This paper places the “Quality by Design” (QbD) in an overall context and provides the following straightforward definition so that QbD can be effectively used to solve a wide variety of important problems:
Quality by Design–During the design stage, to achieve a well-defined goal, iteratively apply science and engineering methods to anticipate, identify, understand, resolve, and control problems that will be encountered during testing, operating, and verifying the goal over its lifecycle.
The viewpoint of the paper is to view QbD as “Success by Design.” The definition is based on answering the following question: What will be required to provide assurance that the enabler developed during the design stage will successfully reach the goal over the entire lifecycle before leaving the design stage? The paper argues that QbD should not be implemented as a program, but used as a tool. To provide understanding, the paper explores underlying concepts, the history of QbD, develops a working definition, and then applies it to biopharmaceutical development and manufacturing…
Category: <span>Biologics Production</span>
As the institutionalized collection, storage, and distribution of bio-samples becomes more commonplace, the attention and adherence to strict and systematic sample handling practices is paramount. An important component of such efforts is the maintenance of bio-samples in a safe and controllable state (e.g., –80°C storage) apart from any downstream processes the samples could be subjected to in the future. CryoXtract Instruments’ CXT 750 Frozen Aliquotter provides repeated and reproducible access to a variety of frozen bio-fluid samples by maintaining samples at –80°C, thus eliminating undesirable freeze-thaw cycles during sample handling processes. The following study was performed by the Cincinnati Biobank Core Facility and the Center for Autoimmune Genomics and Etiology (CAGE) at Cincinnati Children’s Hospital Medical Center, in order to assess the feasibility of frozen aliquotting in conjunction with DNA extraction services provided by the Cincinnati Biobank. The Cincinnati Biobank planned and independently executed the experiment while CryoXtract’s role was to provide technical guidance running the CXT 750. Both groups participated in preparation of the manuscript…
Low sialic acid erythropoietin (Neuro-EPO) is a nonerythropoietic molecule that shows neuroprotective activity in some rodent models for brain ischemia. One reason for poor absorption may be the rapid removal of the drug from the site of absorption by mucociliary clearance. For that reason, bioadhesive polymers are used to increase the residence time of the drug in the nasal cavity. The objective of the current study was to evaluate different bioadhesive polymers to identify Neuro-EPO formulations with characteristics suitable for nasal delivery. For this purpose, four different polymers: (1) hydroxypropyl methylcellulose (HPMC) F4M; (2) HPMC K4M; (3) Carbopol 974P; and (4) dextran 70 were assessed to define the appropriate concentration. The physicochemical evaluation of placebo formulations showed reductions in apparent viscosity, except with dextran 70. With dextran 70, the bioadhesive polymers interacted with other excipients such as buffers, isotonic agents, and antimicrobial preservatives. The decrease of apparent viscosity was observed significantly in the formulation with Carbopol 974P, which also showed the presence of instability. Formulations with Neuro-EPO and HPMC showed adequate physicochemical properties with the pH, isotonicity, and concentrations of protein by reverse-phase (RP) high-pressure liquid chromatography (HPLC), as expected. However, the formulation with dextran 70 showed chemical incompatibility, as evidenced by the reduction of protein concentration and purity. In the permanent unilateral ischemia model, a higher survival percentage was observed with formulations of HPMC F4M and HPMC K4M, evidenced by the analysis of neurology parameters. Both formulations were significantly different from their vehicle…
The global demand for new biologics and vaccines, combined with the growing emergence of biosimiliars, is challenging drugmakers to re-evaluate their processes and seek ways to make them more flexible, reliable, and cost-effective. Increasingly, manufacturers are turning to closed, single-use processing systems to meet aggressive campaign turnaround times, reduce risks, and control costs. Innovative single-use technologies provide biopharmaceutical manufacturers greater flexibility for replacing traditional stainless piping, valves, equipment, or even entire process suites with polymer-based solutions. The benefits of converting to pre-sterilized, single-use systems have been documented in numerous articles and case studies, and these benefits would be lost if manufacturers could not safely and securely connect a variety of systems and components together to create a complete aseptic process. Connectology may appear to be a small part of an overall system design; however, connection and disconnection of tubing for process fluid transfer is a critical aspect of single-use processing. Manufacturers must carefully consider the available options because the right connector not only affects the operator’s convenience, but can be the deciding factor in maintaining process sterility and product quality…
