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TRULY CONTAINED HIGHLY POTENT PHARMACEUTICAL MANUFACTURING.

Looking to stay ahead of competitors in the market and a UK-based contract development and manufacturing organization (CDMO) — Penn Pharma (now PCI Pharma Services) identified an increased need in the solid dose oncology market for the outsourced optimization 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 processes 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 Challenge Penn’s production 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 — it would not have been possible to achieve the production levels now required by international pharmaceutical companies.

To take advantage of the opportunity identified by the company’s extensive market research, a totally new concept in plant design was needed that embraced leading technology, the latest techniques and the ability to upscale operations from research and development (R&D) through pilot-scale testing up to full production, all under one roof.

BUILT FOR POTENCY, ENGINEERED FOR CONTAINMENT. As the pharmaceutical industry faces rising demand for the safe production of highly potent drugs, innovative manufacturing solutions have become essential to ensure market success.

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Key criteria were as follows: • �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.

GEA’s approach was to eliminate the use of isolation suits in favor of containment interfaces (BUCK® MC high- containment valves and Hicoflex®).

These would not only “handshake” 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 tablet 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.

The redesigned plant includes what was then the first commercial “through the wall” PharmaConnect system in Europe. The contained R&D line for wet granulation also includes the dispensing of excipients and potent powders, GEA’s PMA 150 and FlexStream 1000 for granulation and drying, dry milling, granule collection and blending, a tablet press with a Wash-off-Line ECM (exchangeable compression module) and pellet coating.

When dealing with highly potent substances, compression is the most challenging stage of the tablet manufacturing process. To address this issue, eliminate cross-contamination and protect the health and safety of operators, the unique- to-GEA ECM combines containment with productivity. The ECM is a completely removable section of the machine that includes all the product-contact parts; it can be removed, washed and replaced in a quick, safe, and efficient way, which means that the press itself remains powder free, requires no cleaning and can be back in operation in less than 2 hours.

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.

PARTNERING WITH GEA. The CDMO elected to work with GEA because of its proven track record in containment technology and expertise in terms of creating fully integrated production lines.

3 Truly Contained Highly Potent Pharmaceutical Manufacturing.

The project has significantly increased the company’s capacity, which 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 organizations to provide contained engineering as the primary means of protecting operators and the wider environment. It also provides confidence to PCI’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.

Real Benefits The new plant offers increased productivity and flexibility, and a better working environment for staff. Working with a single technology partner ensured rapid and effective

communication, making the project cost-efficient and easy to manage. PCI 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 outset, PCI and GEA worked together to deliver a 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. 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 PCI’s requirements.

TANGIBLE RESULTS.

The CDMO is now a single source for the development and production of highly toxic drugs at one of the world’s most advanced and efficient facilities.

A PCI 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.”

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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 US, Japan, South America and Europe.

Delivery: The facility was designed to be 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 were done to secure cutting-edge equipment at a competitive market price.

People: With an initial team of five project members, supported by an external 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.

Further information GEA Pharma & Healthcare pharma@gea.com gea.com/contact

5 Truly Contained Highly Potent Pharmaceutical Manufacturing.

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