Conversations That Matter
No deviation’s Takeaways from the ISPE Training on Annex 1 Implementation and First Inspector Findings
At the recent ISPE training on Annex 1 Implementation and First Inspector Findings, speakers Tracy Moore (TM Pharma Group Ltd) and Richard Denk (SKAN AG) shared their insights on the progress of the industry’s adoption of the updated Annex 1 guidelines and lent their expertise on common findings and best practices.
Persistent Challenges in Annex 1 Implementation
Recent inspections have identified recurring gaps in the implementation of Annex 1. Findings frequently point to:
- Design gaps relating to barrier technologies: This can occur in two fashions: 1) Inadequate barrier technology built into the process; 2) Poor design of existing barriers leading to contamination risks
- Inadequate operator training in proper aseptic techniques and barrier use
- Inadequate environmental monitoring (EM) program
Proper Implementation of a Contamination Control Strategy (CCS)
One key message that emerged out of the training is that you cannot monitor or control your way out of a poor design. A robust CCS is built on the following (in order of importance):
- Design: Process, equipment, facility and utilities
- Control: Procedures related to personnel training, gowning, cleaning and sanitisation
- Monitoring: Personnel, in-process, material, environmental and utilities monitoring, aseptic process simulation (APS)
The speakers advocated strongly for facilities to be built in such a way that facilitates equipment being replaced easily, as challenging circumstances behind modifying equipment with design gaps has been noted to be one of the key issues in Annex 1 implementation.
Barrier Technologies: Restricted Access Barriers Systems (RABS), Isolators
The speakers emphasized that barrier technology is only effective when it is accompanied by proper design and usage. Key points included:
- RABS design should be done together with cleanroom design to avoid failures during smoke studies. Unexpected airflow patterns often result when the RABS and cleanroom designers do not communicate well in a project.
- Proper use of RABS includes keeping the RABS doors closed most of the time and keeping operators out of the critical zone. If typical interventions require operators to open or cross the barrier, the barrier is no longer effective.
- Take note of hand movements that lead to turbulence above critical zones. These critical zones may differ slightly between operations. An example would be the changing of settling plates, where the zone may include lower heights if open settle plates are placed there temporarily.
- Operators need to be trained to visually inspect gloves properly, as well as perform Glove Integrity Tests (GIT)
- Some design considerations to be explored during process mock-ups:
- Whether left-handed operators can execute the required operations without obstructing first air
- Explore the use of armrests as an ergonomic option to restrict operators from performing prohibited interventions
- Doors for Rapid Transfer Ports (RTPs) should never be designed to open in a way that obstructs first air in critical zones
- The working height at which samplers and probes should be positioned (to weld them in place prior to delivering them to site)
Environmental Monitoring: Plan with Purpose
A common issue is treating environmental monitoring (EM) as a paper exercise to avoid trouble rather than a measure to detect contamination. Recall that per Annex 1, sites are expected to carry out risk assessments to establish their EM program. The speakers highlighted that:
- Viable monitoring of operators is required and difficult to justify omitting in most EM plans
- Monitoring plans for Grade C areas that serve as background to Grade A areas should resemble Grade B plans more than Grade C plans due to the higher risks
- Higher risk areas would include:
- Entrances to Grade A areas
- Filling needles
- Anything not sterilisable in Grade A areas (therefore requiring swabbing)
- The position of sensors or flow velocity measurements are justified by smoke studies
- Sampling method in Grade A: Sieve samplers should be used for high-risk events as they dry out quickly, whereas settle plates or slit-to-agar samplers are more suitable for continuous monitoring.
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