Production product devices for control and regulation of technological processes
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Cell culture processes for monoclonal antibody production
Animal cell culture technology has advanced significantly over the last few decades and is now generally considered a reliable, robust and relatively mature technology.
A range of biotherapeutics are currently synthesized using cell culture methods in large scale manufacturing facilities that produce products for both commercial use and clinical studies.
The robust implementation of this technology requires optimization of a number of variables, including 1 cell lines capable of synthesizing the required molecules at high productivities that ensure low operating cost; 2 culture media and bioreactor culture conditions that achieve both the requisite productivity and meet product quality specifications; 3 appropriate on-line and off-line sensors capable of providing information that enhances process control; and 4 good understanding of culture performance at different scales to ensure smooth scale-up.
Successful implementation also requires appropriate strategies for process development, scale-up and process characterization and validation that enable robust operation and ensure compliance with current regulations. This review provides an overview of the state-of-the art technology in key aspects of cell culture, e. We also summarize the current thinking on appropriate process development strategies and process advances that might affect process development.
With the increasing number of protein therapeutic candidates, especially monoclonal antibodies mAbs entering various stages of development, biopharmaceutical companies are increasingly looking at innovative solutions to deliver this pipeline. For antibody manufacturing process development, maintaining desired quality attributes while reducing time to market, maintaining cost effectiveness, and providing manufacturing flexibility are key issues in today's competitive market, where several companies are often working on therapies for similar targets and clinical indications.
Since antibody therapies may require large doses over a long period of time, manufacturing capacity becomes an issue because the drug substance must be produced in large quantities with cost and time efficiency to meet clinical requirements and pave the way toward commercialization. In response to the strong demand, many companies have built large scale manufacturing plants containing multiple 10, L or larger cell culture bioreactors. In terms of manufacturability and scalability, mammalian cells have historically been considered difficult to work with due to factors such as low yield, medium complexity, serum requirement, and shear sensitivity, although the latter has generally been incorrectly overemphasized.
The enhancement of specific productivity per cell is achieved not only by selection of highly productive clones, but also by optimization of medium composition and bioreactor operation conditions. Today, the combination of high titers and large capacity has gradually shifted the focus of cell culture process development from pursing even higher titers to controlling product quality and process consistency at all development stages and production scales.
Cell culture process development starts with cell line generation and selection, followed by process and media optimization in small scale systems, including well plates, shaker flasks, and bench-scale bioreactors, for high throughput screening purposes. Once conditions are defined, the process is often transferred to a pilot scale to test scalability and produce material for preclinical toxicology studies, and then larger scale manufacturing for production of clinical material under current good manufacturing practices cGMP regulations.
Once development of a commercial cell culture process for production of a biological product is completed at the laboratory and pilot scales, the commercialization process begins with process characterization, scale-up, technology transfer, and validation of the manufacturing process. As cell culture technology is maturing, the biopharmaceutical industry has applied platform processes to satisfy material demand and quality requirements within a short period of time.
The cell culture platform often consists of common host cell, expression vector, transfection and selection methods during cell line generation, and standard cell culture media, process control and scale up methodologies during process optimization. This approach not only enables fast process development, but also provides predictable performances in scale up, facility fit and downstream process integration.
Therapeutic antibodies are mainly produced in mammalian host cell lines including NS0 murine myeloma cells, PER. Murine NS0 cells are non-immunoglobulin secreting myeloma cells that are cholesterol auxotrophs requiring the presence of cholesterol in culture medium for growth; 9 however, cholesterol-independent NS0 cells also have been established.
This sialic acid form was initially believed to present a potential immunogenicity concern in humans. Although NS0 cells have been used in industry to produce therapeutic antibodies, these potential immunogenicity aspects have likely limited use of these cells for therapeutic antibody production. Cells are derived from human embryonic retina cells that have been immortalized by transfecting the E1 genes from adenovirus 5 DNA.
CHO cells are the predominant host used to produce therapeutic proteins. The process for development of a stable cell line starts with expression vector construction and transfection.
After being transfected with plasmids bearing the antibody light and heavy chain genes, as well as selectable marker or markers, cells are screened for high productivity following growth recovery, serum-free suspension adaptation and amplification if necessary and clone selection. The screening and selection of a highly productive and stable clone from the transfectant population in a limited time frame is a major challenge.
