Quality Management Systems for advanced therapies, Part 2: six areas of focus
by Heidi Hagen and Subbu Viswanathan | February 25, 2020
Note: this post is the second in a five-part series on Quality Management Systems (including cGMP and Quality Risk Management) for personalized therapies, such as cell therapies, gene therapies, or neoantigen cancer vaccines. This series focuses specifically on Quality issues, and cGMP, in personalized therapy supply chains. The first post looked at essential aspects of Quality Management Systems in an advanced therapy context.
After our first post on Quality Management Systems (QMS) and the unique aspects of advanced therapies, it’s time for a closer look at six areas of the advanced therapy supply chain QMS that require special attention:
- Lot genealogy (including COI and COC)
- Vendor management
- Standardized processes and controls
- Quality risk management
- Monitoring and continuous improvement (including investigations)
This is a critical, foundational component of any QMS. With advanced therapies, training takes on heightened importance when the patient is part of the process and product - the stakes are high. Every activity must be performed correctly every time, such as:
- The cell collection process via apheresis (or other collection procedures such as bone marrow aspiration, tumor excision, etc.) which require the patient and equipment to be prepared and monitored to the protocol standards that have been demonstrated to yield the appropriate quality raw material.
- Handling, packing and transporting raw material cells and drug products (both fresh and frozen). The timing, packaging, temperature and other factors can seriously affect the quality of both the live cell raw material and finished drug product and, therefore, patient health and safety.
- Manufacturing the drug product for some advanced therapies requires complex manipulations (often performed manually) and activities to which the cells are sensitive. It requires skill and consistency to ensure that each variable raw material is turned into a successful product that passes release specifications.
In addition to the complex nature of this work, other factors compound the potential issues and reinforce the need for rigorous training. In such a nascent space, experienced personnel is in short supply. Or, in the case of a novel process, skills will have to be developed anew. And many of the individuals who participate in the supply chain are employed by partner organizations, not internal to the drug developer, and do not have experience operating in a GMP environment. These participants will not only need training on the specific process they will perform to make the product, but also on basic GMP and compliance standards. Technology solutions such as Learning Management Systems (LMS) can be leveraged to support the training needs of a QMS. And automated supply chain management systems can make the required activities simpler, more repeatable, and more auditable for a diverse group of stakeholders.
Lot Genealogy (COI and COC)
In traditional pharmaceuticals, lot genealogy is a key aspect of a QMS. For advanced therapies, lot genealogy expands to include Chain of Identity (COI) and Chain of Custody (COC). These two data sets provide a record of all the materials, processes, testing, and outputs of a “batch” of a pharmaceutical product. For advanced therapies, COI and COC take on additional importance to adequately account for the live human cells, the complexity of the processes, and to ensure that patients are treated with the specific product meant for them. Traceability of the cells from start to finish is paramount for ensuring patients are treated with the right product. Avoiding product mix-ups is so important that the FDA calls it out in guidance for IND filings, recommending that controls be in place well before process validation is undertaken and also specifically discusses the importance of tracking Chain of Custody.2
(For an in depth discussion of lot genealogy, COI and COC in advanced therapies, see an earlier deep dive blog post here.)
A key step in protecting product quality is ensuring that vendors are qualified and continually perform to the required standards. This is especially challenging for advanced therapies because the supply chain can have many more participants than is typical for other products, some of whom are not already operating in a GMP environment. For example, in the case of a traditional biologic, a key raw material, might have one to three GMP suppliers (e.g. qualified cell banks or media). In an advanced therapy, the key raw material -- live cells -- may have hundreds of “suppliers” that collect the cells from patients or donors and, while they are likely operating to high-quality standards of an accrediting body, they are not inherently familiar with GMP. In addition, the criticality of working with live cells requires a higher level of consistent performance and documentation from vendors than might be typical. Other vendors in this specialized supply chain are just as important, including technology partners, couriers, and contract manufacturing organizations. All suppliers must still be qualified, trained, and produce consistent quality every time. Additionally, they will be periodically audited and be relied upon to manage and resolve issues. Appropriate and efficient vendor management starts with a risk-based approach to ensure vendors are managed at a level commensurate with their inherent risk to the process.
Standardized processes and controls
A fundamental way that a QMS ensures that products are safe, fit for their intended use, and in compliance with regulatory authorization requirements is through the extensive use of standardized, scientifically proven processes for producing a given therapy and through careful control of the sensitive raw materials and drug product at all times. This is clearly and repeatedly articulated in the recent FDA Guidance for Gene Therapy INDs.2
The areas of greatest concern for advanced therapy supply chains are:
- Activities performed outside a GMP environment, in particular, activities related to cell collection and interim or pre-processing prior to arrival at a GMP manufacturing facility.2
- Handling and transportation steps -- for both the cell collection material and finished drug product.2
Key pieces of a supply chain QMS to develop and implement for standardizing and controlling are:
- Work instructions (WIs) and standard operating procedures (SOPs) - that ensure repeatable processing and results within the scientifically proven control parameters. This is key for every part of the process in a very detailed fashion - from collection machine settings, to preparing and packing the validated shipping container, recording the temperature during transport, and inspecting the cells prior to manufacturing. Electronic tools such as Supply Chain Orchestration systems, Manufacturing Execution Systems (MES -- specifically electronic Batch Records (eBR)) assist in ensuring accurate processing every time and also provide accurate data capture.
