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How to Maximize Productivity by Using Closed Systems & Disposables: Annex 1 Implementation Between GXP Compliance & Cost Containment

Richard Denk
Closed Isolator: Courtesy SKAN AG for Cell and Gene Therapy

The 2022 ISPE Pharma 4.0™ and Annex 1 Conference takes place in Vienna, Austria and virtually on 7-8 December, and will offer attendees several unique perspectives, case studies and site tours. This blog posts delves into the topic of track 3 - How to Maximise Productivity by Using Closed Systems and Disposables: Annex 1 Implementation Between GXP Compliance and Cost Containment. It will try to show a differentiated picture of the current situation in the industry, from PUPSIT (Pre-use post sterilization integrity testing) and Filter Sets, Leachables and Extractables, Drug substance closed processing in downstream applications and Aseptic filter validation.

2022 ISPE Pharma 4.0 and Annex 1 Conference

Two special topics are at the heart of this track: the implementation of the EU GMP Annex 1, which should be published by the conference, and closed systems and sustainability. In closed systems, a distinction is made between closed containers, their connectors, and isolators. Both systems minimize the required clean room classes outside the containment area. In Annex 1, clean room class D is required as a minimum for closed isolators. This means a considerable reduction in the requirements of air exchange, room monitoring, air lock systems, and gowning and de-gowning for the operators. Productivity can also be improved with closed systems. All these aspects are described in this blog post.

Closed sterile Transfer SART Port: Courtesy Sartorius
Closed sterile Transfer SART Port: Courtesy Sartorius

What should be considered with closed systems concerning single used systems (SUS)? SUS are widely used in pharmaceutical manufacturing, primarily in biopharmaceutical manufacturing and upstream and downstream area. They can be single-use bioreactors, filter systems, and etc. The different process steps are then connected with so-called aseptic connectors—or sterile connectors. The entire process is carried out as a closed system.

The following aspects should be considered for a successful installation of the SUS:

It is important to consider that SUS can easily be damaged because of their flexible design, so they should be packaged and stored correctly (storage on top of each other should be avoided). Unpacking and assembly can also lead to damage. When dismantling a SUS, care must be taken not to break the containment and contaminate the room.

Since single-use systems are not cleaned after their use but disposed of, there is no need for time-consuming cleaning as with rigid installations. This allows a quicker switch to the following product. If the biopharmaceutical product is a highly active substance or the substance requires a higher biosafety level such as BSL 2, or if viral vectors are being handled, it is advisable to take critical process steps to prevent possible contamination of the environment. For example, by dismantling the SUS and installing it into another barrier such as an isolator. Also, the isolator can form an aseptic barrier around the single-use system if the integrity of the single-use system cannot be assured.

Isolators are seen as another closed system. These are now divided into two categories in the new Annex 1:

  1. Closed isolators that can be installed in clean room class D, and
  2. Open isolators that can then be installed in clean room Class C.

But what is the difference between a closed isolator and an open isolator?

Definition from the EU GMP Draft Annex 1 Version 12:

Closed isolator systems exclude external contamination of the isolator’s interior by accomplishing material transfer via aseptic connection to auxiliary equipment, rather than use of openings to the surrounding environment. Closed systems remain sealed throughout operations.

See picture of a closed Isolator below for the use in Cell and Gene Therapy.

Open isolator systems are designed to allow for the continuous or semi-continuous ingress and/or egress of materials during operations through one or more openings. Openings are engineered (e.g., using continuous overpressure) to exclude the entry of external contaminant into the isolator.

Closed Isolator: Courtesy SKAN AG for Cell and Gene Therapy
Closed Isolator: Courtesy SKAN AG for Cell and Gene Therapy

Isolators not only offer the opportunity to improve sustainability in the manufacture of sterile products and ATMPs, but they also protect workers and the environment from the active pharmaceutical substance. Employees can also move around isolator-systems more easily than with other systems such as RABS “Restricted Access Barrier Systems” installed in a Grade B clean room zone. Due to the boom in biopharmaceutical manufacturing, trained employees are a rare commodity. The lower the Clean Room Class requirements of the environment, the easier and faster it is to train the employees. Closed systems such as isolators are also advantageous when implementing the new EU GMP Annex, as they isolate the sterile product from the environment and support production sustainability.

I hope this insight into contamination and cost containment has prompted your interest. It is one of the many topics of the 2022 ISPE Pharma 4.0™ and Annex 1 Conference, which blends technology-related subjects such as Robotics and Pharma 4.0™ with regulatory aspects from Annex 1 implementation to developing a Holistic Contamination Control Strategy.

As the track leader for Annex 1 - Regulatory and Manufacturing Compliance and co-track leader for Pharma 4.0™ and the Contamination Control Strategy, I look forward to your active participation on this special event. My personal highlight for the Conference is the discussion with Rico Schulze, a GMDP Inspector, and Roland Bauer, the Head of Institute at the Austrian Agency for Health and Food Safety, concerning Annex 1 and computerized Systems. I am also particularly pleased about the venue in Vienna, as the city is famous for its Christmas markets and the cozy get-togethers. I look forward to welcoming you to Vienna!

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