The Quality Product Steward Model: The Genentech Approach

ABSTRACT

The quality product steward (QPS) model, a single point of contact model, was created at Genentech to manage the quality of our clinical products. The purpose of the QPS is to provide quality oversight and a single and consistent quality approach for our CMC (chemistry, manufacturing, and control) teams. The QPS function enables efficient communication and decision-making related to the quality of our products to occur. The QPS performs many key quality tasks supporting GMP manufacturing, product testing and release, regulatory filings, and clinical supply. The QPS acquires product-quality knowledge and acts as the quality expert for the product-quality history throughout the development cycle. This model has been implemented in our clinical quality organization for more than three years and proven to be valuable to both project teams and the quality organization during clinical product development.

Since the first recombinant DNA product based on human growth hormone was successfully approved and launched in the mid-1980s, the biopharmaceutical industry has evolved tremendously. Significant advances have been made in manufacturing technologies and analytical and pharmaceutical sciences. Additionally, the global regulatory environment has been constantly evolving. In the last two decades, the compliance environment has grown ever more complex. The pharmaceutical industry is facing increased expectations; and delivering products that meet the global regulatory requirements is becoming more complicated and challenging. In today's drug development environment, research and development (R&D) is not the only critical player that can help a company gain a competitive edge. Other supporting functions such as a quality organization with agile and flexible business processes also contribute to the speed of the development timeline and quality of drug development as well.

(BIOCONVERGENCE)

At Genentech, we constantly improve our business processes to enhance efficiency and productivity in all chemistry, manufacturing, and control (CMC) functional areas.¹ This is especially important in light of our significant clinical pipeline, the diverse nature of our biopharmaceutical products such as monoclonal antibodies (MAb), MAb-drug conjugates, and drug-device combination products, and the number of global sites and outsourcing activities involved during clinical product development at Genentech. The fast-paced and dynamic environment prompted Genentech's clinical quality organization to reevaluate its business model around quality representation on the technical and manufacturing development team (TDT or project team). As a result, a new functional role, the quality product steward (QPS), was established in Genentech's clinical quality organization.

The QPS represents all of the quality functions on the project team to enable quick and effective decision-making and to ensure that the quality of a released product meets predefined quality requirements (i.e., specifications). In this article, we will describe the rationale for establishing the QPS role, our experience, and its success.

GMP QUALITY DURING DEVELOPMENT

Process (i.e., CMC) development is a critical function in pharmaceutical drug development. To manage the many diverse aspects of process development, a project team is formed that consists of representatives from several key functional areas including process development, analytical development, pharmaceutical development, manufacturing, quality, and regulatory affairs (Figure 1). At Genentech, the quality function includes several functional groups that focus on specific quality aspects such as raw materials, environmental monitoring, in-process testing, drug substance and drug product testing, viral and mycoplasma testing, quality systems (e.g., documentation, change control), and quality assurance. All of these functions contribute to the process development of clinical products. Their activities must align with the timeline and overall deliverables of the development goals. As Genentech's product pipeline grew and became more diverse, having a representative from each of the quality function groups on the project team became unrealistic and unfeasible.

Figure 1. A project team consists of representatives from several key functional areas

Creating a single quality representative, who provides effective and efficient quality feedback, ensures consistent and cohesive quality oversight. Thus, the QPS role was created. A QPS is assigned to a project team and stays with the project from preclinical development to product launch. Then, the QPS hands the product's quality oversight responsibilities and its development history to the commercial quality steward, who shepherds the product through the commercial environment.

One of the immediate benefits in creating the QPS role was the reduction of resources needed in the various quality functions. This role also greatly helps the project team by identifying a single point of contact that is accountable for all quality issues. The QPS serves as a quality expert for the product during clinical development and is responsible for making quality-related decisions and playing the role of the liaison between the project team and other quality functions. This model provides a consistent quality voice on the project team and helps the team to reach decisions more effectively and quickly. One QPS can provide quality oversight for two to three products, depending on the development phase and level of complexity of the products. In the following sections, we will describe the QPS role in detail, the responsibilities of the QPS, and the business processes that support the QPS function.

