	In a biopharmaceutical process, pumps are needed to move fluids (e.g., buffer, media, and water for injection) through tubing and deliver them to the process equipment. Several types of positive displacement pumps are used, including peristaltic, diaphragm, rotary lobe, and gear pumps. 

 spoke with experts at manufacturers of peristaltic and diaphragm metering pumps about some trends in for fluid handling in biopharmaceutical manufacturing and some considerations for using different types of pumps.  


	The move to continuous processing is evolving and will affect the requirements for pumps and other process equipment, says Andreas Frerix, product manager Quattroflow, at PSG, a Dover company. Gary Gaudet, technical leader of bioprocessing at LEWA-Nikkiso America, adds that there is a trend to have more self-contained processes, such as combining buffer dilution, clean-in-place systems, and chromatography skids rather than having separate skids. Steam-in-place systems are also being requested more than in the past, he notes.

	Both multiple-use and single-use manufacturing systems are employed in biopharmaceutical manufacturing.  “Biopharm is naturally risk averse; innovations, therefore, rarely take hold overnight, and the advent of single-use continues to expand into different process areas due to the benefits offered,” says Russell Merritt, marketing manager at Watson-Marlow Fluid Technology Group. “We will continue to see both single-use and hybrid (mixed single/multi use) processes being developed. Peristaltic technology is therefore well positioned to continue to meet customers’ requirements to provide a low-risk fluid handling solution through accurate pumping technology and high quality peristaltic tubing.”

	Another trend is an increase in the need for companies to be able to monitor fluid-path processes from remote locations. “The ability to monitor a process remotely allows the process to be run unattended and to notify users when they are complete, so the next campaign can be set up, which helps maintain productivity and improves efficiency,” says Gregg E. Johnson, global senior product manager for the Cole-Parmer peristaltic pump product lines.   


	There are different types of diaphragm pumps. Air-operated double-diaphragm (AODD) pumps are used for transferring fluids from one place to another and for ultrafiltration or diafiltration, notes Gaudet. AODD pumps, however, do not have volumetric control. Diaphragm metering pumps, which have highly accurate volume control, are used in processes and for dosing. Applications include: chromatography, buffer inline dilution, homogenization, injection of fluids (e.g., liposomes) into extruders, coating operations, filling, caustic dilution, and aseptic transfer of proteins, cells, and other materials, says Gaudet.

	A diaphragm pump uses the reciprocating movement of a flexible diaphragm that decompresses to draw fluid into the pump chamber and then compresses the pump chamber to push fluid out. The diaphragm separates the pump drive from the product-wetted side. This separation means that mechanical seals are not needed, which ensures product safety, simplifies maintenance, and allows the pump to run dry (i.e., without fluid) without being damaged, says Frerix.

	Multiple-use pumps have housings made from stainless steel that can be reused after cleaning in place. Multiple-use diaphragm pumps are still commonly used and are meeting customers’ needs, says Gaudet. Single-use diaphragm pumps have chambers made of plastic that have been designed for one process or batch. “After the process, they are replaced with a new chamber and the new process can begin. Single-use pump chambers save money and time by avoiding cleaning and associated cleaning validation and eliminating the risk of cross-contamination between batches or products. Single-use pumps are most valuable if products are changed frequently and fast product changeovers are needed,” says Frerix.


	In a peristaltic pump, the fluid is contained in a single-use tube that is compressed and decompressed by a moving rotor to move the fluid. Tubing is made from biocompatible materials that meet requirements for purity, and the single-use tubing is disposed of after each process to prevent cross-contamination. Because the fluid is completely contained within the tubing and connectors, process validation is simplified, notes Merritt. “Once the pumps are within a cleanroom environment and remain there, no regular cleaning and little maintenance of the pump itself is required.”

	Although tubing could be treated as multi-use (i.e., cleaned and sterilized between batches), most tubing is treated as “single-use” because this ensures that no cross-contamination occurs and provides new performance for every batch, says Merritt. “The need to maintain fluid path sterility is a key consideration for handling/changing any component in the fluid path. Sterility is another advantage of single-use tubing.  The fluid path is provided assembled and sterile, which minimizes the number of connections which need to be made; each connection presents a risk of the introduction of contamination.”

