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Pharmaceutical Manufacturing and Packing Sourcer

Cold Logic

Successful freeze drying relies on an accurate and detailed understanding of the product and its behaviour throughout the procedure. Indeed, new technologies have emerged over recent years that tighten process control and provide more in-depth analysis of the product before, during and after the freeze drying operation.

Game-changing lyophilisation technologies include controlled nucleation, manometric temperature measurement (MTM) and frequency modulated spectroscopy (FMS). Controlled nucleation gives unprecedented accuracy over the temperature at which freezing occurs; MTM automates many aspects of cycle design; while FMS is a quick, non-destructive method of checking the quality of the dried product.

Together, these technologies have transformed the way manufacturers control, adjust and measure key aspects of lyophilisation cycles, contributing to improved efficiency and better quality results.

Lyophilisation Cycle

Freeze drying is an important process in pharmaceutical production, used to stabilise products for delivery. Many formulations are freeze dried before milling for tablet preparation, with the process widely used for vaccines and blood components. For pharma applications, the product is typically dried in small vials on shelves in a pressure- and temperature- controlled condenser.

There are three main stages to the lyophilisation cycle: freezing, primary drying and secondary drying. During freezing, the temperature of the chamber is reduced sufficiently to ensure the complete freezing of the entire liquid – each vial of product must be thoroughly frozen before effective drying can take place. The next step is primary drying, during which the pressure of the chamber is lowered to induce sublimation of the frozen matter. After the sublimated gas is pumped out of the chamber, secondary drying takes place at a higher temperature. This serves to remove any water molecules that were adsorbed into the product – those not removed by freezing and sublimation. Secondary drying continues until the desired level of dryness is achieved.

Designing a successful lyophilisation cycle means making efficient use of energy and time, while ensuring a consistent and thoroughly dried product. Ineffective cycles risk product collapse if the sample is not completely frozen, or degradation over time if the product is not sufficiently dried. However, overly conservative cycles that lower the temperature more than necessary, or spend longer on the drying phases, are inefficient and expensive.

Controlled Nucleation

The freezing point is the temperature at which the solvent in a product crystallises. Nucleation is the initial formation of ice crystals; it is a random process that can occur within a range of temperatures up to 20°C below the formulation’s freezing point.

Controlled nucleation technology uses pressure variation to induce nucleation within 1°C of a formulation’s freezing point, allowing unprecedented control over the process. It is helpful to induce nucleation for a number of reasons:

  • Freezing at a higher temperature saves time and energy, not only during freezing but also drying. For every 1°C increase in the nucleation temperature, primary drying time can be reduced by as much as 3-4%
  • Since uncontrolled nucleation is random, it can lead to different vials in the same batch freezing at different temperatures – and therefore exhibiting varied drying behaviour
  • The temperature at which crystallisation occurs affects the size of ice crystals that are formed. Large ice crystals create an optimal open structure in the frozen material, making it easy for the sublimated gas to escape during the drying phases. However, large crystals have the potential to damage some delicate biological materials, so it is important to be able to control the freezing step and adapt it to the material being frozen
The freezing step of the freeze drying cycle has a significant impact on the quality of the final product. Controlled nucleation results in a more efficient process and better product consistency – it ensures that all vials nucleate at the same temperature, improving product uniformity and yield. It can be used to create favourable ice structures, generates a constant pore size, and can also cut cycle times by removing the requirement for a large safety margin during freezing.

Personalised Process

To ensure that processes are robust and financially efficient, a tailored freeze drying cycle should be developed for each formulation or product. The use of different excipients in various quantities affects the behaviour of a product during freeze drying, while varying the amount and depth of a product in the vial also affects how it dries. Each time a formulation or parameter is changed, the lyophilisation cycle should be checked and adapted to ensure its effective drying. Developing personalised cycles for each formulation is also good practice from a regulatory point of view. The FDA states: “A manufacturer that has one cycle for multiple strengths of the same product probably has done a poor job of developing the cycle and probably has not adequately validated their process. Investigators should review the reports and data that support the filed lyophilisation cycle.”

Manometric Temperature Measurement

MTM is a semi-automated method of optimising a freeze drying cycle, based on the measurement of pressure levels in the drying chamber at different points throughout the process. Mathematical models are used to analyse the changes in pressure in order to determine the occurrence of critical freezing and drying events, such as cake resistance, product temperature at the ice interface, and mass flow.