THE QPS BUSINESS MODEL

The difference between the QPS role and the quality control (QC) or quality assurance (QA) functions is that this job is not purely function-focused. It is centered on all aspects of product quality and product knowledge, and on being the single point of contact for communication and accountability.

It is important for the QPS to be involved when the product enters development, before toxicology campaigns, and to stay with the product as it moves through development. Early involvement by one person from quality who is knowledgeable of the product and its challenges provides a proactive front-end approach to quality, as opposed to the traditional reactive back-end approach. Typically QC and QA become involved after the manufacturing process has been developed and the product is manufactured. It is the responsibility of the QPS to ensure quality is ingrained and built into the process during development. The QPS can foresee and inform the project team of potential product quality issues during process development, manufacturing, testing, and management of investigations/discrepancies, and can provide strategic direction and decisions to the project team. The combined knowledge of the product, processes, and the quality functions makes the QPS the best decision-maker for the product's quality. When resolving a critical quality issue, the QPS does, however, engage the appropriate quality function and upper management to ensure a sound decision is made and issue resolution occurs.

A biopharmaceutical product can take up to 10 years from initial development to approved commercial product. Along the way, many key functional areas such as process, analytical, and pharmaceutical development have generated and accumulated extensive product-specific knowledge. The importance and value of this knowledge are critical and indispensable for understanding a product and developing a high-quality manufacturing process.

There is also value in generating product-related quality knowledge during the development lifecycle. Although product-related quality knowledge is not as well defined as other scientific disciplines, it can be considered an interdisciplinary knowledge encompassing product characteristics and development history; and how the physico-chemical characteristics and manufacturing process of products are linked to their quality attributes. It is also about knowing stability profiles, specifications (including methods and acceptance criteria), released batches used in various clinical trials (including Certificate of Analysis results and stability data), and major quality-related investigations and discrepancies. In addition, the product-related quality knowledge also includes quality and cGMP principles and systems and relevant regulatory guidelines. The product-related quality knowledge gathered during clinical development is extremely valuable when developing the commercial manufacturing process and setting the final control system.

Because the QPS stays with the product from initial development to commercialization and serves as the single point of contact on the project team, they accumulate a vast amount of product knowledge. Clinical development is a very dynamic environment that requires versatile skills and knowledge. The product knowledge gathered provides the QPS with a solid product history and strategic thinking in the quality approach to deal with the constant changes that occur along the way.

QPS ROLES AND RESPONSIBILITIES

The creation of the clinical QPS at Genentech was the result of a business need and experimentation with a new quality concept to ensure consistent and effective quality oversight during clinical development.

Table 1 lists the main roles and responsibilities we have identified as value-added services and tasks that benefit process development.

Table 1. The quality product steward's (QPS) roles in various CMC-related tasks

As stated earlier, the QPS is involved in the project team's activities early on in development. During GLP toxicology study stage, our QC is normally responsible for testing and releasing the material. The QPS authors the characterization protocol that defines test methods and acceptance criteria. Subsequently, the QPS also drafts the stability testing protocol when the toxicology study is complete to ensure the material used has been stable throughout the study period. Although the material manufactured may not be GMP, it is often considered representative of Phase 1 clinical material. In this situation, the QPS serves as a central role on the project team, accountable for the generation, release, and maintenance of the reference material. Their guidance and communication provided to the project teams and quality functions is very valuable.

Resource Planning

Resource planning is a critical part of every project and organization. At Genentech, the process development functions have been successfully using standardized resource planning tools to forecast resource needs during product development. By collaborating with various quality-related functional groups, we developed a standardized quality–resource-requirements model based on the type and development stage of the product. With this information, the QPS is able to communicate to the project team early on to ensure that resources in quality are in alignment with the overall product timeline and goals. This standardized approach also ensures consistency and eliminates the need for requesting information from various groups every time milestones move or change.

GMP Manufacturing Control System

For each new or changed drug substance and drug product GMP campaign, the QPS authors a product-specific sampling and testing plan. This document defines QC testing requirements at each manufacturing step. It contains sampling quantity, test codes and names, and the corresponding control limits for all of the key intermediates and release steps. Sampling instructions (e.g., aseptically or not) are also included in this document. It is used as the primary source information by manufacturing, QC testing and sample management, and LIMS, ensuring the appropriate samples are pulled, verified, submitted, logged into the sample tracking system, and tested.

