Manufacturers of biological products have come to accept that it makes sense, from both a business as well as a regulatory perspective, to address GMP compliance issues with bioprocessing methods as early as possible in product development. Logically, this same reasoning would also apply to the associated analytical methods used to characterize the product; however, companies still frequently leave methods optimization and validation until later in the developmental timeline which can expose them to unexpected regulatory challenges. In addition, as therapeutics increase in complexity (e.g., cell therapies, transgenics), it raises the likelihood that product characterization will be assessed by novel and increasingly intricate assays—making it difficult to follow a “one size fits all” approach to method selection, development and validation…
Tag: <span>GMP</span>
One of the major concerns facing relatively young biotechnology companies once a lead product has been identified is the issue of manufacturing. Usually this involves the upscaling of a lab-scale process while at the same time, complying with good manufacturing practice (GMP) to ensure a reproducibly-produced and consistent product. It also involves the establishment of specific and robust assays in process controls and release criteria. This issue has become more acute in the EU since 2004 due to the EU Clinical Trials Directive requiring GMP-certified production of investigational medical products even for phase I trials. Startup biotech companies are often limited in their finances and resources, as well as being bound by tight milestones. Quite often the expertise in upscaling and GMP-compliant production as well as the facilities and equipment required are not available in-house…
Key questions for any company planning to build a new facility include processes to be followed for effective design, commissioning, and qualification. Pilot plants need to be flexible, but as flexibility increases, so does complexity and cost. The scope of the new clinical trial pilot plant for bioprocess operations at Eli Lilly and Company (K360) was based on specific technology platforms and extensive benchmarking. Global regulatory issues had to be considered in the design as well because the material it produces will be used worldwide. The K360 plant has the capability to produce mammalian, bacterial, and yeast-based protein and peptide products following typical processes for growth in bioreactors. The protein or peptide of interest is recovered following fermentation and then purified in the facility. The plant’s output is bulk active pharmaceutical ingredient (API)…
Recombinant DNA-transduced cellular products encounter the product development and regulatory issues of both gene therapy and cellular therapy products. The characterization of recombinant DNA-transduced cellular products remains highly challenging for both sponsors and regulatory agencies. The regulatory concerns and product testing for such cellular products are similar to those for all biologicals. These concerns include the demonstration of product safety, identity, purity, and potency; the control of the manufacturing process to ensure the consistency of product manufacturing under a proper quality control program; and the demonstration of reproducibility and consistency of product lots by means of defined product lot release testing criteria…
In today’s aggressive biopharmaceutical market, many drug discovery organizations, including both big pharmaceutical companies and small technology start-up companies, are outsourcing the development and manufacturing of their biopharmaceuticals to specialized contract manufacturing organizations (CMOs). Outsourced biopharmaceuticals range from those in early phase production to products that are well advanced down the development pipeline. As a result, there has been an expansion of CMOs that specialize in all aspects of biopharmaceutical manufacture, from process invention and development, through small-scale GMP production, to process validation and large-scale manufacture. The CMOs provide R&D services, quality function, and state-of-the-art good manufacturing practice (GMP) facilities needed for the production of biopharmaceutics. Using CMOs for biopharmaceutical process development and manufacture provides major cost savings by dispensing with the need to invest in experienced personnel and expensive manufacturing facilities…
Baculovirus infection of insect cells is an established method to obtain large quantities of biologically active recombinant proteins with properties similar to those of proteins expressed in mammalian cells. Insect cells are capable of most mammalian posttranslational modifications that control protein compartmentalization, secretion, targeting to nucleus or cell surface, N- and O-glycosylation, phosphorylation, proteolytic processing, and assembly of multi-protein complexes. The baculovirus transfer plasmids and accessory products utilized for protein expression in insect cells are currently available from several commercial sources. The plasmids often contain his-tags to facilitate Ni-NTA purification of recombinant proteins, and/or signal peptides to promote or enhance secretion of the proteins into the medium. Typically, in most baculovirus cloning vectors the coding region of the polyhedrin gene has been replaced by a polylinker with multiple cloning sites for the insertion of the cDNA of interest downstream of the strong polyhedrin promoter…
As pharmaceutical and biopharmaceutical companies become more global in nature with products that have the potential to reach into the worldwide marketplace, a special understanding is needed of the requirements that are specific to varying geographical areas. Specifically, the regions for worldwide pharmaceutical distribution can be broken into America, Europe, and Asia-Pacific, with each region presenting its own regulation and technical challenges. There are many issues that are common among these regions, but each region’s focus may be different. Typically, an issue arises in one region and then migrates to another as people become aware of the issues and concerns. For example, the use of prefilled syringe systems in Europe and Asia has migrated to the American marketplace, amounting to a more significant volume…
Of the available on-line biomass assays, the radio-frequency (RF) impedance method has a clear advantage for current good manufacturing process (cGMP) because it is an unambiguous reflection of viable cell bio-volume rather than the total number of cells. Although other more approximate methods are available for cells in suspension, RF impedance is practically the only on-line method available for cells in suspension, attached to microcarriers and immobilized cells at high cell densities. Data are presented to show how live cell concentrations are derived from an RF impedance-derived instrument…
The Dale and Betty Bumpers Vaccine Research Center (VRC) at the National Institutes of Health (NIH) was established to facilitate research in vaccine development. The VRC is dedicated to improving global human health through the rigorous pursuit of effective vaccines for human diseases. It was established by former president Bill Clinton as part of an initiative to help develop an AIDS vaccine and is part of the NIAID organization. Since the inception of the VRC, its mission has expanded to include the development of vaccines against bioterrorism and emerging infectious diseases…
One of the fundamental foundations of bioprocess system design is the use of “closed” systems for production. Closed systems and equipment are utilized to prevent contamination of the product. They are also used as a means of containment to protect not only the product, but also workers and the facility environment. The concept of a closed processing system makes common sense. What is surprising is how closed systems are defined and referenced within the body of regulatory guidance documents and how companies differ in their implementation of a “closed manufacturing” concept. What is not surprising is the impact that closed systems have on facility design…