Tbi Bioprocessing Services Sept 25.08

Therapure Biopharma Inc BIOPROCESSING SERVICES www.therapurebio.com 1

CONTENT Overview Quality Charter Technology Transfer Services Process Development Services Testing and Laboratory Services Validation Services Manufacturing Services Manufacturing Facility Warehousing and Distribution Project Management Services Why Choose Therapure Biopharma? www.therapurebio.com 2

OVERVIEW Our customers understand that today’s regulatory requirements are increasingly difficult to meet while cGMP manufacturing processes are becoming more complex. The odds of successfully bringing a product from preclinical through clinical to commercial success are less than 1:100 in today’s regulatory and economic environment. The ability to quickly respond to these requirements, as companies strive to bring their products to market, can be found at Therapure Biopharma. Let us help you succeed by by improving the odds. Therapure Biopharma not only has the expertise in the documentation, testing and control of manufacturing for biological parenteral products but the experience, flexibility and capability to deliver your product. Therapure Biopharma, located in Mississauga, Ontario, Canada, is an integrated biopharmaceutical manufacturing company with comprehensive experience in the development and manufacture of innovative life sustaining therapies. Our business is to serve the outsourcing needs of the biotechnology industry. Leveraging our many years of professional expertise, we can bring our clients’ products to market quickly and cost effectively while ensuring quality and confidentiality. We have the technical expertise, quality systems and modern and flexible facilities to develop and manufacture your product, allowing you to focus on your goal - achieving market approval. As acknowledged experts in the purification of proteins from a biological source we offer cGMP manufacturing, development and testing of large and small volume parenterals, biologics and protein therapeutics to satisfy, U.S., European and Canadian regulatory requirements. We have developed processing systems capable of handling the purification of up to 100 kg of protein per batch. Our quality program is designed to ensure all aspects of manufacturing, testing, storage, and delivery of your product are documented and procedures are in place for regulatory compliance. www.therapurebio.com 3

OVERVIEW Therapure Biopharma’s flexible approach to bioprocessing allows us to tailor our services to our client’s specific requirements. We can perform selected activities or serve as a single source – from product development through to commercial manufacturing. Our experience combined with our capabilities in design, technology, validation and regulatory support help ensure your product will move unimpeded through the manufacturing process and allow you to focus on your goal of obtaining market approval. Commercial Manufacture (cGMP) Clinical Manufacture (cGMP) Pre-Clinical Manufacture Contract Testing Commercial Test Method Development Success Process Development Optimization Scale-Up From pre-clinical to commercial bioprocessing including process development, scale-up and optimization, testing and test method development, purification and aseptic filling, Therapure Biopharma can deliver your requirements. www.therapurebio.com 4

QUALITY CHARTER Therapure believes in the principle that quality must be built into a process or product and not tested in. This not only applies to the compliance and regulatory requirements but to the way we treat our clients and run our business. To this end we put Quality first in all aspects as highlighted in the Therapure Quality Charter provided below. Our vision •A Worldwide leader in protein purification and related biotechnology fields. •Provide services for all phases of the protein purification lifecycle, from bench to market. •Enhance our expertise in advanced biology, complex proteins and regulatory processes to develop effective and innovative solutions for our clients. •To seek long-lasting relationships with our partners/clients by providing product and services, which exceed their expectations. Our mission •Therapure Biopharma Inc. is a Canadian biopharmaceutical company committed to the development, manufacture, purification and packaging of high-quality biological therapeutics. Our value •Understanding our clients needs to ensure customer satisfaction. •Providing expertise, know-how and capability to address client issues. •Professional ethics, principles and adherence to quality beyond the standard. •We can be trusted. •We live the Therapure Quality charter. Our Quality Policy •To consistently exceed all worldwide regulatory requirements. •Live the theme of ‘prevention over correction’ approach. The goal is ‘upstream quality control’ (i.e. “doing it right the first time”) by designing processes to be as error free as possible, within cost/risk constraints. •Promote continuous improvement in all fields of activity through precisely defined goals, measurable indicators and an integrated Quality Management system. •Building and using internal and external customer-supplier relationships to define, measure and improve quality. •Open communication, both internal and external, is the key to ensuring quality in all aspects. •To maintain our skills at the forefront of technology. www.therapurebio.com 5