	Peristaltic pumps are easy to install and set-up, says Johnson. Because they don’t need to be primed, they are flexible in where they can be installed in the fluid path. “Monitoring the tubing performance is probably the greatest concern,” says Johnson. “A catastrophic failure can cost the loss of an entire campaign, but it is easily prevented by monitoring the tube life, use of new long-life tubing materials, and a preventive maintenance program to replace or move the tubing to new position.”

	Look for more on pumps and best practices for preventive maintenance of single-use tubing for peristaltic pumps in 

Articles

Production Trends

Manufacturers of peristaltic and diaphragm metering pumps discuss trends in fluid handling for biopharmaceutical manufacturing and some considerations for using different types of pumps.

Fluid Handling Trends in Biopharmaceutical Processing

	Blister packaging, a common format for solid dosage forms, continues to evolve. Equipment advances combine flexibility, servo controls, compact size, and integration with upstream and downstream equipment. 

	A new entry in the North American market, the MHI Eagle blister packaging machine from Maruho Hatsujyo Innovations (MHI), is an American version of its parent company’s best-selling machine. Established in 2014, MHI provides US-based installation, maintenance, spare parts, and 24/7 technical support. Parent company, Kyoto-based Maruho Hatsujyo Kogyo, ranks as the second largest pharmaceutical packaging machinery company in Japan and has installed nearly 400 blister packaging machines there. “There is no child-resistant (CR) requirement in Japan, so we had to design sealing for CR lidding (push, peel/push, and peelable),” reports Gregory Zaic, president and CEO of MHI.

The MHI Eagle blister packaging machine (see 

) operates at speeds up to 100 blisters per minute at a maximum index length of 90 mm and maximum index width of 130 mm. Designed for lower volume runs, the compact, servo-driven machine with inline inspection and multi-zone preheating is especially well-suited to copackers and lines with frequent changeovers (1). With hand screws to expedite tooling changes, changeover takes less than 10 minutes and requires no tools. Other quick changeover features include recipe-driven format change and a feeder station on wheels that plugs into the main unit. “We sell two feeder stations for the price of one-and-a-half so feeders can be swapped at changeover,” says Zaic. Swapping units moves feeder cleaning offline and minimizes downtime for cleaning. The Eagle blister packager accepts feeders from other manufacturers and is easily integrated with a printer or cartoner.

	A fully integrated, modular line from Körber Medipak’s Mediseal thermoforms, doses, seals, punches (perforates and embosses), diecuts, and feeds inserts and cartons. Direct product transfer eliminates fault-prone intermediate stacking units and minimizes change parts. Cameras confirm an insert is placed on every other blister before pairs of blister cards are stacked for cartoning. A display at Pharma EXPO (Nov. 6–9, 2016) showcased an integrated line on its way to a factory acceptance test. The one-lane CP400 blister packager integrated with a P1600 cartoner featured hot-melt carton sealing but also could accommodate tuck carton closure. Other potential variations include a P3200 cartoner with dual stacking devices, integration of a printer from HAPA for online printing of lidstock, various dosing systems (brush box, roller dosing, automatic spiral conveyor, or dedicated feeder) and choice of roller or platen sealing. Maximum speed of the servo-driven line is 400 blisters per minute (2). A sophisticated human/machine interface (HMI) groups functions for ease of use and helps reduce changeover time to less than 30 minutes. “All the information is in the HMI, which provides detailed instructions by system for format changes,” Kai Trepte, area service manager at Mediseal, explains.

	Blipack, a company based in Argentina, also supplies integrated blister forming and cartoning lines. The centerpiece, the Blistera 200-240 blister packaging machine, combines heavy-duty construction with user-friendly operation and quick and easy changeover and maintenance. The system can be electromechanical or driven by a programmable logic controller and is compatible with thermoforming or cold-forming and a wide range of accessories including printers and semiautomatic, automatic, dedicated, and universal feeders (3). Blipack’s integrated Estuchadora ACM 150 intermittent-motion cartoner loads cartons horizontally. Carton sizes range from approximately 0.6 x 0.5 x 2.0 in. to 3.5 x 2.8 x 7.9 in. (4).

