Lyophilization: How to Meet Scale-Up Challenges Using QbD

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.

ANALYSIS

PharmTech: 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 ErlangenNuremberg): 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 productdrying performance, while the single-vial method determines specific productdrying 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.

Mayeresse (GSK Biologicals): 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.

Nail (Baxter Pharmaceutical Solutions): 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 watervapor flow from the chamber to the condenser in large-scale, freeze-drying equipment.

Page/Steiner (GEA Pharma Systems): 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 largeproduction dryer.

Pikal (University of Connecticut): 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 supercooling, 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.

SCALE UP

PharmTech: What are the key challenges and potential factors to consider when planning to scale up a lyophilization process?

Gieseler (University of ErlangenNuremberg): Examples of challenges include differences in environmental factors (e.g., non-cGMP versus sterile environment) and the different freezing behavior of the product solution in manufacturing. Other challenges are differences in equipment design and performance, such as emissivity of the surfaces, condenser performance, shelf cooling/control performance, vacuum control capabilities and choked-flow conditions, and a lack of appropriate tools to monitor the freeze-drying cycle.

However, the above-mentioned challenges can be overcome if operational qualification testing is performed on pilot–production equipment during a factory test or installation at the customer site. Performance testing can be conducted using a predefined freeze-dryer load (i.e., water or excipient solution) at various shelf temperature and pressureovertime profiles.

Mayeresse (GSK Biologicals): During the early development of a new product, the final facility is not necessarily defined and a product may also be transferred to another factory or CMO. For good scale up, it's important to know the final freeze dryers in which the product will be lyophilized. However, as this is not always possible, the best method is to define a design space that is large enough to transfer towards in the worst-case scenario, such as an in-house industrial freeze-dryer.

Nail (Baxter Pharmaceutical Solutions): Perhaps the biggest mistake development scientists make when developing freeze-drying cycle conditions is to conduct trial cycles using too few vials, in which most, or all, of the vials are in the "edge effect," where vials close to the edge dry at a faster rate than vials in the center of the array. We always use at least one full shelf of product for trial cycles. If there is not enough drug available for this, we use placebo for most of the vials, and put the vials containing active in the center of the vial array.

In addition to this, we consider differences in equipment capability between laboratory- and production-scale equipment, such as lowest attainable shelf temperature, fastest attainable shelf temperature, ramp rate under load, lowest attainable vacuum, and so forth.

Page/Steiner (GEA Pharma Systems): Science and risk management must form the basis of the scale-up process. The impact of changes in heat and mass transfer with scale and equipment design can be measured and predicted by applying basic process engineering techniques. If the process equipment is not properly characterized and understood, then scale-up will be a trial and error process. Where the equipment has been properly characterized, however, there is no reason why the scale effects should not be reasonably estimated and validated.

Pikal (University of Connecticut): There are differences in heat and mass transfer that may constitute scale-up problems. These issues need to be addressed by doing operational qualification testing under conditions of defined thermal and masstransfer load, perhaps using TDLAS, so that the capabilities of each dryer are known. Thus, a process can be designed with this constraint in mind. However, the major scale-up issue is the bias in ice nucleation temperature between freezing in a standard laboratory or pilot laboratory, and that characteristic of the Class 100 environment of a production facility. An easy way to circumvent this issue is to use controlled ice nucleation. In fact, even with the extensive knowledge we have now, good freeze-drying practice must include controlled ice nucleation.

PharmTech: What recent advances are being made in heat and mass transfer theory? How might breakthroughs in this area be applied to more effective scale-up using a QbD approach?

Mayeresse (GSK Biologicals): There are several good mathematical models that can be used, and some have been applied to freeze dryers to facilitate cycle development. One of the benefits of mathematical models is that they can support the thinking behind the physical aspect of the freeze-drying process. These models are a simplification of the reality and allow for better understanding of the underlying rules. In the future, more specific models based on other mathematical theories may arise that will offer more accurate insight into process development. Such models will surely improve the scale-up process in freeze drying.

Nail (Baxter Pharmaceutical Solutions): I don't think any real advances are being made in heat and mass transfer theory, because both disciplines are already very mature, but there are advances being made in application of this theory to freeze drying. In particular, the industry has realized the relative importance of thermal radiation as a heattransfer mechanism. This understanding could result in changes in equipment design and construction that take better advantage of thermal radiation, resulting in a more efficient process.

Pikal (University of Connecticut): I would maintain that the physics of heat and mass transfer, which is quite relevant to the design and control of primary drying, is relatively well understood. There may well be advances in applications, including using heat and mass transfer theory to assess in a quantitative fashion the impact of natural variation in key freeze-drying parameters (i.e., heat transfer coefficient, ice nucleation temperature, fill volume, and shelf temperature variation) on product quality (i.e., thermal history, collapse, and degradation). Indeed, some efforts in this area have started. Use of theory in scale-up is also underutilized, and application guidelines are needed.