Collaborating with key CMC stakeholders, especially analytical chemistry, the QPS proposes an overall control strategy for GMP drug substance and drug product. The control strategy covers in-process, release, stability testing, and their respective acceptance criteria (i.e., limits). The proposal is usually presented to an upper management analytical review committee, which consists of key CMC functional directors, and is implemented only after the committee's endorsement. After this endorsement, the QPS is responsible for drafting and approval of the formal drug substance and drug product specifications documents in the QA documentation system. In this capacity, the QPS works with our regulatory affairs and analytical chemistry groups to ensure the overall quality control strategy meets the standards of the relevant regulatory agencies (FDA, EMA, etc.). This task requires that the QPS be familiar with relevant ICH, FDA, and EMA guidelines and take into consideration the quality requirements that are appropriate for the development stage of a clinical product.

Analytics

Although the QPS is not directly involved in analytical characterization and method development, they are expected to be familiar with all of the methods used in the control system (including in-process, release, and stability testing). The scope of these methods covers analytical, physical, microbial, and viral testing methods. With this knowledge, the QPS understands why and how these methods are used for monitoring and controlling the quality attributes at each manufacturing process step.

In collaboration with various QC testing and analytical chemistry groups, the QPS is responsible for proposing the overall method qualification/validation strategy appropriate with the phase of development and internal quality standards. At the conclusion of method qualification/validation studies, the QPS also drafts a final report that summarizes all of the method validation/qualification studies. This report is a useful reference during regulatory agency inspections. It also serves as a valuable source for the lifecycle management of analytical method development.

Another key responsibility of the QPS is managing the reference materials. During biopharmaceutical development, a product-specific reference material often needs to be generated because there is no international standard available. The reference material serves as the standard for the product and the control for many QC methods. In this capacity, the QPS is responsible for authoring and approving the qualification protocol and coordinating the reference material manufacturing, testing, and release. Afterwards, the QPS continues to maintain the reference material and summarizes the reference material data from QC testing groups to evaluate its stability. These responsibilities can go to outside companies in special cases such as when a contract manufacturing organization (CMO) is used to manufacture and maintain the corresponding reference material. In this case, the QPS will interact with the CMO to ensure the relevant activities are completed from the quality perspective.

Building the Product Knowledge History

Valuable product knowledge can be acquired during development by strategically managing discrepancies, investigations, and change controls. Because the QPS is involved in quality aspects of their product, they are in the position to take full advantage of these experiences. The QPS is responsible for identifying major quality-impacting discrepancies that occur during GMP manufacturing and testing. Quality-related investigations involve the identification of a possible cause, determination of the impact (or not) on quality, and corrective-action implementation. The QPS leads the effort in presenting a conclusion to and seeking endorsement from the appropriate clinical quality review committee (i.e, quality review board, QRB) and seeking the support of senior quality management to bring the investigation to a successful conclusion. They begin with discussions with the QRB chair to determine if the issue is serious enough for a formal QRB meeting. If needed, they coordinate with various stakeholders to present to the QRB, participate in the QRB meeting discussion and decision-making, facilitate the QRB for endorsement and recommendation, and execute the QRB recommendation. The QPS can also be involved in discrepancies or investigations by performing a quality assessment and providing relevant history and recommendations to the QRB committee to facilitate an effective and efficient outcome.

Ultimately, the quality-related discrepancy investigation history is valuable when building the design space in support of Quality by Design. By formally evaluating and documenting these deviations and their conclusions, they can be used as unplanned design of experiments, and they may sometimes represent possible manufacturing variations.

Change control is a quality system that documents changes that impact GMP activities. Its goal is to ensure that the proper assessment is conducted to systematically evaluate potential impact before implementing a change. In this process, the QPS sometimes initiates a change-control record and also participates in the assessment related to the QPS activities stated above. Because the QPS is the quality single point of contact on the project team and knows the product quality history, many proposed changes are often evaluated by the QPS to see if their potential impact on quality has been thoroughly assessed. For various tasks, we have developed a corresponding business process to maintain consistency. As drug candidates advance through development, the manufacturing process usually experiences many changes. The change control system becomes a very valuable source of development history. By capturing and analyzing the development history using discrepancy management and change control, the QPS builds a robust history database that includes all quality aspects of the product.

