By Irwin Hirsh, Q-Specialists AB

Part one of this article explored the rationale behind establishing a team structure for CMC development based on the writings of Matthew Skelton and Manuel Pais in their 2019 book Team Topologies. There I explored the types of cognitive load — intrinsic, extraneous, and germane — and how a clear division of duties helps to ensure the right teams are bearing the right loads to maximize efficiency. Overcoming barriers, such as silo-based organizations and the demand for a return on investment, is discussed.

If you haven’t read it yet, I recommend going back because it sets the stage for the topics covered herein: how to adapt CMC team topologies to a development model wherein parts of the development are outsourced. Additionally, the role of the project management office/project manager is presented. Much of the discussion, aside from the specific outsourcing topics, should apply well to internal projects.

Outsourcing Teams

When certain areas such as formulation or analytics are outsourced, the organizational structure and team dynamics need to be adapted to ensure cohesive integration and effective communication between internal and external teams. Here’s how we can contextualize this setup, incorporating the role of project management to facilitate information and knowledge flows:

1. Internal Stream-aligned Teams

These teams remain focused on core internal processes and responsibilities, ensuring that the in-house aspects of the CMC development process are managed effectively.

Examples:

• Process development team: continues to work on scaling up the manufacturing process from lab scale to pilot and commercial scale
• Regulatory affairs team: provides guidance on regulatory requirements and helps prepare documentation for regulatory submissions
• Quality assurance team: ensures compliance with GMP and other quality standards

Often, I find or perceive that when an activity is outsourced, there is an unspoken belief that the partner will take care of everything, and “we” can focus on in-house activities. This thinking is dangerous from both a compliance and a business perspective.

Compliance: Recall that the pharmaceutical license (marketing authorization) holder is the responsible party for all things related to the pharmaceutical. It is both risky and foolish not to maintain oversight and regular communication with the outsourced elements of CMC development.

Business: Yes, outsourcing can be hugely impactful. It removes the need for large capital expenditures, gives access to the latest and greatest technologies, and provides a trained and capable workforce that has no illusions about job security when the project ends.

However, managing expectations with contractors is complex and critical to achieving desired outcomes. The more a company shifts CMC development to an outsourced mode, the more it depends upon project managers who have access to subject matter experts able to review and challenge the proposals and outputs of the outsourced work. Pharmaceutical companies that outsource an activity often do so because they lack in-house expertise. Therefore, they must consider finding yet another outsourcing partner, a consulting firm that can supply a host of relevant SMEs to the project management group for the above-mentioned work.

2. External Outsourced Teams

These teams are external partners or contractors responsible for specific areas such as formulation or analytics. Effective collaboration and communication with these teams are crucial.

Examples:

• Formulation development partner: an external organization specializing in drug formulation, ensuring stability, efficacy, and safety

The formulation partner must be fully aware of the requirements of the formulation, including timely updates as requirements change.  Often changes in one critical attribute like shelf-life will impact changes to a host of other parameters and the risks, to the business and the patient, of  this cascade of consequences must be managed through communication and a shared involvement in problem solving.

• Analytical development partner: an external lab that develops and validates analytical methods to ensure the quality of the drug substance and drug product.

Often when I have gone to assess a potential partner for analytical services, the newest machines are available, and the quality system seems appropriate, but the level of the staff seems inadequate.  Not in terms of numbers but in terms of experience.   This can lead to delays, misaligned expectations and methods, which themselves seem compliant with ICH Q2, but have little practical impact on supporting critical knowledge about the process variation.   When for business reasons such a provider is selected the cognitive demand on the internal team is quite large and this extra “hand holding” around fit for purpose methods must be budgeted.

3. Internal Enabling Teams

These teams support both internal and outsourced teams by providing necessary resources, expertise, and coordination.

Examples:

• Technology transfer team: facilitates the transfer of technology and processes between internal teams and external partners. Special consideration about enhanced resources to support potential gaps in the service provider, for example, see above discussion about analytics must be considered.  If the SME knowledge is not available in house to close the gap(s) then yet another outsourced knowledge partner is required.
• Supply chain management team: coordinates logistics and ensures the availability of raw materials for both internal and outsourced processes.  Not that in the case where the acquisition of controlled substances is needed, for example, biosimilars for “baseline” testing, the supply chain management team must also include a strong QA/QC input to ensure compliance with the law and proper handling of materials (e.g. cold chain).
• Facilities and equipment team: maintains the physical infrastructure and equipment used in manufacturing, ensuring they are in good working order and compliant with regulations. As mentioned in the previous article, critical control points and bridging the gaps due to design differences is critical and such a group’s input into this is critical, especially on the FMEA of method transfers.

4. Internal Platform Teams

These teams provide foundational services and tools that support both internal and outsourced teams, reducing cognitive load and ensuring consistency.

