In August, U.S. Senator Michael Bennet (D-CO) introduced the Drug Safety and Accountability Act of 2010. This bill is designed to improve regulatory oversight of drug manufacturing facilities and improve related quality standards and monitoring.
With increased government scrutiny, it is not a coincidence that quality is the top-ranked criteria for CMO selection, according to findings from HighTech Business Decisions’ “Biopharmaceutical Contract Manufacturing Report: Expanding Markets, New Capacities and Improved Performance” for which directors from 48 pharmaceutical and biotechnology companies and 29 biopharmaceutical CMOs were interviewed.
Biopharmaceutical contract manufacturers continue to dedicate resources to improve quality and efficiency to meet the increasing demands from their clients and regulatory organizations.
As a result of strict regulatory oversight, once a standard operating procedure is validated and yields drugs acceptable to the FDA or EMEA, companies are reluctant to make any process changes or incorporate innovations. In response to this situation, the FDA issued a draft guidance document, PAT—a Framework for Innovation Pharmaceutical Manufacturing and Quality Assurance. FDA hopes that this guidance will help pharmaceutical manufacturers design, develop, and implement efficient tools for use during product manufacture and quality assurance.
Many companies have followed the PAT guidelines and designed innovative quality improvements into their processes. For example, Boehringer Ingelheim (BI) developed the BI-Purification Excellence (BI-PurEx) strategy to shorten development time while improving process understanding during early development phases.
The strategy is designed around preferred process steps and takes advantage of a set of highly sensitive analytical tools and automated screening technologies to efficiently develop each unit operation in a downstream process.
According to Barbara Esch, director of global marketing and business development coordination, BI-PurEx has resulted in a “more lean development process to reduce timelines in early development. In addition, through the integration of analytical assays and RAPPTor® high-throughput screening, process knowledge is gained throughout process development to maintain a critical focus on future market supply.”
Also following PAT guidelines, RecipharmCobra Biologics recently implemented new analytical approaches for monoclonal antibody development. RecipharmCobra successfully developed high-throughput platform methods for residual host cell protein, DNA, antibody titer, and antigen binding for early potency determination based on the Gyros™ system.
“These platform analytical methods are qualified so that they can be used upon verification under product-specific conditions for GMP release and for the stability testing of drug substances and drug products for early clinical trials,” explained Christel Fenge, GM. “This has allowed RecipharmCobra to reduce effort and time lines for analytical development early on in projects. One of the benefits for the customer is obviously the reduced cost of development associated with bespoke analytical methods and lengthy manual procedures.”
RecipharmCobra also has experience with PAT applied to QbD (quality by design), fostered by its history in product development. This expertise is of particular interest to biotechs, which RecipharmCobra actively supports in the appropriate design of product characterization studies to meet the requirements of the relevant clinical phase. “We consider this to be a competitive advantage and differentiator to other CMOs as we are able to offer a one-stop solution, from the gene of interest to GMP drug product accompanied by a comprehensive documentation and testing package,” Fenge noted.
The Merck BioManufacturing Network, which is composed of two Merck business units—Diosynth Biotechnology and MSD Biologics—builds in QbD in biologics development and manufacture by way of high level of process understanding.
As Stephen Taylor, commercial director of MSD Biologics, explained, “during process development and laboratory process characterization (LPC) studies, the aim is to acquire a good understanding of each unit operation and define operating windows, to ensure acceptable and consistent product quality.
“If a high degree of process understanding is gained, and the process is consistently operated within the defined windows, then theoretically there should be less need to incorporate PAT.” According to Taylor, this approach brings operational and delivery benefits to clients by enabling a relatively high throughput of different products.
PAT is also being used in process development and selected manufacturing campaigns at Merck. “During a typical fermentation, critical quality parameters such as pH, temperature, CO2 evolution, O2 uptake rate, and respiratory quotient are monitored in real time using probes and in-line mass spec analysis,” Taylor commented. PAT has been implemented during downstream processing, though to a lesser extent “where real-time monitoring has been used to determine when process steps have progressed to an optimal level,” he added.
CMC Icos Biologics has integrated analytical characterization of the protein produced during the clonal selection phase of cell-line development with its CHEF-1® expression platform, focusing on selection of clones producing the highest quality product in addition to selecting for productivity and viability.
Jenifer L. Wheat, vp of business development, said that “ensuring choice of a clone expressing protein that matches the specifically desired analytical profile is critical for second-generation processes and biosimilar development. Monoclonality is also assured through imaging of colony outgrowth with Genetix’ CloneSelect, providing higher confidence levels in clonality than traditional limiting dilution cloning.”
Meridian Life Science is actively evaluating and implementing PAT initiatives. Design control, environmental monitoring, process yield improvements, CAPA streamlining, risk management, and process mapping are a few of the initiatives being implemented.
“These processes are helping Meridian increase our competitiveness and fully meet the needs of our customers in domestic and international markets,” commented Alan Rich, director of regulatory affairs and QA/QC. “They are allowing Meridian to shorten lead times for new product releases, reduce costs, minimize headcount, improve quality, and reduce scrap.”