Multi-Purpose, Aseptic Cleanroom "Raises the Bar" for Contract Pharmaceutical Manufacturer

"You can build one bigger, but you can't build one better." These are the words of Edwin R. Thompson, President of Pharmaceutical Manufacturing Research Services, Inc. (PMRS; Willow Grove, PA). PMRS is a full-service ISO 9001 registered contract manufacturer of pharmaceutical products, providing expert support and solutions to the smallest virtual company as well as the largest pharmaceutical companies in the world. PMRS recently completed validation on a 7,000 ft²facility which includes 5,500 ft²of cleanrooms ranging from Class 100,000 down to Class 100 in the aseptic fill rooms.

What is so special about this space? Thompson explains, "We have built a 5,500 ft²multipurpose facility that will be as effective as other 12,00 ft². facilities because we put our time and resources into effective space and utility planning. As a privately owned company, we were able to team up with a privately owned cleanroom company with process design capabilities and negotiate a lump sum fixed price for the entire project. Because both companies have hands-on management and lack the layers found in larger companies, we were able to start demolition in January, construct and validate the facility and ship product in September. In addition to finishing on schedule, the facility costs were maintained at the budget of $2.7 million."

The Design/Build Challenge

Air Energy Systems (Willow Grove, PA) was the design/build firm for the PMRS project which was awarded the 1998 Merit Construction Award of Excellence from the Southeast Pennsylvania Chapter of the Associated Builders and Contractors group. AES Sales Manager Ralph Melfi commented, "PMRS's goal—which became the design criteria for AES—was to build an aseptic manufacturing facility while remaining in production in the existing facility. As this facility was built to supply exclusive manufacturing capabilities for a single client with a highly specialized process, the AES design and project management team paid special attention to the creation of construction specifications that were approved by both PMRS and their client."

Validation and Specification Schedule

Specifications included a detailed scope of work document, regulatory requirements, format for project meetings and progress reports, quality control services and validation services. A daily construction report was submitted to the owner highlighting a list of subcontractors on site, meetings and significant decisions, major equipment received and progress of work.

The general approach for the validation of the facility was to prepare and pre-approve installation qualifications (IQ), operational qualifications (OQ), and performance qualifications (PQ) protocols with stated acceptance criteria, execute those protocols, and prepare a written summary report comparing results to acceptance criteria and stating final conclusions, along with supporting documentation:

• Installation qualification verifies that the installed equipment and utilities used in the GMP manufacturing of pharmaceutical products meet all internal and regulatory standards and design criteria.
• Operational qualification assures that the installed equipment and utilities used in the GMP manufacturing of pharmaceutical products function as per manufacturer's design, operate fully and consistently, and are suitable for their end-user's requirements.
• Performance qualification demonstrates through collected test data that the installed equipment and utilities used in the GMP manufacturing of pharmaceutical products, as used by operating personnel under normal and extreme ("worst-case") conditions, will consistently produce an end product that meets its pre-determined specifications over the range of intended use.

Space planning and structural support were critical since we were building out the remaining square footage in the facility. Our structural analysis had shown that the existing roof and steel could not support the weight of the HVAC equipment and there was no available floor space for air handling equipment.

Air Energy Systems' solution was to design an equipment mezzanine above the cleanroom, which would yield service access to all specialty piping and mechanical equipment outside of the manufacturing space. The chiller was located on a pad and enclosed. To meet FDA GMP requirements, the facility had to be wash-down compatible with smooth, rounded corners (no 90° corners) at wall to wall and wall to ceiling junctions.

Multiple process utility services were brought to each milling room and filling suite, while maintaining cleanable surfaces and sealed penetrations. A clean process services bulkhead design was established for each.

This asceptic process required water for injection (WFI). WFI is defined in the U. S. pharmacopoeia (USP23) as " water purified by distillation or by reverse osmosis. It contains no added substance." WFI must meet the requirements for purified water (USP23), have less than .25 USP Endotoxin Unit per ml and must be produced, stored, and distributed under conditions designed to prevent production of endotoxin. Design considerations included:

• Establishing required use points
• Determining tank size
• Establishing still size
• Balancing tank size with still capacity
• Sizing loop piping and recirculation rate
• Sizing pumps for flow rate and pressure required.

The most significant hurdle for the design team was to establish a validatable HVAC air flow schematic allowing for simultaneous multiple product production without potential cross-contamination. Traditionally that would mean using fully independent HVAC systems for each filling room or 100% outside air. Through value engineering by AES, the design team was able to implement HEPA filtered return from each sterile process room so that the return air would not potentially contaminate the ductwork or cross-contaminate other rooms during recirculation. Ultimately, this design reduced the air conditioning requirements by approximately 40 tons, which also impacted the size of equipment and ductwork for an estimated up-front capital savings of $60,000 and thousands of dollars in annual utility savings.

Architectural Features

The facility features three 14-ft high milling rooms, two sterile preparation rooms, two Class 100 aseptic filling rooms, and sterile packaging and support areas. All operations were certified and validated to meet FDA cGMP guidelines and Federal Standard 209E for cleanrooms.

The facility consists of pharmaceutical grade monolithic sterile wall partitions and ceiling systems. These stick-built walls include an epoxy finish in the Class 100,000 and 10,000 areas, and Mipolan with heat-welded seams in the Class 100 rooms. A radius cove was included in all corners to allow easy wipe-down and to eliminate the build-up of bacteria and surface contamination. All doorjamb details were flush to eliminate ledges. Services included a 2,000-gallon WFI water system, l 70-ton chilled water HVAC system, clean steam, process chilled water, a HEPA-filtered compressed air system, vacuum, a 50-horsepower steam boiler, and nitrogen and oxygen piping.

Extensive electrical system consisted of two 480V, 1,000 amp power building services with associated distribution and featured an 800 amp emergency generator service due to the critical nature of manufacturing pharmaceutical products. The electrical interlock system assures access and air pressure control at each airlock entry. The DDC control system gives the owner remote monitoring capability for the HVAC and water systems.

Process Services Flexibility

Every room has process chilled water, WFI, clean steam oxygen, nitrogen, filtered compressed air, vacuum and plenty of power. 24-hour environmental assessment of air and water and process utilities enables PMRS to address specific customer needs overnight.

Thompson of PMRS summarizes, "We have successfully milled product in unclassified space for years, As a solids and semi-solids facility, now with aseptic capabilities we have raised the bar on what is acceptable quality standards for PMRS, our customers and the industry. This cleanroom is our first entrance into aseptic manufacturing and provides an opportunity to expand our business into new territory as well as apply the controls and procedures to our current business. Many of the aseptic procedures will be carried over to increase the quality of our current solids and semi-solids manufacturing business."

For more information: Ralph Melfi, Director of Sales and Marketing, Air Energy Systems, 2300 Computer Ave., Suite D-18, Willow Grove, PA 19090. Tel: 215-784-0321. Fax: 215-784-9144. aessales@aol.com.