In today’s volatile sera market, it is critical that sera users worldwide thoroughly review their supply relationships and update sourcing and risk mitigation strategies. BioProcessing Journal’s recent article by Siegel and Foster highlighted the impact of selecting the appropriate country of origin as one criterion for purchasing decisions. Many more vital selection criteria exist to ensure a sera supplier provides long-term assurance of supply and integrity of supply. This article identifies critical questions sera users should ask their suppliers and explains why they should ask them…
Therapeutic proteins manufactured in cellular systems contain residual DNA derived from host cell substrates used in production. Risk assessment of the residual host cell DNA is necessary, as some of these DNA sequences may be potentially infectious or oncogenic. Oncogenic potential lies in transmission of the activated oncogenes to subjects receiving the product, thereby inducing oncogenic events. Therefore, it becomes essential for drug manufacturers to show clearance of genomic DNA (oncogenic sequences as well) throughout production processes and to confirm low levels of residual DNA in the final drug substance. This study attempted to estimate the oncogenes in the total residual DNA using a highly sensitive, specific, and robust method—quantitative polymerase chain reaction (qPCR). Routinely, total residual DNA is estimated using either the 18S ribosomal (r)DNA gene or Alu equivalent multicopy gene sequence as qPCR targets. We have determined the copy numbers of these qPCR targets along with the oncogene (Ras gene) and housekeeping genes (ACTB and GAPDH) and established a ratio of their presence in protein samples. Another objective of the study was to estimate the level of oncogenes from several in-process step samples in the manufacturing and purification process and check the clearance of total residual DNA including oncogenes. Upon quantification, the proportions of oncogenes present were one tenth of the quantified residual DNA levels (Ras gene:18S RNA) in the purification stage samples, providing information that the therapeutic protein product was safe from the presence of oncogenes in residual DNA by a factor of ten…
Biobanking is a critical component to realizing the promises of translational research and personalized medicine. The proper collection, processing, storage, and tracking of human biological samples allows researchers to better link molecular and clinical information, which in theory, allows for the development of more targeted therapies for patients. Realizing the scientific potential of well-annotated, properly preserved sample collections has led to the proliferation of large-scale biobanks by biopharmaceutical companies, academic organizations, governments, and non-profit research organizations. To this point, conservative industry projections estimate that in the United States, there are at least 300 million tissue samples in biobanks with an estimated accrual rate of 20 million samples annually…
Batch processing has long been the predominant bioprocessing paradigm, both up- and downstream. Bioprocessing fluids are processed incrementally, piped as a bolus or transferred via vessels from one process and piece of equipment to the next. This continues to work well, including a number of technological advances resulting in improvements that continue to make bioprocessing more efficient. Upstream and overall process yields are essentially doubling about every five years, with this largely driven by improved cell lines, expression systems and genetic engineering, culture media, and equipment. Among the technologies now gaining increasing adoption and market share for biopharmaceutical manufacture is continuous (bio) processing, with perfusion currently the leading technology, in terms of adoption. The use of incremental, one-step-at-a-time, classic batch processing in biopharmaceutical manufacture is different than most other major products manufacturing and high-tech industries, where processing is generally more continuous. In this context, the move toward more continuous processing in manufacturing is a common characteristic of industries starting to reach maturity. Continuous processing is exemplified by assembly lines, and petroleum refining with processing involving a rather continuous flow of the material being manufactured from one unit operation to the next. Continuous processing generally follows and eventually replaces incremental manufacturing…
This article proposes a “design space” structure for using Quality by Design (QbD) to develop processes and control strategies for developing and manufacturing biopharmaceuticals…