In pharmaceutical and biochemical manufacturing processes, the emphasis is on knowable quality levels, defined components, and predictable, repeatable yields and products. This underlines the importance of reliable specification and quality claims, whether they point to cGMP, molecular biology grade, high purity, or simpler grades. The point is to be what they are claimed to be. Naturally, it is not a question of the highest purity possible, but rather the highest purity necessary at a cost that makes sense. It’s all part of driving high-level processes to reliable endpoints, of a sustainable manufacturing scenario that reduces costly repurifications, workloads, and QC failures.
Reliable, Consistent Supply of Essential Reagents
Hand in hand with this concept, of course, is the idea of a reliable, consistent supply of essential or crucial reagents. We have made it more than an idea. Forty years of dedication to becoming reliable, consistent, and flexible isn’t a marketing statement — just a historical fact...
Figure 1: ()
For more than 65 years, Kerry’s Sheffield brand has earned its reputation for reliability and excellence in serving the biotech, pharmaceutical, and nutrition markets. We deliver innovative, animal-component–free supplements to assist customers increase cell proliferation, extend cell viability, and increase target protein production.
Every day we expand our capabilities to meet the changing needs of the biotech market by providing the industry’s most innovative and extensive biotechnologies, including complete supplement systems, hydrolyzed proteins, recombinant proteins, and yeast extracts. We have the vast global resources and technical platform to deliver consistent, high-quality products backed by unparalleled service, technical support, and formulation customization capabilities.
Figure 1: ()
Figure 2: ()
Sheffield rInsulin ACF Tertiary Animal-Component–Free
To meet the challenging needs of the market, Sheffield introduced Sheffield rInsulin ACF as a tertiary ACF, or animal-component–fr...
At ALLpaQ, we’ve enjoyed 12 busy months designing and supplying folding plastic bioprocess containers to the pharmaceutical and biotechnology industries. Thinking outside the proverbial bioprocess box, we’ve also responded to customer demand by growing our consultancy arm. This means we can design your organization’s whole containment needs from start to finish, saving you time and money along the way.
Our Knowledge Is Your Power
With 10 years’ experience developing the preeminent range of plastic large-volume fluid handling containers for the shipping and storage of media and buffer solutions, it’s fair to say we know a thing or two about your industry and needs. So wherever you are on your journey, we can step in and help. A typical start-to-finish process might follow this pathway:
01 Analysis and Design:
strategically planning all dimensions of your containment needs
02 Development:
implementing the strategy
03 Maintenance:
ongoing support.
Building Boxes, Building Businesses
ALLpaQ plastic foldabl...
The purpose of this study was to demonstrate compatibility and performance of SoloHill’s Collagen-coated microcarriers in ATMI Lifesciences’ Integrity™ PadReactor™ system. The solid polystyrene core of the collagen microcarriers prevents absorption of serum or cell products into the core of the microcarrier, and the 1.03 specific gravity and 125- to 212-μm diameter allows them to be maintained in suspension with gentle low stirring speed. These solid microcarriers provide an excellent substrate for cell growth. They can be sterilized by autoclaving at temperatures up to 131 °C or by gamma irradiation at doses of 25–40 kGy with no deleterious effects on function.
Microcarrier Mixing
SoloHill microcarriers with a relative density of 1.03 exhibited an optimal distribution between 30 and 50 rpm. At these speeds the PadReactor’s mixing performance was very high, and therefore these conditions were chosen for subsequent cell growth studies.
Bioreactor Culture
Microscopic examination of a representative sample r...
+1Clinical cellular therapy applications often times require a cell expansion or maturation step before use. Traditionally, cell expansion or cell culture is performed in “open” systems including multiwell culture dishes or tissue culture flasks. These “open” steps present risks and are not ideal for larger-scale manufacturing. The new EXP-Pak™ cell expansion container is a closed-system, gas permeable bag intended for expansion and culture of nonadherent cells.
EXP-Pak™ bags are made from a unique polyolefin film that permits gas permeability required for cell expansion and maintenance of cell viability in addition to excellent clarity (when filled with liquid) for viewing of cultures. The bags also feature a tubing harness that allows for filling, sampling, and manipulation steps to take place in a completely closed, sterile manner.
