Manufacturing facilities for highly potent APIs

The risk of exposure to a chemical is defined as the multiplication of the hazardousness of the chemical by its amount of exposure. The control level of each chemical powder handling is established based on its risk. Our double barrier system consists of a primary barrier and a secondary barrier:
Primary barrier: containment equipment (e.g. negative pressure isolator that locally contains the source of dust generation).
Secondary barrier: negative pressure rooms with a HEPA*2 filter for exhausted air (environment surrounding the equipment for equipment)
* 2: High Efficiency Particulate Air Filter

1) Primary barrier (equipment for containment)

This section provides an overview of the containment equipment of the building for high potent APIs. Operations which easily generate powder dust such as drying, handling of micronized crystals in the milling process and weighing and subdivision are carried out in a negative-pressure isolator to achieve high level of containment.
As in-line monitoring system (for crystallization and milling processes) by PAT*3 has been proactively employed to handle high potent substances, high-level quality assurance has been achieved.

*3: Process Analytical Technology: A system for designing, analyzing, and controlling manufacturing through timely measurements (i.e., during processing) of critical quality and performance attributes of raw and in-process materials and processes with the goal of ensuring final product quality. (ICH Q8(R2)

In-line monitoring of crystallization process

The crystallizer is equipped with PAT tools (in-line particle size distribution tester and particle image analyzer) to reduce sampling operations and achieve high-level quality assurance.

Dry milling operation

・ Use of a counter-jet mill contained in an isolator
・ Capable of dry milling under a nitrogen atmosphere (anti-explosion).
・ PAT tool (in-line particle size analyzer) is used to assure high-level quality assurance.
・ WIP and cleaning with organic solvents can be conducted.
・ Isolators for milling and weighing and subdividing are connected with each other to enable a range of operations from milling to weighing and subdividing to collecting of milled materials into drums in a contained environment.

2) Secondary barrier

Local containment is conducted by the primary barrier. The secondary barrier is used for just in case where some leakage occurs from the primary barrier for some reason. To contain the leakage, as the secondary barrier, air pressure of all rooms relating to the manufacturing are controlled to maintain negative pressure. The HVAC system for each room which has contained equipment inside is equipped with HEPA filters for supplied and exhausted air. This HVAC system uses once-through air system (all fresh air system). Particularly for rooms where dry powder is used, double HEPA filters are used for the exhausted air. A bag-out system is used for the HEPA filters so that workers can safely change the filters.
The figure below shows as an example of the secondary barrier the layout of the changing room and pass room leading to the room where powder is handled.

The blue lines show personnel flow. Personnel flow is separated between entering and leaving the workroom to enable one-way changing. Workers move along these lines and change their clothing to enter and leave the work room where powder is used. The yellow line shows material flow. The material flow is not separated between entering and leaving. As for air flow (red lines) and room pressure, the pressure of gowning/degowning room and that of the pass room is the highest and the air flows from these rooms into the workroom where powder in handled.
This characteristic layout shows construction design that meets both requirements of containing high potent APIs, our highest priority, and requirements for the secondary barrier. The green lines mean the boundaries between hazardous area and non-hazardous area. The gowning/degowning room and the pass room are being used with the concept of not bringing out high potent substances in mind.

Qualification of the containment equipment as the primary barrier was implemented following SMEPAC*4 published by ISPE (International Society for Pharmaceutical Engineering) using placebo powder (lactose). Measuring procedure, sampling points, and analysis were based on SMEPAC.
As for actual powder, monitoring of the scattered powder was conducted outside the secondary barrier and the air exhaustion system from the viewpoint of prevention of cross contamination and protection of environment.
Shionogi Pharma provides services not only for contract manufacturing but also for supporting our customers regarding designing of facilities that handle high potent substances, consulting about risk assessment. Shionogi Pharma also provides analytical services such as exposure assessment and scattered dust measurement.
Don’t hesitate to contact us if you are interested in our services.
* 4: Standardized Measurement of Equipment Particulate Airborne Concentration

Topics