtration experience, our unique performance test approach assures LRV performance. End-user testing Pre- and post-use air diffusion tests ensure that no defects are introduced in shipping, handling and use. • 100% Pre and/or Post Use Air Diffusion Test Device tests Patented Binary Gas Test aims to demonstrate the absence of small defects that could decrease retention performance. • Water Flux, Pressure Hold, Air/Water Diffusion, Binary Gas Test Device lot release tests Demonstrates the device lot meets retention, mechanical strength and cleanliness specifications. • F-x174 LRV, Hydraulic Stress Test, Conductivity, TOC, LAL Membrane process control and release tests Assures target membrane performance and consistency in terms of virus retention, protein passage, and capacity by testing with model protein and virus. • LRV Correlated in-process testing, F-x174 LRV, Protein Capacity, Passage and Flux (IgG), Patented Selective Layering Process and product validation Performed to meet development requirements with the necessary qualified equipment, manufacturing facilities, trained personnel and documentation to consistently manufacture the product. • Scaling, Mammalian Virus Retention, Caustic Stability, Shelf Life, etc. • Design Space Validation Process parameters that impact viral clearance in the down- stream process LOCATION Virus filtration steps may b implemented at multiple po in a given downstream proc Based on size exclusion, virus filtration applies an orthogonal removal mechanism that is complementary to inactivation and chroma- tography technology. Viral filters are broadly classified into two categories: large virus removal, typically the 80-100 nm endogenous retroviruses, and small virus removal, typically the 18-26 nm parvoviruses.
  9. 9. With over 20 years of virus filtration experience, our application, process development, and virology experts are available to help you implement the Viresolve® Pro Solution into your process. 9 Single-use solutions for virus removal The Mobius® FlexReady Solution for Virus Filtration features an optimized, single-use flow path designed to fully support your parvovirus filtration needs. Viresolve® Pro Modus Shields and Devices are easily integrated into the flexible, easy-to-use systems from pilot to full-scale manufacturing. This easy-to- use, single-use system is designed to fully support your virus filtration needs. It consists of single-use Flexware® assemblies and process-ready hardware systems to deliver optimal operational flexibility, from process development to clinical production to small-scale commercial manufacturing. Mobius® FlexReady for Virus Filtration features Viresolve® Pro Modus Devices, the next- generation parvovirus safety solution delivering robust parvovirus clearance at pilot and medium volume processing scales. Single-use flow paths reduce risk to operators and minimize downtime between runs. be oints cess. FEED CONCENTRATION Feed solution concentration can affect the virus filtration process by reducing product throughput. The level of impact will depend on the interaction between the filter and the components in the solution being filtered. PREFILTRATION Prefiltration of the feed solution can have a dramatic impact on filter performance. Prefiltration is targeted at removing various impurities and contaminants such as protein aggregates, DNA, and other trace materials. PROCESS TIMES Parvovirus filters can be broadly classified into two groups - those with high protein flux but low-to-moderate volumetric capacities, and those with high protein capacities but with low-to-moderate protein fluxes. Both of these filters have advantages and disadvantages. When a process must be completed in a short amount of time (2-4 hours), high flux filters require less filtration area than high capacity filters. STERILE FILTRATION FINAL FILL
  10. 10. Through our relationship with the PDA® task force, we collaborate with a team of subject-matter experts from industry, academia, and government agencies to develop and revise highly-valued industry guidelines and to prepare comments for the PDA® on regulatory issues of a global nature. 10 Strategy: Partner with a leader in viral clearance Bacteriophage We conduct investigative studies with model viruses to ensure that your process performs as expected at reduced cost, which contributes to the success of full panel mammalian virus studies. Contact us to find out how this exclusive capability can help ensure the success of your next virus validation study. Virus Preparation Purity We continue to advocate for purity in mammalian virus stocks, and to develop advanced methods for virus stock preparation. This results in improved consistency and the ability to simulate the conditions of an adverse event in production. Our TrueSpike™ technology* produces virus preparations of exceptional quality for filter validation studies. TrueSpike™ technology enables removal of cell debris, DNA, and non-viral proteins from virus preparations used to validate biomanufacturing process virus clearance. Our strong relationship with regulators worldwide allows us to develop products and services designed to help you meet or exceed regulatory requirements. VIRUS BARRIER VIRUS CLEARANCE *TrueSpike™ technology is licensed to Charles River Laboratories for their manufacture and use in Virus Validation Studies.
  11. 11. Whether at your site or in our lab, our comprehensive range of products, integrated technologies and support services will help solve your process development, optimization, validation and monitoring challenges. 11 Virus filtration process development and services • Design, technology selection, filter sizing and protocol development • Process scaling, optimization and yield improvements • Validation and engineering • Process monitoring, quality control and technical support Virus validation study consulting services • 1-4 virus panel consultation on spiking protocol and data analysis • Expert guidance in regulatory requirements and guidelines interpretation • Consultation on study report to ensure the results of the validation study and methodology are accurately represented STERILE FILTRATION FINAL FILL
  12. 12. EMD Millipore, the M logo, EMPROVE, Fractogel, Eshmuno, ProSep, Viresolve, Flexware and Mobius are registered trademarks of Merck KGaA, Darmstadt, Germany. TrueSpike is a trademark of Merck KGaA, Darmstadt, Germany. PDA is a registered trademark of the Parenteral Drug Association. Triton is a registered trademark of Union Carbide Corporation. Tween is a registered trademark of ICI Americas, Inc. © 2014 EMD Millipore Corporation, Billerica, MA U.S.A. All rights reserved. Lit No. PB3318EN00 Rev. B DP-SBU-11-05551 Printed in the USA. 12/2014 www.emdmillipore.com/offices To Place an Order or Receive Technical Assistance In the U.S. and Canada, call toll-free: 1(800)-645-5476 For other countries across Europe, call: +44 (0) 115 943 0840 For other countries across Europe and the world, please visit www.millipore.com/offices For Technical Service, please visit www.millipore.com/techservice