March 3, 2020

Quality Management Systems for advanced therapies, Part 3: a risk based approach – what does this mean for advanced therapies?

Note: this post is the third 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. You can find the prior installment here

Advanced therapies carry additional risk due to their uniqueness and complexity. This can seem overwhelming at first. But as discussed in our posts on QMS essentials and six areas of focus for advanced therapies, utilizing tried and true QMS principles, including a risk based approach, provides the foundation for ensuring each patient receives a safe and effective advanced therapy – every time.

Both the FDA and EMA recognize and reinforce the importance of risk assessment and a risk based approach. The FDA’s recently published guidance for Human Gene Therapy INDs indicates that the “FDA may place the IND on clinical hold if the IND does not contain sufficient CMC information to assess the risks to subjects in the proposed studies.”2 The EMA emphasizes the application of a risk based approach for both clinical stage and authorized advanced therapies in its guidance on GMP for advanced therapies.3 

In the context of a QMS and risk management, a risk is defined as “The combination of the probability of occurrence of harm and the severity of that harm.”1 And harm is defined as “Damage to health, including damage that can occur from loss of product quality or availability.”1 This definition of harm is key for advanced therapies because of the special nature of human cell-based products and the often delicate health of the patient populations being treated.

Quality Risk Management (QRM) defined
A Quality Risk Management (QRM) approach for biopharmaceuticals is the proven methodology for continually identifying and managing risks to product quality. It is defined as “A systematic process for the assessment, control, communication, and review of risks to the quality of the drug product across the product lifecycle,”1 and it is an important part of any well-functioning QMS. There are known, effective practices that can be leveraged for advanced therapies to proactively identify risks and either avoid them or have processes in place to mitigate their impact.

There are three phases to the QRM approach as outlined in ICH Q91:

  1. Assessment (for a closer look at the FMEA assessment methodology, see a related post here)
  2. Control
  3. Review 

QRM is an iterative and continuous process that should start early in the product lifecycle and continue through, and beyond, commercialization. When approaching QRM at various stages of the lifecycle, there are two principles1 to keep in mind that will guide the effort, keep teams focused, and ensure appropriateness:

  1. Risk evaluation should be based on scientific knowledge and linked to the protection of the patient.
  2. The level of effort, formality, and documentation should be commensurate with the level of risk.

The EMA echoes this, explaining that “The evaluation of the risks and the effectiveness of the control/mitigation measure should be based on scientific knowledge and the accumulated experience. Ultimately, this evaluation is linked to the protection of patients.”3

As product and process knowledge increase, more patients are treated, and the ecosystem expands, so should the approach to QRM. In other words, QRM should scale up and out with the product just like the QMS, to ensure ongoing drug quality and patient safety. Additionally, the distributed and complex nature of the advanced therapies ecosystem provides an ideal opportunity for a collaborative approach to quality risk management and the utilization of modern technology to identify, reduce, and manage risk.

ypes of risk and the critical risks for advanced therapies

Basic risk types
During the risk assessment process, the team will identify a number of risks and determine the significance of the risks. It is important to understand not only which risks are significant, but also if each risk is controllable or uncontrollable and if it is likely to be detected. The ability to detect and control risk, or not, will drive the approach to avoidance or mitigation. The output of the assessment phase should yield something like the figure below to prioritize the areas most in need of consideration.

Critical risks are those that require the most attention from the earliest point in development. If the risks are controllable, then identifying how best to avoid them is time and money well spent. This is also an area where implementing technology solutions can play a key role in reducing risk and providing a level of error free execution by replacing manual processes. Uncontrollable critical risks require careful attention as well. Having clear processes and procedures in place to identify, manage, and limit the impact of issues should they arise is important for maintaining patient safety at all times.

The four most critical risks for advanced therapies are:

  • Patient/Product mix-up 
  • Patient health
  • Cell collection quality
  • Drug product quality  

Patient/Product mix-up: The right drug product must be delivered to the right patient every single time. The FDA identifies this as a key risk and recommends that even “early stage INDs have information on methods used to prevent…product mix-ups.”2 For a traditional pharmaceutical or biologic, this is a fairly straightforward process that involves matching an off-the-shelf product with a specific patient name. With advanced therapies, however, extremely severe adverse events (such as graft vs. host disease or anaphylactic reactions), even death, can occur should a patient be treated with the wrong product. The underlying complexities in producing advanced therapy – more people, systems, and processes – create many more opportunities for gaps and mixups in the Chain of Identity and Chain of Custody. Even though this is a critical risk, it is largely controllable, as we’ll discuss later in this series.