TECHNOLOGY TRANSFER SERVICES A key step to achieving commercial success is understanding the manufacturing process. The technology transfer process defines and evaluates an existing process to allow for scale-up, site transfers or process modifications. Technology transfer is vital to ensuring an optimal process that is both efficient and cost effective. Defining a viable commercial process for a biopharmaceutical product is paramount to that product's success. Prior to cGMP production, the process should be well understood, robust, scalable and documented. While this can be challenging, this step is crucial for the development of a well defined process for biopharmaceutical manufacturing. The technology transfer process is unique for each project; however there are standard activities which must take place. 1. The development of a comprehensive scope of work is essential to the success of the project. This will define, in detail, the work to be performed, deliverables, milestones and scheduling. The responsibilities of both parties will also be delineated and the change control process approved. 2. Due Diligence involves the detailed transfer of information to the new manufacturing site. This includes all existing process and formulation documents, raw material requirements, testing specifications, standard operating procedures, equipment requirements, regulatory commitments and quality specifications. This step is essential to form a basis for manufacturing and testing in compliance with cGMP and CMC commitments to ensure product integrity, quality and purity. 3. Verification Batches will be run once the set up and installation of all manufacturing process steps and in-process analytical methods is achieved. These verification batches will be produced at the existing scale to demonstrate successful transfer of the current manufacturing process. They will also establish a baseline for product yields and recoveries as well as identifying potential scale-up issues. 4. Qualification Batches verify that the biopharmaceutical product can be consistently and reproducibly manufactured to specifications and executed at scale. Draft Batch Production Records and Standard Operating Procedures will also be prepared according to cGMP guidelines. www.therapurebio.com 6

TECHNOLOGY TRANSFER SERVICES The result of a successful technology transfer is an executable cGMP process with the quality systems in place for commercial manufacturing. Therapure Biopharma has the knowledge and skill sets to move a product from bench-top through clinical and greater scale. Our team has the experience to evaluate processes, determine scale-up and optimization requirements and document the processes required to fulfil regulatory requirements. www.therapurebio.com 7

PROCESS DEVELOPMENT SERVICES Therapure Biopharma understands the sensitivities, complexities and potential limitations in bringing a product to market. Determining the most efficient and cost effective manufacturing methods as early as possible in the process is essential. At the same time, using cGMP methodologies for scale up and optimization reduces or eliminates the need to recreate clinical trials. Our goal is to devise a process for cGMP manufacturing that establishes procedures to minimize manufacturing downtime, streamline scale-up and maximize product yield and purity. Our extensive knowledge in protein based processes allows us to examine current procedures and techniques and determine the most comprehensive plan of action to ensure manufacturing success. Therapure Biopharma’s process development and engineering teams have taken biopharmaceutical methods developed in the lab, generating milligram quantities of protein/product, and successfully transferred them from pilot scale through to commercial level operations designed to produce up to 7,500 kilograms of protein/product per year. The team includes engineers, Master’s and Ph.D level scientists experienced in protein, carbohydrate, lipid and nucleotide chemistry and their associated analytical tools. Our team has expertise in many areas including: • Filtration; • Cell separation; • Viral inactivation; • Oxygen sensitive products; • Chromatography; • Protein modification; • Aldehyde reaction chemistries; • Cross-linking technologies; • TFF/crossflow filtration; • Centrifugation; • Aseptic and sterile filling; • Cell culture services; and • Mammalian cell fermentation. Our knowledge includes design, scale-up/scale-down and validation of viral clearance technologies. Our expertise in working with oxygen sensitive materials stems from our hemoglobin experience. Reaction kinetics and yields can be optimized through our extensive chemical and biochemical knowledge. We are committed to maximizing yield while minimizing cost, maintaining product purity, process robustness and satisfying cGMP requirements. www.therapurebio.com 8

