Lyophilization presents challenges in defining and accurately measuring critical process and product parameters (CPPs) in laboratory and commercial scales. Pharmaceutical Technology spoke to Henning Gieseler, group leader, Freeze Drying Focus Group, in the Division of Pharmaceutics at the University of Erlangen-Nuremberg; Yves Mayeresse, director, Manufacturing Center of Excellence Filling and Freeze-Drying Operations, at GSK Biologicals; Steven Nail, principal scientist at Baxter Pharmaceutical Solutions; Trevor Page, group technical director, and Manfred Steiner, area sales manager, both at GEA Pharma Systems; and Michael J. Pikal, professor of pharmaceutics at the School of Pharmacy, University of Connecticut, to discuss analysis and scale-up methods.

 What analytical tools and techniques are essential for a quality by design (QbD) approach to a lyophilized product? Are there any gaps in current technology in this area?

Gieseler (University of Erlangen-Nuremberg):

 An innovative, process analytical technology (PAT) approach to freeze-drying requires a PAT tool that allows for the determination of CPPs, such as product interface temperature and product resistance, for the batch as a whole (i.e., batch method). Ideally, the technology should be applicable in all scales of equipment. As a compromise, two different technologies (i.e., one applied in the laboratory and one in production) can be used, but they must provide reliable and comparable measures of the same parameter without an inherent scale factor.

In addition to the batch method, it is also necessary to have a noninvasive measurement (i.e., no contact with the product) of a CPP in a single vial. The reason for such a combination is simple. A batch method gives a global, average picture of product-drying performance, while the single-vial method determines specific product-drying performance at a given spot in the freeze dryer. This would help to delineate drying heterogeneity between vials (e.g., edge effects or hot or cold spots on the freeze dryer shelf), which is always present in a freeze dryer in whatever scale and which might even change over time in a given unit.

 One of the current weak points of freeze drying is the absence of direct measurement during the process. In the past, product probes were used to monitor the freeze-drying cycle, but they were not really reliable. There are many reasons for this, but mainly they are invasive. As you modify the freezing of a vial with a metallic wire probe, it creates void around the wire that allows vapor to escape more quickly. Today, automatic loading systems mean that these probes cannot be used anymore. However, new PAT tools are appearing on the market.

 We use tuneable diode laser absorption spectroscopy (TDLAS) as the main PAT for design-space development. It isn’t essential, but it greatly decreases the time and effort required to construct a design space. We have found TDLAS to give accurate mass flow rates on laboratory-scale equipment, usually within about 6% as compared with gravimetric determination. We do this by weighing the filled vials and stoppers before and after freeze drying. However, TDLAS on production-scale equipment is considerably less accurate because of complexities in the dynamics of water-vapor flow from the chamber to the condenser in large-scale, freeze-drying equipment.

 The most important aspects of understanding the lyophilization process are those that provide insight into the individual vial rather than simply measuring the integrated effect on the headspace. Simple aggregated measurements, such as chamber pressure, or more complex measurements, like the application of mass spectrometers to the chamber gas, all have value for overall process control.

To understand the range of process conditions caused by both forced and natural variation within the overall system (i.e., equipment, vials, and product), it is important to be able to characterize the range of experiences of individual vials. However, the problem is that techniques examining the individual vial that can be used during development and validation are frequently difficult to deploy in a large-production dryer.

 The key properties to measure are product temperature and primary drying time. Unfortunately, product temperature in given vials cannot be measured in a representative way. Inserting temperature probes reduces the degree of super-cooling, making the measured temperatures nonrepresentative of the batch as a whole. This problem can be circumvented by using controlled ice nucleation. However, although this technique is available in both laboratory and production equipment, it is not routinely used in manufacturing. Hopefully, this will change in the near future. There are also indirect ways to measure batch average temperature, such as manometric temperature measurement or, particularly, TDLAS, that could be used in manufacturing, but so far, this is not common practice.

Articles

In the Mixer

Experts share insights into analytical tools and techniques.

Analytical Tools for a Quality-by-Design Approach to Lyophilization

Q. We have developed an in-house broth to neutralize a preservative for traditional microbiological testing following 

 <61> Microbiological Examination of Non-Sterile Products: Microbial Enumeration Tests.  We would like to use a rapid-test method to release product faster, but is there a broth that will be effective on our products?

A. Choosing the right rapid-test method is important.  Some rapid-test method manufacturers require use of their proprietary broth while other systems are more flexible.  Flexible rapid-test method systems allow users to closely follow their validated, traditional method, including the type of media and incubation temperature used.  Flexible systems allow users to incorporate additional neutralizing agents or use broths developed in-house. 

Trypticase Soy (Soybean-Casein) and Letheen are typical broth options for testing many pharmaceutical products. For products that are particularly difficult to neutralize, Trypticase Azolectin Tween (TAT) broth is commonly selected as an enrichment medium. TAT broth is low in ATP, supports the growth of a wide range of micro-organisms, and contains the neutralizing agents polysorbate 20 and lecithin.   

Single broth enrichments, with and without added neutralizing agents and at appropriate product concentrations, have been validated using rapid-test methods for effective microbial-limits testing across a wide range of products. If you have successfully validated your product using the traditional, growth-based method, adopting a flexible, growth-based rapid method that allows the use of your validated, in-house broth is highly likely to be successful. 

With the availability of flexible systems capable of using a variety of broths, concerns about product neutralization should not prevent microbiologists from looking seriously at rapid microbiological methods.

—Lori Daane, PhD, vice-president for scientific affairs at Celsis.

