Draft Guidance for Industry-Process Validation: General Principles and Practices

 provides a life-cycle approach for validating pharmaceutical processes and aims to help pharmaceutical companies achieve consistently high product quality. The document includes several concepts that are familiar to the industry but also contains ambiguities and recommendations that might be difficult for some drugmakers to follow.

The draft guidance suggests manufacturers establish links from their clinical process to their commercial-manufacturing process. This approach is similar to the one FDA has used in its preapproval inspections. If the guidance becomes final as it currently stands, manufacturers may be expected to use the data that they gain during formulation and development to define a product’s critical attributes, which would be the basis for the manufacturing-process parameters. 

The agency points out that development and formulation data can improve a company’s understanding of its processes during scale-up and commercial manufacturing. This understanding would help companies control variability and increase product quality, says Chris Ames, director of global validation at Catalent Pharma Solutions (Somerset, NJ). Companies would submit these data to FDA to establish links between clinical and commercial processes.

But the draft guidance does not advise manufacturers about how to identify the most important characteristics of its product or manufacturing process, or about how to demonstrate links from the clinical to commercial process. “They’ve left it completely open to interpretation as to what data you provide and what format you use,” says Jim Agalloco, president of Agalloco and Associates. This ambiguity would suit Big Pharma because it frees companies to use their experience and discretion in deciding how to follow the guidance, says Agalloco. Small and emerging drugmakers, however, would likely be confused because they don’t have the depth of knowledge that would help them define critical attributes.

Some elements of the draft guidance resemble a Six Sigma approach to manufacturing, which is familiar to the pharmaceutical industry. The main similarity is the draft guidance’s recommendation of a statistical link that demonstrates that variability remains constant from the clinical through the commercial manufacturing stages. The statistical link is intended to confirm that processes are the same throughout all phases.

Although the draft guidance suggests statistical analysis, it leaves industry with only a broad understanding of what that means. FDA does not explicitly suggest that manufacturers use particular statistical tools, the agency simply recommends that companies apply good statistics to establish the links, says Agalloco. 

The draft guidance suggests manufacturers define a process that can be measured, analyzed, improved, and controlled, and this approach is closely related to Six Sigma. The benefit of the Six Sigma technique is that it provides a mechanism for scientific review of a process, for assessing variability, and for identifying improvements, says Ames.

On the other hand, it is unclear whether the draft guidance recommends a product be refined in the way that a Six Sigma approach would. “To me, Six Sigma implies an acceptance by FDA that you might not have done a sufficient job in development and scale-up and are allowed to improve product and process while it is in operation,” says Agalloco. Patients’ experiences with a product might persuade a manufacturer that it should adjust one of the drug’s parameters to improve it. Six Sigma would allow postcommercialization changes to a product, but the draft guidance may not be compatible with them, Agalloco says.

Before it could submit a regulatory filing, a company would have to spend a great deal of time and money to better understand its ingredients, its product, its manufacturing process, its material handling, and associated variables. Pharmaceutical companies might object to the draft guidance’s approach because it suggests this expensive work be completed before commercialization, but the costs would not be recoverable before commercial-scale manufacturing began.

Although it is based on good science, if the final guidance is approved as drafted, it could easily increase drug-development time by one or two years, thus costing a manufacturer millions of dollars, says Warren Charlton, a consultant at WHC Bio Pharma Technical Services. Manufacturers would need to use smart strategies to shorten development time, but not knowing how much data regulators expect in a submission would make this strategy difficult.

The draft guidance inspired a huge volume of comments that will likely take FDA a long time to review, says Agalloco. Even though the guidance might not be final for at least a year, manufacturers would be wise to study it now and seek advice about interpreting it. In this difficult time for the pharmaceutical industry, no company can afford to ignore regulators’ recommendations, and advance preparation would be to a manufacturer’s benefit.

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The US Food and Drug Administration?s Draft Guidance for Industry?Process Validation: General Principles and Practices provides a life-cycle approach for validating pharmaceutical processes and aims to help pharmaceutical companies achieve consistently high product quality.

Is FDA's Draft Process-Validation Guidance a Mixed Blessing?

AEC
 Controller enables flexible material handling


 The 10/80 unit is the latest addition to AEC’s (Schaumburg, IL) VacTrac series of conveying-control equipment. The device allows operators to control 10 vacuum conveying pumps, 80 loading stations, and 80 purge valves. The 10/80 facilitates manifold sharing, which reduces the need for tubing and purge valves. The device can stage and sequence six vacuum pumps per manifold line. 

Each loading station can be assigned to any of the pumps connected to the same manifold. If several loaders on the manifold need material simultaneously from different pumps, the controller’s manifold-sharing function stages the pumps so that they can use the same manifold.

The 10/80 machine’s controller includes a touch-screen operator interface. The setup screen allows users to name loading stations, pumps, purge valves, and material sources. This feature enables personnel to track what material is in each hopper and where it is located.

