While many risk analysis methods describe how execution or performance risks originate and propagate through pharmaceutical and biopharmaceutical manufacturing processes and systems, few provide methods for efficiently estimating the uncertainty of an execution risk’s occurrence. This article describes prospective causal risk modeling (PCRM) for estimating the risk’s uncertainty of failures associated with executing processes, particularly when little process performance information or data is available. Building upon a basic unit of risk, the process-based system risk structure (SRS) approach is combined with PCRM to provide a method of carrying out quality risk management (QRM) exercises that properly assess both the severity and uncertainty of process execution risks. After the risks are structured using an SRS, PCRM provides a straightforward and effective method for using subjective human judgement and thought experiments to evaluate the risk process’s causal mechanisms for analyzing, evaluating, and controlling the uncertainty, including its likelihood of occurrence, of significant risks associated with developing and manufacturing pharmaceuticals. Using an SRS/PCRM-based QRM exercise, a wide variety of process execution risks can be efficiently evaluated and accepted or rejected so that important risks requiring mitigation can be identified for additional evaluation, control, and eventual acceptance.
Category: <span>Risk Analysis and Management</span>
It is a common belief that fetal bovine serum (FBS) collected from certain geographical regions, such as New Zealand, is of superior quality to material collected from South America. Whilst it is true that origin does have an impact on the price of serum, it does not affect the quality or biological performance of the product. FBS collected under similar conditions from any geographical region will demonstrate comparable ability to support cell growth. For FBS, the term “quality” is frequently confused with “health status.” It is the health status of the geographical region from which the serum is collected that will dictate its potential use, the availability of material for import, and eventually, the price. It should be noted that health status should be considered a result of more than just the geographical source of the material, but also the regulatory infrastructure and how well regulations are enforced by the countries within that region…
This is the sixth and last in a series of articles describing and demystifying the processes involved in the gamma irradiation of serum. This serum treatment is intended to mitigate the risk of introducing adventitious contaminants into cell cultures. In this article, we discuss the regulatory environment under which gamma irradiation of serum is performed, and provide additional details on best practices for documentation of the irradiation process, selection of the contract irradiator, evaluation of risk versus benefit needed to arrive at the radiation dose range to be used, as well as an understanding of the level of remaining risk following irradiation at that dose range. Gamma irradiation should not be viewed as a means of totally eliminating risk, but rather as a means of reducing the risk of introducing adventitious agents into cell cultures. A balance must be achieved between the desire to eliminate all adventitious contaminants, and the need to retain the desired performance characteristics of the serum, once irradiated…
Gamma irradiation is a well-established process for reducing or eliminating the bacterial and viral load in medical devices, biologics, and other products such as animal sera. This process can lead to alterations in both the materials being treated and the product containers in use. High-energy radiation produces ionization and excitation in materials, generating energy-rich ions which undergo dissociation, abstraction, and additional reactions in a sequence that may lead to chemical alterations. The resulting chemical stabilization process, which occurs during, immediately following, and occasionally days after irradiation, often leads to physical and chemical cross-linking or chain scission. The physical changes to materials can include embrittlement, discoloration, odor generation, stiffening, softening, and enhancement or changes in chemical structure. This paper discusses how and why irradiated polymeric materials, including those of biological origin, may change their structure and effectiveness during and after exposure to gamma irradiation, and the potential impact of these changes on serum during irradiation…
Medicago manufactures influenza vaccine virus-like particles (VLPs) in an unusual production platform consisting of Nicotiana benthamiana plants. During the in vitro adventitious agent test (AAT) of certain Medicago B strain influenza vaccine VLP test samples, positive hemagglutination of guinea pig red blood cells was observed on day 14, but not on day 28. The positive result in the assay was surprising because the production process uses no animal-derived raw materials and contains a viral inactivation step. Plant-associated viruses would not be expected to infect the mammalian cell-based assay. No cytopathic effects or hemadsorption of red blood cells was observed in these AATs. The positive hemagglutination was observed at 2–8°C, but not at 36–38 °C, and only in a few of the six detector cell lines used in the assay. Because this is quite an unusual pattern of responses for an AAT, Medicago and the contract testing lab, Eurofins Lancaster Laboratories (ELLI) investigated the positive responses thoroughly for the presence of an adventitious agent or an alternative explanation not involving a viral contaminant. Investigation results indicated that the hemagglutinating activity associated with the vaccine test sample itself was responsible for the positive hemagglutination response. The positive hemagglutination on day 14 of these AATs was deemed an assay artifact, and preventive actions were taken to prevent recurrence of this type of false positive response…
Achieving very high levels of pharmaceutical product quality, particularly for the next generation of biologics, will require proactive use of a broad range of quality and process development tools throughout the therapeutic’s development and manufacturing lifecycle. These tools are most effective when integrated using an expanded form of FDA’s 2011 process validation guidelines. This article explains how process validation can be combined with quality by design (QbD), ICH Q8 design space (DS) and control strategies (CS), process analytical technology (PAT), and quality risk management (QRM) tools to provide a path to manufacturing very high-quality products. The approach establishes clear goals and then proactively builds appropriate control systems during process development to assure continuous control and verification of all manufacturing activities. Prospectively using the tools over the complete manufacturing lifecycle, from preclinical through commercial manufacturing, is particularly important to assure comparability from early product research and development all the way to commercialization. The continued evolution of these quality tools, as well as building new tools, will provide a path for the pharmaceutical industry to reach and maintain Six Sigma levels of product quality…
Biopharmaceutical manufacturing process risks can be described as a network of processes that may include some combination of unit operations, equipment, instruments, control systems, procedures, and personnel practices. The system’s risks can be modelled by a system risk structure (SRS) that describes how threats originate and flow through the network to result in negative consequences (risks). The SRS is a quality risk management (QRM) tool a team of subject matter experts can use to prospectively identify and evaluate a wide variety of risks over the product’s entire development and manufacturing lifecycle. Based on the understanding developed from an SRS analysis, control strategies can be developed by modifying or adding new processes to mitigate the threats, thus reducing the likelihood of the risk consequence being realized. The SRS tool extends the ICH Q9 QRM approach described in a series of articles. Two examples are used to demonstrate how an SRS can be assembled and then used to prospectively identify, understand, and reduce significant risks by controlling the source and flow of threats within the systems described…