Lyophilization, or freeze drying, is the most common processing method for removing moisture from biopharmaceuticals, and it can increase the stability, temperature tolerance, and shelf life of these products. Although lyophilization is well established within the industry, it requires expensive equipment that takes up a great deal of space within a production facility. Lyophilization also can take days to complete, and manufacturers that need a powdered product must incorporate a granulation step to the process. In an environment where budgets are tightening, and where time and facility space are at a premium, lyophilization might be a difficult option for some companies.  

Spray drying is an alternative technique for preserving biopharmaceuticals, but it is relatively new to the industry. 

 (EPR) talked to Satoshi Ohtake, research and development scientist at Aridis Pharmaceuticals (San Jose, CA), to find out when spray drying might be a reasonable alternative to lyophilization.

 EPR: What is spray drying? How is the process performed?  

Ohtake: Spray drying is a process whereby a liquid formulation is converted into a dry powder in a single step. The process is typically performed by first atomizing the solution into fine droplets that are then dried quickly in a large chamber by using warm gas. The resulting dry particles are collected with a cyclone.  

EPR: What process conditions must be maintained for spray drying to be successful?  

Ohtake: The solution feed rate, the atomization pressure, and the outlet temperature, to name a few. All of these parameters affect the stability of the biopharmaceutical and are correlated with each other. If fast drying is desired, then the solution feed rate can be decreased, and atomization pressure increased. This way, the evaporative load is lower, and droplets are made smaller. By coupling that effect with high outlet temperature, the drying kinetics can be increased.  

EPR: What challenges does the spray-drying process pose?  

Ohtake: Spray drying exposes biopharmaceuticals to shear stress during the atomization step, which could destabilize labile biopharmaceutical compounds such as proteins. Complex biological molecules are difficult to spray dry because they are sensitive to high shear stress. The amount of shear stress encountered depends on the type of atomizer and the amotmization pressure used. At our facility, we use a sonic nozzle that can operate at a relatively low pressure of less than 20 psig, which minimizes the shear stress and allows us to process complex biopharmaceuticals such as vaccines.  

EPR: For what kinds of biopharmaceuticals would spray drying be appropriate?  

Ohtake: Spray drying has been conducted for a wide variety of biopharmaceuticals. Aridis has successfully spray dried proteins, enzymes, antibodies, viruses, and bacteria.  

EPR: How can spray drying increase a biopharmaceutical’s stability, temperature tolerance, or shelf life? 

Ohtake: The process removes water and restricts the biopharmaceutical’s mobility, which results in a significantly lowered degradation rate.  

EPR: Does spray drying stabilize a product to the same extent as lyophilization does?  

Ohtake: It depends. The fact that the end product in each case is a dried biopharmaceutical stabilized in an excipient matrix suggests that the stability profiles will be similar. However, we have observed significant differences between the storage stability of the same biopharmaceutical processed by spray drying and freeze drying. One of the reasons is the difference in the way the biopharmaceutical was dried. Another reason may be that the physical properties of the final dry product are significantly different. The processes’ relative abilities to increase stability, however, depend highly on the biopharmaceutical. In one study of manufacturing a dry powder viral vaccine, lyophilization resulted in the worst stability profile of all drying processes examined. On the other hand, lyophilization produced a more stable dry bacterial vaccine than spray drying did.  

EPR: Does spray drying have advantages over lyophilization?  

Ohtake: The main advantage of spray drying over freeze drying is that it makes particle engineering more feasible. By manipulating the conditions of the spray-drying process, manufacturers can adjust various particle properties such as size distribution, dispersibility, and surface enrichment of biopharmaceuticals. The size of freeze-dried biopharmaceuticals can only be reduced by milling.  

In many instances, it is advantageous to have the dry biopharmaceutical in a powder format, which facilitates its conversion into capsules, tablets, and thin films. In that sense, spray drying is a convenient one-step process that converts the biopharmaceutical directly from a liquid to a powder. Lyophilization, on the other hand, requires a milling step. Another advantage is scalability. Spray drying is more scalable at lower costs with regards to equipment, facility, and utilities. Furthermore, the cycle time for spray drying is hours instead of days, and thus operational costs can be lower than those for lyophilization.  

EPR: When might lyophilization be preferred to spray drying?  

Ohtake: Lyophilization might be preferred for a single-dose, injectible biopharmaceutical that requires reconstitution. Vials can be enclosed aseptically at the end of this process, whereas spray-dried powders must be distributed into vials or blister packs using another instrument. The choice of process is determined partly by the final dosage format and partly by the biopharmaceutical’s sensitivity to temperature and shear. 

Articles

Production Lines

Equipment and Processing Report talked to Aridis Pharmaceuticals (San Jose, CA) to find out when spray drying might be a reasonable alternative to lyophilization.

Is Spray Drying a Viable Alternative to Lyophilization?

For decades, companies have recognized the importance of understanding what is happening in their businesses at the enterprise level and using that information, known as business intelligence (BI), to make informed business decisions. This recognition led to the decision-support systems created in the 1970s and ultimately, in the 1990s, to the evolution of today’s more advanced BI systems. In the past decade, manufacturing intelligence (MI) systems, which access and aggregate manufacturing-related data from multiple sources, have gained significant momentum and increased their ability to focus on operational excellence.  

