BioPharm: The scale-up of lyophilization processes can be challenging. Can you discuss the key challenges and propose potential factors
to consider when planning a scale up lyophilization process?
Gieseler (University of Erlangen-Nuremberg): Challenges include, for example, differences in environmental factors (non-cGMP versus sterile environment) and the obstacle
of a different freezing behavior of the product solution in manufacturing. Moreover, 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 side. Performance testing can be conducted using a predefined
freeze-dryer load (water or excipient solution) at various shelf temperature/pressure over time profiles. Then, product temperature
profiles and mass flow rates are studied as a function of the loading and process conditions used. One of the key challenges
in scale-up is a thorough understanding of the performance attributes of different freeze-drying equipment.
Mayeresse (GSK): The scale-up and transfer of a product is a challenging process. 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 work-case scenario, such as in-house
Nail (Baxter): Perhaps the biggest mistake development scientists make when developing freeze-dry cycle conditions is to conduct trial
cycles using too few vials, where 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. For robust formulations that can be dried under aggressive conditions, the 'choke point' of the equipment becomes
important. This is the maximum sublimation rate that can be supported while maintaining the set point of chamber pressure.
Page/Steiner (GSK): 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
Process understanding is demonstrated when outcomes are reliably predicted. Factors to be considered may include:
- temperature distribution on each shelf under real load conditions
- gas velocities and impact of shelf packing/gas flow patterns
- thermal effects of walls and doors (particularly as development units may suffer significant effects in this respect)
- control principals for drying pressure and shelf temperature
- tolerances on measuring devices.
Featured in the roundtable: Henning Gieseler, group leader, Freeze Drying Focus Group, Division of Pharmaceutics at the University of Erlangen-Nuremberg, Yves Mayeresse, director, Manufacturing Center of Excellence, filling and freeze-drying operation, GSK Biologicals, Steven Nail, principal scientist at Baxter Pharmaceutical Solutions, Trevor Page, group technical director at GEA Pharma Systems, Michael J. Pikal, professor of pharmacetics at the School of Pharmacy, University of Conneticut and Manfred Steiner, area sales manager at GEA Lyophil GmbH.