There are many biopharmaceutical CMOs in the industry who would gladly take your promising molecule and develop it to the best of their ability. But when your company’s future is dependent on getting that molecule through testing, scale-up, regulatory filings and production as quickly and efficiently as possible – there are only two things that matter when choosing a biopharm CMO for your product – experience and expertise.
This is where a CMO like Laureate Biopharma in Princeton, NJ can provide the qualities needed to bring your biopharmaceutical product to market with the assurances only an experienced player in this market can provide.
Background and Overview
“We’ve always been in the biopharmaceutical space,” says Michiel Ultee, Ph.D., the company’s Chief Scientific Officer who has been with company for most of its 30 year history. “We are particularly adept at recombinant production of mammalian cell produced proteins, and over the years we’ve added different capabilities enhancing our analytical capabilities, our purification capabilities and added larger bioreactors.”
Laureate analyst operating capillary
Laureate’s range of services for biopharmaceutical customers begins right after the discovery phase. “Pure research or discovery is not our area,” says Ultee. “However, we do enable the companies that provide these services to turn their R&D into a product. We do all the additional development, the scale-up, the cGMP production and testing required before it’s suitable for a safe and effective product. All we need to know is the identity of the protein and we can produce a cell line and take it from there.”
For companies that are further along the road to production, Laureate can transfer that product into their facility, including products that are ready for final filling.
Laureate views this tech-transfer process as critical to ensure success. “It’s a critical process, “says Ultee. “We have to understand their molecule very well – they have to understand our process – there is a lot of exchange of information and collaboration between scientists.” To ensure that all Requests for Proposals (RFPs) from potential clients are handled in a timely and comprehensive manner, the company follows up all RFP’s with a technical call with the new customer’s scientists to make sure all parties involved understand the project’s scope, parameters and goals. A project management group is brought in as early as possible to detail the expected timeline, project activities, and responsible subject matter experts and map out what needs to be done when.
The Quest for Quality
For any biopharmaceutical CMO implementing the right systems and strategies to ensure a quality product is paramount to success. At Laureate, discussions with customers related to quality systems and strategies are really dependent on the project’s current stage.
Laureate analyst running UPLC with MALS analysis.
Lisa Cozza, Laureate’s Vice President of Business Development explains that since every customer is unique and projects come to Laureate at different stages – the quality systems discussion can take many different forms. “With companies where the goal is to get into the clinic or animal studies, the focus is on the immediate technical challenges of the protein and its production, and less on quality systems. In other scenarios, we have clients that might already have their bulk drug substance and are looking for fill/finish, or they are looking for process improvements at larger scale or to launch out of our facility. In those cases, the quality conversation starts right away – and a quality audit is done by the potential customer early on to vet our facilities and capabilities.”
“Pretty much all of our customers do a quality audit,” says Ultee. “They want to be sure that when they develop a product with us it will be done under GMP and will meet regulatory approval for their clinical testing program.”
A Complex World
With biopharmaceuticals growing in importance not only to the financial health of the pharmaceutical industry but also to the health of consumers - one might think that the complexity of making biopharmaceuticals has increased over the years.
“I don’t know if it has become more complex,” says Ultee. “I think it has become more rigorous, as people have come to understand proteins better, we have come to know what matters more and what matters less. We have evolved from the process making the product to the product being sufficiently well-defined and characterized that process changes can be accommodated. There is a lot of analytical testing that is done now which is a change from the early days of biopharmaceutical development – where you had a process and you couldn’t change it because the process defined the product.”
Laureate scientist monitoring chromatographic elution from small-scale run. “It is definitely not what it was 20 years ago” says Cozza. “The expectations of the regulatory agencies have become so comprehensive – that although it may be easy, physically, to go out there and make some product, the additional hurdles of regulatory, analytical comparability and reporting make for a much tougher assignment. This has evolved the talent pool as well. Today it has become easier to find manufacturing talent – where in the past it wasn’t easy – but meeting the tougher analytical and technical reporting requirements require a different talent pool.”
