Introduction
With the evolution of cell therapies and personalized medicine, tissue institutes are being called upon to play an increasingly central role in the management of biological material destined for both autologous and allogeneic hematopoietic stem cell (HSC) transplantation and the production of advanced therapy medicinal products (ATMPs), such as CAR-Ts. The safe execution of these activities requires the implementation of complex quality systems capable of ensuring traceability, reproducibility, and regulatory compliance.
In this context, the concepts of validation, validation, risk assessment, and change control represent fundamental pillars, as outlined by both the JACIE international standards and the State-Regions Agreement No. 49 of March 25, 2021, which introduced specific requirements for the collection and handling of HSCs in clinical and manufacturing settings.
The Italian Regulatory Framework: JACIE and State-Regions Agreement 49/2021
The JACIE (Joint Accreditation Committee ISCT-Europe & EBMT) standards, in their seventh edition in 2021, are a benchmark for quality in transplantation and cell therapy programs. They include very stringent requirements on several aspects of handling activities, including change and risk management mechanisms.
In parallel, the State-Regions Agreement No. 49/2021 strengthened the Italian regulatory framework, defining minimum requirements for tissue establishments operating as collection centers for starting material used in the production of CAR-T and other ATMPs. The agreement states that processes must be validated and managed with formal quality systems, including change controls, risk analysis and end-to-end traceability.
Validation and Validation: Operational Fundamentals
Within a tissue institute, validation is a systematic activity designed to ensure that the processes employed-from the collection of HSCs to their storage and distribution-are capable of producing compliant and repeatable results. There are three types of validation:
- Prospective: carried out prior to the deployment of a process or equipment;
- Concomitant: realized during early supervised clinical productions;
- Retrospective: applied using already available historical data (where warranted).
It is critical to examine individual processes within a tissue institute to define critical points for validation and validation.In the case of starting material for CAR-T, validation involves:
- The evaluation of collection conditions (temperatures, timing, sterile materials);
- The qualification of the personnel involved (according to JACIE and GMP);
- The control of transport and storage equipment;
- The verification of container integrity and labeling according to ISBT128;
- The evaluation of indicators associated with the processes associated with the handling activity itself.
Analytical validation is therefore required for test methods such as cell count, post-thawing viability, bacterial contamination, and endotoxin testing.
Risk Assessment: Prevent to Ensure
According to the State-Regions Agreement No. 49/2021, each stage of the process must undergo a formal risk analysis. The main purpose of this process is to identify critical control points (CCPs), prevent adverse events related to product nonconformity, and ensure business continuity even in extraordinary situations.
Methodology
The most widely used technique is FMEA (Failure Mode and Effects Analysis), which involves:
- Analysis of each step in the process;
- Assignment of scores to severity, probability, and detectability;
- Risk Priority Number (RPN) calculation and corrective action planning.
Through a mathematical calculation, a score associated with the detectability, severity and frequency of a given event is quantified, thus enabling the introduction of changes that bring a calming of the calculated risk for a single event. The very change thus introduced must be part of a further evaluation system:
Change Control: Managing Change
Change management (change control) is another mandatory requirement for ensuring process consistency and quality. It applies whenever something new is introduced, such as a new supplier or reagent, a change in the mode of operation (SOP), upgrading of management software or registration forms, replacement or relocation of critical equipment, and more generally any change that can be configured as "impactful" in the continuation of the processing unit's operations.
Each change is recorded in a change log and evaluated for impact on both the quality and safety of the biological material, the validity of existing certifications, and the need for revalidation or document review. This approach allows the Institute to prevent deviations and maintain compliance even in dynamic and expanding environments such as gene therapy.
Results and Benefits of the Integrated Approach
The combined implementation of validation, validation, risk assessment, and change control has thus led to an approach that succeeds in ensuring reduction of document errors with a significant decrease in serious deviations at the inspection stage notified by the National Transplant Center. This has also led to an improvement in the efficiency of collection and handling processes and specifically better synergy with CAR-T-producing centers, thanks to the standardization of flows that have undergone variations based on requests from, for example, CROs.
Conclusions
Quality management in a modern tissue institution can no longer ignore a systemic approach that integrates validation, validation, risk assessment, and change control. This model, in full adherence with the JACIE standards and the State-Regions Agreement 49/2021, guarantees not only patient safety but also the reliability of the entire process vis-à-vis manufacturers and regulatory authorities.
In an era when personalized medicine and advanced therapies are becoming increasingly widespread, it is essential that tissue institutes position themselves as strategic partners, capable of combining scientific innovation, regulatory rigor, and a culture of quality.
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