March 11, 2020

Quality Management Systems for advanced therapies, Part 4: practical tips for de-risking the critical risks in the advanced therapy supply chain

Note: this post is the fourth 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 previous post in the series here.

Advanced therapies provide new hope to patients with life-threatening and rare diseases — and new challenges. This blog series aims to help readers understand how proven Quality Management System (QMS) practices can help ensure safe and effective treatments, and de-risk the unique and complex supply chain required to deliver these life-saving treatments to patients. Emphasized in the recent FDA guidance for gene therapy INDs, a risk-based approach and decreasing risk for patients utilizing QMS principles, is central to regulatory acceptance of any new advanced therapy.1 The EMA also promotes a risk-based approach in its GMP guidelines for ATMPs, driving home the importance of applying a risk-based approach for “all types of ATMPs,” especially because they are cutting edge and complex.3 This post provides practical tips from industry experts on how to de-risk the critical risks and prepare for the uncontrollable.

The first three posts in this blog series set the stage by taking an advanced therapies-specific angle on Quality Management Systems and risk. Part #1 and Part #2 covered the need-to-knows of QMS specific to the advanced therapies supply chain and Part #3 took a closer look at a risk based approach and identified the most critical supply chain risks for advanced therapies. 

Once the fundamentals of a robust QMS are established – which goes a long way toward lowering the overall risk of the supply chain – it is time to turn attention to the critical risks identified in the Risk Assessment phase of the Quality Risk Management (QRM) process and begin Risk Control efforts (for an overview of the QRM process, see Part #3).2

The four critical risks identified in advanced therapies include:

  1. Patient/Product mix-up 
  2. Patient health
  3. Cell Collection quality
  4. Drug product quality  

Derisking — where to start? 

Critical risks: highest investment in people, process and technology for avoidance and mitigation; continuously monitor and measure
High risks: second highest investment in resources to avoid and mitigate excursions; continuously monitor and measure
Medium risks: invest resources as available to reduce risk; ensure excursions are handled appropriately and monitor at reasonable frequency
Low risks: opportunities for process improvement, resources permitting; monitor periodically to ensure risk remains low

risk assessment visualization

De-risking the critical risks

The key to risk-based efforts is to understand what drives the risk, what can actually be controlled and avoided, and what has to be “accepted.” But when talking about accepting risk in the context of risk management efforts, that does not mean sitting idly by and letting things happen. It means relying on the robust QMS practices that have been established – especially the six areas of focus as shown below – and putting plans in place to efficiently and appropriately handle excursions that arise.2 The FDA helps drug product developers by clearly outlining expectations related to mix-ups, collections and drug product quality in the newly released guidance for gene therapy INDs.1 It is also at this point that modern technology solutions can be utilized to make the highest impact and achieve regulatory expectations. Both risk avoidance and acceptance will be demonstrated in the walk through of each critical risk that follows, along with some targeted ways to leverage technological solutions for reducing risk.

QMS focus area

Derisking the advanced therapy supply chain


Focusing on these six key areas of the QMS helps de-risk the critical risks by controlling and avoiding risk when possible, and setting the ecosystem up for success in dealing with excursions when they do occur.

More detail on each focus area can be found in the posts on QMS essentials and six areas of focus for advanced therapies.

Patient/Product mix-up

Patient safety is the cornerstone of everything a drug developer does, from IND acceptance1 to product approval, especially in advanced therapies where the adverse events can be extreme. The right drug product must be delivered to the right patient1 every time, meaning a complete, unbroken, and verifiable lot genealogy, in particular the Chain of Identity (COI) and Chain of Custody (COC). The EMA specifically calls out a traceability system requirement for ATMPs and starting or critical raw materials and states that “The records should enable the entire history of a batch to be traced” and “adequate systems are implemented to ensure traceability of the ATMPs and of their starting and critical raw materials.”3 The good news is that this is a largely controllable risk, where control starts with a robust and proven approach to QMS  (see call out box above).

The complex process from patient identification and collection to drug product manufacturing and treatment involves many people, systems, and potential points of failure. Early in the development lifecycle, it may be possible to carefully manage COI and COC manually for simple and low volume processes, but as the product progresses through clinical trials, and ultimately to commercial approval, manually securing COI and COC becomes unwieldy and error prone. The best way to scale-up in volume and scale-out across sites and geographies is to implement a validated, Title 21, CFR Part 11 compliant digital traceability system to manage COI and COC. When threaded through and layered on top of a solid QMS foundation, this can effectively eliminate the risk of patient/product mix-up. Each step in the process and every hand-off is tracked and checked against patient/donor unique identifiers to ensure a complete chain from start to finish.

Expert tip: Securing COI and COC by leveraging modern technology is one of the highest impact opportunities for de-risking the advanced therapy supply chain. It significantly increases the robustness of a basic QMS framework and provides confidence to patients, healthcare providers, and regulators that product quality and patient safety are the highest priority. The Vineti platform provides one such de-risking opportunity through digital, automated COI/COC management. 

