More than three years have passed since the entry into force of Annex 1 of the GMPs, and, as expected, the timelines for implementing some of the required changes have not always met the demands of such a stringent regulatory framework.
It is worth highlighting the efforts made by sterile product manufacturers, who have undertaken an exhaustive review of their processes, facilities, and quality systems, resulting in a robust Contamination Control Strategy (CCS). This document has served as a roadmap to identify deficiencies and prioritize actions, ranging from the redefinition of workflow layouts to the completion of pending disinfection validations.
Time to Review the CCS
An important aspect to consider within the pharmaceutical quality system lifecycle is the periodic review of the CCS, with a frequency established based on risk assessment or evidence-based rationale. At this stage, most CCSs developed in 2022 are reaching the moment for review and evaluation of the completion of planned actions. The expectation is that these actions have been finalized—many of them related to barrier technology requirements.
Nevertheless, the pharmaceutical industry is diverse in terms of size, technological capacity, and resources, and not all organizations have been able to adapt their facilities to the new requirements of Annex 1. In this context, numerous legacy lines persist—those inherited from consolidated plants that continue manufacturing sterile products compliant with their quality specifications, but which could hardly be requalified according to today’s most demanding standards for sterile manufacturing.
There are no public data on how many legacy lines remain active, but GMP consulting experience suggests that the number is significant and, in many cases, far from the state of the art required by current regulations.
Main Risks and Mitigating Measures
The main risks associated with these lines are well known: the absence of effective barrier systems (RABS or isolators) in accordance with Annex 1, and dependence on manual operations during contact part assembly and production processes. To address this, companies have reinforced procedures and measures that partially mitigate identified risks—stricter in-process controls, operational procedure reviews aimed at automation, and continuous personnel training—to maintain product quality.
However, the risk of non-compliance in the design and maintenance of barrier systems is not limited to legacy lines. Several FDA Warning Letters have documented deficiencies in lines equipped with RABS, both in operation and design: interventions under unidirectional airflow, open vial handling, or the absence of appropriate gloves in supposedly closed systems.
Review, Update, and Redesign
This underlines the importance of periodically reviewing production lines and updating CCSs to incorporate actions that directly impact the design of equipment and facilities dedicated to sterile drug manufacturing. Some plants have already chosen to redesign their legacy lines, integrating physical barriers that limit manual access and preserve unidirectional airflow, together with automated systems that eliminate the manipulation of contact parts. When properly implemented, these solutions achieve Annex 1 compliance with significantly lower investment than full line replacement and acquisition of new equipment.
To approach such projects, a suitable proposal is to perform a Gap Analysis that assesses compliance point by point with the standard, thereby determining the associated risk level. For this, an objective risk analysis tool such as FMEA is recommended. Once risks are evaluated, mitigation actions are proposed, followed by re-scoring to establish the residual risk. It is essential to work with collaborators experienced in the design and construction of sterile manufacturing equipment. This ensures that the proposed actions are ad hoc, technically feasible, and easily integrated into the existing quality system.
Reducing Risk: The Principle that Unites It All
Ultimately, all these requirements align under one principle: reducing the risk of sterile product contamination. Therefore, any adaptation action must be evaluated within a comprehensive risk analysis, considering the technical characteristics of the current equipment, existing workflow, and implementation feasibility.
We therefore advocate for a realistic and strategic review of legacy lines, aimed at their modernization. With redesign based on risk management and a feasible investment plan, these lines can evolve toward compliance with Annex 1, ensuring both product quality and operational continuity within pharmaceutical plants.
In summary, the implementation of Annex 1 has marked a turning point in sterile drug manufacturing, compelling the industry to rethink the design, operation, and control of its production lines. Although legacy lines pose challenges due to technical limitations, they also represent a strategic opportunity to evolve through redesign based on risk management, barrier technology integration, and process optimization. With periodic CCS reviews, realistic investment planning, and the support of specialized technical partners, it is possible to transform these facilities toward a sustainable compliance model that preserves product quality and secures the competitive continuity of pharmaceutical manufacturing in today’s regulatory landscape.