- Training - which was discussed in detail above, but is important enough to mention again.
- COI and COC - are crucial to maintaining control of the raw materials and drug product - and ensuring patient safety. From the outset, accurate capture and linking of each unique identifier to the COI, AND creation of an immutable chain of custody (the “who, what, when and where”), are essential.2 Not only must this information be carefully captured and linked, but it must also be readily accessible for internal use, collaboration across the ecosystem, and review by regulators. This is most easily accomplished with a Supply Chain Orchestration system that captures key data points and integrates with other systems in the QMS ecosystem.
- Labeling - of raw material, in-process product, and final drug product is a key tool for all pharmaceutical products for traceability and to demonstrate authorized use. In the case of advanced therapies, labeling provides the most readily available, visible information during each step from pre-collection to treatment that identifies the product and patient. (You can find a deeper dive on labeling and advanced therapies here.)
Quality Risk Management
Risk is essentially the possibility of error and/or harm. In ICH Q9 it is defined as “The combination of the probability of occurrence of harm and the severity of that harm.”1 A key goal of a QMS is to identify and reduce risk. This is integral to every part of a QMS, and so important that it is emphasized as a separate component called Quality Risk Management (QRM). A proven approach to the identification and rating of risks is the Failure Mode Effect Analysis (FMEA). This tool and process help participants assess the different ways each step, or mode, of the end-to-end value chain can fail, what the effects of failure might be, and which risks are the highest priority for avoidance and mitigation strategies. (FMEA is discussed in more detail in Vineti’s previous blog post on Supply chain readiness: quality risk management, and we’ll also be discussing aspects of a risk-based approach in upcoming blog posts)
Monitoring and Continuous Improvement
The day-to-day, batch-level details are an extremely important part of any QMS system. Equally important is the ability to view quality-related performance from a higher, more aggregate level. In the advanced therapies supply chain, the volume and complexity of data increase exponentially and will yield key insight into operations, quality issues, and risk. Consider the following:
- A deep understanding and the ability to track and trend investigations, root cause, and CAPA effectiveness helps to ensure that quality issues are identified and resolved quickly, sustainably, and effectively - before there is any impact to patient safety.
- Constant monitoring of processes and quality indicators helps ensure a consistent quality product and any areas for improvement are quickly identified.
- The ability to capture, synthesize and analyze supply chain performance, especially as it relates to quality, simplifies collaboration across the ecosystem and with regulatory authorities.
- Areas of risk can be identified, eliminated where possible, and closely monitored with quicker response times when robust monitoring systems are in place.
The ideal situation is an automated, interoperable, seamlessly integrated set of systems that not only drives consistency and standardization in day-to-day activities but also provides real-time data capture and insights into supply chain performance. A key reason to strive for this ideal is that it enhances an organization’s ability to take a data-driven, risk-based approach to quality management instead of making decisions from an uninformed, risk-averse position.
Advanced therapies hold significant promise for revolutionary treatments, but come with increased challenges and risks. By building on the solid foundations of a Quality Management System - with a risk based approach - the challenges can be successfully managed and risk will be reduced in the advanced therapy supply chain. It is important to remember that good quality and compliance not only ensure patient safety, but are also good business. Integral to a company’s brand is the assurance of a safe, high quality product. One mixup - or near miss - that impacts patient safety can damage a brand in the marketplace. Quality is your brand, and your brand is your quality.
Next up in this blog series on QMS: what does risk - and a risk-based approach - really mean, and what are the biggest or unique risks for advanced therapy supply chains?
If you have Quality-related questions for us in the meantime, please contact us. We’ve focused this blog series specifically on supply chain issues. If you have questions about other aspects of Quality in advanced therapies, such as rapid microbial testing, the Standards Coordinating Body is a helpful resource.
Quality management systems for advanced therapies series:
Part 1: the essentials
Part 3: a risk based approach - what does this mean for advanced therapies?
Part 4: practical tips for de-risking critical risks
Part 5: what does a successful QMS look like in advanced therapies?
Heidi Hagen is the Chief Strategy Officer and a Co-founder of Vineti. Over the course of her career, she has overseen the operations and delivery for more than 100,000 doses of cell therapy. Subbu Viswanathan is Vineti's Vice President of Quality, Security, and Compliance, with 20 years of experience in life sciences. If you'd like to see how Vineti's Personalized Therapy Management (PTM) platform can help you solve your advanced therapy data challenges, please contact us to schedule a demo.
- Guidance for Industry Q9 Quality Risk Management, US Department of Health and Human Services Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER), June 2006, ICH, P. 9. (https://www.fda.gov/media/71543/download)
- Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs), Guidance for Industry, US Department of Health and Human Services Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER), January 2020; All and Section A.2.c P16-17, Section A.2.e P27, Section D P7. (https://www.fda.gov/media/113760/download)