Regulatory Challenges in the QbD Paradigm

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BioPharm International, BioPharm International-09-01-2012, Volume 25, Issue 9

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

With the dawn of the 21st century came the realization that changes must be made by both the pharmaceutical industry and regulatory authorities across the globe. These changes are necessitated by a plethora of issues that are faced by companies and the regulatory agencies alike. The number of blockbuster drugs launched each year has remained relatively constant at 6.5 per year (1). The nearly threefold increase in R&D spending over the past decade has resulted in an increase in the number of drug candidates entering Phase I trials. However, this increase has been almost completely neutralized by an increase in attrition, with the probability that a candidate entering Phase I will become a successful product decreasing from 10% in 2002 to 5% towards the end of the decade (1). This decline in success rate, along with the increasing scrutiny of healthcare costs in developed economies, has resulted in unrelenting pressure on the pharmaceutical companies to control drug-development costs.

Anurag S. Rathore, PhD

On the other hand, regulatory authorities are also grappling with the increasing complexity of pharmaceutical manufacturing. Most pharmaceutical products sold in the US are manufactured outside the US. Even for those drugs that are manufactured in the US, a significant portion of the raw materials and process intermediates is imported from manufacturers outside the US. It's no wonder that "Supply Chain Management," "Accountability in a Global Environment," "Foreign Inspections," and "International Compliance" were some of the key sessions at the 2011 PDA/ FDA Joint Regulatory Conference. Implementation of quality by design (QbD) in this environment has further contributed to the need to clarify what information needs to be included in a regulatory filing and how it should be presented. FDA has addressed this gap to some extent through its ongoing QbD pilot program, but more guidance is needed from the regulatory authorities to ensure widespread successful implementation of QbD (2).

Overall, the regulatory authorities must make changes to address the drug safety dangers that the global environment poses as well as make changes to the drug review and approval processes to encourage regulatory and pharmaceutical innovation and faster product availability to patients. Regulators also must offer more flexibility regarding manufacturing changes and application supplements based on science and risk assessment, so that limited resources on both the industry and regulatory sides will be available for drug development and innovation.

In this 28th article in the Elements of Biopharmaceutical Production series, the authors focus on the regulatory challenges that arise in the QbD paradigm, in particular on how review and inspection practices have been and are evolving.


In 2002, FDA launched Pharmaceutical CGMP for the 21st Century–A Risk-Based Approach, an initiative to encourage the adoption of modern and innovative manufacturing technologies (3). Another aspect of the initiative was to ensure that "the product review and the inspection program operate in a coordinated and synergistic manner." The desired state was defined as "a maximally efficient, agile, flexible pharmaceutical manufacturing sector that reliably produces high quality drug products without extensive regulatory oversight." FDA and the pharmaceutical industry are spending considerable efforts to understand how to achieve this incredible feat and to identify the necessary elements required. This section discusses some of these elements.

The desired state must be defined first in more detail. The roles of manufacturers and regulatory authorities must also be defined. Under this paradigm, manufacturers have extensive knowledge about product, process, and quality attributes and strive for continuous improvement to reach the desired end point of consistent, safe and effective, pure and potent, drug products. They share this knowledge with FDA. The agency develops the expertise to evaluate products and processes using a science- and risk-based approach through the review of submitted data in applications and performance of prelicense and preapproval facility inspections. Subsequent, postapproval changes do not need the submission of supplements if these changes are to happen within the design space of critical process parameters as established and approved in the original application. Surveillance inspections are conducted periodically using a risk-based approach to verify the changes. The desired state includes the potential for less inspectional oversight for a facility or firm that has maintained an acceptable compliance status and has reached a state of quality excellence. Therefore, in addition to the expertise that application reviewers need to develop, field investigators also must develop expertise to address the demands of the new desired state. An integrated model of review and inspection should be in place to complement and coordinate the attainment of the desired state for new pharmaceutical products. New guidance documents and compliance program guidance may need to be created.

It appears that the new desired state can be achieved or at least approached with the adoption of two main elements by the pharmaceutical industry and by FDA: QbD and effective, agile quality systems with good quality risk-management principles.