The aim of this study was to investigate the ability to culture and expand cells in the EXP-Pak™ (Charter Medical, Ltd. Winston-Salem, NC) and to also compare expansion rates ...
+1 Unlike traditional pharmaceuticals, cell therapy products (CTPs) require geographically dispersed networks of cell/tissue collection, manufacture, distribution, and clinical treatment facilities. Regardless of source (allogeneic, autologous) or formulation (e.g., fresh, frozen, scaffold), the vast majority of CTPs are clinically administered on a per-patient basis. A CTP will be clinically effective, and therefore commercially viable, only if it is robust enough to be delivered to the patient in an efficient, controlled, and reproducible manner.
In the context of CTPs,
delivery
is not a synonym for
shipping
. It entails some (or all) of the following:
QC release
and
shipping
from the manufacturing site,
receipt
and
storage
at the clinical site, preadministration
processing, formulation
and
QC release
at the clinical site, and
administration
by the clinicians.
Based on our experience and understanding of CTP delivery, Progenitor Cell Therapy coined the term
direct delivery
for CTPs formu...
The large numbers of ex vivo expanded cells that are required in many clinical cell therapy protocols (>100 million per patient) make standard culture conditions problematic and expensive, resulting from the need for extensive personnel and facilities resources and the high potential of contamination. To meet such clinical demand, a robust, automated, and closed cell-expansion method is optimal. The Quantum Cell Expansion System (CES) is a functionally closed, automated, hollow-fiber bioreactor system designed to reproducibly grow both adherent and suspension cells in either GMP or research laboratory environments. The Quantum CES has successfully been used for the ex vivo expansion of clinical-scale quantities of adult bone marrow–derived mesenchymal stem cells (MSCs). It has now been demonstrated that a second adherent cell type of clinical interest, adult normal human dermal fibroblasts (NHDF), are ex vivo expandable with the Quantum CES.
Methods
NHDF from two different donors were cultured at two diff...
+4 Many current cell-based products are produced, frozen, stored, and delivered to the clinical site in intravenous (IV) bags or polypropylene screw-cap containers. Although IV bags are sufficient for small-scale processes, they may not be suitable for commercial scale. Bag failures can lead to microbial contamination of the cell product, increased product preparation time, increased antibiotic use, and increased resource expenditure to replace products.
Plastic resins (such as polypropylene) have been used in R&D or early preclinical/clinical activities. The regulatory environment for container–closure integrity, extractables, and scalability can be challenging for screw-cap containers. As the industry expands and moves to commercialize cell-based therapies, there is a clear need for a scalable, vial-based packaging system for pharmaceutical fill finish operations.
A system incorporating a sterile Daikyo Crystal Zenith
®
vial and a stopper adapted for cryogenic use offers an ideal solution for low-temperat...
Althea is a contract developer and manufacturer of biopharmaceutical and injectable products with fully integrated product development and cGMP manufacturing expertise to support client projects from preclinical development through commercial supply. Each project program at Althea is tailored to the specific needs of your product, allowing you to leverage our entire integrated manufacturing approach, or just the parts you need. While realizing all of the tangible benefits of consolidating your development and manufacturing steps, you’ll also have the confidence of knowing that your product is being championed by seasoned professionals who boast an impressive track record of more than 250 cell banks, 150 cGMP protein and plasmid DNA lots, and more than 1,300 cGMP fill-and-finish lots delivered-to-date.
Biologics Manufacturing: Recombinant Proteins and Plasmids
Whether it is protein or plasmid production, Althea’s experienced staff can take your microbial-expressed product from cell banking to final filled ...
BioPharma Solutions, a business unit of Baxter Healthcare Corporation, works with pharmaceutical companies to support their commercialization objectives by providing scientific expertise, sterile manufacturing solutions, parenteral delivery systems, and customized support services needed to meet the unique challenges that parenteral products face.