Given the collapse temperature (Tc) or the eutectic melt temperature (Teu) for a given formulation, MTM can be used to propose a safe freeze drying cycle. It will automate the monitoring of the temperature and pressure data, adjusting the cycle in response.

The Tc or Teu is measured using freeze drying microscopy, which involves observing the behaviour of the product as it is frozen and dried. It allows for the determination of key critical temperatures, as well as the identification of crystallisation phenomena and skin or crust formation.

How Does it Compare?

MTM does not cover sophisticated considerations such as annealing and production equipment, so cannot compete with bespoke cycle design by a lyophilisation expert. However, it is very useful for labs with numerous products or formulations. It can be used to monitor and optimise the cycle for each formulation, reducing the manual workload as well as the time and energy expended on lyophilisation, which can enhance the quality of the dried product.

Trials of MTM in R&D divisions of pharma and biotech firms have shown that it can be used to reduce the number of experimental runs during cycle development by 78%. Not only can it make the development process more efficient, it also leads to more effective freeze drying cycles. Recent work by Cancer Research UK demonstrated a reduction in cycle time from around 160 hours to just 60 hours (1).

Moisture Analysis

Moisture analysis gives a measure of how well a product has been dried. It is used to give vital feedback when designing a cycle, as well as being an important quality control tool throughout manufacturing and product storage.

The moisture content in a freeze dried material has a direct effect on the glass transition temperature of the material – the point at which a material can be observed to undergo structural change. This in turn impacts on the long-term stability of the product, and on the temperature at which it can be stored.

Traditional moisture analysis methods include Karl Fischer titration and thermo-gravimetric analysis. These methods are slow and involve the destruction of the tested sample. They are therefore unsuitable for large-scale testing for complete batch validation, or for longer-term quality control tests.

Frequency Modulated Spectroscopy

FMS is a fast, non-destructive method of analysing the moisture content in a sealed vial. It can be used in cycle development and for quality control during production and storage. It can also be automated for batch validation as part of the manufacturing process.

Most samples are freeze dried in small vials. After drying, the vials are sealed to store the dried product. However, if the product is not completely dried, or if the vial is incorrectly sealed, there will be higher levels of moisture in the headspace between the product and the top of the vial.

FMS uses frequency modulated laser light to measure these moisture levels in the vial headspace. The laser is tuned to 1,400nm, a near-infrared frequency that matches the absorption frequency of water molecules. When the light is directed through the vial headspace, it is absorbed by any water molecules present. The level of absorption is measured by a detector, and used to calculate the moisture in the vial. Calculation of the width of the absorption profile gives the total headspace pressure.

The technique can also be used to monitor a number of different stability-related parameters such as moisture, oxygen levels and pressure. Once calibrated, the analysis takes just a few seconds and can be built into inline monitoring systems.

Process Factors

Several process factors can cause variations in moisture levels throughout a single batch, including the efficiency of heat transfer, the degree of shelf contact, and whether or not an annealing step was included in the freezing method, which affects the ice crystal size and the resultant pathways for vapour escape. The material characteristics of the active material and excipients also affect how easy it is to obtain uniform moisture content.

A fuller understanding of these processing and material factors can assist in understanding the results of an FMS analysis across a batch, and help to assess and recommend appropriate changes to achieve target uniformity. FMS has transformed the way in which results are quantifi ed during cycle development, as well as how batch quality is checked during manufacturing.

Furthermore, since it is quick and non-destructive, FMS is used to make multiple measurements on the same sample in order to monitor the oxidation of samples over time. This delivers valuable feedback on product lifetime and helps ensure optimal storage conditions.

Together, controlled nucleation, MTM and FMS are yielding signifi cant improvements in effi ciency and product stability through the precise engineering of freeze drying cycles – and facilitating the adoption of freeze drying as it moves into new areas in biotech and advanced materials.


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Katriona Scoffin is a freelance science writer working for Biopharma Technology Ltd. The company is experienced in all aspects of freeze drying technology, from pre-formulation through to full-scale production and dried product analysis. It has successfully processed more than 1,000 substances on behalf of clients. 
Katriona Scoffin
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