Closing the Gap in the Annex 1 Era
EU GMP Annex 1 has sharpened the focus on contamination control across the industry. However, its impact on drug substance (DS) filling is proving particularly significant.
The challenge
Many legacy DS filling operations were designed at a time when robust procedures, cleanrooms and skilled operators were considered enough to manage risk. In practice, many of these systems still perform well today.
However, Annex 1 - supported by Annex 2 - has shifted the regulatory conversation. The emphasis is no longer on outcomes alone, but on process design, human dependency, and long term sustainability.
“The message from regulators is increasingly clear. Prevention through engineered controls is more effective than reliance on procedures, monitoring, or operator behaviour alone."
Alan Kelly
SME Aseptic Fill Finish
Reducing exposure
That doesn’t mean open DS filling is suddenly non compliant. But it does mean it must be risk assessed, justified and actively managed, with a credible plan to reduce exposure over time.
“At PM Group, we’re seeing clients grapple with a very practical challenge. How to maintain supply and operational continuity today, while moving decisively toward Annex 1 aligned future states,” said Alan.
The answer is rarely a single step change. Instead, the most successful strategies apply ICH Q9 Quality Risk Management to clearly distinguish between:
- risks that can be acceptably controlled in the short term, and
- design limitations that are no longer defensible as a long term solution.
Strengthening interim controls
In practice, this often means strengthening interim controls. It involves error proofing manual set ups and reducing subjectivity in aseptic technique. It includes improving equipment hygiene and cleanability while simultaneously planning for engineered protection.
Improving consistency
On new projects and upgrades, barrier technologies and closed filling systems are now the norm. These include closed RABS, automated closed bottle filling and closed single use bag and bottle systems.
They reduce the need for operators. They also improve consistency and help to maintain low bioburden. Industry benchmarks show these solutions are no longer ideas for the future. They are quickly becoming standard practice.
"Open DS filling should be positioned as an interim, managed risk - not an acceptable steady state."
