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.
INSPECTIONS UNDER THE QBD PARADIGM
Traditionally, inspections have been conducted using the FDA systems-based approach and in accordance with CDER's Compliance Program 7356.002M "Inspection of Licensed Biological Therapeutic Drug Products" (15). However, questions arise as to the expected impact of QbD and recent initiatives on prelicense or preapproval inspections for therapeutic proteins. Other questions, such as how these inspections will differ from those of the past, what types of documents should the firms have available for inspection, and whether there are any other changes envisioned under the auspices of QbD will be examined in the following paragraphs.
During prelicense or preapproval inspections under a QbD paradigm, the FDA inspection team will evaluate the implementation and effectiveness of the process design as described in the application and whether knowledge and risk management have been transferred successfully from development to manufacturing. It will be crucial to have FDA involved early on in product development to establish consensus of critical elements. The inspection will evaluate the quality system and its effectiveness regarding consistent product quality, change control procedures, process improvements, deviation management, and knowledge and risk management during the product lifecycle.
The oversight of the quality system is crucial under a QbD paradigm for the release of consistent product and perhaps even real-time release. Change management is of the utmost importance to ensure that opportunities for process improvements are acted upon as process and product knowledge increases during the product lifecycle and as data are gathered and technological advances made. Under QbD, a firm should be able to make process improvement changes without being constrained by regulatory requirements as long as these changes are justified through quality risk management. The inspection team would review these changes that may not require the submission of supplements. Because the members of the inspection team are also the reviewers of the applications, they understand and know the product history to evaluate the risk of these changes.
Screening and testing of raw materials, such as cell banks, would receive more scrutiny on inspection, as frequently the starting materials define a process. Vendor qualification, supply chain oversight, and sampling and testing plans would be reviewed during the inspection. Variability of raw materials and change management would be assessed. Current emphasis is on excluding complex biologically derived raw materials whenever possible and/or treating materials for inactivation or limitation of adventitious agents. This trend is expected to continue. Such approaches are in agreement with a QbD paradigm where risks are eliminated or mitigated through process design.
With respect to microbial control, elements of a QbD-based inspection could be the evaluation of risk assessment and analysis for identification of in-process controls and the establishment of appropriate limits based on process capability for bioburden and endotoxin. In addition, investigators would review sampling and testing plans for in-process monitoring at crucial manufacturing steps in lieu of end-product monitoring, and evaluate process analytical technology and in-line or at-line sensors for early detection of microbial contamination. There is even the possibility of real-time release through the implementation of alternate and rapid microbiological methods and through the use of an effective microbial control strategy. A QbD inspection would evaluate the overall control strategy, including elements of facility and equipment qualification and maintenance as well as raw material screening and supplier management. Special emphasis would be placed on process design, testing, and monitoring programs that demonstrate robustness and consistency. Even though these control-strategy elements exist today, they would be optimized for best performance results and would be scrutinized more by investigators under the QbD paradigm. The inspection team would review documents that present and justify the control and optimization of such important aspects of product quality assurance.
The emphasis of inspection would be on in-process testing in lieu of end-product testing. Crucial steps of the process would be identified and appropriate sampling and testing plans implemented through the following:
• Development studies
• Risk assessments
• Process vulnerabilities to microbial contamination
• Microbial growth potential of product and other process solutions
• Impact of microbial contamination on process failure or variability
• Identification of open operations prone to contamination
• Studies to support extensive hold times, if needed, or limited hold steps where appropriate
• Lifetime use studies for purification media (i.e., resins and membranes)
• Validation and verification of cleaning processes, especially resins and filter membranes
• Use of microbial reduction filters at critical steps
• Effectiveness of process design for microbial control
• Validity of risk assessments and periodic evaluation and updates as knowledge increases.
Under a QbD paradigm, new manufacturing facilities will be designed for appropriate containment and segregation of operations, best practices for cleaning and disinfection, and appropriate level of environmental monitoring. Risk assessments for adventitious agent ingress, contamination, and cross-contamination would be reviewed on inspection. It is important to note that different considerations apply to single and multiproduct facilities, product changeover, new product introductions, open versus closed operations, and sanitization versus sterilization of equipment.
The inspection of the future will focus more on process and product consistency based on manufacturing history and data. The history of microbial or viral contamination would be reviewed along with any measures implemented to prevent and mitigate future occurrences. The disposition of possibly contaminated product and quality oversight will be assessed. Investigations and root cause determinations, corrective and preventive actions, and periodic review of risk assessments would be evaluated.
Furthermore, it is becoming more evident that inspections of manufacturing and testing sites of the future will rely more heavily on technology. More elements of the quality system continue to be managed through computerized systems. Investigators will need to know how to navigate through these systems and request appropriate documents for review as well as understand the integration of these systems for consistent process and product quality.