The US Food and Drug Administration requires that all equipment used to manufacture pharmaceuticals be qualified. Put simply, qualification demonstrates that equipment is what it is purported to be and does what it is supposed to do. Installation qualification (IQ), operational qualification (OQ), and performance qualification (PQ) are the three steps of equipment qualification. 

Although most drug companies either have a knowledgeable qualification group or rely on outside experts to perform these qualifications, some manufacturers make common mistakes that thwart their qualification projects. These mistakes often result in qualification failure, which costs companies time, money, and effort.

The most common, and the most consequential, mistake is a lack of planning. The pressures of commercial manufacturing can lead many drugmakers to spend little time planning for qualification projects. Some believe that extended planning is inefficient; their goal is to release the equipment for production quickly. But insufficient planning-not extended planning-is inefficient, according to Jeff Hall, consultant at MHP Consultants (Roswell, GA). “With poor project planning, typically the project-completion date shifts incrementally because of delays in the project or poor oversight,” he says. Poor planning can also result in failed validation.

Even when manufacturers take time to plan qualification projects, they sometimes ignore important considerations. Companies often fail to take a science- or risk-based approach, based on product and process knowledge, to define the extent of qualification, says Steve Wisniewski, director of compliance at Integrated Project Services (Lafayette Hill, PA). 

 agrees that risk analysis is essential to the planning process for an IQ, OQ, or PQ project. Risk analysis identifies the critical and noncritical work to be done and helps companies focus on the appropriate elements of the qualification project. Validation should address the critical areas, and commissioning should address the noncritical.

Because it identifies the factors that have a direct effect on product or process quality, risk assessment can also reduce the number of systems requiring qualification and robust commissioning, Wisniewski says.

During the qualification-planning process, manufacturers sometimes do not consult all of the employees who will be responsible for using, maintaining, or approving the equipment. This oversight leads to inadequate plans that delay the completion of qualification projects or result in failure to meet requirements. “A successfully executed qualification is difficult to obtain without a good core knowledge of the equipment and its operation,” Hall says.

Another widespread mistake is the failure to apply sound project-management principles to commissioning and qualification projects, explains Wisniewski. Companies should define commissioning and qualification activities and clarify who will be responsible for each one. In addition, manufacturers should map the documentation control that the qualification project requires, says Wisniewski.

Qualification plans must be monitored, says Hall. Companies should use a project-plan approach to assign milestones to each test completion. Also, management should be notified of successful test completions and delays or problems that the testing team encounters. “Regularly scheduled updates on the progress of the qualification are ideal,” Hall remarks.

By taking several steps, pharmaceutical manufacturers can improve their IQ, OQ, and PQ projects. For example, Hall points out that the intent of equipment and instrument qualification is given in FDA’s 

Guideline on General Principles of Process Validation

 “The intent of the qualification process must be met with every qualification, no matter the type of equipment or instrument,” he says.

Regulators and manufacturers use different terms to discuss IQ, OQ, and PQ, and this lack of uniformity can cause confusion. Manufacturers can decrease the confusion by including detailed definitions within their sites’ qualification plans or protocols, Hall remarks.

Finally, drugmakers should allow sufficient time for qualification projects, says Pluta. After a company budgets adequate time to plan the qualification and subsequent development work is complete, IQ, OQ, and PQ should begin. Companies need to devote as much time as necessary to understanding their systems fully before such programs begin.

Collaboration, prioritization, planning, oversight, and clarity of purpose can greatly improve pharmaceutical-equipment qualification projects. These factors can save drugmakers a lot of time, sweat, and money.
 

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Qualification demonstrates that equipment is what it is purported to be and does what it is supposed to do. Installation qualification (IQ), operational qualification (OQ), and performance qualification (PQ) are the three steps of equipment qualification.

Qualification Pitfalls and How to Avoid Them

LiquaJet 
 Technology mills resistant materials


 LiquaJet (Moorestown, NJ), a new company created by the Jet Pulverizer Company (Moorestown), offers jet-milling services based on a new, proprietary technology. The technology uses high-purity compressed liquid nitrogen rather than compressed gas. The compressed liquid nitrogen expands after entering the jet-milling chamber and provides greater pressure and force than compressed gas does.

The process mills materials that were previously ungrindable. For example, the technology grinds plastic and polymers that could previously be reduced to 100–200 µm to less than 30 µm, according to the company.

The LiquaJet technology contains no moving parts, prevents contamination, and does not create additional heat. The technology minimizes material loss and produces high yields that comply with good manufacturing practices. The company is inspected by the US Food and Drug Administration.

Yokogawa Corporation of America 
 Production-control system has new features


 Yokogawa Corporation of America (Newnan, GA) has added pharmaceutical batch-control capabilities to its “Centum VP” integrated production-control system. New features include recipe-management and process-management functions in addition to the application’s unit-supervision and process-control tools.

The Centum VP software now provides a configurable unit faceplate that lets users monitor and execute batches through an interface. The application also features standard displays for product overview, product control, and unit control for recipe and product selection. The displays offer automatic, current documentation of the batch logic.