“It is definitely not what it was 20 years ago” says Cozza. “The expectations of the regulatory agencies have become so comprehensive – that although it may be easy, physically, to go out there and make some product, the additional hurdles of regulatory, analytical comparability and reporting make for a much tougher assignment. This has evolved the talent pool as well. Today it has become easier to find manufacturing talent – where in the past it wasn’t easy – but meeting the tougher analytical and technical reporting requirements require a different talent pool.”
The Impact of Technology
Laureate’s history in the biopharmaceutical manufacturing business has given them a unique insight as to how technology has changed over the years and also how vendors of biopharmaceutical manufacturing equipment have improved their products.
Laureate scientist adjusting small-scale bioreactor.
“We have close relationships with the equipment and materials vendors we work with,” says Ultee. “Improvements in bioreactor design, cell-line construction, cell-culture media and feed solutions, have resulted in dramatic increases in cell-culture titers. These have allowed us to ensure that the cells both grow well and produce well.”
“On the downstream side – we have seen a tremendous shift in purification strategies which have transformed from overnight slow processes in cold rooms many years ago to the current high-speed, synced, two or three step a day processes – that produce a much purer product. This is the result of advances in separation sciences.”
Perhaps the greatest development in biopharmaceutical manufacturing has been the advent of single-use/disposable technologies.
Laureate scientist controlling 1000L single-use bioreactor (SUB)
“Disposables have advanced,” says Ultee. “The early things that were disposable – pipettes and roller bottles were good because it eliminated the need to wash them. Shake flasks are disposable and bioreactors are now disposable – and pre-packed chromatography matrices that allow us to work very rapidly – they are not necessarily disposable - but they offer a lot of advantages.”
“The use of disposable flow paths where you do not have to worry about product change over, is really ideally suited to CMO’s.” says Cozza.
Laureate has been using single-use disposable fluid paths in their fill/finish area for the last 12 years, citing reduced changeover times and elimination of carryover from one product to another as two of the main benefits of this technology. In addition to using disposables in their fill/finish operations Laureate also employs the technology in its bioreactors. In fact the company regularly does beta testing on the newest single-use bioreactor designs in order to stay current.
Laureate manufacturing scientist adjusting 2500L stainless-steel bioreactor
“We want to stay current and innovate and keep up with latest technology because it makes for a faster and a more robust process,” says Ultee.
Biosimilars and Biobetters
In the biopharmaceutical industry there is perhaps no hotter topic than that of biosimilars and biobetters.
With a vested interest in the race to develop and produce biosimilars and biobetters, Laureate is keeping a watchful eye on this rapidly developing topic.
“The production of biosimilars is taking up a lot of capacity,” says Cozza. “There are a lot companies and CMOs collaborating on these programs. At the same time" Cozza continues, “the acceptance of using CMOs to get bulk drug products developed and launched is growing.”
Cozza says that Laureate is getting a lot of interest from “virtual” companies who would never consider building a facility – and therefore must rely on the experience and expertise of a company like Laureate.
“I think with biosimilars you are going to see the same thing that happened with small molecule production – a lot of it will eventually go to CMOs,” says Cozza. “The biosimilars race is going to be very similar to the generics race.”
“I have a very optimistic view on biosimilars and biobetters," says Ultee. “In the clinical space – there are a lot people trying and they will come to CMOs like us to try out their product. I also think it will focus interest in good analytical capabilities – which we have added in the last few years – we have doubled the size of our analytical team. We have put a lot of focus on that in part because of the advent of biosimilars – and the related molecules – biobetters. I’m more interested biobetters because, like biosimilars, I think the indication for the drug is already known, but you just don’t have to make it match precisely to the innovator drug. There are therefore improvements you can introduce to provide for higher potency, longer half-life, etc. You can make improvements that maybe the innovator had also thought of but didn’t do because the drug in its present form was doing well.”
