Regulators and manufacturers have worked to ensure that enough influenza A (H1N1) vaccine will be available for patients. Debate has focused on whether Merck’s (Whitehouse Station, NJ) human papillomavirus vaccine is beneficial for boys as well as girls. These developments have kept biological drugs in the public consciousness. Biological drugs are largely administered through injections and often must be lyophilized to increase their stability, temperature tolerance, and shelf life. The manufacturing process, which influences a drug’s safety and efficacy, is particularly critical for drugs administered through injection, and personnel must closely supervise lyophilization to ensure product quality.

  One factor that manufacturers must monitor during lyophilization is 

, which occurs when a product’s temperature falls below its actual freezing point. Supercooling tends to lead to the formation of small ice crystals in the formulation, resulting in a dense ice matrix, says Brian Bucur, associate director of lyophilization and sterilization at Ben Venue Laboratories (Bedford, OH). A highly dense ice matrix can impede the release of sublimed moisture from the formulation and thus lengthen the time needed for primary drying. Supercooling also can result in inconsistent drying, which can cause heterogeneity in the finished product, adds Bucur.

  The manufacturer’s choice of freezing method influences the freezing rate, which, in turn, affects the degree of supercooling. Rapid freezing generally increases the risk of supercooling. “It is important to make sure that the first ice crystals nucleate to facilitate consistent and thorough product freezing,” says Bucur. “Slow freezing of the product in a well-developed cycle will allow the ice crystals to nucleate and cause the desired ice to form consistently. This normally minimizes the risk of supercooling,” he adds.

  Shelf freezing (i.e., freezing a product in a lyophilizer rather than in a separate unit) entails the least risk of supercooling, notes Jameel Feroz, principal scientist at Amgen (Thousand Oaks, CA). Consistent and controlled shelf-temperature ramps during the freezing process can lower the risk of supercooling within a lyophilization chamber.

  Yet shelf freezing might not be the only way to reduce supercooling. “Fast freezing using liquid nitrogen may help bypass supercooling altogether, provided that an amorphous structure is acceptable for the resultant product,” says Mark Williams, senior research and development group leader at Hospira (Lake Forest, IL). An annealing step can further reduce product variability from vial to vial, he adds.

Variation in vial thickness also can affect the extent of supercooling within a batch, even when the vials are within specifications. Tubing glass vials or ampuls are preferable because they have thinner, more consistent bottom thickness than molded containers, which enables the product to be cooled and heated uniformly through the lyophilization shelves, says Bucur. The bottom thickness of molded vials tends to vary more, and this variation can increase the risk of supercooling.

When scaling up the lyophilization process, supercooling must be controlled to achieve consistent process and product profiles. “The desired outcome is uniformly dried product across a batch,” says Bucur. Minimizing the extent of supercooling in any batch size can contribute to consistent drying.

It is difficult to model the scale-up of lyophilization because the process contains a high number of variables. The rates of cooling, supercooling, and freezing depend not only on the programmed rate of temperature decrease, but also on chamber size, the flow of thermal fluid, the smoothness of the lyophilizer shelves, and thermal-transfer rates from the shelf to the vial bottoms and from the vial bottoms to the rest of the vials, says Michael Akers, senior director for pharmaceutical research and development at Baxter BioPharma Solutions (Bloomington, IN) and member of 

  Mathematical modeling helps to predict drying rates based on variables such as temperature, pressure, and vial thickness. “Modeling can give you targets, but cannot give you dependable and actual final parameters for a well-designed cycle,” says Akers. Optimal drying cycles are based on actual experimentation. 

  A design-space approach to experimentation that explores key process parameters may offer the best approach to scale-up, says Williams. Ultimately, scale-up is restricted by the performance capabilities of the manufacturing lyophilizer, which may not be able to reproduce the cooling rate that was experimentally determined as optimal with a pilot unit. “Therefore, it is important to develop a process that can be reproduced by the lyophilizers that will be used for final manufacturing,” says Williams.

  Scientific understanding of the chemical, physical, and thermal aspects of lyophilization has improved over time, thus bringing manufacturers greater control over the process. This understanding, combined with mathematical modeling and practical experience, can help personnel predict and control the extent of supercooling. Today, it is easier for drugmakers to develop optimal lyophilization processes that yield uniform batches of safe biological drugs that have the desired characteristics.

Articles

Production Lines

The manufacturing process, which influences a drug's safety and efficacy, is particularly critical for drugs administered through injection, and personnel must closely supervise lyophilization to ensure product quality.

Reducing Supercooling during the Lyophilization of Biologicals

Emerson Process Management
 Wireless solution enables full redundancy


 Emerson Process Management (Austin, TX) now offers full redundancy for Smart Wireless monitoring and control through its DeltaV S-series digital automation system. The enhancements include redundant wireless input–output cards and redundant Smart Wireless remote links. Users can now create a hot backup scheme by installing two remote links in the same space. If the first link fails, the system switches to the second link almost instantaneously. The second link sends data to the control system, thus ensuring the consistent presence of one reliable link. This configuration virtually eliminates data loss resulting from failures.

