2. Focus on barrier technology

One rationale of the new Annex 1 is the separation of the aseptic process area from the operator environment. For the first time, the document clearly recommends the use of appropriate barrier technologies – isolators and RABS (Restricted Access Barrier Systems) are considered equal. Pharmaceutical manufacturers will therefore require at least RABS for the approval of new products; new approval on existing cleanroom lines will only be possible in exceptional cases. In the year following the publication of the guideline, the industry witnessed a veritable “run” on RABS upgrades of existing cleanroom lines, which continues to this day. The aim is to fulfill the requirements of Annex 1 for the operation of RABS as completely as possible – which is quite a challenging task. Pharmaceutical manufacturers must decide whether to retrofit an existing cleanroom line for a new product or invest in new filling equipment that runs with isolator (or RABS). Isolator technology will become the new “normal”, as automatic bio-decontamination processes and the pressure difference from the operator environment provide additional safety. RABS is more likely to come into play for frequent product changes and with experienced operators.

3. A question of sterility

To establish and maintain sterility as required by Annex 1, pharmaceu- tical companies must conduct a contamination risk analysis and docu- ment it with measures in the form of a Contamination Control Strategy (CCS). Advanced equipment makes an important contribution here. In the second chapter of Annex 1, automation and robotic systems are highlighted under the heading “Appropriate technologies”. By using these technologies, gloves and human intervention in barrier systems can be reduced to an absolute minimum or even eliminated. The issue of gloves presents many challenges, which are acknowledged in sepa- rate paragraphs. For example, gloves are to be additionally tested in operation during longer campaigns – which is not possible with the glove testing equipment used to date without risking the integrity of the sterile room.

In fact, the new Annex 1 requires high level disinfection as soon as the gloves have been exposed to the RABS environment. Besides the aseptic setup situation, this also concerns the intervention involving door opening during production. This makes the disinfection process very demanding, as the final steps must be performed with the doors closed. At the same time, the disinfection reagents should not affect packaging materials, components, and unsealed products. A switch to gloveless systems with robotics that handle these manipulations represents the “grail of solution scenarios”. One example is Syntegon’s new Versynta microBatch2 for processing very small batches. The fully automated isolator production cell fills between 120 and 500 containers per hour with virtually no product loss and 100 percent in-process control. Glove interventions are no longer necessary in this solution.

4. “First Air” as major challenge

Annex 1 also sets clear requirements for air flow: unidirectional air flow (UDAF) is mandatory for open isolators and RABS in all class A areas and should not be interrupted between the air inlet and the open product. The air velocity (0.45 m/s +/- 20%) and its measurement are located “at working position”. This does not refer to the vertical position (“working height”), but the area of the critical, quality-relevant processes on the machine, such as filling, stoppering, and gassing. UDAF has the task of carrying any potential residual particles away from the product. This can also be achieved well at lower air speeds at product height3.