Meeting Parenteral Manufacturing Challenges
Parenteral manufacturing can be a complex process. Cytotoxics, antibody-drug conjugates (ADCs), highly potent compounds, biologics, and lyophilized products require specialized understanding. BioPharma Solutions offers a dedicated facility with experienced operators, sophisticated equipment and systems, and robust standard operating procedures, training and risk assessments. Our contract manufacturing services provide customers access to world-class scientific expertise, state-of-the-art facilities, and processes designed to help ensure a reliable supply of quality product to the market.
Baxter is the only company worl...
The commercial prefilled syringe line at Cook Pharmica can process up to 600 syringes per minute, 36,000 syringes per hour, or 70 million syringes per year. The automated, high-speed syringe line is fully enclosed in a barrier isolator to provide the highest level of aseptic processing available by removing the human element from the entire process. With the ability to operate in smaller batches or full-scale campaigning, the prefilled syringe line is capable of bridging clinical programs into commercial production.
The process starts in a separate tub-loading room where tubs are loaded onto a pass-through conveyor and sent into the isolator for automatic debagging. After the tub is removed from the bag, it passes through a tunnel utilizing E-beam technology for tub decontamination. When it exits the E-beam tunnel, robotic arms remove the lid and liner to prepare the syringes for denesting and filling.
The line is capable of time-pressure or peristaltic filling, with temperature-compensating recirculation...
Covance is one of the world’s largest and most comprehensive drug development services companies with more than 10,000 employees in 60 countries. Through its broad portfolio of services, Covance has helped pharmaceutical and biotech companies develop one-third of all prescription medicines in the market today.
Working with clients of all sizes, Covance recognizes that your development program is as unique as the product you bring to our facilities. With over 250 different biomolecules successfully supported annually, Covance Biopharmaceutical Services provide you with a global, multidisciplinary team of experts and specialized state-of-the-art infrastructure to help achieve your development and commercialization goals.
The comprehensive Covance biopharmaceutical service capabilities include extensive expertise and experience in:
Covance has a complementary portfolio of discovery, nonclinical safety assessment, clinical development, and market access capabilities for full development of biopharmaceutical p...
Challenging conventional process technologies with innovation and forward-looking solutions lead to the next generation of manufacturing processes. With its biotechnology, chemistry, and fine chemistry capability, DSM has an extensive toolbox for developing the most economic and sustainable solutions for customers. DSM’s biotechnology uses microorganisms, enzymes, and mammalian cells to produce novel ingredients and improve existing food ingredients, (bio)pharmaceuticals, plastics, and chemicals.
Mammalian Cell Culture–Based Manufacturing
A state-of-the-art facility, located in Groningen, The Netherlands, is dedicated to the development, scale-up, and CGMP manufacturing of recombinant proteins and monoclonal antibodies. Proprietary technologies and standard fed batch or perfusion processing are utilized across a bioreactor scale of 50-, 250-, 500-, and 1,000-L disposable technology. Commercial production will begin in 2013 in a new Brisbane, Australia, facility.
Examples include
Microorganism Fermentation...
Established at the forefront of current good manufacturing practice (cGMP) cell-based potency assay contract testing, Eurofins Lancaster Laboratories, Inc. provides assistance in all aspects of bioassay development, validation, method transfer, and long-term assay maintenance. Characterization of a biological product — which includes the determination of physicochemical properties, biological activity, immunochemical properties, purity, and impurities — is necessary to establish the safety and efficacy profile of a given product (as per ICH Q6B guidelines). Cell culture–based potency assays are often the preferred format for determining biological activity because they measure the physiological response elicited by a product and can generate results within a relatively short period of time — unlike typical animal-based assays. Cell-based potency assays are also often the only functional assays used for product-release and stability programs. Other uses of cell-based potency assays include qualification of...
Rentschler Biotechnologie GmbH is a global, full-service contract manufacturer with over 35 years of experience in the development, production, and approval of biopharmaceuticals in compliance with international GMP standards (EMA/FDA). As part of the Rentschler Group and headquartered in Laupheim, Germany, Rentschler is one of three leading European CMOs operating globally. Dedicated to delivering high-quality biopharmaceuticals produced in mammalian cell culture, Rentschler has nine stand-alone GMP suites with volumes of 30 L, 250 L, 500 L, 1,000 L, and 2,500 L, which allows producing material for clinical trials and supplying the market. As a pioneer in the development and production of biopharmaceuticals, Rentschler was the first company in the world to gain market authorization for an interferon-containing drug. The company is an independent, family-owned business and currently has about 650 employees.