QbD is not a new concept (4). It was introduced decades ago and adopted by the automobile and food industries to enhance process design and consistency by employing effective and measurable in-process controls with less reliance on end-product testing. The intent was to allow for corrections in real time for the manufacture of quality product with less variability and with the expected attributes. Furthermore, this principle led to Six Sigma processes and lean manufacturing concepts. QbD was introduced relatively recently in the pharmaceutical industry and embraced by FDA as a means to enhance the regulatory process.

QbD is defined in the International Conference on Harmonization (ICH) Q8 guideline as "a systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management" (5). The publication of FDA's guidance, PAT—A Framework for Innovative Pharmaceutical Manufacturing and Quality Assurance, initiated an effort that eventually evolved into QbD (6). The underlying principles of science- and risk-based process and product development and commercialization are also reflected in the contents of the quality guidelines ICH Q8 Pharmaceutical Development, ICH Q9 Quality Risk Management, and ICH Q10 Pharmaceutical Quality System as well as by the recently issued guidance on process validation from FDA (5, 7–9). The past five years have seen QbD gaining widespread adoption in the biopharmaceutical industry with several publications attempting to elucidate a path forward for its implementation and resolution of the various issues that serve as detriments to its success (10–12).

The key steps for QbD implementation include: identification of the product attributes that are of significant importance to the product's safety or efficacy (i.e., target product profile and critical quality attributes); design of the process to deliver these attributes; a robust control strategy to ensure consistent process performance; validation and filing of the process demonstrating the effectiveness of the control strategy; and finally, ongoing monitoring to ensure robust process performance over the lifecycle of the product (10, 11). Risk assessment and management, raw material management, use of statistical approaches and process analytical technology (PAT) provide a foundation to these activities.

There are many significant differences that contrast a QbD-based process and product development from traditional practices. In the traditional approach, the process defines the product, and as a result, the process needs to be performed within narrow operating ranges to get consistent product quality. In QbD, the product defines the process, so as long as the process stays within the defined design space, product quality is acceptable. Product specifications in the traditional approach are set based on process performance, and regulators expect them to be narrowed after enough process history has been established. On the other hand, in QbD, product specifications are set based on process and product knowledge and this allows them to be kept wider, resulting in greater operational flexibility. The regulatory filing in the traditional approach describes the process and presents data on product characterization. The focus is on presenting the status quo. In a QbD filing, the focus is instead on process and product knowledge. Data are presented to explain how the process affects the quality attributes (QA) of the product and how the QA affect the safety and efficacy of the product. Postapproval support through product lifecycle requires high maintenance in the traditional approach. The regulatory burden is high for process changes and, therefore, process improvements are few.


Many postapproval supplements are focused on alleviating repeat violations of the approved ranges and limits even though these violations do not necessarily affect product quality. Many postapproval supplements introduce new filling lines and manufacturing sites for similar processes. In a QbD paradigm, the regulatory burden is low because there are wider ranges and limits based on product and process understanding. Changes within these ranges and limits do not require prior approval. Resolution of nonconformances is faster because the required process knowledge already exists.


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.


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.


An overview of current FDA regulations and guidance is helpful to discover hidden opportunities and how they can be leveraged for the QbD paradigm for therapeutic protein products moving forward. The requirements regarding changes to an approved biologics license application are described in 21 CFR 601.12. With respect to product and process changes, the regulation states that each change in product, production process, quality controls, equipment, or facilities must be reported to the agency (16). This section also describes the need for conducting appropriate validation, including clinical and nonclinical studies to demonstrate that the change has no adverse effect on the identity, strength, quality, purity, or potency of the product. Reporting of the change must be in accordance with regulation or guidance that provides for less burdensome notification of the change. The changes requiring submission of supplements and approval prior to distribution of product made using the change (major changes), changes requiring supplement submission at least 30 days before distribution of product made using the change, and changes to be described in an annual report (minor changes) are provided in 21 CFR 601.12(b). The 1997 Guidance for Industry: Changes to an Approved Application for Specified Biotechnology and Specified Synthetic Biological Products provides additional guidance on the reporting categories (17). The comparability protocol described in 21 CFR 601.12(e) is used to demonstrate the lack of adverse effect on the safety and effectiveness of a product for specific types of manufacturing changes. A comparability protocol approach can be used to effect changes under a QbD paradigm with more regulatory flexibility. This approach has been used successfully for drug substance manufacturing site transfers when certain requirements were met.