	Another turnkey blister packaging line integrates the TF1e thermoformer and the TC1 cartoner from Pharmaworks. The unified system results in a compact footprint, operates from a single control system, and produces up to 100 blisters/80 cartons per minute. A robotic pick-and-place module transfers blisters from die punch to cartoner flights and eliminates the need for change parts. The number of blisters transferred to the cartoner flights is controlled from the operator interface (5).

	Robotics also play an important role in the Integra 520 V integrated blister packaging line from Marchesini Group. The servo-driven system fits in 10 m of floor space and features a balcony design for the thermoforming and cartoning sections. Capable of producing 520 blisters and up to 500 cartons per minute, the Integra 520 V line succeeds the Integra 320 model and incorporates an innovative pusher, a drum-type carton-opening system to manage higher speeds, and a new leaflet pickup and insertion system. Separating product loading from electrical and mechanical zones ensures quick and straightforward cleaning and changeover. An enclosed oil bath system protects mechanicals from wear and tear and extends service life. Maximum forming depth measures 9 mm, although a 12-mm option is available. Carton sizes range from 35 x 16 x 75 mm to 90 x 90 x 150 mm (6).

	Uhlmann Packaging Systems, which has offered integrated blister packaging lines for some time, offers three models: the single-lane BEC 300 model for up to 300 blisters/150–300 cartons per minute; the dual-lane BEC 500, rated at 500 blisters/300–500 cartons per minute; and the three-lane BEC 700, capable of outputting 700 blisters/300–500 cartons per minute. Upgraded in 2015, the BEC 300 model features the latest control and drive technology, tool-free format changeover, and smooth surfaces for faster line clearance (7).

	Existing BEC 300 systems can be retrofitted to shorten the forming cycle, simplify cleaning, and minimize abrasion marks on forming materials. Uhlmann’s Rebuild Packaging Systems Center performs electrical and mechanical retrofits using genuine Uhlmann parts to extend equipment lifespan and meet the latest GMP requirements and legal regulations. Upgraded equipment comes with detailed rebuild documentation, validation services, and one-year warranty. Rebuilding typically saves 30–70% compared to the cost of a new machine (8).

		Maruho Hatsujyo Innovations, “At Pharma Expo, Maruho Hatsujyo Innovations to Introduce Blister Machine Specifically for U.S. Market,” Press Release, Aug. 25, 2016.	

		Mediseal, “Flexibility All Along the Line,” Brochure, undated.	

		Blipack, “Blister Packaging Machine 200-240,” www.blipack.com.ar/eng/factory/200.htm, accessed Nov. 23, 2016.

		Blipack, “Cartoning Machine ACM 150,” www.blipack.com.ar/eng/factory/acm150.htm, accessed Nov. 23, 2016.	

		Pharmaworks, “TF1e/TC1 Line (New!), the All-in-One Solution,” www.pharmaworks.com/index.php?id=210, accessed Nov. 23, 2016.

		Marchesini Group, “All4Pack Paris: Marchesini Group Showcases the Amazing Integra 520 V Line and Two New Stand-Alone Machines,” Press Release, Sept. 22, 2016.	

		Uhlmann Packaging Systems, “Blister and Cartoner Module in One Productive Unit,” www.uhlmann.de/products/blister-lines.html, accessed Nov. 23, 2016.	

		Uhlmann Packaging Systems, “Uhlmann USA to Ramp Up Machine Rebuilding Services at New Jersey Facility,” Press Release, Aug. 24, 2015. 

 Packaging Forum editor, 4708 Morningside Drive, Cleveland, OH 44109, Tel. 216.351.5824, Fax 216.351.5684, editorhal@cs.com.

Packaging

New pharmaceutical blister packaging equipment offers flexibility and integration.

Blister Packaging Equipment Advances

	The use of airlocks is a principle that is well-established in the design of cGMP facilities. Despite the apparent simplicity of inserting small rooms into the plan of a pharmaceutical manufacturing facility, there is confusion regarding their proper use and definition. Airlock seems like a simple enough term, but airlocks have several distinct functions that, although closely related, are freely mixed and often cause confusion. This article looks at these functions and definitions.

