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API Manufacturing Plant

 

The production area includes two distinct sections:

     High Containment area
     Chemical Plant and Process
     Safety laboratory

 High Containment area

The High Containment Area is segregated from the Chemical plant and is divided in suites completely independent.

The suites are dedicated to manufacturing of APIs intended for human use. A single project can be carried out in each suite.

Development work is carried out in separate labs, also equipped with glove boxes, but intended for non GMP work. Our approach to high containment is to isolate in glove box any manipulation of powders, as dissolution, filtration, sieving, drying and packaging.

The reactors workcenter is connected to the glove box by means of fixed piping in a closed-cycle system. The volumes rank from 50 to 250L reactors. The batch size can vary from 0.5 to 4.0 kg.

Remote control of the reactions ensures additional safety and accurate monitoring of the reaction parameters. Because of the high activity of the compounds, limits for cleaning are very demanding (normally LT 0.01 micrograms per squared cm).

Isolation of solids is carried out by Buchner filters in the smaller suites, (0.5 to 2 kg) while there is a 0.06 m2 filter drier inside a glove box for larger batches (4-5 kg). There are several different columns for chromatographic purification. The largest can hold 48 kg silica/resin.

  Safety aspects:

  Deactivation of all waste streams must be carried out in place (and analytically tested) before sending anything to incineration.

  All gas emissions are conveyed to blow down, scrubbers and activated carbons, to prevent pollution of the environment.

  The glove boxes are fed with nitrogen through absolute filters; internally there is a negative pressure compared to the room. There are additional absolute filters for the outlet nitrogen.

  All suites have sprinklers fire-extinguishing system.

  Technology transfer:

Beyond supplying material for the clinical studies, the goal of the scale up is to set up conditions to be implemented in an industrial plant.
The use of the same type of equipment that will be found in the industrial plant makes the technology transfer easy.

  Summary of capabilities

  Smaller suite equipped with 2 x 25 L glass reactors, 2 x 50 L separators. T range -20 °C to 120 °C. Max batch size 500 g

  2 suites equipped with 2 x 50 L glass reactors, 2 x 50 L. 1 x 200 L separators. T range -20 °C to 120 °C. Max batch size 2 kg

  The largest suite includes 50 and 100 L reactors, 250 and 400 L separators, filter drier inside a glove box. Max batch size 4-5 kg.

  Column chromatography up to 48 kg of silica under pressure or 100 kg of resin gravimetric.

  A smaller separated area is dedicated to lower scale preparations or supply of reference standards.

  All these areas are GMP, development is carried out in dedicated labs with the same level of protection.

 Chemical Plant and Process

Often the synthesis of APIs for Oncology involves a large number of steps.

Normally the need for high containment is limited to the last steps, when the molecular structure becomes more similar to that of the API. Anyway the risk assessment for these intermediates is often incomplete. We prefer therefore to protect all the loading and discharge operations.

The chemical plant is multipurpose and includes a variety of reactors from 25L to 250L in glass, glass-lined and hastelloy, two of them can operate at low T (-70 °C). Most reactors are also equipped with spray-balls.
Solids are isolated either by centrifuge or filter drier.
Max batch size currently 30 kg, with a filter dryer in hastelloy.

Equipment includes:

  Chromatographic column, holding 200 kg of silica.

  Large volume vessels to make up the mobile phase or collect core fractions (up to 3,000L).All pipings to/from the vessels converge to a manifold where the desired connection can be done, avoiding dead-legs and making cleaning easier.

  Three independent vacuum lines prevent the risk of back-flow of solvents.

  A 50L hydrogenator in hastelloy is located in a safe area outside the pilot plant.

 Process and Safety Laboratory

 

The Process Safety Lab performs activities aimed at ensuring safe scale up, including determination of thermal stability of the intermediates, compatibility with the materials, study of runaway reactions, but also substantially contributes to the engineering of the process. Every synthetic step must be subject to process safety review before implementation at pilot scale.

Equipment includes:

  Adiabatic calorimeter ARC 2000

  Differential Scanning Calorimeter Mettler DSC822, TC15

  FT-IR Mettler probe (continuous monitoring of reaction)

  Lasentech probe (particle size distribution during crystallization)

  Calvet calorimeter Setaram C80 Setaram

   Reaction calorimeter RC1 Mettler Toledo

   DTA hot stage microscope system Mettler Zeiss FP90

  Kuhner apparatus

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