Mammalian expression vectors typically contain one cassette for antibody genes and selectable marker gene s for expression in mammalian cells, and a second cassette for the genes enabling plasmid replication in bacteria. Commonly used polyadenylation signal sequences are the SV40 late or early polyadenylation signal sequences and the bovine growth hormone polyadenylation sequence.
In addition to transcription, translation and secretion are also required for antibody production. A variety of transfection methods have been developed to stably introduce vector DNA into mammalian cells, including calcium phosphate, electroporation, cationic lipid-based lipofection, and polymer or dendrimer-based methods.
Transfected cells are then selected, relying on different selectable markers that can be categorized into two groups; metabolic selectable markers and antibiotic selectable markers. Some commonly used selectable markers are listed in Table 1.
CHO stable cell lines have often been selected using metabolic selective markers including methotrexate MTX dihydrofolate reductase gene mediated and methionine sulphoximine MSX glutamine synthetase gene mediated. It has also been reported that an antibody-producing cell line can be generated using two different selectable markers together.
The unique feature of this approach is that each plasmid contains both the heavy chain and light chain genes, and one selective marker. The productivity of clones generated using this approach was higher than that of clones transfected with either plasmid alone, as shown in our well productivity assay Fig. To our knowledge, this is the first time that simultaneous transfection with two expression constructs and selection with two different selective markers has been successfully demonstrated as a means to generate highly productive stable CHO cell lines expressing antibody.
For each case, 72 clones were screened. To generate stable cell lines with adequate productivity for clinical or commercial material production, hundreds to thousands of clones may be screened.
The primary screen is usually an ELISA assay with or without cell number normalization, to eliminate non- or low producers. While high producers are scaled up, additional assays are performed to measure cell growth, cell specific productivity, and volumetric productivity titer in order to choose the top 12—24 clone candidates, which are typically further analyzed in a fed-batch cell culture scale-down models such as shake flasks or laboratory scale bioreactors.
Product quality attributes such as glycosylation profile, charge variants, aggregate levels, protein sequence heterogeneity, as well as cell culture characteristics including growth, specific productivity, volumetric productivity, and clone stability, are assessed to enable selection of the top 4—6 clones for further evaluation in bioreactors, after which the final production clone and backup clone are chosen.
A significant amount of work has been done to genetically engineer production host cells to improve or modify the product quality or improve the host cell robustness. Glycosylation control has received a lot of attention because glycan structures on antibodies can have substantial effects on clearance rate and bioactivities.
RNAi and gene deletion technologies have also been used to decrease or eliminate the fucose on antibodies to dramatically increase ADCC activity. Other areas of host cell engineering include approaches to decrease programmed cell death, reduce lactate accumulation, and manipulate cell growth. Overexpression of anti-apoptotic gene or genes and RNAi-technology mediated knock-down expression of apoptotic gene or genes have been used to extend the culture viability that leads to improved productivity.
A significant amount of work 30 — 32 has been performed to reduce lactate accumulation; however, the usefulness of this approach may be very clone dependent. Another area of research has focused on the use of inducible expression systems in mammalian cells.
This strategy has the advantage of decoupling cell growth from product formation. Growth arrest in NS0 cultures via the inducible expression of p21 was reported to result in a significant increase in cell specific productivity. Coroadinha et al. Fukushige and Sauer 36 demonstrated the use of a lox recombination vector to obtain stable transformants with predictable gene expression profiles. The positive selection vector system was designed to directly select Cre-mediated DNA integration at a lox target using an inactive lox-neo fusion gene previously placed into the genome of cultured cells.
This technique ought to allow the rapid and efficient exchange of a single copy of the transgene of interest with no change in expression levels. Overall, these methods should result in greater efficiencies in cell line screening for high producers and a further reduction in development timelines. Several alternative expression systems such as Pichia pastoris and Escherichia coli have recently emerged as promising hosts for mAb secretion.
This study demonstrated a fold increase in binding affinity, as well as enhanced ADCC activity with the glycan-engineered proteins compared with Rituximab. Controlling the glycan composition and structure of IgGs thus appears to be a promising method for improving the efficacy of therapeutic mAbs that utilize ADCC for biological activity.
Coupled with the use of well-established P. The technology described offers a rapid and potentially inexpensive method for the production of full-length aglycosylated therapeutic antibodies that do not have ADCC functionality. Mazor et al.