	Airlocks are an architectural device that helps implement heating, ventilation, and air conditioning (HVAC) control of air classification or quality. Their purpose is to allow a shift between cleanliness levels, for example, from ISO 8 to ISO 7 or Grade C to B. This shift is achieved by maintaining room pressurization (by the direction of air flow through doors) and isolating the levels from each other. This common understanding of airlocks is defined in industry literature (1).

	An airlock is a space that provides segregation of cleanliness zones. While always designed for the higher level of cleanliness, when in use, the room will switch back and forth between levels as the doors open and close. When one door is opened, the opposite door maintains the boundary. And when opened to the lower classification level, the airlock effectively downgrades (see

). Once all the doors are closed, the room re-establishes itself at the higher level. Similarly, when a door is opened, air flows into or out of the room, and the pressurization at the open door goes neutral; the door opposite becomes the new boundary. 

	Whenever there is a change in air classification, a gowning activity also occurs. Personnel are the dirtiest entity entering a cleanroom. Contaminants generated by personnel must be properly encapsulated to restrict particulate counts to the levels appropriate for the cleanliness level in question. Depending on the nature of the process (i.e., oral solid dose, aseptic, biologic), restricting particulates may mean adding more coverage or possibly a change of garments. Upon leaving a cleanliness zone, the potential to carry contaminates out of the higher air classification must also be considered. In any case, a garment adjustment is necessary when moving to a new zone.

	Because airlocks and gowning rooms are both required between air classifications, they are often considered the same. There are instances, however, when gowning occurs and a change of air classification does not. A case in point could be a multiproduct facility where containment is crucial. In this example, gowns exposed to product in a processing area need to be considered contaminated and should not be introduced back to a common corridor serving adjacent processing rooms. Given that gowning rooms are not necessarily airlocks, it is important to be clear on the need and purpose of the gowning room and to deploy them accordingly; not just whenever airlocks occur.

	Transition spaces are the odd duck. They are essentially airlocks, but they do not meet the classic definition. While airlocks are indispensable to the proper segregation of air classifications, the term “transition space” is used to distinguish those instances when there is no change in cleanliness level. In these situations, the air classifications on both sides of the transition space are the same, but maintaining pressurization and direction of air flow is still crucial. Such conditions are primarily found where containment is required. A good example is in a biological facility where a transition space is necessary to maintain a biosafety boundary. Both sides may be Grade C, but to properly segregate the adjacent processing rooms or rooms served by a common corridor, it is necessary to confine contaminants to within each room. In an oral solid-dosage facility, containment could be needed where there are adjacent processes using dusty operations. In both cases, the transition space allows for containment within the process room through the control of pressurization and the direction of air flow.

	The term “airlock” is often used loosely, which can result in a lack of understanding of process segregation. The primary role of an airlock is the isolation of cleanliness zones. Like airlocks, gown rooms are always needed when moving between different cleanliness zones, but gowning rooms are needed in other instances as well. For any facility, a gowning strategy needs to be thought through independent of the cleanliness zones and, if appropriate, additional gown rooms provided. On the other hand, transition spaces are functionally airlocks, at least in terms of pressurization. Sometimes, process spaces need to have the segregation that airlocks provide even though there is not a change in air classifications. Again, process segregation is a topic that needs to be thought of independent of the extent of cleanliness zones. Given that these functions are so closely related and even overlap, it is easy to understanding the blending of these terms together as airlocks. When looking at a pharmaceutical manufacturing facility design, however, it is important to recognize that these different cGMP aspects need to be considered based on their own criteria. When these factors are considered carefully and employed deliberately, a more effective facility can be achieved that is both cGMP compliant and operationally efficient. 

ISPE Baseline Guide, Vol. 3: Sterile Product Manufacturing Facilities

, Second Edition (Bethesda, MD, Sept. 2011.)


	When referring to this article, please cite it as E. Bohn, "Airlocks for cGMP Facilities," 


	Eric Bohn is partner at JacobsWyper Architects, 1232 Chancellor St., Philadelphia, PA 19107,  tel: 215.985.0400, 

Troubleshooting

Airlocks, gowning rooms, and transition spaces have different uses and should be considered separately in cGMP pharmaceutical facility design.

Equipment and Processing Report-01-18-2017

Fluid Handling Trends in Biopharmaceutical Processing

Blister Packaging Equipment Advances

Understanding Airlocks for cGMP Facilities