If you have a problem with your equipment or process, an industry expert may have the solution. Please send your question to 

, editor of Equipment and Processing Report, and we may be able to provide an answer in a future issue. All questions will remain anonymous.

Troubleshooting

We have developed an in-house broth to neutralize a preservative for traditional microbiological testing following USP <61> Microbiological Examination of Non-Sterile Products: Microbial Enumeration Tests. We would like to use a rapid method to release product faster, but is there a broth that will be effective on our products?

Product Neutralization for Rapid Microbiological Test Methods


 Sterilizing-grade filter improves biopharmaceutical manufacturing efficiency


 Sartorius Stedim Biotech’s (SSB) Sartopore Platinum sterilizing-grade filter for biopharmaceutical manufacturing improves product yields and filtration performance. The surface of the polyethersulfone filter membrane has been modified using a hydrophilic, thermostable polymer. This surface modification increases wetting properties, which reduces the amount of water for injection needed to wet the cartridge, and minimizes protein binding, which increases product yield. The membrane has been pleated using SSB’s newly developed, proprietary TwinPleat process. The alternating long and short pleats of the membrane increase the filter area of a 10 in. cartridge by more than 60%. At the same time, this geometry ensures that liquids flow through the entire filter area so that the filtration capacity of the cartridge is used to the fullest extent, which improves filtration performance and lower filtration costs. The filter cartridges can be dry-steam sterilized in the forward or the reverse direction without altering the properties of their membrane.  The filters can be used in the entire pH range from 1 to 14. 

Waters
 Mass spectrometers with increased sensitivity reduce laboratory downtime


 Waters added its StepWave ion optics technology to its new Xevo G2-S QTof and Xevo G2-S Tof benchtop, time-of-flight mass spectrometers (MS), which makes them up to twenty times more sensitive than earlier-generation instruments.  StepWave ion optics technology transfers ions efficiently while actively filtering out undesirable neutral contaminants. As a result, MS signals are increased and, because critical components in the device stay clean for longer periods of time, quantitative results are more reproducible and laboratories experience less downtime due to routine cleaning and maintenance.  The instruments are designed to work with Waters ACQUITY UltraPerformance LC System and are capable of achieving low detection limits with minimal sample volumes.

PharmTech's monthly newsletter, Equipment and Processing Report, reviews the Editor's Picks for the July 2012 edition from Sartorius Stedim Biotech and Waters.

July 2012 Editor's Picks: Products from Sartorius Stedim Biotech and Waters

The continuous process of hot-melt extrusion (HME), which is useful for making solid dispersions of poorly-soluble drugs and controlled-release dosage forms, lends itself well to quality-by-design (QbD) principles such as defining a process design space. Design space, by ICH Q8 definition, is the “multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters that have been demonstrated to provide assurance of quality” (1). Because HME is a well-understood industrial process, it has the sound body of data needed to establish the critical process parameters (CPPs). HME, by nature of being continuous, is run at steady state, which allows multiple, steady-state iterations to be tested while minimizing material use during the process of establishing a design space, notes James DiNunzio, PhD., principal scientist at Hoffman-La Roche.  “A structured approach to process design can greatly increase your chances of success,” said Josh Shockey, P.E. and principal at Green Ridge Consulting, in a presentation at last month’s Pharmaceutical Extrusion Seminar organized by Leistritz (2). The TSE incorporates a series of unit operations (e.g., feed, convey, mix, melt, devolatilize). In designing the HME process, one should understand the overall goal, the goals of each of the unit operations, and how these operations interact, Shockey explained.

When producing an amorphous solid dispersion using HME, the overall goals, or critical quality attributes (CQAs), are acceptable levels of degradation and acceptable levels of residual crystallinity. The CPPs in the extruder can be said to be residence time, melt temperature, and an energy component that can be defined as shear rate, shear stress, or specific energy input. These CPPs are not easily defined during extrusion, however, because shear, temperature, and time are distributional in nature, says DiNunzio. “Development scientists need to define these behaviors based on controllable inputs to the process, such as screw speed, screw design, feed rate and process section temperature.” An advantage of a twin-screw extruder is that these inputs have a wide range that can be easily adjusted to get the desired output. Because the extruder is modular, even screw design can be relatively easily modified by changing the segments of the screw. 

Since the extruder is operated at steady state, materials that enter the extruder at a given feedport experience a certain residence time distribution and shear distribution within the control volume. Both residence time and shear rate are functions of mass flow, screw speed, and screw design, explained DiNunzio in a presentation (3). Melt temperature is a function of melt pressure, barrel temperature, and viscous heat dissipation. CQAs are affected by a complex interaction of these process parameters. Too low a level of temperature, residence time, or shear will not produce enough mixing to create a stable amorphous dispersion, but too high a level will result in degradation. 

The design space becomes further refined as developers move through the development process from early development to optimization. If the process is designed such that the operational space can accommodate normal perturbations, the system parameters can be adjusted to support processing with different material properties (e.g., different API particle size) while remaining in the design space, concludes DiNunzio.

J. Shockey, presentation at the Leistritz Pharmaceutical Extrusion Seminar (Clinton, NJ, 2012).

J. DiNunzio, presentation at the Leistritz Pharmaceutical Extrusion Seminar (Clinton, NJ, 2012).

Production Lines

Continuous manufacturing of amorphous solid dispersions in a twin-screw extruder is well-suited to quality by design processes such as defining design space.

Equipment and Processing Report-07-18-2012

Analytical Tools for a Quality-by-Design Approach to Lyophilization

Product Neutralization for Rapid Microbiological Test Methods

July 2012 Editor's Picks: Products from Sartorius Stedim Biotech and Waters

Defining Design Space in Hot-Melt Extrusion