Patient health: Many of the patient populations currently being treated with advanced therapies are in delicate or poor health. This can affect both the ability to collect starting material (in the case of autologous therapies), and/or the ability to treat the patient with the finished drug product. Unfortunately, this uncontrollable component is a reality of serious or advanced health conditions. Another aspect of patient health is the effect of product failure or poor product quality that happens in-process. Imagine, a patient undergoes tumor excision or apheresis (or possibly both), which are taxing processes for ill patients, then the cells are rendered unusable for manufacturing from an excursion in transport or the drug product lot does not meet release specifications after an issue in manufacturing. The patient misses out on potentially life-altering treatment, and, unfortunately, their health may have deteriorated to a point that another collection is not possible. While the patient’s health is an uncontrollable risk for the drug sponsor, ensuring successful product quality and release is largely controllable and can be ensured by a robust process and solid QMS.

Collection quality: Consistent, high-quality starting material that is within parameters is requisite for high-quality drug product. Raw material quality is not a new risk in pharmaceuticals or biologics, but the variability and high touch nature of the material, patient health, and the collection process in personalized therapies adds a completely different dimension – and elevates this to a critical risk. Further complicating this is that some of the risks to collection quality is uncontrollable, as was discussed above related to patient health. The good news is that some are controllable, aided in large part by robust QMS practices such as training, vendor management, and standardized processes and controls. Indeed, the FDA calls out the collection as a key point of risk and recommends that for “Cells – Autologous and Allogeneic Cell or Tissue…Establishing well-designed process controls and standard operating procedures (SOPs) for manipulating and handling starting and in-process materials can help reduce variability in the manufacturing process and ultimately in the DS and DP.”2

Drug product quality: High-quality drug product is the primary goal of any advanced therapy company, yet it is inherently difficult to achieve due to the myriad potential risks in every step of the supply chain. Collection quality is one key precursor to the final drug product quality. Equally important is ensuring that the raw material and, eventually, the drug product is produced and handled in a standardized, consistent way and remains within validated parameters throughout every step of the process through the point of patient treatment. The FDA indicates that “Proper control of the finished [drug product] DP is critical to investigational studies”…and “your IND should include a description of how the product will be shipped to, received, and handled at the clinical site to ensure safety, product quality, and stability.”2  Managing the risks and ensuring quality drug product is paramount to obtaining an IND or product license and, while especially challenging for advanced therapies, can be done by taking a data-driven, risk based approach, knowing the product and process, and careful implementation of QMS.

Reducing critical risks for advanced therapies

Advanced therapies present a number of challenges not seen in traditional pharma and biotech. Yet companies still need to ensure consistent, repeatable quality time after time and be able to demonstrate this to regulatory bodies. The FDA recommends that Human Gene Therapy INDs include details in the Quality Overall Summary (QOS) that assists the reviewers in understanding quality information and relating the information to potential patient risks.2 The critical risks discussed above are significant and may seem daunting, yet staying grounded in the basics of good Quality Management Systems – and Quality Risk Management – will go a long way toward ensuring patient safety and product success. 

Next up in this five-part series, industry experts will provide practical tips for implementing QMS and QRM practices that de-risk the critical risks of the advanced therapy supply chain. For more on the topic of Quality Management Systems for advanced therapies, see the first two posts in this series.

Quality management systems for advanced therapies series:
Part 1: the essentials
Part 2: six areas of focus
Part 4: practical tips for de-risking critical risks
Part 5: what does a successful QMS look like in advanced therapies?

If you have Quality-related supply chain 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.

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.


  1. 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. 3,9. (
  2. 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 Biologics Evaluation and Research (CBER), January 2020, P. 2, 5, 7, 17, 44. (
  3. Guidelines on Good Manufacturing Practice specific to Advanced Therapy Medicinal Products, EudraLex, The Rules Governing Medicinal Products in the European Union, Volume 4, Good Manufacturing Practice, November 2017, P. 8-15; P. 10 Section 2.17. (