Examples:

• Manufacturing IT Systems Team: manages the IT infrastructure and software systems, such as electronic lab notebooks (ELN) and laboratory information management systems (LIMS).
• Knowledge Management Team: ensures that all relevant information and data are captured, stored, and accessible to both internal and external teams.

IT and OT professionals must be included in the discussions about how knowledge sharing will flow between teams starting at the design stage.  IT and OT are expected to be experts on the flow of information.   This knowledge is critical to making the teams successful.  If there is no Knowledge Management Team, consider creating one or expanding the IT/OT groups’ purview to include this discipline.

5. Project Management Office

The project management office (PMO) plays a critical role in coordinating activities, managing timelines, and ensuring effective communication and knowledge flow between internal and external teams.

Responsibilities:

• Coordination and integration: acts as the central point of contact between internal teams and external partners, ensuring that all activities are aligned and integrated
• Timeline management: develops and monitors project timelines, ensuring that internal and external teams adhere to deadlines and milestones
• Communication: facilitates regular meetings, updates, and reporting between internal and external teams to ensure transparency and address any issues promptly
• Risk management: identifies potential risks associated with outsourcing and develops mitigation strategies to ensure project continuity
• Documentation and knowledge sharing: ensures that all project-related documentation is up to date and accessible to all relevant stakeholders, promoting knowledge sharing and reducing information silos

The PMO, like the synthetic chemistry group, must be filled with professionals who know their trade. Although there are always challenges to finding people with deep and broad skill sets, it is important to recognize project management as a distinct and real profession. Many tech companies are heavily science-based. This is fundamental to the discovery stage and at least supportive throughout the life cycle of a product.

However, when a discovery company moves to focus on the industrialization of their lead compounds, it would be foolish to believe that giving their best scientists iPads and new job titles will make them capable of handling the outsourced CMC development. Technically, they may not even be able to challenge the decisions by the CDMO from a cost-of-goods or GMP basis. Investing in the resources to professionalize the PMO is a key enabling factor for success.

Changes, Planned Or Otherwise

In the proposed structure, the primary accountability to ensure that the information generated by the development group about the performance of the process and its capabilities aligns with and achieves the product requirements would rest with the PMO. The PMO acts as the central coordinating body, ensuring that all teams are aligned with the product requirements and any changes that arise.

Responsibilities of the PMO:

• Alignment with product requirements: The PMO ensures that all development activities and outputs are in line with the product requirements. They coordinate with different teams to ensure that the process performance and capabilities meet the specified standards.
• Change management: The PMO is responsible for managing changes to product requirements due to business needs or clinical needs. They ensure that these changes are communicated effectively and integrated into the development process.

Process For Integrating Changes

When changes to the product requirements arise, they must be communicated and integrated into the development process via the following steps:

1. Change identification and assessment:
   • Changes are identified by business or clinical teams and assessed for impact by the PMO.
   • The PMO evaluates the potential impact on ongoing development activities and the feasibility of incorporating the changes.
2. Communication and coordination:
   • The PMO communicates the changes to all relevant teams, including stream-aligned, enabling, complicated-subsystem, and platform teams.
   • Regular meetings and updates are conducted to ensure all teams understand the changes and their implications.
3. Implementation and monitoring:
   • The PMO oversees the implementation of changes, coordinating with the specific teams responsible for adapting their work to the new requirements.
   • For instance, the modeling group may need to adjust their models to reflect the new product requirements, while the process development team may need to modify process parameters and update quality risk assessments.
   • The PMO monitors the progress of these adaptations to ensure they are completed on time and meet the new requirements.
4. Verification and validation:
   • After changes are implemented, the PMO coordinates verification and validation activities to ensure that the updated processes and outputs meet the new product requirements, including the fulfillment of documentation requirements for the changes.
   • Collaboration occurs among the quality assurance team and other relevant teams to conduct thorough testing and documentation that ensure changes do not increase patient safety risk to unacceptable levels.

By placing the PMO at the center of accountability and change management, the organization ensures that all information generated by the development group aligns with the product requirements and any changes are effectively integrated into the development process.

About the Author:

Irwin Hirsh has nearly 30 years of pharma experience with a background in CMC encompassing discovery, development, manufacturing, quality systems, QRM, and process validation. In 2008, Irwin joined Novo Nordisk, focusing on quality roles and spearheading initiatives related to QRM and life cycle approaches to validation. Subsequently, he transitioned to the Merck (DE) Healthcare division, where he held director roles within the biosimilars and biopharma business units. In 2018, he became a consultant concentrating on enhancing business efficiency and effectiveness. His primary focus involves building process-oriented systems within CMC and quality departments along with implementing digital tools for knowledge management and sharing.