Rentschler Excels with Expertise and Full Service from “Gene to Drug Product”
Rentschler provides c...
Sandoz is one of the leading specialists in biotech development and manufacturing. Comprehensive know-how is based on more than two decades in microbial and mammalian cell culture production at commercial scale. Today Sandoz offers a broad variety of integrated services including innovative expression systems, process development, scale-up, and production of recombinant products derived from microbial systems and mammalian cell culture in state-of-the-art facilities.
Our expertise is based on numerous projects successfully performed in collaboration with our customers. Currently, Sandoz is manufacturing more than 25 different recombinant products for well-known pharmaceutical and biotechnology companies located in USA, Europe, and Japan. Our FDA approved facilities fulfill worldwide quality requirements.
Services Offered
Production of Recombinant Peptides and Proteins:
150-L, 1,300-L, 3,000-L, 13,000- L, and 40,000-L fermentors are available in our facility in Kundl, Austria. Each fermentation unit is fu...
Recent advances in the research of therapeutic biologics have resulted in increased market demand for novel manufacturing systems to help meet the growing production need. Recent data resulting from increased research into the human immune system has resulted in the development of innovative treatments for a number of diseases with large unmet need both as vaccination and therapy. To compliment this growth, new approaches in pharmaceutical manufacturing help to fill complex biological products, not only to secure supply, but also to achieve gains in productivity that help create affordable end-user prices. As an internationally recognized leader among contract development and manufacturing organizations (CDMOs) that acts as a strategic partner for the pharmaceutical and biotech industries, Vetter has been addressing these market needs. A newly designed and constructed, innovative, high-speed manufacturing line at its Ravensburg location enables efficient and high-quality filling of up to one million syrin...
Wacker Biotech is a dedicated contract manufacturer of biopharmaceuticals with more than 20 years of experience in microbial systems. We offer proprietary technologies (ESETEC
®
, DENSETEC
®
) that significantly lower the cost of goods. Our customers benefit from a comprehensive service for the development of robust and highly efficient processes and GMP-compliant manufacturing for clinical trials and commercial supply. We opened recently a new process-development unit to optimize the entire process-development chain, from gene to purified protein. A second extension at the Jena site came on full stream in March 2010 after a multimillion investment. We doubled the production area in the existing GMP plant and added a brand new downstream processing suite.
Services
We work in close collaboration with our customers. Projects are managed by dedicated project managers supported by cross-departmental teams. Depending on our customers’ requirements, we have the flexibility to perform the whole process, or trans...
Small-pore, virus-retentive nanofilters are designed to remove even tiny viruses from a biological product intermediate as it flows through the filter membrane. During process development, manufacturers carefully optimize filtration conditions to maximize product throughput so that at manufacturing scale, the number and size of these expensive virus filters can be minimized. During the viral clearance study, an attempt is made to filter a targeted volume based on preceding process development studies. If the filter’s pores become plugged with impurities from the virus spike, the total volume that can be filtered may be limited. Because the maximum filtration volume at manufacturing scale is based on throughput achieved during the viral clearance study, it is important to reduce any impurities in the virus prep that might plug the filter and potentially threaten filter capacity. This concern can be mitigated by the use of a high-purity virus stock.
BioReliance’s standard virus stocks, BioPure Virus™, have ...
Clarifying cell culture broth is the first downstream unit operation in an elaborate sequence of steps required to purify a biological therapeutic. The availability of large-scale, single-use depth filtration technology in recent years has given process developers the capability to improve and simplify downstream processes.
The Zeta Plus™ Encapsulated System is a single-use depth filtration system designed for the bioprocessing industry where upstream cell culture clarification or downstream impurity removal is required. The Zeta Plus Encapsulated System consists of a variety of products deisgned to help a user scale-up processes from the laboratory to the production facility.
