Regulatory Challenges in the QbD Paradigm - The authors demonstrate how an integrated model is helping to achieve regulatory flexibility. This article is part of a special section on biopharmaceutical


Regulatory Challenges in the QbD Paradigm
The authors demonstrate how an integrated model is helping to achieve regulatory flexibility. This article is part of a special section on biopharmaceutical trends.

BioPharm International
Volume 25, Issue 9, pp. 44-53


QbD cannot exist without an effective quality system that oversees and manages process variability and product quality through appropriate control strategies, documentation, data trending and analysis, risk assessment, and continuous review. It is a living system that incorporates gained knowledge and historical experience to effect updates and changes whenever and wherever necessary. From the regulatory side, FDA develops the expertise to understand and assess QbD elements. Decisions are made based on science and risk to patient safety and are documented under the umbrella of an effective quality system. Knowledge is managed effectively to serve as reference in the future. Precedents and regulatory decisions are recorded and managed. Data and trends are collected and analyzed to identify any patterns or trends for specific categories of products or similar products even after drug approval. Metrics are developed to understand the impact of regulatory decisions. Under the QbD paradigm, the success or failure of a marketed pharmaceutical product is assessed to incorporate lessons learned into future reviews of drug applications.

An integrated model of review and inspection for approval of a regulatory drug application serves as the platform for achieving the desired state. This model is especially evident in FDA's Center for Drug Evaluation and Research (CDER) as used for therapeutic biological products, such as proteins and monoclonal antibodies. These products were transferred from the Center for Biologics Evaluation and Research to CDER in 2003 and are rather complex, because they are produced from living organisms that are variable and not as easily controlled (13). Review and inspection responsibilities are shared between the Office of Pharmaceutical Science/Office of Biotechnology Products (OBP) and the Office of Compliance/Office of Manufacturing and Product Quality/Biotech Manufacturing Assessment Branch (BMAB). As described in FDA's MAPP 4730.3, issued in 2009, a team approach is followed for review of drug applications and conduct of prelicense/preapproval facility inspections (14). This approach enables integration of the two functions, review and inspection, as well as a more thorough and efficient assessment of firms' process understanding and quality oversight. Both offices share regulatory oversight and cGMP implementation of CMC standards as described in the biologics license application (BLA) and supplements. Both offices assess standards, inspect manufacturing facilities, and observe operations while the subject product is being manufactured as stated in 21 CFR parts 600 and 601. The same team of individuals performs review and inspection. This approach is complementary and helps to ensure that a thorough evaluation is performed for the issuance of a biologics license and marketing approval of a biologic therapeutic drug.

The prelicense or preapproval inspection verifies the application of cGMP, execution of commitments, and data presented in the application. OBP leads the overall assessment for product quality as described in the application and approves the manufacturing process and final specifications. On inspection, OBP assesses product-specific elements, verifies data and conformance to commitments in the BLA or supplement. BMAB provides a microbiology quality assessment of drug substance and drug product sections of the applications, including microbiological specifications. BMAB leads the inspection team. Additional BMAB responsibilities on inspection include the evaluation of the cGMP compliance status of a firm and conformance with commitments in the BLA or supplement.

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