The full-length secreted heavy and light chains assembled into aglycosylated IgGs that were captured by an Fc-binding protein located on the inner membrane. Flow cytometry was used after permeabilization of the membrane and attachment of the antibody to a fluorescent antigen. Aspergillus niger has also been used for the production of mAbs or antibody fragments; Ward et al.
In addition, the use of cell-free protein synthesis for recombinant protein production is emerging as an important technology. Goerke and Swartz 43 recently demonstrated the utility of the technology using E. Due to the high degree of uncertainty associated with clinical studies, process development for biopharmaceuticals is often divided into an early and late stage, with each having different emphasis Fig. The goal of early stage development is to rapidly develop bioprocesses to produce materials for Phase 1 or 2 clinical trials and animal toxicology studies.
In order to accelerate filing of an investigational new drug IND application for proof-of-concept clinical studies, it is becoming increasingly necessary for companies to deliver their pipelines efficiently by utilizing streamlined cell culture platform processes that include standardized process conditions and procedures.
Use of a platform process allows acceleration of early stage cell culture process development activities, e. The similarity of molecular characteristics and properties among different mAbs makes the platform approach feasible, although the processes may not be fully optimized for every molecule.
Clinical and process development flowchart. As the product moves into late stage development, i. Late stage process development is focused on improvements of process yield, robustness, scalability and regulatory compliance. Optimization of the process is an integrated activity involving clone selection, medium development, and bioreactor condition optimization, which is followed by scale-up to an appropriate manufacturing facility. Product quality and comparability needs to be closely monitored when process changes occur during both early and late stage development to ensure patient safety.
To gain regulatory approval for commercialization, processes also need to be characterized to evaluate the effects of process parameters on process performance and product quality; the process should also be validated to demonstrate process consistency before commercial cGMP production. Selection of the final production clone is generally considered to be one of the most critical decisions in both early and late stage cell culture process development.
Since changes in production cell lines during clinical development are considered major process changes, product comparability must be demonstrated if the cell line is changed during late stage development. Changing the cell line after Phase 3 clinical study typically requires additional human clinical studies. It is thus important to select the right clone prior to Phase 3 production of drug substance, and preferably at the Phase 1 stage.
After being transfected, cells are diluted and cultivated in well plates with a basal growth medium and screened for robust cell growth and high productivity. At this stage, in order to predict clone performance in large-scale production bioreactors, an enriched medium that is similar to the final production medium formulation and a similar feeding regime can be tested in shake flasks or in small-scale bioreactors.
Several clone attributes should be considered and evaluated for features such as product quality, manufacturability, and volumetric productivity. Maintaining consistent and comparable product quality is a challenge if changes to cell line, media or other process changes are made as product candidates move forward from small-scale development lab to pilot plant scale, and eventually to commercial scale cGMP manufacturing. Some common analytical assays and quality assessment criteria employed during clone selection to test mAb molecular properties are summarized in Table 3.
Process yield is another critical criterion used to select the production clone. Since antibody expression rate in mammalian cells is usually non-growth associated, the final titer is equal to specific productivity Qp multiplied by the integral of viable cell density over culture duration, i. Cell line stability is another factor that should be considered since volumetric and specific productivity decline as cell age increases for some cell lines.
Such unstable clones are not suitable for large-scale production since cell age increases with scale as the cell culture process is scaled up through serial culture passages of the seed train and inoculum train. In addition to cell line stability, growth and metabolite characteristics that can affect process robustness and scalability also need to be assessed. Robust cell growth with high viability and low lactate synthesis is usually desirable.
High lactate producing clones are not preferred in order to avoid the dramatic osmolality increase that accompanies the addition of base needed to maintain pH. Screening and selection of highly productive and scalable clones among the transfectant population in a limited time frame is still a major challenge because the product quality, productivity and even cell metabolic profiles are often dependent on cell culture conditions. Using miniaturized high throughput bioreactors with full process parameter controllability to mimic the large-scale bioreactor environment could help to identify the best production clone at a very early stage.
In general, medium development for a fed-batch process involves batch medium and feed concentrate development, as well as feeding strategy optimization.