Lab, R&D, and Scale-Up
The Zeta Plus devices at this scale consist of the BC25 capsule with 25 cm
2
of depth filter media and scale-up capsule filters (below) with 170 cm
2
, 340 cm
2
, and 1,020 cm
2
of depth filter media. These tools are designed for media-grade screening, intermediate scale-up studies, and lab-scale protein pro...
Background
Tryptic soy broth (TSB) is a general-purpose medium used for cultivating numerous microorganisms including
Serratia marcescens,
a Gram-negative rod commonly found in water and involved in pharmaceutical contaminations (
1, 2
). This study examines the growth characteristics and bacterial retention of
S. marcescens
(ATCC #14756) in five types of TSB: EMD TSB (type 1), EMD Irradiated TSB (type 2), EMD Non-Animal Origin TSB (type 3), EMD Non-Animal Origin Irradiated TSB (type 4), and Competitor ATSB (type 5).
Materials and Methods
To compare the growth characteristics of
S. marcescens,
standardized cultures were prepared in each TSB and incubated at 30 °C. OD
600
and titer measurements were taken at 0, 2, 4, 6, 8, 20, 24 and 28 hours.
S. marcescens
cells (24 ± 0.5 h) were imaged using a FEI Corporation Quanta 200F field-emission scanning electron microscope, and ≤100 cells were measured with Image Pro Plus v7.0 using a calibrated measuring standard.
To assess the effect of different TSB t...
+1 Influenza vaccine has historically been produced in embryonated chicken eggs. However, to meet the needs for pandemic preparedness and the scalability of vaccine production, cell-based processes are now being developed and implemented in the industry. The methods for purification processes have typically involved a combination of sucrose density gradient ultracentrifugation, ultrafiltration/diafiltration (UF/DF) with hollow-fiber membranes, and chromatography using affinity, ion-exchange, and/or gel filtration media (resins). In these processes, both sucrose density gradient ultracentrifugation and gel filtration have limitations in scalability and throughput. Clearly, new techniques are needed to improve productivity and economy in vaccine production.
Capto™ Core 700 is a member of GE Healthcare Life Sciences’ Capto line of chromatography media (
1
). The Capto Core 700 medium has a core bead design and consists of an inactive outer layer and a ligand-activated core. Small contaminant molecules enter int...
Figure 1: ()
Antibody fragments (e.g., Fab, scFv, DAb, etc.) are set to become the next important class of protein-based biotherapeutics after monoclonal antibodies (MAbs). One of the advantages is that due to their structure and smaller size, antibody fragments possess unique properties (e.g., easier tissue penetration) that suit a range of diagnostic and therapeutic applications.
The industry standard for purifying MAbs is a platform approach using affinity chromatography with protein A as the capture step. The high purification factor and generic conditions associated with this approach have proven particularly attractive to biopharmaceutical manufacturers. Antibody fragments, however, have previously lacked such a platform solution.
With the introduction of Capto L, the first industrial platform for the purification of antibody fragments, is now emerging (Figure 1). With its recombinant protein L ligand, Capto L is a BioProcess™ chromatography medium with a broad range affinity for antibody fragments ...
Protein A chromatography is still the preferred capture step in monoclonal antibody (MAb) production because of its high selectivity and robustness, although cation-exchange (CEX) or multimode chromatography techniques are claimed as alternatives. Kaneka Protein A Cellulose increases the value of protein A affinity chromatography for MAb production.
Kaneka’s unique combination of a proprietary designed alkaline stable protein A ligand and a highly cross-linked cellulose base matrix meets customer requirements for improved performance, high binding capacity, alkaline and chemical stability for cleaning in place (CIP), mild acidic elution pH, small nonspecific binding, and scalability with good pressure flow characteristics. Kaneka’s new Protein A Cellulose is therefore a powerful tool for the improvement of your current MAb purification platform.
Dedicated Design of Protein A Ligand
The elution profile of a Protein A column at the industrial scale is one of the most critical factors. For example, the VH3 s...
