What do inspectors find in ATMP production facilities?
Countless ATMP facilities have been inspected resulting in several re-occurring issues (see Table 1). Many findings have led to new guidances and improved facility designs enabling robust process designs and lowering contamination risks. Despite these improvements, inspection findings in ATMP facilities remain high.
From a regulatory observation, upgrading a clinical trial drug product manufacturing site to commercial manufacturing can be a daunting task. For example, a facility design may be ill-suited for a process commercial production campaign, the procedures may be too general or unspecific, and the staff may have the habit of prioritizing yields (a process development goal) over process controlling aspects of manufacturing. Historically, many ATMP manufacturing sites emerge from multipurpose facilities such as university hospitals or clinical trial phase I production facilities. These facilities required a high degree of manufacturing flexibility, as they were designed for clinical supply, and thus introduced a degree of academic or sometimes hospital (exemption) rules into the cGMP playbook. The more established players – apart from having larger budgets – build facilities where the process defines the product and they may encounter fewer facility risks, along with a reduced need to retrain staff to break habits.
Table 1. GMP inspections at ATMP manufacturing sites, focus EudraLex Vol. 4 Part I Annex I.
On a positive note, progressively more nonprofit organizations (e.g., university hospitals) work closely together and support each other. For example, some organizations share extensive (and expensive) validation protocols and cleanroom designs so processes can be more easily transferred between centres and mistakes can be minimized. What remains, manufacturing ATMP is expensive to produce, generally of small-scale (USP-runs are generally < 500 litres compared to antibody products easily reaching 10.000 litres), and frequently produced in multipurpose cleanrooms. This often results in a low number of batches produced in many different ATMP facilities with the difficulty of establishing robust processes, having experienced operators (high turnover rate ), and an increase in (viral) cross-contamination (line cleaning).
The challenges need to be carefully addressed, especially given the more elaborate process descriptions in the updated Annex 1 (2022). We also see an industry-wide push for automation in documentation, implementation of Pharma 4.0 principles, intensified (or continuous) production processes, and in-line live monitoring. The transition to these systems will be challenging for many ATMP facilities (See also ISPE GAMP-5 guideline or ISO 14644-4:2022 Part IV).