Jacintha Griffin - Site Lead for Technical Services, Operational Excellence & Innovation at Pfizer CentreOne explores how drug delivery methods have evolved to deliver complex formulations using multiparticulate technology - with a focus on extrusion-spheronisation coated bead technology.
Futuristic Pharma
A flexible delivery platform
The increasing complexity of molecules in the drug development pipeline calls for flexible and patient-centric drug delivery platforms.
Multiparticulate technology offers many advantages over conventional tabletting methods. These drug delivery systems provide the flexibility to design complex oral solid dosage (OSD) formulations that require controlled or extended release.
Multiparticulates are discrete drug-containing particles that together make up a single dose. Preparation methods are varied and can be adapted according to target drug-release profiles.
Extrusion-spheronisation as a technology platform accommodates a wide range of drug loading with the process flexibility to deliver immediate release, extended release, or combination products. It has the added advantage of dose flexibility that can be achieved by changing capsule fill weight without altering the manufacturing process. In addition, multiparticulates eliminate dose dumping, a challenge often observed with single-unit dosages.
From a patient perspective, multiparticulate dosage forms are more desirable as they can be adapted to a once-daily, extended-release dosing, are easier to swallow, and can be coated for taste-masking.
Robust and reliable
From a manufacturing perspective, extrusion-spheronisation is a highly robust, reliable, and predictable technology platform achieved by an integrated process design approach:
- Characterization of material inputs and variability;
- In-depth process understanding; and
- Process modelling and control
Material Characterization
The foundation of a robust manufacturing process is an in-depth characterization of input materials to understand any lot-to-lot variability and potential impact on critical to quality attributes (CQA) & downstream manufacturing.
At Pfizer CentreOne’s facility in Newbridge, Ireland, advanced characterization of inputs and fingerprinting of different lots of active pharmaceutical ingredients (APIs) and critical excipients using Process Analytical Technology (PAT) are completed to ensure optimised, controlled, and consistent manufacturing processes.
Process Understanding
Robust processes are designed and developed using development data from small-scale manufacturing to establish normal operating ranges and to understand process inter-dependencies and intricacies, thereby reducing the risk of unexpected challenges during scale-up and commercialisation.
Process Modelling & Control
The resulting manufacturing processes can be modelled to allow seamless scale-up from development through to commercial manufacturing. Critical process controls are established and monitored as part of an integrated process control strategy.
A Multiparticulate Process using Extrusion-spheronisation
An example of a multiparticulate process that has successfully performed for over 20 years at the Newbridge facility is the extrusion-spheronisation process. This consists of a six-unit operation – dry blending, wet granulation, extrusion, spheronisation, pellet drying, and, if required, pellet coating. Each unit operation is optimised to ensure seamless transition from one operation to the next downstream process.
Dry blending
Optimisation of dry blending to achieve a homogeneous blend is established during process design. Critical parameters include: the order of addition of APIs and excipients, the optimum batch size, blender fill level, mixing action, speeds, and blending time.
At Pfizer CentreOne’s Newbridge facility, PAT is used to develop blending end point as part of a process control strategy. One example of PAT is near-infrared (NIR) spectroscopy.
Wet granulation
This process forms liquid and solid bridges between the particles which coalesce to form granules.
The critical process parameters for a wet massing granulation process are:
- the rate of addition, quantity of the granulation solution, nozzle design, mixing action, and granulation time; and
- process control strategy includes granulation endpoint and intermediate hold times which are established as part of the process design.
Extrusion and spheronisation
The next two-unit operations – extrusion and spheronisation – begin with feeding the wet mass through an extruder screen.
The critical parameters include: granulate moisture level, impeller and feeder speed, screen thickness, and diameter of perforations, and extrusion force.
The spaghetti-like extrudate is fed into the spheronisation unit where, extrudate characteristics, rate of extrusion, spheroniser setup, spheronisation time, speed, and load will determine the quality and consistency of pellets for downstream drying and coating processes.
At Pfizer CentreOne, a multivariate design of experiments approach is used to optimise these processes to ensure high pellet sphericity for subsequent coating.
Pellet drying and coating
For pellet drying and coating, process parameters and equipment set-up must be carefully controlled and thermodynamically balanced to achieve consistent and uniformly coated pellets.
Key process parameters to ensure uniformly coated pellets include:
- Incoming pellet characteristics, e.g., size and shape;
- Batch size;
- Coating solution characteristics; e.g.; viscosity;
- Equipment set up, e.g., nozzle design;
- Process parameters including spray rate, atomising air pressure, inlet air temperature, and volume and product temperature.
The resultant pellets can be filled into hard gelatine capsules, sprinkle capsules or sachets, flexibility being the hallmark of a multiparticulate process.
Final thought
Extrusion-Spheronisation is a highly flexible multiparticulate technology platform that can deliver increasingly specialised medicines.
With the appropriate technical expertise, robust, predictable, and scalable processes can be designed that enable seamless transfer from development through commercialisation.