The Chemistry, Manufacturing, and Controls (CMC) Strategy Forum held on 22 January 2012 in San Francisco, CA, focused on selected scientific and regulatory aspects in the development of biosimilar products. Such products are an increasingly important area of interest for both the biopharmaceutical industry and its regulatory agencies. Biosimilars are highly complex, so scientists have been unable to demonstrate identity to a level typically possible for small molecules. Consequently, specific scientific and regulatory approaches are required to ensure the high degree of similarity sufficient to reflect the safety and efficacy of reference products.
The purposes of this forum were to highlight scientific and regulatory challenges for developing and assessing biosimilar products and to discuss industry opportunities. Presentations included case studies of experiences gained with the first biosimilar products (e.g., in Europe and Canada), examples addressing recent efforts in developing biosimilar monoclonal...
+2Whether cell-based or molecular biology focused, most assays performed in biopharmaceutical laboratories involve liquid solutions. Increasingly, automated liquid handlers (laboratory robotics) are demonstrating utility in these labs, especially for high-throughput screening and optimization of cell culture media, chromatography conditions, formulations, and so on. Some experts say that screening 100,000 samples/day will soon become routine. But the robots haven’t condemned all manual pipettes to the trash heap — far from it.
With multichannel and electronic pipettes improving throughput and reproducibility of results, many companies don’t have to purchase expensive automated systems. From small-scale “automated pipetting technologies” to testing services such as Alphalyse that can perform assays you (or they) design, many alternatives are available.
Meanwhile, laboratory automation is putting robotics and software to work at expediting and increasing the efficiency and effectiveness of large laboratories....
Implementation of postlicensure process improvements in the biopharmaceutical industry can benefit patients and drug manufacturers alike. Here we demonstrate through a case study how a change to the cell culture medium and process can be taken from proof of concept through scale-up to demonstration of feasibility. We further illustrate the scope and complexity of implementing a change in commercial manufacturing to realize significant benefits such as increased production capacity over an existing legacy process.
The Importance of Postapproval Improvements
Drug development is a complex process, and related business drivers typically shift through a drug’s life cycle. Before market licensure, the emphasis is on ensuring product safety and efficacy during clinical trials in addition to speed to market (Figure 1). The need to lock a process in as soon as possible limits opportunities for optimization. As a consequence, process optimization and capacity improvements are often postlaunch activities performed w...
+1 Manufacturers of biopharmaceuticals using mammalian cell culture must have processes in place to minimize the likelihood of virus contamination of their products. Regulatory agencies provide guidelines for testing strategies and best practices to assure raw-material safety and control of the manufacturing process. Safety assurance relies on an interdependent matrix of managed risks, including characterization and control of raw materials, extensive testing of process intermediates, and demonstration of the virus removal capabilities of purification unit operations
A dedicated component in most downstream processes is the small-virus filter used to reduce levels of parvovirus and larger viruses from a process stream by size exclusion (
1
). In recent years, expectations for levels of parvovirus removal by small-virus filters have increased, both as a consequence of improvements in performance of those filters as well as from an industry expectation for better viral clearance levels across individual unit o...
+4 Food and Drug Administration (FDA) and European good manufacturing practices (GMPs) require integrity testing of sterilizing-grade filters for producing injectables and other biologics. The diffusion test (also called the
forward-flow test
) and bubble-point test (also called the
disk test
) of a sterilizing-grade filter are both filter-integrity tests. The accuracy of both relies on calibration of a pressure sensor in the respective integrity test unit.
Calibration of the pressure sensor of a filter-integrity testing device is an essential part of quality assurance in lot release. If yearly calibration reveals a pressure reading offset outside specifications, then a common conclusion is that the accuracy of all integrity test results from the past year must be questioned. Generally, for a maximum allowable offset of 9 mbar, for example, all test results since the previous calibration are considered reliable if the yearly calibration shows an offset of ≤9 mbar. If the yearly calibration shows an offset ...
Increasing demand for monoclonal antibodies (MAbs) — useful as immunodiagnostic reagents in basic research applications and potential immunotherapeutics — has created a need to optimize protein production techniques. Many developers have attempted to increase MAb output from cell culture by addressing both equipment and consumables. For example, recent advances in improved bioreactor designs and bioreactor operation have increased antibody outputs by increasing cell densities and extending cell life in culture.
Bioreactors can operate in batch, perfusion, and continuous modes. The modified “fed-batch” process was developed based on feeding cultures with a growth-limiting nutrient substrate to improve their longevity and cell health. The fed-batch strategy is typically used in bioindustrial processes to achieve high cell densities in bioreactors and extend the production phase of cultures. This process has been implemented for many cell types including hybridomas and Chinese hamster ovary (CHO) cell cultur...
+1 On 27 January 2012, the US Centers for Medicare and Medicaid Services (CMS) published a much-anticipated proposed average manufacturer price (AMP) rule for implementing related prescription drug provisions of the Patient Protection and Affordable Care Act (PPACA). The new rule will create serious financial, administrative, and operational challenges for the life-sciences industry.
Nearly two years later, the final rule has not been issued. Without official direction, we can look back at the proposed rule’s purpose and recommendations for manufacturers based on that. It aims to lower costs for states and taxpayers by
Manufacturers should focus on some major items included in the rule that will fundamentally change the way they do business. First, it would include US territories in the AMP calculations. Rebate agreements would include prescriptions paid by Medicaid and fee-for-service. That would require Medicaid managed-care plans to capture use data and provide those data to the states, exempting only pre...