TESTING AND LABORATORY SERVICES Quality control is key to the successful development, transfer and subsequent manufacturing of any product. Therapure Biopharma’s Quality Control team provides a broad range of services to ensure our clients’ product meets all necessary conformance standards. Our established quality program is designed to fulfil requirements set by regulatory authorities and is continually being updated to ensure cGMP compliance. We have a diverse range of skills in several areas including large and small volume parenterals, biologics, blood products, aseptic and sterile processing. To ensure reliable results, Therapure Biopharma’s established quality assurance program includes systems for control of documentation, test samples, reagents and standards, test methodology, test instruments, failure investigations and method validation. CONTRACT TESTING Therapure Biopharma has 12,500 square feet of laboratories for research and development, in- process and finished product testing, analytical and microbiological testing and stability studies. We have the laboratory control systems and equipment in place to accommodate cGMP test requirements. In addition to the Quality Control tests provided by Therapure Biopharma, we have agreements with qualified off-site facilities to perform custom testing. STABILITY STUDIES Therapure Biopharma has a broad range of stability programs and services including: • Stability program design; • Preparation of protocols and reports; • Controlled stability sample storage; • Stability testing; and • Stability data statistical analysis. Custom stability programs can be designed and executed for raw material, process intermediate and final product shelf-life determination. www.therapurebio.com 9

TESTING AND LABORATORY SERVICES METHOD DEVELOPMENT As important as the process development of a product is the development of the test methods for measurement of purity, activity and potency as well as other product specifications. Therapure Biopharma has extensive knowledge in the test method development for products of biological origin. In order to document your test method procedures we: • Research current literature; • Evaluate sample matrices; • Identify appropriate characterization methods (chromatography, spectroscopy); • Design and optimize analytical methods (column types, flow rates, sample preparation, etc.) including evaluation for robustness; • Provide a preliminary evaluation of precision, accuracy, specificity, etc.; • Develop test system suitability controls; and • Establish a test development record for our clients’ use and filing. We establish scientifically sound test procedures to assure the conformance of your product to the appropriate standards of identity, strength, quality and purity. www.therapurebio.com 10

LABORATORIES Therapure Biopharma has 12,500 square feet of laboratories for research and development, in-process and finished product, analytical and microbiological testing and stability studies. Designed to meet our clients’ requirements the Raw Materials, Analytical Chemistry and Microbiology Laboratories operate in compliance with cGMP requirements and can handle testing of a wide variety of chemical and biological agents. Therapure Biopharma performs tests using fully qualified laboratory instruments and ensures continued control by performing routine calibration, maintenance and demonstration of system suitability. • Raw Materials o Raw Material control, sampling, ID and purity testing and reserve sample storage in compliance with regulatory guidelines o Establishment of Raw Materials Specifications, Raw Materials Qualification and Supplier Quality Monitoring. • Analytical Chemistry o Services a variety of needs for protein and chemical analyses including identification testing, purity assessments, quantitation of impurities and contaminants, characterization and measurements of biological activity www.therapurebio.com 11

LABORATORIES • Microbiology o Utilizes fully validated Isolator technology to perform microbiological testing including sterility testing, bacteriostasis/fungistatis, bioburden, bacterial endotoxin (LAL), particulates and environmental monitoring • Research o There is 5,700 square feet of Research laboratories available to provide support for Product Development and Quality Control activities Large fume hoods and lab bench exhaust vents allow work with potentially hazardous chemicals. Freezers, refrigerators and incubators are temperature and humidity controlled and monitored to address most sample/material storage conditions. The laboratories house controlled and monitored stability storage chambers capable of meeting ICH temperature and humidity requirements with a temperature range of -80° to +70°C and humidity range of 55 to 100% RH. Validated Isolator technology is used to perform microbiological testing. www.therapurebio.com 12

