Q: We have changed the brand of our stoppers for a product that we freeze-dry in vials. Since the change, we have observed a significant increase in rejects for collapsed cakes. Why are the cakes collapsing? What can we do to prevent this problem?

A: When selecting stoppers, we take great care to specify various details, such as the formulation of the rubber, the quality of its surface, and the surface treatment, out of concern for the stability of our product. One important specification, however, is sometimes overlooked. This specification is the surface area of the openings or windows in the stopper that result when the stopper is placed on the vial at the prestoppering stage. The window is the route by which water vapor exits the vial during sublimation and desorption; it restricts the passage of vapor.

When you changed the brand of stoppers, you may have reduced the surface area of the window inadvertently. Smaller windows provide greater restriction and could increase the pressure inside the vial, thus causing a consequent increase in sublimation-front temperature. If this temperature exceeds the collapse temperature, you will find an increased number of collapsed cakes. Examine the window geometries of your old and new brands of stoppers and evaluate whether they have equivalent surface areas.

—Robert Bullich, process development manager at TELSTAR

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Troubleshooting

We have changed the brand of our stoppers for a product that we freeze-dry in vials. Since the change, we have observed a significant increase in rejects for collapsed cakes. Why are the cakes collapsing? What can we do to prevent this problem?

Collapsed Cakes

Sartorius Stedim Biotech
 Membrane binds contaminants at high conductivities


 The Sartobind STIC PA membrane from Sartorius Stedim Biotech uses free primary-amino ligands at high density to bind contaminants at high conductivities through ion exchange. Unlike traditional quaternary ammonium membranes, the Sartobind STIC PA membrane does not require the cation ion-exchange pools to be diluted to bind the negatively charged contaminants. This characteristic can help users reduce buffer consumption and buffer-tank costs. The Sartobind membrane also removes host-cell proteins, DNA, viruses, and endotoxins at salt conditions as high as 20 mS/cm. 

The series of membranes includes six capsule sizes from 0.08 mL to 1.6 L. All of the membranes are suitable for flow-through polishing, and users can maintain a 4-mm bed height to scale up to larger devices. The membrane-adsorber capsules are plug-and-play devices that can be used like filters. Personnel can discard the materials after a single use, thus reducing validation costs.

Thermo Fisher Scientific 
 Roller bottles help improve yields and scale-up


Thermo Fisher Scientific has introduced its Thermo Scientific Nunc TufRol PS roller bottles for cell-culture production. Nunc TufRol PS roller bottles use polystyrene materials, thus minimizing the effort required to validate cell culture scale-up processes. Designed with indentations at the bottom to facilitate manual and automated handling, TufRol roller bottles are also available with vertical pleats to facilitate emptying and reduce product retention.

TufRol roller bottles were added to the existing Thermo Scientific Nunc InVitro PETG roller-bottle product line. Nunc InVitro PETG roller bottles are molded of polyethylene terephthalate, which is stronger than glass under normal culture applications. These bottles can withstand temperatures as low as –40 °C to accommodate freeze–thaw release protocols. Nunc InVitro roller bottles are available with a poly-D-lysine coating, which is used to promote cell attachment for cell lines that are difficult to grow. In addition, the bottles’ surface area of 1450 cm

 can result in larger product yields, compared with traditional roller bottles.

PharmTech's monthly newsletter, Equipment and Processing Report, reviews the Editor's Picks for the November 2011 edition from Sartorius Stedim Biotech and Thermo Fisher Scientific.

November 2011 Editor's Picks: Products from Sartorius Stedim Biotech and Thermo Fisher Scientific

Tough economic conditions, global competition, and regulations that increase chemical producers’ environmental responsibilities are prompting pharmaceutical manufacturers to eliminate waste in their manufacturing processes. Some companies are attempting to avoid sending waste to landfills, and some organizations are focusing on a zero-waste strategy. Rather than simply cutting down on landfills, this strategy seeks to eliminate waste when possible, and reduce or reuse it in other situations. Rising commodity costs provide an opportunity to view waste not just as a potential risk, but also as a finite resource. Thus, implementing a zero-waste strategy is not merely an option, it can be seen as a crucial business imperative.

Manufacturing in the pharmaceutical industry is a complex process that varies from plant to plant and from product to product. Making that process more environmentally friendly can be challenging and therefore must take into consideration regulatory issues, safety, compliance, and economic objectives. Developing a clear and concise road map for the effort is the key to achieving and sustaining the economic benefits associated with zero-waste programs.

A zero-waste strategy requires a systematic approach. Facility location, material composition, and waste volumes are among the crucial components that determine how much value can be extracted from waste. Recycling materials, reusing or repurposing them, and converting them into energy traditionally have been popular methods for eliminating waste. The systematic approach also identifies areas for improvement and cost reduction related to the collection, handling, and packaging of waste materials. For example, as manufacturing outputs and waste volumes change, the process periodically reviews waste-container sizes and pick-up schedules. Using waste to generate energy diverts material from landfills, thus eliminating costs associated with landfill tipping fees and helping achieve the goal of zero waste.