Patient Health

Patient health is both an uncontrollable and (to some degree) controllable risk of the advanced therapy supply chain. Where possible, patient selection and clinical trial protocols can support the enrollment of the best patient candidates for the therapy, but the patients requiring advanced treatments are generally in poor health. The patient health-related risk that the drug developer can control is ensuring the successful delivery of every dose after a patient’s cells are collected. This is commonly referred to as “right first time” and the FDA considers this important enough that they suggest manufacturers track and submit a similar metric called “lot acceptance rate.”4 This means that the collected cells and final drug product are carefully controlled and traceable from start to finish, they are handled appropriately, and remain within specifications every step of the way – during collection, transportation, processing, and storage – and there are solid processes and procedures in place to address any issues that may arise, ideally enabling successful completion of the manufacturing and treatment process. Having complete, transparent, real-time access to the product journey provides the ability to accommodate uncontrollable events like patient health issues, increasing the likelihood of successful processing and treatment. When product journey monitoring is coupled with the key QMS basics, each point in the supply chain is set up for ongoing success.

Expert tip: Know the product and know the process to achieve “right first time.” Focusing on monitoring and continuous improvement are keys here and repeatedly emphasized industry guidance from the FDA and EMA such as ICH Q9CMC Information for Gene Therapy INDs and Guidelines for GMP Specific to ATMPs. With so many possible points of failure, and the valuable knowledge gained from experience, gathering and analyzing many data points across the supply chain and over the cumulative lots processed will provide key insights for improvement and repeatable process success. The many systems and points of data capture across the ecosystem will yield the most actionable and timely information when integrated electronically.

Cell collection quality

Ensuring cell collection quality is challenging in advanced therapies due to patient health, the inherent variability in human biology, and the unusual origin and complex processes for procuring this key raw material. Focusing on the last item, the most controllable of the variables, de-risking potential issues with collection quality relies largely on QMS fundamentals with a focus on training, vendor management, and standardized processes and controls. The FDA specifically emphasizes the importance of standardized processes for cell collection1  Vendor selection and management is critical. Ideal collection sites, transportation vendors, and technology partners will have specific experience in the advanced therapies space. Well-designed, hands-on training programs will ensure that collection site staff are prepared to execute standardized work instructions or standard operating procedures for collections and careful monitoring of sites via the vendor audit process keeps tabs on performance. In the guidance on GMP for advanced therapies, the EMA reiterates the importance of “…training on the principles of GMP that affect them and receive initial and periodic training relevant to their tasks.” and recommends that collection sites be subject to audit.3 Technology platforms such as Learning Management Systems (LMS), document control systems, and supply chain orchestration systems can be implemented to reduce errors and increase efficiency.

Expert tip: Simple, intuitive training programs and automated workflows build in fail-safe, compliant processes and ensure cGMP rigor for the entirety of the collection process and transportation to the manufacturing facility. Measures and checks are built in to monitor and ensure collection quality each step of the way and participants have standardized and consistent guides to ensure repeatable success.

Drug product quality

Proactively avoiding and managing the other critical risks discussed in this blog is a key starting point for ensuring drug product quality. Additionally, the raw material and subsequent drug product, must be handled and produced in a standardized consistent way and remain within validated parameters throughout every step of the process going forward – from raw material receipt at manufacturing to patient treatment. There should be “controls in place to ensure product quality,” starting materials and components should be qualified, and specific processes for shipping to, receiving and handling the drug product at the clinical site prior to administration.1 The challenges are slightly different than with collection. Manufacturing will take place in an established GMP environment, and while training and vendor management (if a CMO is used) are important, the participants will be well-versed in GMP basics and there may already be assisting technology in place such as Manufacturing Execution Systems (MES), including electronic Batch Records (eBR), and electronic QMS to support training, standardization, consistency, and traceability which are more easily be managed and de-risked in the GMP environment. Nevertheless, the manufacturing process is often complex and high-touch, requiring many manipulations, and the variability of human biology is still a factor for products that utilize the living cells in the final product.

Expert tip: Know the product. Use a data-driven approach to understand the product’s characterization, specifications, and variability – and ultimately what the normal, in-control range is. This will avoid unnecessary product failures, ensure the ability to prove manufacturing comparability across sites, and streamline communications with regulators and health care providers – and de-risk this critical part of the supply chain.


At this juncture, understanding the critical risks and de-risking the advanced therapy supply chain may perhaps seem more manageable. Utilizing what is already proven to work – a risk-based approach to Quality Management Systems and leveraging modern technology – will reduce errors and increase the ability to make data-driven decisions so patient safety and drug product quality can be ensured every time. 

The final blog in this series will paint a picture of what success looks like and provide strategies establishing and managing a QMS that supports a de-risked advanced therapy supply chain. You can find prior installments at the links below.

Quality management systems for advanced therapies series:
Part 1: the essentials
Part 2: six areas of focus
Part 3: a risk based approach – what does this mean for advanced therapies? 
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.

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  1. 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, 7-8, 16-17, 27, 44 (
  2. 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, 5, 9. (
  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, 30, 33, 40. (
  4. Submission of Quality Metrics Data, Guidance for Industry (draft guidance), 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), November 2016, P. 7. (