VALIDATION SERVICES Validation is essential in demonstrating that tests and processes developed for a product are robust and under control. Therapure Biopharma, as a cGMP manufacturer, is committed to using the principals of validation to ensure that a specific process will consistently produce a product meeting pre-determined specifications and quality attributes. TEST METHOD VALIDATION One of the most important steps before filing a marketing application is the early validation of analytical test methods used to determine the potency, purity, identity, quality, safety and stability of a drug and its intermediates. Analytical method validation is typically an ongoing process in parallel with product development. Therapure Biopharma has the capability to perform full test method validation in accordance with the current ICH guidelines. Therapure Biopharma’s Quality system requires that test methods have a written and approved test procedure and a trained operator prior to initiation of validation. Method validations are executed according to an approved validation protocol. The validation plan ensures that there is documented evidence of suitability including accuracy, precision, sensitivity (LOD, LOQ), specificity, linearity and range. PROCESS VALIDATION Our validation expertise extends to Process/Performance Qualification (PQ) of many typical biopharmaceutical operations such as: • Viral clearance • Filtration/clarification • Purification • Aseptic filling • Scale-up operations www.therapurebio.com 13

VALIDATION SERVICES Therapure Biopharma has extensive experience in the writing and execution of Installation and Operational Qualification (IQ/OQ) protocols for a broad range of systems including: • GMP utilities • Clean In Place (CIP) & Clean Out of Place (COP) skids • Cold rooms • Steam in Place (SIP) • Incubators • Solution Preparation • Autoclaves • Filtration • Chromatography • Filling systems We also possess the in-depth knowledge and the ability to address process cleaning validation requirements. www.therapurebio.com 14

MANUFACTURING SERVICES Therapure Biopharma’s manufacturing capabilities extend from the laboratory bench-top to large-scale commercial production. We have the ability to provide protein purification and aseptic processing at any scale and to produce sterile injectable protein solutions. Designed for flexible operation, Therapure Biopharma’s modern manufacturing and testing facility meets or exceeds the existing standards of the FDA (U.S.), HPFB (Canada), EMEC (Europe) and MCA (U.K.). The facility has over 26,000 square feet of clean space. The clean room manufacturing areas are organized into pressurized zones, meeting cGMP requirements. The facility is designed and serviced to accommodate modular equipment. Strategic placement and use of removable clean room panels, roll-up doors and removable exterior walls allows the creation of custom areas and facilitates easy installation and removal of processing equipment. Manufacturing suites range from Class 100,000 and 10,000 downstream processing areas to Class 100 filling areas. Explosion rated rooms are equipped with blow-out panels which are suitable for operations involving solvents and/or flammable material. Containment areas are under negative pressure to allow processing of items such as biohazardous materials. The facility is readily adaptable to manufacture bio/pharmaceutical products that satisfy preclinical, clinical or commercial requirements. • Chromatography capabilities with columns sizes ranging from 0.4 cm to 1 meter in diameter; • Equipped to handle both biohazardous and flammable solutions in dedicated suites; • Normal flow filtration equipment ranges from disposable capsules to stainless steel housings capable of holding eighteen 30quot; filters; • Extensive tangential flow filtration (TFF) capabilities range from stir cells and 'slice' holders on the bench top scale to dedicated TFF skids with membrane areas up to 80 m2; • Solutions preparation capabilities extend from small volumes using standardized laboratory glassware through to a 6000-L stainless steel mixing tank; and • Stainless steel process tanks range in size from 10 L to 3000 L allowing for a wide range of processing possibilities. Therapure Biopharma is fully equipped to perform sterile filling operations into IV transfusion bags using a semi-automated filling machine or into bottles or vials in the dedicated fill suite. www.therapurebio.com 15

