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After conducting extensive market research, Penn Pharma identified an increased need in the solid dose oncology market for the outsourced development and production of highly toxic drugs. Its production site had been manufacturing potent solid dosage products for more than 20 years but needed additional capacity.
Truly Contained Manufacturing
Penn Pharma (Tredegar, Wales) is one of the UK’s longest established pharmaceutical companies and was established 30 years ago to provide integrated drug development, clinical trial supply and manufacturing services to the international healthcare industry. After conducting extensive market research, the company, which operates from a single site and employs approximately 280 people, identified an increased need in the solid dose oncology market for the outsourced development and production of high quality, highly toxic drugs. Initiating an investment project to upgrade its site capabilities to support this market need, the aim was to create a new multiple active pharmaceutical ingredient (API) facility that could produce 1–120 kg batches using full containment according to ISPE guidelines.
The standard scope would be geometrically scalable dispensing, granulation and blending process that would be capable of producing coated tablets or single/combination API hard gel capsules. Using a quality by design (QbD) approach, the objectives for the expansion project focused on the pillars of Lean manufacturing: safety, quality, delivery, cost and, above all, the people.
The site had been manufacturing potent solid dosage products for more than 20 years but needed additional capacity. Without both innovation and investment to provide better solid dosage technology, and dispense with the cumbersome isolation suits that restricted development and were uncomfortable for operators, Penn Pharma would not be capable of achieving the production levels required by international pharmaceutical companies and business would only grow at the same pace as the global outsourcing market. To take advantage of the opportunity identified by its research, Penn Pharma would require a totally new concept in plant design, incorporating leading technology, the latest techniques and the ability to upscale operations from research and development, through pilot-scale testing, up to full production, all under one roof.
Penn Pharma made the decision to convert its 30-year-old facilities into a market-leading containment site in 2012 and chose GEA to be its technology partner, based on the following technical decision factors:
- complete solution provider to ensure responsibility for integration
- local, rapid UK support for parts and service
- containment solutions to fit requirements
- technical solutions for all challenges
- experience with similar projects
- best overall solution.
The plant development timeline is shown in Table I: it would have the highest standards of cGMP production; provide R&D, pilot scale and full production facilities from powder to capsule; and eliminate the need for isolation suits, thereby freeing up the staff and processes to enable enhanced production. It would also provide confidence to its international pharmaceutical customers that they were exercising a full duty of care throughout their supply chain by employing a manufacturer with the latest technology and safe working practices.
Partnering with GEA
Penn Pharma elected to work with GEA because of its proven track record in containment technology and for its process expertise in creating fully integrated production lines. GEA worked with Penn Pharma from the outset to develop an initial concept and select the technologies required, then co-operated with the engineering consultants to ensure that the plant was optimally designed for containment.
For example, small and large-scale process flows were fully mapped, covering all aspects of people and material movement, before the final cleanroom layout was fixed in place. All utilities and services in technical areas have been designed using a three-layer sandwich concept that facilitates maintenance. The HEPA filtration and dust extraction systems are designed to be “safe change filters.” The equipment design began with a value stream map to minimize the number of transfers between process steps (both small- and large-scale process streams have full flexibility). All containment valves were standardised to a 150 mm orifice and the intermediate bulk containers (IBCs) have geometric scale-up capacity (1–120 kg). A disposable Hicoflex® Bag option is available to preclude the costs and delays associated with cleaning validation.
GEA’s approach was to use its containment expertise to eliminate the use of isolation suits in favor of containment interfaces (BUCK® MC high-containment valves and Hicoflex®). These would not only interface with GEA’s advanced granulation, containment and compression technologies, but also with third-party equipment such as the powder dispensing isolator and, further downstream, the capsule filling and tablet coating elements to produce a fully contained, powder-to-capsule facility, in an open working environment. From a safety perspective, every item of equipment was designed to run at a negative room pressure to ensure maximum containment; every cleaning process is automated and validated to prevent cross-contamination; and all the equipment has been independently SMEPAC (Standardized Measurement Equipment Particulate Airborne Concentration) tested.