With a well-established reputation as being a leader in biopharmaceutical manufacturing, Laureate is looking towards the future with an eye on growth and to continue to supply the level of service and quality it has become known for in the industry.
Speaking to the company’s current and future capabilities, Cozza has this to offer, “We are a stand-alone CMO that can provide services across the entire CMC chain. You can come to us with a protein and we will help you file your IND or BLA with the material we generate and data we supply. The fill/finish and regulatory services we provide sets us apart. A lot of CMOs have some of the same things – we all have process development and tanks of various sizes – but what we’ve done, including investments in our analytical capabilities, quality systems and our facility, enable our scientists to stay on the leading edge of new and challenging products. This keeps us unique.”
“I see us as being one of the top tier CMOs in five years due to our investments and growth. Our leadership has pushed the envelope toward growth and has made a lot changes and innovations,” says Ultee.
At the end of the day, what really matters to companies looking for a CMO is if they can get the job done - at Laureate it’s an everyday occurrence.
“I believe our science sets us apart,” says Ultee. “We have a reputation for tackling difficult proteins.”
“Clients come to us with big challenges,” concludes Cozza, “and we help them succeed.”
Laureate Biopharma's Range of Services & Capabilities
• Unbiased assessment, recommendation and consultation of applicable mammalian expression systems, including: GS, DHFR, UCOE, S/MAR, Freedom™ CHO and BI-HEX
• Design and synthesis of optimized cDNAs, cloning into the vector and confirmation of its expression competency via transient transfection or mini-pool cultures
• Rapid provision of antibody or protein materials via transfectant pool-based production
Cell Line Development
Laureate utilizes high throughput screens via an automated liquid handler (TECAN) to identify and isolate rare high producers with desired activity levels.
• Use of bioreactor cultures for selection of lead clones in conjunction with bioactivity analyses
• Host cell experience includes: CHO DG44, CHOk1 and variants, CHO-M, CHO-S, NS0, Hybridoma, PER.C6, SP2/0, BHK and HEK293
• Clients have the opportunity to select clones based on product comparability parameters
Cell Line Optimization
• Advanced immunoassays to determine the potential of existing cell lines to achieve higher productivities
• Selection of higher-producing clones from existing lines using rational-design schemes, including increased selection with single-cell sub-cloning
Laureate’s upstream processing scientists develop robust processes for mammalian-cell production of monoclonal antibodies and other recombinant proteins
• Cell line development
• Medium and bioreactor process development
• Scale-up and technical transfer
• Mammalian production cells, including GS SYSTEM ,TM dhfr, sure system,TM UCOE , BI -HEX and Per.C6,® and different types of cell lines, including various CHO cells, NSO , SP 2/0, BHK , Hybridoma and HEK 293
• Process validation and characterization
• Platform and custom processes available
• Scale-up from process development to CGMP at the 200-L, 250-L, 1,000-L and 2,000-L scales
• Data Historian collection of critical run parameters
• Overnight automated calling for process alarms and on-site monitoring by trained facilities mechanics
• Daily interaction and cooperation between process development and clinical supply teams
• Extensive experience and excellent success rate with stainless steel and disposable bioreactors
• Extensive experience with all chromatography column models, resins and diameters in addition to various packing techniques such as flow packing, axial compression and pack-in-place
• Accommodates scale-up to 2,000L from development or direct manufacture of a tech transfer process
• Experienced in membrane chromatography using disposable ion-exchange filters
• Experienced in virus-reduction filtration using materials and equipment from all major suppliers to the biopharma industry
• On-site production of buffers used in pilot and CGMP runs using QA-approved raw materials which includes validation of buffers
• Platform processes
• Quality-by-design approach ensures process quality, robustness and cost savings
Analytical and Formulation Development
Laureate offers comprehensive services for protein characterization and formulation of biologics as a stand-alone service.