MANUFACTURING FACILITY Therapure Biopharma’s 130,000 square feet manufacturing and testing facility is conveniently located in the heart of the biopharmaceutical area in Mississauga, Ontario (part of the Greater Toronto Area). The building is just minutes from Lester B. Pearson International Airport – Canada’s largest airport and borders on two of Canada’s major highways. The facility incorporates the Raw Materials, Analytical Chemistry, Microbiology and Research Laboratories, as well as clean room manufacturing areas and warehouse storage. Mechanical Base Utilities Penthouse Process Clean Rooms Explosion Clean Utilities Rated Room & Buffers Central Service Chase The building was specifically designed to allow flexibility of use with a variety of features that are ideal for bioprocess manufacturing. Therapure Biopharma’s multiple HVAC systems allow for segregation of process areas, positive and negative pressurization schemes and areas where no recirculation/mixing of air is allowed. Selected suites are configured under negative pressure for containment of biologic materials prior to pathogen removal/inactivation steps, preventing cross contamination to subsequent downstream purification areas. The system also utilizes terminal HEPA-filters dedicated to various production areas meeting specific requirements for air cleanliness. The facility has large capacity grey utilities available including chilled water, plant steam and compressed air. The clean utilities include USP water, WFI, clean steam, CIP, process air and medical gases. These utilities are distributed through a central service chase, which provides all utilities to any production suite or process unit. This central service chase also allows for independent utility changes, significantly reducing down time in the clean rooms and provides adaptability for routing of process piping. A bulk solvent storage and delivery area and bulk liquid nitrogen and oxygen gas storage facility have also been integrated into the building. Waste treatment, Clean-In-Place (CIP) systems, buffer and solution preparation and water purification systems are housed in the basement away from the main process areas. www.therapurebio.com 16

MANUFACTURING FACILITY – STERILE FILLING CAPABILITIES Aseptic Fill Capabilities Therapure has aseptic filling capability in the formulation and filling of sterile liquids into glass vials or preformed IV infusion bags. Aseptic vial filling suite includes: • Vial wash • De-pyrogenation • Autoclaving • Filling • Dedicated HVAC • Inspection • Packaging • range of fill volumes include 2ml to 200ml glass vials, with rubber stoppers and capping. • batch sizes (based on a single shift) range from 35,000 for the 2ml size, to 12000 for the 50ml and 3000 for the 200ml size Sterile Preformed Bag Filling • Preformed sterile bags and are aseptically filled using a robotic filler and sealer that is manually fed • Secondary packaging • bags can range from 50ml-1000ml • up to 800 bags/hour Lyophilization Services • Development on line by Q2, 2009 • Commercial vial and bulk on line Q3, 2009 www.therapurebio.com 17

WAREHOUSING One of the challenges facing any successful company is the need to properly store and ship finished product. Therapure Biopharma’s cGMP compliant warehouse and distribution service can provide specialized product handling and tracking. Warehousing Therapure Biopharma’s 28,000 sq. ft. warehouse and distribution area is fully secured and can be segregated to meet each client’s requirements. The monitored and secure warehouse is capable of holding up to 544 composite plastic pallet positions that can be expanded to ~900 pallet positions of high density storage. Therapure Biopharma elected to use the composite pallets to ensure that there is no contamination transferred from the wooden shipping pallet into the warehouse or other process areas. Segregated shipping and receiving docks ensure full control of all materials entering or leaving the facility. We have an established and controlled raw material system. The materials department inspects all shipments to ensure correctness and to check for damage. All items received are input into our inventory control system and given a unique number for traceability. Raw materials are segregated and labeled “quarantine” until being processed under Therapure Biopharma’s raw material approval procedure. cGxP Storage Spacious storage is available for raw materials and finished product. We offer a broad range of storage conditions, temperature, humidity controlled and monitored including: • 18,000 sq. ft. of warehouse space for • Incubators covering a range of room temperature raw material storage; temperatures from 25° to 70° C; • Freezer storage ranging from -85° to - • Explosion rated rooms for the 20°C; storage of hazardous raw • Walk-in cold rooms ( 2° to 8°C) for the materials; and storage of both raw materials and • Ambient storage. manufactured product; www.therapurebio.com 18