Scope of Supply
The new plant can boast the installation of the first commercial PharmaConnect® “through the wall” system in Europe. This allows pharmaceutical formulation scientists to plug into a range of processing technologies to evaluate techniques and optimize product quality during development-scale granulation and drying. With the addition of Buck® MC split butterfly valve containment interfaces and disposable Hicoflex® couplings, this innovative technology delivers high levels of cGMP production and ensures the safe transfer of potent ingredients between IBCs and/or the processing equipment. The contained R&D line for wet granulation — incorporating the PharmaConnect® system — also includes the dispensing of excipients and potent powders, PMA™ granulation and FlexStream™ fluid bed processing, dry milling, granule collection and blending, tablet compression using a MODUL™ P tablet press with a wash-offline ECM (exchangeable compression module) and pellet coating. The production line features GEA’s PMA™ 150 and FlexStream™ 1000 for granulation and drying.
In addition, the plant also has a contained R&D line for direct compression and a separate production line that offers containment interfaces for powders, API and excipient dispensing, dry milling and powder collection and blending. All the equipment can be cleaned-in-place except the MODUL™ P tablet press, which features a wash-offline ECM that contains all the machine’s product contact components and can be removed and exchanged within 30 minutes to maintain high productivity even during product changeover.
The new facility has transformed Penn Pharma into a single source for the development and production of highly toxic drugs at one of the world’s most advanced and efficient plants. The project has significantly increased the plant’s capacity and the company can now manufacture approximately 500 additional batches during a standard two-shift operation. The entire production facility has been designed for maximum containment to ensure a safe working environment for the operators without the need for isolation suits. This meets the demands of the pharmaceutical industry and health and safety organisations to provide contained engineering as the primary means of protecting operators and the wider environment. It also provides confidence to Penn’s international customers that the environmental impact of their manufacturing operations is being closely managed, allowing them to maintain their increasingly stringent corporate ethical responsibilities.
The new plant offers increased productivity and flexibility, and a better working environment for staff. Working with a single technology partner has ensured rapid and effective communication, making the project cost-efficient and easy to manage. Penn Pharma has benefited from interface security, no need to pay an engineering contractor to manage the interfaces, one contract in one currency according to GEA terms and scope savings. From the offset, Penn and GEA worked together to deliver an end-result on budget against a demanding timescale: the first product batch of coated tablets was delivered within 12 months of GEA receiving the initial order from Penn Pharma. The whole FAT, IQ and OQ process was jointly managed to provide an appropriate level of validation before going into PQ and production.
Similarly, regarding the building and utility selection, GEA helped to secure off-the-shelf systems from HVAC and purified water units to modular cleanrooms, securing the necessary lead times and effective budgetary control. The whole process was expertly implemented and, even though equipment had to be sourced from various countries, every item was installed into its respective cleanroom on time. The plant now provides R&D, pilot production and full production facilities under one roof with a seamless transition and scale-up between the production levels. And, because all the interfaces underwent stringent containment tests in line with SMEPAC requirements, GEA has used its expertise in containment technology to ensure a safe and productive plant in accordance with Penn Pharma’s requirements.
A Penn Pharma representative commented: “We believe that we have created an innovative and unique facility for our customers in the outsourcing market. This potent solid dosage facility is truly a contained manufacturing operation (CMO) with leading edge engineering at its heart. Not only does it provide the flexibility to deliver speed to market for our clients but, just as importantly, it ensures the highest levels of cleaning, operator safety and environmental effluent controls.”
Review: The Project Objectives
Safety: The facility was designed to handle multiple APIs with occupational exposure limits (OELs) down to 0.01 µm/m3, based on an 8 hour time weighted average (TWA). The approach was somewhat unconventional, as it started with a negative pressure equipment philosophy that would eliminate the need for personal protective equipment in routine operations.
Quality: The new contained manufacturing operation had to meet the regulatory needs of the global markets supported from the site, including the USA, Japan, South America and Europe.
Delivery: The facility was designed to flexible enough to support customers through development, early phase and commercial supply. It had an accelerated timescale and aimed to turn a car park into an operational facility in 12 months.
Cost: Nothing could be compromised on quality or safety; successful equipment sourcing was key. A robust FMEA selection process and commercial bid analysis was done to secure leading edge equipment at a competitive market price.
People: With an initial team of five project members, supported by an external project design and construction team, the focus was on speed to market. Armed with a full complement of formulation, quality, validation, engineering, regulatory and operational skills, and budgetary control, everything was put in place to create a unique, market-leading facility.