• Analytical method development and qualification
• Analytical method validation in accordance with ICH guidelines
• Protein structure elucidation and Post-Translational
• Modification (PTM) characterization
• Pre-formulation and formulation for therapeutic protein
• Stability testing
• Extensive analytical method development with antibodies, enzymes, cytokines and protein conjugates
• Chromatography: Affinity, lEX, SEC, HIC, RP-HPLC, peptide mapping
• Electrophoresis: SDS-PAGE densitometry and IEF
• Potency: Binding ELISA, enzymatic activity assays, cell-based potency assay
• Impurity and contaminants: Residual Protein A, HCP, residual DNA (qPCR)
• Quantitation: Protein A/G HPLC, ELISA titer assay, A280nm
• Protein conformation characterization using Differential Scanning Calorimeter (DSC)
• Molecular weight determination by mass spectrometry
• Sequence coverage and terminal sequencing by LC-MS-MS
• Amino acid analysis
• Capillary electrophoresis (CE-SDS, cIEF)
• Glycan profiling by fluorescence-labeling and normal phase HPLC
• Sialic acid content and NANA/NAGA ratio measurement
• Design of Experiment (DOE) for method development, method validation and pre-formulation screening
• High-throughput immunoassay with robotic liquid handling system
• High-throughput CE-SDS and glycan profiling with microfluidic instrument
Supply Chain Capabilities
• Supply-side security with long-term relationships with multiple vendors of specialty biopharmaceutical materials, equipment and instrumentation
• Management of 1,400 SKUs of material/inventory
• Ample cold storage and shipment of temperature controlled materials
• 2° to 8° C
• –20° C
• –70° C
• Ample warehousing, including on-site process warehouse
• Long-term storage available
• Alarmed liquid-nitrogen freezers for storage of cell lines
• Full emergency electrical power back-up for all critical equipment and instrumentation
Fill/Finish SuiteVial Filling
• Equipment can fill 1, 2 or 4 vials at a time; all product contact parts are single disposable
• Low line loss and shear process
• Filling and stoppering of liquid into glass or plastic vials
• Capability to fill using ready-to-use components
• No 483 observations in 2010, 2011 and 2012
Glass Wash, Equipment & Component Preparation
• Vials are washed using a Metromatic Vial Washer and depyrogenated using a Gruenberg Depyrogenation Oven
• Filling equipment and stoppers are sterilized using a Getinge Autoclave (steam)
• Autoclave and Depyrogenation Oven are requalified annually
• All stoppers used are ready-to-use or ready-to-sterilize and come with bioburden, endotoxin and particulate specifications – no washing or packaging required
• 100% manual inspection of filled vials by qualified filling personnel
• Inspection is paced and uses white and black background with fluorescent overhead lighting
• Quality Control (QC) Testing performs line opening and closing, AQL inspection after 100% inspection is complete and sampling of release, stability and retain samples per Filled Product Specification after AQL inspection is complete
• All personnel (Filling & QC Testing) are re-qualified on an annual basis with vision screening test and test set of vials with known defects
• Formulation of liquids up to 200L volume, greater volumes available upon request
• Single-use disposable formulation and mixing vessels
• HPLC assays: SEC, RP-HPLC, IEX-HPLC, HIC-HPLC, WCX-HPLC, Protein A-HPLC
• Horizontal IEF
• Potency assays: Binding ELISA, Enzymatic activity assay
• Host cell protein (HCP) assay
• Residual DNA testing by qPCR
• Compendial methods (USP/EP)
• Standard wet chemistry assays and A280
• Radio chemical testing
• Method transfer and method validation
• Robust environmental monitoring program: viable air and non-viable particulate, surface RODAC, swab, settling plate, humidity, air velocity and temperature monitoring
• Utility sampling: Water (Clean Steam, WFI, and DI) and Process gasses
• Endotoxin: Kinetic Turbidimetric and Chromogenic, and Gel Clot
• Bioburden testing
• Growth promotion
• QC of media, Vitek cards, reagents, etc.
• Microbial identification (VITEK 2)
• Mold identification