Many pharmaceutical companies’ production assets are supported by time-based maintenance programs. Such programs preserve the equipment but usually not its function, and they do not mitigate equipment failure for the balance of a machine’s life cycle. In addition, most time-based systems do not collect data that are needed for failure analysis or criticality analysis. It is thus impossible to determine whether components that fail critically (i.e., shut the equipment or process down) affect the quality of the product. Consequently, all process components are treated as critical, and this approach exposes the organization to needless regulatory scrutiny. 

Misperceptions about what makes maintenance compliant lead organizations to adopt exclusively time-based programs. In such programs, the maintenance organization is only allowed to add new preventive maintenance (PM) inspection steps or increase PM frequency. But a vast majority of failures are not effectively addressed by time-based maintenance. After several PM cycles, the equipment often fails again, the process starts over, and the failure is not clearly defined or mitigated. Despite this inefficiency, the maintenance program meets the requirements of 21 

 Part 67.211. Yet companies are still exposed to avoidable audits, fines, and recalls.


 In the past four years, publications such as the Good Automated Manufacturing Practice 5 guidelines and the US Food and Drug Administration’s process analytical technology initiative have promoted alternatives to time-based maintenance programs. These publications are intended to encourage innovation and enable greater regulatory flexibility through scientific study and analysis. They suggest that asset maintenance be managed proactively using methods that address known and potential failure modes and improve asset reliability. 

The proactive approach originated in 1978, when Nowlan and Heap published 

(RCM), the results of a 10-year study in the aviation industry (1). This analysis examined equipment function, common failures, the results of those failures, and the controls necessary to mitigate the consequences of failure. RCM showed equipment breakdown cycles to be radically different from what they were thought to be. Before this report, industry assumed that the probability of failure increased as equipment aged and that reliability could be ensured by equipment replacement or overhaul. Nowlan and Heap identified six different equipment behavior curves for equipment failure and found that most failures have no relation to age (see Figure 1). 

The outline of a proactive maintenance approach


 Because most equipment fails at random ages, equipment should be examined regularly using predictive technologies such as thermography, vibration, ultrasonics, and oil analysis. For example, all laminar-flow blower units should be subject to a vibration-analysis program, and maintenance should only shut down a cleanroom when it finds a condition that creates failure. Time-based PMs should primarily be used to measure and identify age-related deterioration. A well-managed planning and scheduling process should ensure that the corrective actions are performed in an efficient manner.

This kind of program minimizes exceptions and investigations for equipment failure. The maintenance group sends the quality and operations groups weekly or daily reports, and important findings for each piece of equipment are stored in the maintenance-management system database. This program increases the equipment’s capacity and reduces its costs of operation. 

A proactive maintenance model fits perfectly into the corrective and preventive action (CAPA) process. Many companies from other industries have already adopted proactive maintenance programs. The programs’ key principles are the following: 

Start at the beginning. When qualifying a new asset, start planning the maintenance program for it during validation. Develop a maintenance program to support each machine’s expected life cycle and anticipated failure modes. This technique enables a reliable maintenance program that supports the CAPA process.

Develop measurable assessments of asset health. Make sure the tasks supporting production assets address the failure modes. This information comes from RCM or failure modes and effects analysis.  

Apply technology to the CAPA process. More information can be obtained through predictive technologies than through human observation.


To develop an effective maintenance program, a maintenance organization must involve the quality and operations groups in the process, educate them about active maintenance concepts, and prepare a plan of action for the entire company. When quality and operations organizations are involved, educated, and trained in the methods that will be employed within the reliability program, the company will see a return on its investment. Because the pharmaceutical industry relies so much on its production assets, it has a strong incentive to adopt a focus on reliability, which can increase efficiency, reduce costs, and minimize regulatory problems. 

 
 1. F.S. Nowlan and H.F. Heap, “Reliability-Centered Maintenance,” DOD report number A066-579, (US Department of Defense, Washington, DC, Dec. 29, 1978).

Jason T. Price is a consultant at Management Resources Group, 555 Heritage Rd., Southbury, CT  06488, tel. 203.264.0500, fax 203.267.1493, 

Articles

In the Mixer

Time-based maintenance programs preserve the equipment but usually not its function, and they do not mitigate equipment failure for the balance of a machine's life cycle.

A Proactive Maintenance Approach Increases Efficiency and Reduces Costs

PortaFab
 Cleanroom wall system accommodates wiring


 The PharmaSystem cleanroom walls from PortaFab (Chesterfield, MO) have a cavity to accommodate wires, process pipes, air ducts, and chemical lines. The system also accepts structural loads for a walkable or load-bearing deck. The walls can be configured into a full enclosure with a roof. Equipment can be installed on top of the walkable ceiling if the roof of the building itself cannot support it, according to Wayne McGee, president of PortaFab.

Horizontal Z clips let clients hang the panels onto standard 3.625-in. metal-stud framework. The panels can be configured for rooms of any size or shape or used as a liner-wall system to cover existing walls. The panels have formed and cut edges to connect directly to each other and are sealed with a caulk joint, gel coat, or chemical weld. The walls are designed to provide a flush surface, inhibit bacterial growth, and control noise.