Comparability protocols can be leveraged to effect many different manufacturing changes that include many products and manufacturing sites. They are not recommended for one-time changes as the protocol must be submitted as a preapproval supplement (PAS) and be followed by additional filings. Regulatory flexibility is achieved by submitting the same change approved in a comparability protocol for other products or facilities as changes being effected supplements (CBEs) or even as annual reports. Therefore, such protocols are a good regulatory strategy tool when a particular change affects multiple products. For example, if the container–closure system is modified for many products that use the same system, or if a stopper changes, then the comparability protocol offers a way to submit one PAS containing the studies to be performed, the acceptance criteria, and the quality risk-management concepts to be followed, especially regarding container-closure integrity aspects. Once the protocol is approved, the first product with the change can be introduced to the market through a PAS or CBE. Subsequent products can be introduced immediately and reported in annual reports. It is important to note that the submission strategy should be agreed upon between the firm and the FDA. Therefore, meetings are recommended when such strategies are followed. The comparability protocol offers advantages as the submission strategy for new in-process testing methods as well. For example, if a traditional method is replaced with a new more advanced and rapid microbiological method (i.e., polymerase chain reaction mycoplasma testing for cell culture instead of traditional microbiology methods) at many facilities and for many different products, a comparability protocol can serve as the platform to effect these changes without submitting a PAS for each product and facility.

The expanded change protocol (eCP) presents a tool that has been used successfully by some biotechnology product manufacturers to reduce postmarketing reporting requirements. A variation of the traditional comparability protocol, this protocol is gaining popularity, especially in its use for manufacturing site changes of drug substance. In this global environment, many biotechnology product manufacturers have multiple manufacturing sites and/or partnerships with CMOs. Their products are supplied to a global market. The need to propose changes to the manufacturing process and facilities in such a global market is expected during the product lifecycle as it offers increased network mobility. Associated with the need to implement changes in a timely manner and have greater flexibility in manufacturing is the need to review changes in an efficient manner and reduce the number of postmarketing submissions to the agency.

Traditionally, a comparability protocol is submitted to the agency to support the proposed changes. In July 2008, a notice was issued in the Federal Register seeking participation of pharmaceutical companies in a pilot program for the submission of quality (CMC) information in an eCP consistent with the principles of QbD and risk management in pharmaceutical manufacturing. This protocol can cover changes to manufacturing scale, changes across unit operations, changes to equipment, and/or manufacturing site transfers previously submitted as comparability protocols. The ICH Q5E guidance, Comparability of Biotechnological/Biological Products Subject to Changes in Their Manufacturing Process, applies to eCPs as well as traditional comparability protocols to demonstrate product comparability (18). Expanded change protocols describe the holistic QbD and risk-based approaches to demonstrate the lack of adverse effect on safety and efficacy of a product and focus on critical quality attributes. Such submissions allow for decreased filing requirements for postapproval changes.

The eCP approach leverages existing regulation as contained in 21 CFR 601.12(e) and current FDA initiatives. In addition, this approach leverages product and process knowledge to develop a design space and control strategy through the use of quality risk management. The potential applications of quality risk management in quality systems, regulatory operations, development, facility and equipment design, material management, production, laboratory control, stability, and packaging and labeling are described in ICH Q9 Quality Risk Management (7). The use of these principles allows for defining the scope of an eCP and presenting an appropriate quality risk management plan to prevent and mitigate sources of risk. For example, a manufacturing site transfer eCP could define the scope of the protocol based on the licensed product to be transferred, the approved process, and facility knowledge. When similarities between processes and equipment exist, the eCP elements are easier to define.