WAREHOUSING Distribution Therapure Biopharma’s distribution services make certain your product gets to you when you need it. Our shipping protocols are efficient and effective - we have successfully established next day delivery throughout North America. Tracking and look back procedures are established specifically for the quick traceability of raw material usage Shipping protocols, validated through several trial programs, ensure temperature and time sensitive materials retain their integrity even during transit. We have alliances with numerous carriers throughout North America and Europe familiar with these specialized requirements. In addition, our established relationships with customs brokers have made the International border between Canada and the United States appear invisible when dealing with shipments of approved IND products. We are familiar with the specific packaging required for protein derived products and will work with you to ship your product in the shipping containers most applicable to your needs. www.therapurebio.com 19

PROJECT MANAGEMENT SERVICES Successful management of every project is a priority for Therapure Biopharma. Our objective is to ensure we fulfil our clients’ needs and expectations and that all parties are positioned for success. Through our project teams we build solid, ongoing communications and joint ownership of the process – from development to manufacture. We enable strong partnerships between our clients’ and ourselves. A well managed project means there are no surprises – for anyone. The key to any successful project is ongoing communications between the parties. Thus, each project is assigned an experienced project manager to manage the relationship between our client and ourselves. Through ongoing interaction exceptional service is achieved. The project manager is responsible for: • Managing the project plan • Chairing meetings • Overseeing internal teams • Preparing reports and reviews • Managing the change control process Timing represents one of the most critical elements in any project. Therapure Biopharma’s project management teams ensure our clients’ product is delivered on time and on budget. Our clients are integral participants in the planning process. A schedule will be developed jointly and managed by the project team. Through the use of comprehensive Gantt charts all project deliverables and tasks are tracked and monitored to achieve our clients’ goals. If changes to the project are required, Therapure Biopharma’s change control procedure allows for the flexibility necessary in today’s biopharmaceutical environment while maintaining visibility of the impact on costs and timelines. Through the vigilant monitoring of project changes successful project execution can be achieved. Through proper management we ensure our clients’ expectations and requirements are met. www.therapurebio.com 20

WHY CHOOSE THERAPURE BIOPHARMA? Therapure Biopharma’s unique and flexible features allow Therapure to attract local and international partnerships with companies that require protein production and processing services: ● Scale of production – capable of producing metric tonnes of protein annually; ● Range of production covered, from manufacturing to purification, to testing, formulation and packaging; ● Flexibility of equipment and facility to accommodate a wide range of processes sequentially and simultaneously; ● Scientific, manufacturing and regulatory expertise. We can provide our customers with custom testing and technical advice including: ● Initial product characterization; ● Establishment of product specifications; ● Stability studies; and ● Product release programs. Our manufacturing expertise can ensure rationale process design early in the process to avoid expensive changes. Our laboratories can establish proof in principle for your product design. We can conduct feasibility studies to help work out difficult steps. We can ensure that regulatory requirements are incorporated early to guarantee compliance later. We also support our customers in the preparation of the required documentation for regulatory submissions. At all times we can provide guidance to ensure GLP/GMP compliance. Please call us at +1 905-286-6200 or email to info@thereapurebio.com to discuss your specific requirements and learn more about how Therapure Biopharma can assist you to bring your product to market. www.therapurebio.com 21

Tbi Bioprocessing Services Sept 25.08

by Thomas Wellner

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Tbi Bioprocessing Services Sept 25.08 Document Transcript