+2 LEWA developed its first pulseless pump for liquid chromatography in the late 1970s and delivered its first chromatography system in the early 1980s. LEWA is the leader in supplying pumps used for pilot and industrial HPLC, SMB, and LPLC chromatography worldwide.
A customer came to us several years ago requesting a low-pressure liquid chromatography system with a flow range of 20–2,200 L/h. They also wanted the ability to achieve linear gradient from 1 to 99%. We designed and built the system, and it is now in a validated process. This was a very challenging task. Upon completion, this question was asked: “Is there a better way?” The Intellidrive technology is the answer. LEWA has now integrated this technology into chromatography skids.
The LEWA EcoPrime brings wide dynamic flow range, low-pulsation flow, and accuracy to modern chromatography as unique features. We have combined state-of-the-art functionalities into one unit: It can be a buffer dilution skid, or directly connected to a column to be a chr...
Anion-exchange (AEX) products are commonly used as a polish step in product flow-through (FT) mode to bind impurities. Comparing resins with membranes and membranes with membranes is challenging because of the complicated and unique scaled-down model formats of the products offered by different vendors. A novel approach to AEX FT using a short, 5-cm length, packed-bed format with a faster operating flow rate is explained. The performance of commonly used AEX resins and membrane adsorbers, detailing dynamic binding capacity performance, efficiency, and a new prepacked column option for chromatography are compared. The data presented show that a high-performance AEX resin, when combined with the convenience of a GoPure™ prepacked column, competes well with the performance of membranes. It provides similar processing times and the added benefits of ease of packing at different scales in various column formats, with the ability to implement initial process design from early phase manufacturing to commercial m...
+2 The capture step in the downstream processing of monoclonal antibodies (MAbs) is often the bottleneck and the most expensive step due to the use of protein A media. In recent years, several new-generation protein A media have been launched on the market claiming improved MAb capture, or improved resistance to cleaning agents.
AbSolute
®
High Cap, the new revolutionary protein A media by Novasep, maintains excellent DBCs at low and high velocities, therefore, providing substantially improved productivity and strongly reduced costs compared with all existing protein A media.
Outstanding Dynamic Binding Capacity
AbSolute® High Cap combines the benefits of a new-generation Protein Awith rigid particles providing improved mechanical resistance. Due to a very uniform particle size distribution and a homogeneous pore size distribution, AbSolute® High Cap has outstanding performance at low and high velocities. As an example, DBCs at 10% breakthrough were determined for AbSolute® High Cap and several industry sta...
Figure 1:
Sartopore
®
Platinum TwinPleat
()
Sterile filtration using 0.2-µm rated filters is a critical step in upstream and downstream biomanufacturing alike. Typical applications comprise sterile media addition into the bioreactors, cell harvest clarification post-depth filter, chromatography column protection, and final sterile filtration of purified bulk drug substance. Total throughput, flow rate, unspecific adsorption, and wettability of sterile filters can have direct impact on total cost of ownership.
There have been innovative application-specific approaches in sterile filtration such as the Sartopore
®
2 XLG 0.8/0.2 and Sartopore
®
2 XLI 0.35/0.2 PES filters from Sartorius Stedim Biotech (SSB). Both filters have different prefilter membrane retention ratings designed for optimum performance with fluids having specific particle-size distribution characteristics. Sartopore
®
2 XLG shows higher capacities for serum-free, hydrolysate supplemented media and cell culture harvests, whereas Sartopor...
Speed to market has become a key factor of success in the biopharmaceutical industry, yet it can be difficult to achieve without compromising product quality. By seeking out products that are able to provide maximum efficiency while simultaneously maintaining first-rate quality, companies can not only get to market quicker, but also gain a competitive advantage. A new bag port line, manufactured by Value Plastics (VP), both addresses these concerns and tackles them head on by incorporating them into the product design.
Two aspects new to the industry and unique to the Bag Port Series are flow alignment ribs and parabolic entrance geometry. These features, respectively, promote a uniform flow by guiding the product into a consistent, rotational path while reducing flow separation from the wall. Design functionality and performance were validated in extensive testing and analysis, and then used in comparing the ports to other commercially available products.
Flow Test Results
To test volumetric flow rates, ...
