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14 BioPharm International ® Partnerships for Outsourcing eBook May 2024 www.biopharminternational.com Quality have the right quality structure and staffing. Start by requesting the CDMO's organization chart for quality personnel. If the organization chart shows the quality team reporting to manufacturing, that's a problem. The quality team must be independent, free from potential influence from business concerns. Then, looking beyond the reporting structure, ensure that quality personnel do not wear too many hats; the same staff should not be involved in manufacturing, reviewing quality control (QC) test data, and then approving QC test results. Next, ask, "What percentage of your team consists of quality personnel?" The organization must have suffi- cient quality staffing, based on the facility capacity and the number of active projects. Even well-trained staff, if stretched too thin, will make mistakes, and worse, could be tempted to cut corners. Then inquire about the background of the quality team. Note the names of personnel in key roles during a plant visit, then ask later to see their resumes. FDA regulations state that quality staff must have the edu- cation, training, and experience, or combination of the three, to perform the assigned functions (2). While ed- ucation and training are important, nothing replaces years of experience. Diverse experience also makes for a strong quality team. Have the quality staff worked only in CDMOs, or in sponsor companies as well? With experience at spon- sor companies, they will better understand the concerns of their clients. Has the head of quality assurance (QA) worked only in QA, or did she start on the manufactur- ing floor or in the QC laboratory? With hands-on expe- rience performing the tasks involved in quality, a super- visor is better prepared to oversee those activities and to know where errors are most likely to occur. If your company is a start-up, ensure the CDMO's quality staff has experience manufacturing clinical trial materials. A quality team with only commercial experience can overburden an early phase manufac- turing process with good manufacturing practice (GMP) expectations that are not necessary until later in development. They should have experience applying phase-appropriate GMPs. Ask about quality management systems A CDMO should be happy to share information about its quality management systems (QMS) and its procedures for corrective and preventive actions (CAPA). Ask for a list of non-conformances for the past two years. With a strong QMS in place, managed with advanced soft- ware, they should be able to provide this list in a matter of minutes; a long delay is a red flag. Ask about the inves- tigations into deviations, including how they addressed them. Records showing repetition of the same error in- dicate that they never identified the root cause. Ask how often they perform internal quality audits, and who is involved. The answers will give a good indication of the management's commitment to quality, and the CDMO's overall culture of continuous improvement. Request a list of standard operating procedures (SOPs). Then ask how those documents are developed, including who is involved, and how often procedures are reviewed. Request that a staff member on the manufac- turing floor or in the laboratory guide you through a pro- cedure while you observe, SOP in hand. Observe if the operator skips any steps and inquire about the reasons. The response might be that those steps are redundant; if so, investigate the validity of this claim. If the steps are indeed unnecessary, query why the SOP has not been revised to reflect that. Ask about vendor qualification Another critical aspect of quality systems is vendor qualification. Just as a pharmaceutical company is re- sponsible for the quality produced by its CDMO, a CDMO is responsible for the quality of products and services it receives from its vendors (3,4). Start by asking how the organization vets suppliers. Ask the CDMO team to share their active materials list and their vendor qualification list, with status. Then ask how they perform vendor audits. In general, pharmaceutical manufacturers can fol- low a risk-based approach to managing supplier quality, applying greater scrutiny to the suppliers of the most critical ingredients, components, or services. As part of that process, supplier audits may be per- formed on-site or remotely, depending on not only the criticality of the product or service but also on the phase of development and regional requirements. Eu- ropean Union regulations require on-site audits for critical vendors, even for early phases of drug develop- ment (5–8). FDA regulations are less specific, leaving it up to the manufacturer to perform sufficient auditing according to risk assessments, including decisions on conducting on-site audits. In any case, whether in the United States or Europe, the CDMO should conduct on-site audits of its most critical suppliers, such as those that supply starting materials (i.e., APIs and excipients). If the CDMO out- sources any laboratory testing, the analytical testing provider is also a critical supplier, and must be audited on-site. Additionally, pharmaceutical manufacturers must monitor supplier performance on a regular basis, through periodic audits. Diverse experience also makes for a strong quality team.