Clinical Trial-Enabling Activities

Because the QPS is actively involved in establishing the release specification, stability strategy, reference material, and QC testing and control during manufacturing, they author the relevant sections of an investigational new drug (IND), IND amendments, and regulatory filings for other countries. The QPS is also responsible for addressing quality-related questions from various regulatory agencies. Clinical development is a dynamic environment. Regulatory and quality requirements are quite different from those of commercial products. In addition, different countries may have different expectations regarding these requirements for clinical trials conducted in their countries. The QPS is expected to be familiar with these different requirements during clinical development and ensure their product meets them.

For clinical trials conducted in Europe, the product specification file is required by a qualified person (QP) for releasing the investigational drug. This document generally includes and refers to such information as specification and analytical methods for starting materials, intermediates, bulk and finished products, and packaging materials; the manufacturing process and in-process testing methods; stability data, storage, and shipment conditions; and relevant clinical trial protocols. The information in the product specification file forms the basis of the assessment of the suitability for certification and release of a particular batch by the QP. Thus, the product specification file contains comprehensive information about the manufacturing process and controls. Because of their comprehensive role in quality, the QPS authors this document. In this capacity, the QPS collaborates with various process-development functions and quality groups. This document is valuable not only for QP release but also for many internal customers because it contains key manufacturing and control information in a single source.

The QPS is accountable for the GMP stability program of the clinical product. The GMP stability study is a critical element of the overall control strategy during clinical development. The data from the study are used to support the expiration dates of drug substance and drug product used in clinical trials; a product quality evaluation in the event of a temperature excursion during shipment and storage; and acceptable ranges that are established for critical quality attributes at the time of the commercial regulatory filing. The QPS is accountable for drafting the study protocol, reviewing and approving the time point data, trending the stability data, and managing the out-of-trend or out-of specification (OOS) investigations. In addition, the QPS participates in the review committee for setting the overall stability strategy throughout the product lifecycle.

The QPS proposes the product's shelf life based on updated GMP and supportive R&D data (generated by pharmaceutical development) and generates the appropriate documents to justify the proposed shelf life. The shelf life of a clinical product is critical to ensure the successful completion of clinical trials. As stability studies are continuous, the QPS is responsible for updating the shelf life of the drug substance and drug product. In this role, the QPS collaborates with QC testing and pharmaceutical development to evaluate stability data to determine if a product meets its quality requirements. Certain non-US countries require either notification or a formal approval process for updating shelf life. The QPS ensures that, before labeling the product with the newly proposed shelf life, it is approved in those countries where the clinical trial is conducted. In this regard, regulatory affairs is responsible for notifying and filing with the relevant countries to obtain approval.

Ensuring uninterrupted clinical supply is critical to achieve a successful clinical trial. In this regard, the QPS also plays key roles. During shipping to and storage of clinical materials at clinical sites, temperature is usually controlled to a certain range to ensure product quality. However, temperature excursions often happen because of various reasons. This is especially true if it is a global trial involving multiple countries on different continents. When such an event occurs, the QPS is responsible for assessing if the materials impacted can still be used for the intended clinical trial. The QPS uses available stability data obtained from stability-indicating assays to determine whether the temperature and duration the material was exposed results in potential degradation that warrants quarantine of the material, or is not significant as to impact the product quality. During the evaluation process, the QPS interacts with a formulation scientist for technical discussion and QA for capturing the event in a QA discrepancy system. In addition, the QPS is accountable for timely communication to clinical operations on the quality decision made at a quality review board meeting to reduce impact on the clinical material supply. Under this scenario, once a discrepancy is discovered and under investigation it may affect the timely shipment of clinical materials. The QPS will work with the clinical operation group closely so that they are informed of the material's suitability for use.