There are two primary cases where the eCP approach has been used successfully. First, is the multi-use eCP for introducing multiple products into multiple manufacturing sites covering the introduction of previously approved commercial products and new clinical products into licensed manufacturing facilities with an acceptable cGMP compliance status. The products can be produced from the same host or from different hosts but must be from well characterized cell lines (e.g., ICH Q5A) and not highly toxic or potent. The second case is the site transfer eCP and covers the introduction of an approved product into an additional licensed multiproduct facility. This eCP establishes a network of sites that provide the approved commercial product and those that receive the transferred product. In the site transfer eCP, there are additional considerations such as scale modifications, raw materials changes, and the use of disposable materials that may be different from the first manufacturing site. Cross-contamination considerations are more concerning for the multi-use eCP, while comparability considerations are crucial for the site transfer eCP. In any case, all eCPs must provide adequate quality risk management, and predefined requirements and acceptance criteria in enough detail to allow for subsequent reduced reporting requirements following eCP approval.

It is important to note that eCPs are recommended for already licensed products and manufacturing facilities. They are not indicated for nonapproved products and facilities. However, the manufacture of clinical material may be allowed as long as the cross-contamination risks are considered and included in the eCP. It is also important to make a distinction between drug substance and drug product manufacturing operations and facilities for biotechnology products, because each case would require the consideration of different risks. Although potentially both drug substance and drug product manufacturing site changes could be included in an eCP, the broader the scope, the more complex the elements of the eCP become. Another consideration is that firms wishing to follow the eCP approach are advised to request and hold meetings with the agency to discuss the proposed approach and risk management plan and agree on scope, strategy, and submission requirements. Although this can be time consuming at the beginning of this approach, the benefits can be reaped immediately once the eCP is approved. Additional products can subsequently be transferred without submitting prior approval supplements and waiting for FDA approval for market release. In addition, the preapproval facility inspection can be waived based on licensure and cGMP compliance status.

The eCP approach helps to identify the various risks across the subject manufacturing sites and to develop a quality risk management plan with site-dependent versus site-independent risks. Such a plan should be an integral part of the quality system and address risks from environmental, personnel, material, equipment, measurements, and methods. There are multiple considerations to be integrated into an eCP. The authors present some factors that are relevant to drug substance manufacture as examples.

Equipment and layout of a production facility should be reviewed to address multiproduct or multihost facility aspects for drug substance manufacturing operations, as risks will vary significantly. If containment is a concern, it should be appropriately addressed when introducing a product to another facility. Additionally, supplier and raw material concerns can impact the risk assessment considerably. The acceptability of risk by a firm may vary depending on whether it uses manufacturing sites within its network or contract manufacturing facilities. When contract facilities are used, a well-written and enforced quality agreement is cruical.

Embedded in the site transfer may be changes to the manufacturing process resulting from facility equipment and layout (i.e., fit) or continuous improvement considerations. These changes may affect controls for contamination or cross-contamination of product and should be assessed. When scale-up of the process is part of a site-transfer eCP, comparability process and criteria should be well defined, along with control parameters and strategy to ensure product quality and safety. Based on the risk assessment, existing validation studies may be used or new validation studies may need to be performed. As with traditional comparability protocols, the comparability of product based on test method and acceptance criteria and technology transfer aspects should be part of the eCP. As indicated in current guidance, change of the manufacturing site or addition of a new site to an approved application is reported as a prior approval supplement and triggers a facility inspection. The site transfer eCP can address compliance risks leading to a waiver for the inspection.

There are many opportunities today to leverage all available information relevant to compliance and cGMP requirements as regulatory agencies work on harmonized guidance and inspection cooperation (e.g., the Pharmaceutical Inspection Cooperation Scheme). Consistency in risk management and change control operations across sites and well defined thresholds for acceptable risks are helpful in understanding management of an eCP once approved. Following approval, other products can be introduced with more regulatory flexibility when the principles outlined in the approved eCP are followed.


The authors would like to thank Patricia Hughes and Kalavati Suvarna, both from FDA, for helpful discussions regarding this article.

ANASTASIA G. LOLAS (not pictured) is president of Visionary Pharma Consulting, Olney, MD, and ANURAG S. RATHORE, PHD*, is a consultant at Biotech CMC Issues and a member of the faculty in the department of chemical engineering at the Indian Institute of Technology. Rathore is also a member of BioPharm International's Editorial Advisory Board.

*To whom correspondence should be addressed,


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