Sterling 
 Temperature-control units enhance water flow


 The 2012 Series temperature-control units (TCUs) from Sterling (New Berlin, WI) are constructed entirely of stainless steel for washdown in pharmaceutical applications. The units’ pumps are designed according to customers’ specifications and provide high flow rates at low pressures. The products are intended to enhance water flow and temperature control.

The 2012 Series devices have an operating leaving-water temperature range of 32–250 °F. The machines are designed to hold temperatures within ±1 °F and are appropriate for gelcaps and other aqueous solutions that require tight temperature control, according to Jim Walsh, the company’s industrial products manager.

An optional cast-and-flange design reduces the product’s number of connection points and enables operators to plumb directly into the heaters. The machines feature half- and full-heat capacity and forward-facing liquid-filled “To” and “From Process” pressure gauges. 

PharmTech's monthly newsletter, Equipment & Processing Report, reviews the Editor's Picks for the February 2009 edition from PortaFab and Sterling.

March 2009 Editor's Picks: Products from Portafab and Sterling

The spotlight on the biopharmaceutical industry is intensifying, as recently evidenced by Pfizer’s (New York) ongoing acquisition of Wyeth (Madison, NJ), which was initiated partly to reduce the former’s dependence on small-molecule drugs. Rising titers and the adoption of disposable technologies are among the recent changes witnessed in the industry. These and other developments will shape the biopharmaceutical production process and the design of large-molecule manufacturing facilities in the future.

 
  Developments in proteomics and genomics have broadened the range of possible applications of new biopharmaceutical drugs. The number of new drugs will keep rising, but each new medicine will serve a much smaller, more focused market than previous therapies have, says Doug Parker, quality-control microbiology manager at Xcellerex (Marlborough, MA). Smaller market demand, increasing titers, and higher product yields will result in smaller batch sizes. For these reasons, companies will have to establish flexible, multidrug production facilities, Parker says.

  For example, MedImmune’s (Gaithersburg, MD) new production site in Frederick, Maryland, was designed to enable flexibility and rapid capacity expansion, says Ben Machielse, the company’s executive vice-president of operations. The facility includes two modules fitted out with full utilities such as water for injection and steam. One module was developed into a full bioreactor and purification facility, and the second module can be converted to a bioreactor facility and begin production in two years if necessary.

  The “FlexFactory” production line at Xcellerex’s Marlborough facility illustrates another strategy for designing flexible manufacturing. The FlexFactory platform is based on disposable technologies and uses a controlled environment module (CEM) to reduce the size of the cleanroom around each unit operation. The CEM approach enables all unit operations to be located in one hall with basic utility requirements. The platform also allows production lines to be reconfigured quickly as multidrug lines, Parker says. 

 
  In multiproduct facilities, long changeovers create downtime, reduce efficiency, and waste money. MedImmune set standards to shorten changeover times to significantly less than one day, says Machielse. One of the company’s strategies is to use disposable components, which reduce changeover to a matter of hours and also minimize the need for cleaning validation. 

  Bottlenecks remain problems for biopharmaceutical companies, and they can arise during various stages of production. MedImmune’s aggressive operational-excellence (OE) program analyzes processes and capacity using the standard OE concepts to help the company understand where bottlenecks occur and how to manage them, says Machielse.

 
  In recent years, increased bioreactor yields have moved the main site of bottlenecks from the bioreactor to the purification phase. Designing a facility with multiple purification suites has become the norm, and companies will spend more time and money to make their purification suites flexible, Machielse says. 
  For example, microfiltration steps present challenges because they have low throughput and do not cope well with large bioreactor capacities or high cell densities. To expand downstream capacity, MedImmune replaced microfiltration steps with continuous-flow centrifugation, which is more easily scalable and has a higher throughput.

  Disposable components and in line dilution of buffers could also expand downstream processing capability, according to Saul Edenbaum, director of process engineering at Integrated Project Services (Lafayette Hill, PA). Concentrated forms of buffers and other solutions can be made in single-use bags and pumped to an in line dilution station that adds the concentrate to appropriate amounts of purified water. In addition, the entire line containing the flow of the solutions can be replaced by single-use tubing to create a flexible processing scenario for multiproduct purifications, says Edenbaum.

  The purification stage itself is changing, too. Protein A resins have been the standard first step, but many biopharmaceutical facilities are looking to abandon them because they are expensive. MedImmune has replaced protein chromatography in the new purification process.

  Also, manufacturers are considering exchanging traditional column chromatography for membrane-bound chromatography media to maximize throughput. Membrane-bound chromatography speeds up flow through chromatography, according to Machielse. The technology also enables companies to perform several steps (e.g., ultrafiltration and chromatography) at the same time.

 
  Scientific and technological advances have brought many changes to biopharmaceutical production. The heightened focus on large molecules and the demand for potent, personalized medicines will surely spur further research and innovation. Enabling flexible production and improving purification efficiency will be major concerns for the industry in the near future.

Production Lines

The spotlight on the biopharmaceutical industry is intensifying, as recently evidenced by Pfizer's (New York) ongoing acquisition of Wyeth (Madison, NJ), which was initiated partly to reduce the former's dependence on small-molecule drugs.

Equipment and Processing Report-03-18-2009

A Proactive Maintenance Approach Increases Efficiency and Reduces Costs

March 2009 Editor's Picks: Products from Portafab and Sterling

The Shape of Biopharmaceutical Facilities to Come