In addition, the software separates recipe data from equipment data and provides unit-based exception handling. The latter function allows batch engineers to create modular procedures for main production activities, engineer exception handling through unit monitors, and interrupt processing if necessary. Thus, automation engineers can execute failure-handling logic one time, rather than during each phase of production.

PharmTech's monthly newsletter, Equipment & Processing Report, reviews the Editor's Picks for the September 2008 edition from LiquaJet and Yokogawa.

September 2008 Editor's Picks: Products from LiquaJet and Yokogawa

Pharmaceutical companies show increasing interest in developing biopharmaceutical products, and observers believe these products could represent the industry’s future. Because most large-molecule drugs are delivered by injection, they require aseptic liquid processing and fill–finish operations. Piston pumps have been a traditional liquid-filling technology, but new challenges, stricter validation requirements, and design innovations have led manufacturers to consider peristaltic filling technology.

A piston pump is a mechanical device that cycles through a suction phase and a pressure phase to move fluid. A peristaltic pump continuously applies external pressure to a silicone tube to move fluid. Internal parts of a piston pump (e.g., gaskets, seals, valves, and internal surfaces) are in direct contact with the fluid. The peristaltic pump contains the fluid or product inside the pharmaceutical-grade tubing, which is the only part in contact with the fluid. For this reason, peristaltic pumps can be used for single-use aseptic filling. Single-use fluid paths eliminate the risk of cross-contamination between batches (see Figure 1).

Piston pumps are well-established and popular in all areas of a biopharmaceutical facility. Peristaltic pumps are convenient and often the preferred choice for fluid transfers in laboratory environments. They are now regularly used instead of piston pumps in small- to large-scale production applications.


 Piston pumps and other mechanical pumping devices such as time or pressure filling systems are known for their reliability and accuracy. On the other hand, they require regular maintenance and disassembly for cleaning and sterilizing. In addition, cross-contamination between batches is a big concern for piston pumps during the filling of biological drugs. Therefore, multiple piston sets need to be managed: one for each injectable drug being filled. 


 High-end peristaltic dispensing pumps have benefited from improved pulsation-free pump head design, a precise drive motor, and a state-of-the-art calibration algorithm. They are exceptionally accurate at microliter fill volumes.

Peristaltic pumps offer several benefits over piston pumps. For example, if an operator changes a peristaltic pump’s tubing size, then the pump can fill 0.1–250 mL. Several piston pumps would be required to achieve a similar fill range. 

Peristaltic pumps that incorporate single-use tubing eliminate cross-contamination and do not require cleaning because the tubing is the only product-contact part. Likewise, the cleaning validation of peristaltic pumps with single-use tubing is significantly easier than for piston pumps. The cost of labor and supplies for writing and executing protocols, cleaning, and documenting the cleaning process is higher for a multiple-use piston-pump filling system.

Adjusting the flow speed, and therefore preventing foaming or splashing, is easier for a peristaltic pump than for a piston pump. Operators can also use a ramp-up and ramp-down feature to determine how fast a peristaltic pump reaches its fill speed. This option helps optimize overall fill time and increase throughput.

Many biological drugs are shear-sensitive, and peristaltic pumps protect them by applying low pressure and providing gentle handling. In contrast, a piston pump’s valve system generates fast flow through small orifices, potentially damaging biological products. Even valveless piston pumps apply high pressures and high shear factors that could harm a biological product.

Peristaltic pumps operate as quickly as piston pumps. Piston pumps must cycle through a recovery or suction phase between each dispensing stroke, but peristaltic pumps require no downtime. In addition, some peristaltic dispensing pumps operate at high speeds to minimize fill time. It is common for a filling line of peristaltic pumps to dispense more than 400 bottles/min.

On the other hand, viscous products can be problematic for peristaltic pumps. The pumps apply only approximately 1.3 bar of pressure, and their accuracy suffers when they handle products more viscous than 100 cP. Piston pumps, which generate greater pressure, handle products more viscous than 100 cP. Biopharmaceutical products are mainly aqueous, however, and so the viscosity limitation does not usually affect peristaltic pumps.

 
 Because of recent technological advancements, peristaltic dispensing pumps now offer filling speed and accuracy that is comparable to those of piston pumps. Peristaltic pumps also accommodate single-use fluid paths, and single-use filling is becoming a must for cost-efficient biopharmaceutical drug development and production. For these reasons, biopharmaceutical manufacturers see peristaltic pumps as a good option for dispensing applications.

Peter Lambert is the filling-division manager for Watson-Marlow Flexicon, 37 Upton Dr., Wilmington, MA 01887, tel. 800.282.8823, 

In the Mixer

Piston pumps have been a traditional liquid-filling technology for biopharmaceutical manufacturers, but new challenges, stricter validation requirements, and design innovations have led manufacturers to consider peristaltic filling technology.

Equipment and Processing Report-09-17-2008

Qualification Pitfalls and How to Avoid Them

September 2008 Editor's Picks: Products from LiquaJet and Yokogawa

Dispensing Biopharmaceuticals with Piston and Peristaltic Pumps