Interactions with External Partners and CMOs

As Genentech's clinical pipeline became more diverse, we had an increased need for collaboration with CMOs or partners to use their specialized technologies for process development and clinical manufacturing. To effectively manage the development activities with the CMOs or partner, the project team needs a single point of contact identified from each of the key functional areas (e.g., project management, process development, quality (QC and QA), etc.) to be responsible for the interactions with the CMOs or partners. In this situation, Genentech's external QA serves as the point of contact for the quality assurance function and ensures that the product is compliant, reputable, and reliable for patients, while the QPS serves as the point of contact for quality control function and manages the QC activities from method transfer to various QC testing and QC investigations. In many cases, multiple QC laboratories and sites are involved in the QC activities for a project. This requires the QPS not only to have the ability to manage multiple issues at the same time, but also to have the broad knowledge and technical skills to dive deep into issues when guidance is required. This eliminates the need to have all of the QC groups involved in interactions and ensures quick responses to QC issues.

The QPS is also involved in the due diligence evaluation for selection of the CMOs. This allows the QPS to identify the gaps and risks from a QC perspective and address them in advance of a contract.

Drug-Device Combination Products

Drug-device combination products have increasingly become a competitive edge in product marketing. The QPS, with comprehensive knowledge of the specific regulatory and GMP requirements for devices, plays an important role on the development team. In this regard, the QPS oversees the development of the design control strategy and assists the project team in the interpretation and implementation of design-control procedures. The QPS is responsible for initiating the design-history file, defining the design inputs, and creating and approving the design and development plan. During development, the QPS evaluates the prototypes, conducts risk analysis and design review, and accounts for risk management lifecycle activities. The QPS works in collaboration with external quality in ensuring adequate interface between the CMO's and Genentech's design history files.

QPS BUSINESS PROCESSES

In order for the QPS to provide a consistent quality approach to project teams, we have developed business processes that standardize our key activities at each stage of clinical development. The business-processes include tasks, deliverables, timelines, roles and responsibilities, and decision points. These business process documents are incorporated into an online tool that has links to various templates, guidance documents, and folders. The standardized business processes have greatly improved the efficiency and consistency of the QPS function. It also serves as good training material for new QPSs and as a reference for other CMC functional areas so they have a clear understanding of the role of the QPS.

Figure 2a. A quality product steward (QPS) business process diagram - 1

Figure 2a and 2b are examples of QPS business process diagrams that describe the main flow of the quality-related activities and the QPS roles. Although the QPS oversees the overall quality activities during the process development, he or she also has specific responsibilities for key processes and documents (as highlighted in the diagram). For each of these specific activities, a detailed business process has been developed. For example, the business process for an expiration dating assignment (Table 2) specifies the step-by-step activities required, the deliverables, key stakeholders, end users, and timelines. The links to the templates and guidance documents are also included.

Figure 2b. A quality product steward (QPS) business process diagram - 2

The business process documents are living documents and are continuously evolving as gaps or opportunities for improvement are identified. In developing the business processes, the phase-appropriate GMPs for clinical product were applied. Establishing a new business process or changing an existing business process involves extensive discussions with the key stakeholders and end-users. The effectiveness of the business process is also monitored for its accuracy, consistency, and compliance with the Genentech quality systems (policies, standards, and standard operating procedures) and applicable regulations.

Table 2. Example of QPS business process: expiration dating assignment and extension for clinical products

QPS QUALIFICATIONS

The quality environment during clinical development is much more dynamic than during commercial product manufacturing. The QPS is required to have both a basic understanding of GMPs and quality requirements, and the business and technical acumen to tackle various types of challenges.

As described above, the QPS role is quite different from other traditional quality functions. It requires a comprehensive skill set that not only includes scientific and quality-related knowledge and analytical thinking, but also requires competency in such skills as influencing, negotiating, problem solving, decision-making, collaborating, organizing, and project management, as well as the ability to manage many diverse issues at the same time. Prior experience as the quality decision-maker is very desirable.

Candidates with strong science and engineering backgrounds plus prior experience with process-development are very important as they are instrumental for the QPS to understand both quality and other process development issues. The individual with the aforementioned competencies are usually very successful in executing the QPS functions. The goal is to enable the QPS, who has experience in science disciplines, to understand other process development functions and instill scientific thinking into quality oversight and decisions. Although the combination of the above requirements may not be typical for personnel in a quality unit, we have been successful in recruiting many talented R&D scientists and managers from other quality and science functions with diverse expertise. Their prior experiences have proven to be extremely valuable in handling the QPS job.

