Lorcan McGarry, general manager at Hovione Cork, describes the GMP spray drying facility at the Loughbeg site acquired in April this year
Hovione Cork, in Loughbeg, Ireland, is the newest site in the Hovione group. Purchased from Pfizer this year, and officially opened by Hovione in April 2009, the Cork site is an active pharmaceutical ingredient (API) plant comprising two main API production buildings and a spray dryer building.
Established in 1984 from green fields by Angus Fine Chemicals, the 32-acre site has had a succession of owners. In 1997, Warner Lambert purchased it for the manufacture of Lipitor intermediates, then in 2000, following a merger between Pfizer and Warner-Lambert, the site became a part of Pfizer until 2009.
The spray dryer building is one of the latest additions to the site. Construction of this facility commenced in 2002 and was completed in 2005. The main elements of the building are:
A five-storey building with 5,020m2 floor area
A Niro PSD 5 spray dryer, fed by nitrogen and with a maximum working temperature of 160°C
An 8,000 litre, stainless steel solvent preparation tank for pre-heating the spray dryer train
Two 16,000 litre stainless steel product makeup feed vessels for the spray dryer
A 16,000 litre solvent collection tank for collecting condensed solvent from the spray dryer
A 7,500 litre secondary dryer for secondary drying of spray dried product if required.
The facility is a multipurpose drying plant designed to produce both APIs and drug product intermediates. It was originally constructed by Pfizer to produce material for clinical trials of a new cholesterol lowering drug. In terms of scale, it is one of the largest spray dryers of it type applied in a high GMP pharmaceutical environment.
The spray dryer can handle either aqueous- or solvent-based drying and has several solvent drying safety features. Drying from a flammable solvent is carried out in a closed loop nitrogen-inerted system, continuously monitored for oxygen for safety reasons. Additional safety measures (some of which were a first for a dryer of this type) such as explosion pressure resistant design and explosion venting/isolation were also incorporated into the design.
Product is recovered from the spray dryer via a cyclone, which discharges into a high containment closed IBC system. Evaporated solvent is recovered using a condenser in the nitrogen gas loop. The dryer is designed to a high GMP standard and incorporates a full inline clean-in-place (CIP) system.
The facility has three area classification zones: the unclassified offices, fire escape area, etc; a GMP transition area, which includes control room, material marshalling, etc; and a GMP manufacturing area that includes dispensing and manufacturing areas.
pressurisation philosophy
The building is generally under positive pressure compared with the external environment to ensure minimal incoming contamination. The service corridor has a positive pressure compared with the production suites, providing a barrier to cross contamination and also a level of containment for the suites during process upsets. The minimum pressure differential between areas is 15 Pa. The classified clean areas in the GMP manufacturing areas are all provided with 20 air changes per hour and all clean areas have terminal HEPAs on the supply, and local safe change HEPAs on the exhaust.
The building and equipment are designed to minimise product exposure, protecting both the product and the operator. The facility can handle materials with an OEL down to10µg/m3. The design includes a range of containment technologies to provide primary and secondary containment. Primary containment methods include closed processing systems, closed Matcon IBCs, contained discharge systems, laminar airflow booths and contained sampling systems. Secondary containment systems include HVAC systems to give the desired air changes and cascade pressure profiles, HEPA filters on supply and exhaust ducts, weak effluent sump tank, relief receiver and double contained underground process drains. The HVAC system is designed to meet class ISO 8 standards to ensure product cross contamination does not occur.
materials handling
All powder transfers inside the building are carried out using Matcon bins. The incoming powder is transferred into a Matcon bin in a dedicated charging station and finished product is transferred from the Matcon bin to drums in a dedicated pack-off area. The volumes of material being handled in the original design necessitated the use of 1,500 litre IBCs and FIBCs for raw materials and process intermediates. A new solution was therefore developed to facilitate interchangeable use of IBCs and FIBCs on the same handling equipment. Drums can also be used when handling small batch sizes.
The process equipment train is cleaned using a fully automated CIP system. The system is designed to allow use of either solvent or aqueous plus detergent (e.g. CIP 100) cleaning.
The process control system for the spray dryer facility is an Emerson Process Management DeltaV Batch Distributed Control System comprising 12 MD controllers, remote and conventional I/O and seven Operator Interface Terminals for plant visibility. The system uses Emerson Process Management's Plant Web digital control architecture and has more than 2,600 installed I/Os, which interface via Foundation Fieldbus for measurement and modulating control devices. Devices are also wired back to local remote I/O panels in the field that, in turn, are connected back to the process control system via a dual redundant Profibus network.
Insum Direct Motor Technology is used for communication with and control of fixed speed motor control units, providing increased diagnostics and intelligent capabilities for each motor.
The plant control system has been configured to be recipe driven. The DeltaV Batch system is fully S88 compliant, giving the plant the flexibility to change quickly and easily using a recipe structure. Having a recipe driven batch process has several advantages, including: reduced operator exposure as less operator intervention is required; increased safety due to consistent control of operation; consistent product quality and increased yield; data for regulatory compliance; increased flexibility and optimal capacity utilisation and efficiency.
Process Analytical Technology (PAT) is applied in three key areas of the plant:
An inline particle size analyser is installed on the outlet duct of the spray drying chamber. This uses laser diffraction technology to monitor continuously and in real time the particle size distribution of the spray dried product leaving the spray drying chamber. This is useful in analysing the performance of the spray dryer and the response of particle size to changing process parameters.
A Near Infra Red (NIR) spectrometry system is installed in the secondary dryer to monitor residual solvent content during drying. The required end point of drying can be accurately detected in real time without the need for sampling and offline testing.
A UV spectrometer has been installed on the CIP system, which allows the CIP return fluid to be monitored during CIP for residual product content. It serves as a useful tool for predicting the degree of CIP washes and rinses required to ensure the plant is cleaned to specification, minimising water or detergent use.
This year, Hovione is celebrating its 50th year in API development and manufacture. With four FDA inspected sites in the US, China, Ireland and Portugal, the company continues to focus on API manufacturing, inhalation drug development services, particle design and formulation development for enhance API performance and generics API production.
The Cork site is important as spray drying is currently employed by Hovione to manipulate the physical attributes of particles in a controlled manner in three approved commercial APIs and in dozens of other APIs in various phases of development. The company expects another two spray-dried compounds to see their NDAs filed at FDA in the next 12 months. mc