October 2, 2018 PAP-Q3-18-CL-012
Contract development and manufacturing organizations (CDMOs) face intense scrutiny as outside vendors involved in drug development and manufacturing. They must provide a very high level of confidence in the analytical data they generate to both their pharma customers and regulatory agencies.
CDMOs must also transfer in fit-for-purpose analytical methods for use during manufacturing processes, which can be quite challenging if there is a lack of historical knowledge available from their clients. This poses greater issues for projects in which the client has already filed an application with the regulatory agency and optimization of methods is no longer possible.
The rapid growth of industry understanding of diseases and disease mechanisms has led to the development of increasingly complex drug substances that require associated advances in testing; validation of these methods has become more challenging. Keeping abreast of advances in medicinal chemistry — as well as separation and detection technologies — requires a great deal of analytical experience and expertise, along with continuing education.
Regulatory requirements also evolve as more understanding is achieved. For instance, new requirements for the detection of elemental impurities (USP 232/233) became effective in January 2018. There have also been updates to ICH Q3C regulations on residual solvent exposure limits and ICH Q3BR2 on drug product impurities. As new requirements are implemented to eliminate gaps, many pharma companies find themselves receiving complete response letters from the FDA owing to deficiencies in their filings relevant to these new requirements, forcing them and their outsourcing partners to revise and revalidate their existing analytical methods.
CDMOs must have a comprehensive process in place to track new regulatory changes and ensure ongoing compliance. Investing additional time and effort to maintain experienced staff and continually develop state-of-the-art, validated analytical methods ensures that customers have confidence in their regulatory filings
The key to success for CDMOs and their clients is accelerating development and commercialization to reduce time to market. Analytical teams must remain up-to-date on new technologies, techniques and regulatory requirements, while taking into account business considerations and phase-appropriate methods.
Analytical development is a cost center and thus must be continually evaluated in order to maintain cost control. To accomplish this, lean operation is essential, with client collaboration paramount to success. Transparent and close communication between the CDMO and the client when transferring methods is crucial for efficient and timely project implementation. It is also critical to apply previous experience to the identification and prevention of potential problems, along with excellence in troubleshooting, to rapidly resolve any issues that may arise.
An understanding of how methods evolve to ensure phase-appropriateness as drug manufacturing processes are developed is equally important. As the product and process are refined, the analytical requirements become more specific. At the beginning of a project, a CDMO often has only vague product quality specifications to guide method development. Knowing which additional tests are needed to gain process knowledge and build the larger data set needed to allow the development of robust methods increases project efficiency and minimizes cost.
People with the right talents and experience are central to the effectiveness of a QC group. Since taking our roles at UPM, we have focused on recruiting and hiring the right people to address those needs.
All members of our AD team have considerable experience in analytical development, and many have also worked in pharmaceutical development and manufacturing. Significantly, many of our staff have extensive experience from a business as well as a technical perspective. As a result of this dynamic background, they have a well-rounded understanding of how the QC department should operate and how business should be conducted with UPM’s clients.
The constantly shifting nature of the pharmaceutical industry requires continuous education to ensure that all QC team members are briefed on the latest advances in analytical technologies and translational medicine. To ensure that we are continuously improving, we have implemented a partnering strategy and are working with external experts to increase our internal knowledge base and expertise.
Instrument manufacturers and other vendors are providing basic as well as intermediate-level training on important aspects of chemistry and analytical method development and troubleshooting related to specific techniques, such as high-performance liquid chromatography. We are also providing training to increase our internal expertise in metrology.
In addition to partnering with external entities to enhance our scientific expertise, UPM is providing opportunities for our analytical scientists to improve their business acumen. We want our QC team to go beyond being technical experts by becoming well-rounded subject matter experts who understand the business impacts of their activities, so we can provide our clients with comprehensive support.
We are also pursuing another approach to continuous improvement through the development of a formal process for performance and professional goals management. This process is wide-reaching but tailored to the needs of each individual with respect to performance and professional growth. With a standard process for driving continuous improvement in our employees that includes measurable investment, UPM is demonstrating its commitment to making our employees more valuable members of the company. Doing so benefits the employees, the company and our customers.
An internal training program was successfully implemented to help our analytical experts think and work together as an effective and cohesive team that can drive business success and make certain that the QC staff at UPM have the capabilities necessary to exceed client needs. Established internal training programs have found ways to help employees improve their time management skills with the goal of increasing the efficiency of operations in the QC department.
Investment in advancing the capabilities of our scientists can only be truly leveraged if they have access to advanced equipment and instrumentation. UPM continually invests in new equipment and tools that will expand our analytical capabilities. Recent examples include an inductively coupled plasma mass spectrometer (ICP-MS) for elemental impurity analysis as required by the aforementioned new regulations. With this addition, UPM is able to perform these analyses in-house rather than outsourcing them, which streamlines the service we provide to clients and reduces concerns about negative impacts on time and cost.
We are also leveraging other tools designed to minimize the need to outsource analytical work, such as Malvern particle size analyzers and a thermogravimetric analysis–differential scanning calorimeter (TGA-DSC).
All of these investments enable UPM to better characterize drug products and meet regulatory requirements using robust methods. Historical analytical techniques generally take only a limited number of product impurities into account. In anticipation of growing requirements for impurity analysis, we are revisiting our existing analytical methods and making them not only more robust but capable of identifying unknown impurities.
UPM is also establishing internal programs for routine monitoring of equipment and processes to reduce equipment downtime and increase the efficiency of maintenance efforts. Across the board, our goals are to achieve right-the-first-time data delivery with a high level of confidence and to reduce any chances for lost production time.
In the past, many companies did not place much emphasis on validation of USP methods. These methods were typically taken at face value; because they were pre-validated, they were assumed to be effective. At UPM, however, we have observed significant complexity in many USP methods that leads to ambiguity. Consequently, we are in the process of verifying and validating these complex USP methods to ensure that we have the necessary in-house capability and knowledge to provide robust analyses with a high degree of accuracy and reproducibility. Doing so will provide more confidence in the data we generate and the likelihood that client regulatory filings will be successful.
The ultimate target for all changes taking place within UPM’s QC group is to enhance the organization’s agility and flexibility while increasing the trust both our clients and the regulatory authorities have in our analytical work. For instance, a new analytical method protocol template with a streamlined format is speeding up the method development process. Our forward-thinking, quality-by-design (QbD) approach allows us to identify and close gaps before they become issues, thereby mitigating risks early on. By providing a range of analytical services needed throughout the project life cycle from development to filing and commercialization, we can increase efficiency while reducing cost.
Overall, we are developing robust systems and building the highest possible level of expertise that, when combined with our greater agility and flexibility, allows us to rapidly meet the specific needs of each of our clients and ensure the greatest likelihood of success.
Daniel Dixon joined UPM in November 2017, taking the position of Vice President of Quality Control. His charter is to bring in processes and programs that will enhance the robustness of the quality control group. With 21 years of experience in quality assurance, quality engineering, process improvement, manufacturing, R&D, process scale-up and process/software validation for drugs and medical devices, Daniel is ideally suited to oversee UPM’s Analytical Testing & Development groups and the Microbiological & Raw Material Testing Labs. He brings a unique set of skills and insight that will enable him to continue the drive for excellence and leading performance in the analytical organization at UPM.