OUR EXPERIENCE

Looking back at our experience with the QPS role, its evolution seemed natural, a result of addressing a rapidly increasing clinical product pipeline, the diverse nature of our biopharmaceutical products, an expanded global network, and greater outsourcing strategies. Although the QPS is relatively new, so far our experiment in the clinical quality organization has been well received by both the project teams and many of the quality groups, achieving a win-win for both sides. For the project teams, one owner is identified to oversee the quality activities and address quality issues. For the quality organization, the QPS allows a harmonized and consistent quality approach and prevents communication gaps. Additionally, it reduces the requirement of quality resources.

One of the valuable lessons learned is that it is very important to clearly define the scope of QPS responsibilities. At the early stage of implementing the QPS model, there was some confusion about QPS job functions. As a result, people were hesitant to accept the QPS role. To address the situation, we spent a significant amount of time with the key stakeholders to define QPS roles and responsibilities, discussed concerns and questions openly with various partners and customers, and finally reached a business agreement. Then, we did road shows to convey a consistent message about QPS. In the meantime, we kept our focus on the project and customer needs, and successfully helped the project teams resolve many important issues.

One good example of such success is a product specification file (PSF). As our clinical trial became more global, different requirements for releasing clinical material from various countries became apparent and needed to be addressed in a consistent way. In EU countries, QP release of investigational medicinal product (IMP) requires PSF. This document contains key product information from manufacturing, analytical methods, stability to clinical protocol, and shipping and handling conditions, among other information. At the time, there was no such document for our products and no functional group was taking responsibility for it. We identified the gap, seized the opportunity, and subsequently created PSF with the standard content and format.

QPSs have comprehensive product quality knowledge and become the natural owners of the PSF. Now the PSF document is fully implemented for every clinical product. It is not only used for EU release, but also acts as a useful single-source document containing all the key information about a product manufacturing profile.

Another success example is the QPS role in change control (CC) process. Process change during clinical development is typical for biopharmaceutical products. Evaluating and documenting these changes can be very daunting. When the CC process was initially started by the clinical organization, the QPS took the initiative in helping project team and QA groups defining detailed business processes and instructions for each type of change. In the end, transitioning to the new CC had minimal impact to the project timeline. Here, the QPSs used their combined knowledge in product development and GMP compliance to benefit project development.

Through many of the success stories, the project teams and various functional groups recognized the values of QPS and began to accept and value the QPS role and contribution. Now it has become natural that when a new CMC project team kicks off, the team requires a QPS as a formal member. At Genentech's technical development area, we embrace an efficient decision-making process. This culture is also conducive to QPS success because the QPS's quality and product knowledge enables timely decisions on the quality aspects during product development.

From our perspective, this QPS concept may have utility for other established biotechnology and pharmaceutical companies. For other companies (such as small companies) that are resource conscious, having a quality SPOC on their project team may also add value because the efficiency aforementioned is a key aspect of such a role. We also acknowledge the challenge in implementing the QPS role, because it is not a traditional quality function and may require significant effort in defining its roles and responsibilities. It is important that the QPS's specific job functions are adjusted to the organization's needs and process development philosophy.

In the current competitive pharmaceutical development environment, being adaptable and agile can be critical to success. In this article, we introduced a new concept and role in quality that emerged from our business needs. The dynamic role that the QPS plays requires him or her to maintain a quality philosophy that is compliance conscious, flexible, and scientifically based. The key to being a successful QPS is to act as a single point of contact for consistent product quality oversight and to maintain product knowledge while helping project teams achieve their goals.

ACKNOWLEDGMENTS

We would like to acknowledge Gail Burnett for proposing and supporting the QPS model, and her critical review of the manuscript. We sincerely thank all the past and current staff members in our department (IMP Quality—Biologics) for contributing to the establishment and acceptance of this new role at Genentech, making it a critical and successful CMC function during clinical development.

Zhengyu (Jerry) Dong is a senior manager, Sharon Ma, PhD, is a senior QPS, and Dian Feuerhelm is director, IMP Quality- Biologics, Pharm Technical Development, Genentech, A Member of the Roche Group, South San Francisco, CA, 650.225.6747, zdong@gene.com.

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