Although MI gives companies valuable benefits, it does not provide the specific knowledge that all process manufacturers need. The key performance indicators (KPIs) that MI typically tracks and displays in dashboards are an important component of understanding what is taking place in the manufacturing organization. But once the enterprise level sees that yields are not in the expected range, for example, then the company must understand why, so that improvements can be made.  


What MI is not delivering today is process intelligence, a critical subset of MI (see Figure 1). Process intelligence helps users gain a specific understanding of their manufacturing processes and how to control their sources of variability. Once this information is widely available, it can be used to achieve manufacturing-process excellence throughout the entire product life cycle using appropriate technological tools.  

MI shows what is happening in the manufacturing process, and process intelligence explains why it is happening. Process intelligence solutions enable an understanding of the physics, biology, and chemistry of materials, recipes, and manufacturing processes. This understanding helps manufacturers improve process predictability, reduce start-up risks, improve product quality, decrease cycle times, and increase yields and compliance—especially in complex production environments regulated by good manufacturing practice (GMP) and the US Food and Drug Administration.  

Process intelligence solutions improve control  


Building process intelligence into overall MI and BI portfolios using a self-service data-access platform linked directly to the operational data stores of existing manufacturing-data infrastructure systems allows users to understand the sources of process variability. This technique enables them to achieve better process control from the process-design stage (i.e., in process development) throughout the entire product life cycle. Appropriate technology solutions for process intelligence use a hierarchy to help access and contextualize data for users across multiple levels of the ISA-95 model, offering a full view of manufacturing and process-development data.  

For example, one global pharmaceutical manufacturer needed to reduce the burden on end users who wanted to examine their process data easily with standardized tools without waiting for the data and then massaging it for hours in spreadsheets before it could be analyzed. The manufacturer needed a single common system to access, contextualize, analyze, and report data and help interdisciplinary global teams compare batches manufactured at different plants.  

The manufacturer planned to replace its proprietary system and provide self-service data access, contextualization, and analysis in a single, validated environment. Previously, every scientist used Excel spreadsheets to prepare reports, and these files would end up scattered around on various desktops. The company needed a robust system that could withstand a good manufacturing practice (GMP) audit.  

The company looked for the following characteristics in a new system:  

The IT department evaluated available commercial, off-the-shelf (COTS) systems according to these requirements and ultimately chose a COTS process intelligence platform for integrated self-service data access, contextualization, and analysis. The company realized that the data-aggregation, -contextualization, and -analytics offerings of commercially available data historians, enterprise resource planning systems, and statistics packages were not adequate to the task. The manufacturer needed the process-intelligence layer above these systems that made data available in a meaningful context to all levels of the enterprise.


 After the company deployed the process-intelligence platform, it reduced the amount of time required to gather data for annual product reviews (APRs) by more than 90%. The high burden on IT for the support and development of in-house systems was eliminated.

In the end, process manufacturers usually see the following significant business benefits when adding the previously missing process intelligence piece:

 Capitalization on previous IT investments

In the Mixer

Process intelligence helps users gain a specific understanding of their manufacturing processes and how to control their sources of variability.

Process Intelligence Is Critical to the Pharmaceutical Enterprise

Sepha
 Leak-testing machine reduces waste


 Sepha’s (Belfast, Northern Ireland) Blisterscan is a nondestructive, noncontact leak-testing machine for blister packs. The machine scans blister packs with a laser beam before and after applying a vacuum to them. It examines the difference between scans to determine the size of the hole in the blister pack. The instrument detects leaks as small as 7 µm in diameter and locates the exact pocket that leaks.

Because the Blisterscan method is nondestructive, packs that pass the test can be returned to the production line. If a pack fails the test, an operator can empty its contents for repackaging. The Blisterscan unit thus reduces the amount of wasted product. In addition, the unit can be fully validated, unlike the blue-dye test, which requires a subjective operator decision about whether a pack passes or fails. The Blisterscan machine is intended to automate the quality-assurance process and facilitate compliance with current good manufacturing practices standards.

AdvantaPure
 Identification method improves trackability


AdvantaPure (Southampton, PA) has introduced its DocuLink method of distinguishing silicone manifolds after installation. The company assigns each manifold a unique identification number and permanently molds a silicone-encased label with this information within the manifold’s silicone connector. This method can be applied to T, Y, cross, reducer, or molded Tri-Clamp connectors. Operators can use a manifold’s identification number to view its related documents such as certificates of compliance, component specifications, and validations on an online data-management site.

AdvantaPure’s DocuLink labels and silicone manifolds withstand autoclaves, gamma irradiation, clean-in-place, and steam-in-place sterilization processes. The DocuLink labels do not contact the products within the manifolds. The DocuLink method is designed to facilitate manifold trackability and ease users’ safety concerns. Because the unit eases document retrieval, it could reduce the time and expense related to audits and validations.

PharmTech's monthly newsletter, Equipment & Processing Report, reviews the Editor's Picks for the December 2009 edition from Sepha and AdvantaPure.

Equipment and Processing Report-12-16-2009

Is Spray Drying a Viable Alternative to Lyophilization?

Process Intelligence Is Critical to the Pharmaceutical Enterprise

December 2009 Editor's Picks: Products from Sepha and AdvantaPure