PHARMACEUTICALS
Figure 2 - Route of synthesis for olaparib
Engineering controls typically rely on purpose-built containment systems , such as isolators . These are used to ensure the maximum safety for the personnel . Containment performances are generally assessed through Standardised Measurement of Equipment Particulate Airborne Concentration ( SMEPAC ) testing .
The growth in the number of HPAPIs in development has created increased demand for capacity at CDMOs . To address this , Cambrex has commissioned a new high potency laboratory at its Milan site to support process and analytical development . This new lab adds to the company ’ s US capacity for HPAPI development and manufacturing . In this paper , we will describe the approach used for the design and qualification of the isolators , along with a case study on a product we developed using the newly commissioned facility .
Hardware design , qualification & operations
The Milan HPAPI laboratory was designed to include two highcontainment isolators , both working
under inert atmosphere and negative pressure . Each consists of several connected sections with cascading air differential between sections . One of them is dedicated to chemical processing .
The processing isolator ( Figure 1 ) is configured to follow the chemical process needed . The raw materials , reagents and solvents are introduced and weighed out in the first section before moving to the section containing the reactors . This section can accommodate jacketed reactors from 250 to 2,000 ml . It connects to a section for isolation , which can be equipped with filtration equipment and includes a built-in vacuum tray dryer .
The final section is dedicated to packaging the material . A completely separate section within the same lab is dedicated to analytical development and testing , housing equipment such as balances , titrators and IR spectrophotometers . In the case of both isolators , all materials entering and exiting the isolators are managed through continuous liners or rapid transport ports . Both isolators were customdesigned , with a target containment performance of 0.1 µ g / m 3 .
Following commissioning , draft operational procedures were developed for all the unit operations expected to be performed within the lab and isolators . Procedures , developed through detailed risk assessment , included all the expected unit operations from reaction setup to work-up , isolation , drying and analytical sample preparation .
Once the procedures were in hand , the unit operations were carried out as drafted , using lactose as the surrogate for an HPAPI and SMEPAC testing was performed . This methodology was used to qualify the isolators and demonstrate the desired level of containment .
A different risk analysis was applied for the definition of the cleaning procedure used between projects or when the isolators need to be opened and subject to maintenance . For each highly potent compound , intermediate or API , a specific cleaning procedure needs to be defined , based on solubility and recovery data from
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