Sensor Products 
 Sensor film enhances packaging operations


 Sensor Products (Madison, NJ) has introduced its Pressurex pressure-indicating sensor film, which can help validate and calibrate sealing-die pressure during pharmaceutical packaging operations. The product is a thin film containing microcapsulated color-forming material. When pressure is applied to the film, a red color impression is formed, the intensity of which depends on the amount and distribution of pressure. Operators can consult a color calibration chart to determine whether the appropriate pressure was applied and whether it was applied evenly.

Manufacturers can use the Pressurex film to test packaging machines during installation or maintenance. Films can be kept on file as records of proper equipment calibration. The flexible film can be cut to various sizes and shapes and is available in rolls and by the foot. The product is available in pressure ranges from 2 to 43,000 psi.

PharmTech's monthly newsletter, Equipment & Processing Report, reviews the Editor's Picks for the August 2009 edition from AEC and Sensor Products.

August 2009 Editor's Picks: Products from AEC and Sensor Products

Cooling water is a critical component in the research and development, bulk manufacturing, and packaging of pharmaceuticals. For example, batch processing in multipurpose reactors requires water for chemical reactions to take place at high temperatures and for final products to crystallize at low temperatures. 

Many operations that convert bulk substances into their final, usable form need process cooling. The most notable example is the creation of capsules, which requires precise control of the temperature of the molding process that forms the gelatin. Other operations that need process cooling include the sterilization of liquid pharmaceuticals and the wet granulation process of forming tablets.

Other applications that rely on cooling water include condenser cooling, vacuum systems and chambers, calorimeters, power supplies, heat exchangers, jacketed vessels, and plastic molding and extrusion equipment. 


Although cooling water is critically important in the processing of pharmaceutical end products, traditional process-cooling systems have big drawbacks. The systems entail significant costs because they require maintenance and consume a lot of energy, water, and chemicals.

Many pharmaceutical facilities contain large, energy-intensive cleanrooms. Traditional chillers can account for more than 50% of the energy use in cleanrooms because of the amount of cooling needed and the level of filtration that the US Food and Drug Administration requires (1). It is estimated that the pharmaceutical industry spends more than $1 billion on fuels and electricity today.

Despite concerns about energy use, the associated harm to the environment, and maintenance challenges, most pharmaceutical companies in the US have not replaced their traditional cooling towers and chillers. Manufacturers may not be aware that an alternative to these systems has been used in Europe for years and is becoming more common in the United States. 


The alternative technology is a closed-loop, dry-cooling system that prevents the water it contains from evaporating. The system also eliminates the need to dispose of the water after it has run through the process. The clean, often chemical-free, water is reused repeatedly for a plant’s heating or cooling needs, and the system reduces water, energy, and chemical consumption by 95%. This technology is appropriate for cleanrooms and other pharmaceutical processing needs. It can also help drugmakers conserve their manufacturing resources.

 Traditional cooling towers do not achieve optimum performance at high ambient temperatures (e.g., 85° F). The new closed-loop technology maintains water temperature in hot weather by using an adiabatic chamber. Outside air passes through this chamber, and misters pulse water into the chamber. The humidified air lowers the water temperature to the desired point. The pulsed water evaporates instantly, cooling the air before it reaches the cooling coils that carry the process water. The coils remain dry, thus the process is called dry cooling. 

Even in cold weather, a closed-loop, dry-cooling system does not accumulate ice because no water evaporates from the unit. Because it is not exposed to the elements, a closed-loop system does not face other maintenance issues (such as requiring water treatment) that are common to traditional towers. In addition, the system’s controls drain water from outside pipes to inside pipes when the air temperature reaches 32 °F. This feature keeps water from freezing and eliminates the need for glycol. A dry-cooling system also offers ample opportunities for free cooling, which occurs when outdoor temperatures drop below process temperatures. 

 The closed-loop technology incorporates an intelligent control platform that adjusts the system so that it runs at optimum efficiency, conserves resources, and enables the production of high-quality products. Depending on ambient temperature and process-water temperature, the controller adjusts the system’s fan speed, water pressure, and pump rotation to generate the required cooling capacity efficiently. 

A pharmaceutical manufacturer that switches from traditional cooling systems to this technology can expect to reduce energy consumption by 60–95%, depending on the system it currently uses. The energy savings may provide a remarkable return on the company’s investment. The technology requires little maintenance and reduces companies’ water, energy, and chemical consumption. Dry-cooling systems can provide economic and environmental advantages that are particularly important to the drug industry today.


1.	M. Neelis, E. Worrell, and E. Masanet, “Energy Efficiency Improvement and Cost Saving Opportunities for the Pharmaceutical Industry: An ENERGY STAR Guide for Energy and Plant Managers” (Ernest Orlando Lawrence Berkeley National Laboratory, June 2008).

Steve Petrakis is president of Frigel North America, 150 Prairie Lake Rd., Unit A, East Dundee, IL 60118, tel. 847.540.0160, s.petrakis@frigel.com.

In the Mixer

Cooling water is a critical component in the research and development, bulk manufacturing, and packaging of pharmaceuticals.

Equipment and Processing Report-08-19-2009

Is FDA's Draft Process-Validation Guidance a Mixed Blessing?

August 2009 Editor's Picks: Products from AEC and Sensor Products

Reducing Energy and Water Use in Process Cooling