Ultimately, a zero-waste strategy must be customized to address the financial, environmental, and societal needs of the company. A six-step process can help companies address these concerns. The steps include a review of the company’s operations and waste-generation levels, the proposal and evaluation of waste-reduction and -elimination strategies, implementation, and monitoring for continuous improvement. Changes in production levels, fluctuating commodity prices, logistics, and the opening and closing of recycling outlets are the primary reasons that environmental programs require close attention. A company’s resource-management program should work in tandem with the zero-waste program and address the pharmaceutical firm’s changing needs. 

A zero-waste strategy requires the ability to measure and track performance not only at the manufacturing facility, but also across the supply chain. The drugmaker’s data-management system needs to present comprehensive information. The system also must enable users to manage all waste categories, as well as returned or recalled products, and commodity recovery. Access to this information will allow a company to establish baseline data from which to measure its progress toward the goal of zero waste. Ensuring that one person can manage this comprehensive data-management system is a crucial success factor for a zero-waste program.

Some pharmaceutical companies operate their own waste treatment or on-site disposal technologies, and some maintain a fleet of waste trucks. Funding these services can be an economic drain, and most pharmaceutical companies that perform these operations have curtailed them or plan to do so in the near future. Besides providing a poor return on investment, maintaining waste-treatment operations can conflict with the goal of eliminating waste.

An effective environmental-action plan requires a detailed assessment to identify opportunities and solutions for implementation. A comprehensive zero-waste strategy can bring economic benefits and reduce environmental risks.

Mel Panko and Dave Carson are strategic account directors at Waste Management

, 720 Butterfield Rd., Lombard, IL 60148, tel. 630.572.8936, 

In the Mixer

Implementing a zero-waste strategy is not merely an option, it can be seen as a crucial business imperative.

Pharmaceutical Manufacturers Seek to Eliminate Waste

In January of this year, FDA published its new guidance for process validation, and drug manufacturers are still grappling with its implications. Until now, the industry has adhered to the tradition of producing three batches of product to validate its manufacturing processes. The new guidance does not prescribe any number of batches that is necessary for compliance, however. As a result, companies have been wondering how many batches they must produce to validate their processes.

But this might be the wrong question to ask. “The number of batches should not be considered as an acceptance criterion,” says Hal Baseman, COO of ValSource and coleader

 of the of Parenteral Drug Association’s process-validation interest group. “Instead, it should be considered as a means to acquire the samples and information needed to ensure process control.”

Unlike the 1987 guidance, the new document takes a life-cycle approach to validation and places great emphasis on data and statistical analysis. “You need to demonstrate statistically that you are in control and the process is working as it’s supposed to work,” says Steve Ostrove, president of Ostrove Associates. 

Along with statistical analysis and the science of the process, an evaluation of risk to the patient will help manufacturers determine how many validation batches are required. Companies will have to determine which parts of the process entail risk and how great the risk is. Understanding the type of risk at issue is also crucial. “Is the risk patient death, or is it that somebody’s going to get an upset stomach?” asks Ostrove. 

As in the past, the number of batches required to validate a process will depend on the company’s process understanding, as well as on the type and variability of the process. “Validation with fewer than three batches will require good statistical and scientific justification,” says John Krewer, global validation director of Catalent Pharma Solutions. “The less documented knowledge there is about a process, the greater the number of validation batches that will be required.”

The more time and effort a company invests into process design, the easier it will be to qualify and verify the process later on. “If a company develops a product following quality by design principles, there may be sufficient scientific justification for using three batches for validation, depending on the amount of data that is gathered during development,” says Margaret M. Szymczak, an independent pharmaceutical consultant and chair of the Product Quality Research Institute’s Manufacturing Technical Committee. Early in development, drugmakers should ask statisticians to design the experiments in a way that will increase confidence in the process, she adds.

“Another approach a company may take is to make three validation batches prospectively, review the data and release the lots for commercial use, then continue to manufacture validation batches concurrently until robustness is assured,” says Szymczak. At that point, the manufacturer could reduce the amount of testing it requires for release of the product. This approach could be used for products in low demand or those used for niche therapies.

Drug manufacturers have made progress toward understanding their critical process parameters (CPPs) and their products’ critical quality attributes, but work remains to be done. “A lot of companies, in my experience, develop the product, and then almost go into the process-validation part,” says Ostrove. “A lot of times what I see is that they don’t really understand the impact of their CPPs or why they’re controlling to these points,” he adds.

On the other hand, most firms are complying with the section of the guidance that relates to process qualification, according to Ostrove. And, by including a review of in-process testing in their annual product reviews (alongside a review of equipment, the production process, and process changes), many companies also are carrying out the continued process verification that the guidance recommends. Although manufacturers may still have unanswered questions about the new guidance, the industry at large is on its way toward gaining the process and product understanding that FDA has been recommending. 

Production Lines

Until now, the industry has adhered to the tradition of producing three batches of product to validate its manufacturing processes. But FDA?s new process-validation guidance does not prescribe any number of batches that is necessary for compliance.

Equipment and Processing Report-11-16-2011

Collapsed Cakes

November 2011 Editor's Picks: Products from Sartorius Stedim Biotech and Thermo Fisher Scientific

Pharmaceutical Manufacturers Seek to Eliminate Waste

Is Three Still the Magic Number for Process Validation?