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ISO specifies requirements for a quality management system where an organization needs to demonstrate its ability to provide medical devices and related services that consistently meet customer and applicable regulatory requirements. Such organizations can be involved in one or more stages of the life-cycle, including design and development, production, storage and distribution, installation, or servicing of a medical device and design and development or provision of associated activities e. ISO can also be used by suppliers or external parties that provide product, including quality management system-related services to such organizations. Requirements of ISO are applicable to organizations regardless of their size and regardless of their type except where explicitly stated. Wherever requirements are specified as applying to medical devices, the requirements apply equally to associated services as supplied by the organization.
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Back in , I started my career as a medical device product development engineer. At that time the FDA Design Controls regulations were still fairly new -- not only to me -- but the industry in general. ISO and corresponding design and development requirements for medical device industry were also very new to the industry in the late 90s. In those days, we all struggled to understand how and what to do with respect to Design Controls.
Note: If the process chosen is sterilization, evaluate the process according to the "Sterilization Process Controls" chapter of this handbook. Note: Control and monitoring procedures may include in-process and or finished device acceptance activities as well as environmental and contamination control measures. Note: If the process chosen is Sterilization, evaluate the process according to the "Sterilization Process Controls" chapter of this handbook. In order to meet the Production and Process Control requirements of the Quality System Regulation, the firm must understand when deviations from device specifications could occur as a result of the manufacturing process or environment. Discuss with the Management Representative or designee the firm's system for determining whether deviations from device specifications could occur as a result of the manufacturing process or environment. The firm may accomplish this requirement via Product and Process Risk Analyses.
An effective quality system takes a total systems approach to satisfy safety, effectiveness, and performance requirements. Quality should be considered at all stages of production, starting at the earliest stages of product design. To ensure that finished devices will be safe and effective, current Good Manufacturing Practice cGMP requirements govern the facilities and controls used for the design, manufacture, packaging, labeling, storage, installation, and servicing of all medical devices. Vinny Sastri, President of Winovia LLC, who highlighted some of the key elements of effective production and process controls. We present some excerpts below.
This section of the HPRA website includes information for the medical devices industry. Explanatory information and relevant HPRA guides and forms are provided as appropriate under each topic as well as links to relevant external sources. The HPRA encourages communication with the medical device sector.
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Automatic process control in continuous production processes is a combination of control engineering and chemical engineering disciplines that uses industrial control systems to achieve a production level of consistency, economy and safety which could not be achieved purely by human manual control. It is implemented widely in industries such as oil refining, pulp and paper manufacturing, chemical processing and power generating plants. There is a wide range of size, type and complexity, but it enables a small number of operators to manage complex processes to a high degree of consistency.
Animal cell culture technology has advanced significantly over the last few decades and is now generally considered a reliable, robust and relatively mature technology. A range of biotherapeutics are currently synthesized using cell culture methods in large scale manufacturing facilities that produce products for both commercial use and clinical studies. The robust implementation of this technology requires optimization of a number of variables, including 1 cell lines capable of synthesizing the required molecules at high productivities that ensure low operating cost; 2 culture media and bioreactor culture conditions that achieve both the requisite productivity and meet product quality specifications; 3 appropriate on-line and off-line sensors capable of providing information that enhances process control; and 4 good understanding of culture performance at different scales to ensure smooth scale-up. Successful implementation also requires appropriate strategies for process development, scale-up and process characterization and validation that enable robust operation and ensure compliance with current regulations. This review provides an overview of the state-of-the art technology in key aspects of cell culture, e.
Safety and quality are non-negotiables in the medical devices industry. Increasingly, organizations in the industry are expected to demonstrate their quality management processes and ensure best practice in everything they do. It has recently been revised, with the new version published in March ISO A medical device is a product, such as an instrument, machine, implant or in vitro reagent, that is intended for use in the diagnosis, prevention and treatment of diseases or other medical conditions. ISO is designed to be used by organizations involved in the design, production, installation and servicing of medical devices and related services. It can also be used by internal and external parties, such as certification bodies, to help them with their auditing processes.
From pedometers to applications that manage cardiovascular risks and monitor diabetes, there has been a boom in e-health applications in recent years. Between and the estimated number increased from , to ,, and the market is expected to triple by Digitization is being used by pharmaceutical companies and in the field of life sciences to help find a balance between patient centricity and performance. These innovations make it possible to develop patient-centered medical products and services, and are bringing about a change in prevailing business models.