The DeltaV digital automation system provides process-control and predictive maintenance to enable accurate control decisions. The product also includes a complete set of control algorithms and batching software that allows operators to run processes such as biopharmaceutical batch applications. The DeltaV system offers complete audit trails. 

Minitab
 Software enables value-stream mapping


Minitab (State College, PA) offers version 3.2 of its Quality Companion software for managing and executing quality-improvement projects. The software now includes a tool for value-stream mapping (VSM) that helps users find inefficiencies and eliminate waste. The VSM tool facilitates the tracking of variables such as cycle time, lead time, and work-in-progress time and automatically performs timeline calculations to help improve manufacturing, supply-chain, and product-development processes. In addition, the software lets users add custom data and enables data sharing during a project.

Quality Companion has built-in roadmaps to which users can directly add the tools they need. Users also can design their own roadmaps. Project charters, failure mode and effects analysis, fishbone diagrams, and process maps can be created in the software and stored within a roadmap.  When a project is complete, users can archive all of their data in a single file that includes records of all actions taken during the project.

PharmTech's monthly newsletter, Equipment & Processing Report, reviews the Editor's Picks for the October 2009 edition from Emerson and Minitab.

October 2009 Editor's Picks: Products from Emerson and Minitab

Economic pressures are forcing pharmaceutical manufacturers to look for ways to become more competitive. Many companies realize that they must reduce operating costs but maintain or improve product quality. Recognizing their clients’ needs, many equipment vendors’ process engineers are writing specifications to ensure that the latest innovations will lower energy consumption, reduce product waste, and minimize maintenance requirements. These specifications also improve the materials of construction, documentation, and testing while ensuring the sterility that critical processes require.

Manufacturers of sanitary pumps for the pharmaceutical industry have recently developed options to help meet the industry’s needs, including the following examples: 

	Single-seal piping arrangements for internal seals eliminate the need for double mechanical seals and product-flush piping arrangements. These arrangements save money because they do not use the product as the flushing medium. This configuration option also creates high pressure in the low-pressure seal area to keep hot product from “flashing” or pitting the seal faces, and increases the life of the seal.

	Seal-piping designs require lower flush flows than traditional pumps. For example, some models require the external seal to be flushed with flows of 2–3 gal/h (rather than flows of 10–20 gal/min) before draining.

	New pumps include front-loading seal configurations that can be serviced quickly. These pumps do not need to be pulled out of line for seal changes. This option reduces the downtime needed for maintenance.

	Liquid-ring pumps for clean-in-place (CIP) return applications (e.g., Fristam’s FZX unit) retain their prime, unlike standard centrifugal pumps, which sometimes become airbound. The liquid-ring pumps are more efficient and less wasteful for the complete evacuation of tanks and lines during CIP processes.

The drive assemblies that rotate the pumps can greatly influence pumps’ efficiency. The following units are designed for improved operation: 

	Premium efficient motors require less energy, operate at lower temperatures, and have a longer life expectancy because of their insulation materials, which allow the motor to run cooler.

	Variable-frequency drives (VFDs) allow operators to fine-tune processes and reduce energy costs. A VFD that controls a pump motor usually operates at less than full speed, thus reducing energy consumption by as much as 50% compared with a motor that runs at constant speed for the same period.

Pump manufacturers also have begun to use special materials to manufacture components that contact the product. Materials intended to improve cleanliness and sterility include the following:

	Low ferrite 316L stainless steel or Hastelloy materials may reduce rouging buildup that occurs in water-for-injection stills upstream of the pump.

	Disposable pumps and complete disposable systems made of plastics eliminate the risk of cross-contamination, reduce the validation burden, lessen change over time between batches, and eliminate the need for cleaning cycles.

	United States Pharmacopeia Class VI elastomers are made of pharmaceutical-grade rubber compounds to ensure sterility. 

Increasingly stringent documentation requirements for pumps’ materials of construction and for the traceability of the components have put pressure on the industry. In response, some manufacturers etch the metal manufacturer’s heat numbers onto all of their wetted metal components to facilitate traceability.

New regulations typically require testing such as ferrite testing, baseline vibration testing, X-ray material verification, certified-performance and net-positive-suction-head testing, certified finish mapping, drainability testing, hydrostatic testing, welder certification, and noise testing. The testing ensures that the pumps will meet the material and performance specifications.

Recognizing drugmakers’ need for cost-efficient production processes and their goal of creating high-quality products, pump manufacturers are continually pursuing innovation. Their engineers seek to provide highly efficient pumps that require minimal maintenance and afford maximal cleanliness. By combining their efforts, pumpmakers and pharmaceutical manufacturers can achieve their mutual goal of providing safe and effective drugs to patients around the world.

Sam Raimond is a customer service supervisor at Fristam Pumps, 2410 Parview Rd., Middleton, WI 53562, sraimond@fristampumps.com.

In the Mixer

Economic pressures are forcing pharmaceutical manufacturers to look for ways to become more competitive. Many companies realize that they must reduce operating costs but maintain or improve product quality.

Equipment and Processing Report-10-21-2009

Reducing Supercooling during the Lyophilization of Biologicals

October 2009 Editor's Picks: Products from Emerson and Minitab

New Pharmaceutical-Pump Designs Can Provide a Competitive Edge