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Lyophilisation: The Truth

Lyophilisation, or freeze-drying, is a widely used method of stabilising pharmaceutical products for storage, distribution and delivery. A well-designed lyophilisation process delivers reliable results in a timely and efficient manner. However, there are many myths about how best to achieve optimum results – here we consider ten of the most common.

1. The method of freezing the product is irrelevant; it is the drying stages that are important

“It doesn’t matter how I freeze the product, I just wait until it looks frozen on the shelf. Sometimes I dip it in liquid nitrogen; sometimes I just put it in the -20°C freezer overnight.”

The purpose of lyophilisation is to create a dry product, therefore the focus is often on the drying stages rather than the freezing. However, the manner in which the product is frozen has a significant impact on how the drying stage progresses.

Fundamentally, it is important to ensure that the product is thoroughly frozen before primary drying starts. The application of a vacuum will cause any unfrozen product to boil, leading to product damage and collapse.

The crystal structure of the frozen product also affects how vapour is released during drying; larger crystals create a more open structure with larger paths for vapour flow. As a rule, fast freezing, such as dipping in liquid nitrogen, creates small crystals; slow freezing, for example putting the product in the freezer overnight, creates large crystals. Generally, large crystals create large vapour paths and an open matrix through which this vapour can escape, facilitating easier drying, whereas small crystals imply smaller vapour paths with consequent impedance to vapour flow and potentially longer drying times.

Large ice crystals can also be damaging to cells. As the product freezes, the solutes concentrate and this imbalance can cause damage to cells or proteins. Some proteins adsorb to the interface between ice and liquid, which can lead to perturbations of their native conformation and consequent denaturation. Surface-induced denaturation is proportional to the total surface area of ice crystals. Since slower cooling rates give larger ice crystals and a lower total surface area, slower cooling may be better for proteins that are susceptible to surface-induced denaturation.

Freezing on the shelf of the freeze-dryer is the best method of ensuring batch repeatability as the freezing rates can be controlled.

2. I can use the same lyophilisation cycle for different formulations

“I have a cycle that works fine so I’ll use that for my other products too.”

In both manufacturing and development, it is not uncommon to find one cycle borrowed for other applications, particularly for older systems where trial and error might have been adopted when originally defining parameters. In one case we have seen, the same cycle was adopted for over 200 different products.

When ‘borrowed’ cycles are successfully transferred it is likely to be because they are inefficient: either because the cycle is very conservative, or because the equipment control is poor. A more common occurrence is that the borrowed cycle is not successful, but the product failure is ignored or not recognised. This will lead to high batch rejection rates, poor stability and low activity rates.

Designing freeze-drying cycles that are optimised for each formulation and the production equipment will save time and energy and lead to fewer product failures.

3. Vials can be filled to any depth

“This cycle works for my 10ml vials so I can use the same cycle for my 5ml vials if I use the same fill volume.”

Frozen products dry from the top down, therefore product depth is more important than actual volume. As the cycle progresses, a layer of dried product gradually builds up over the remaining frozen product (see Figure 1, page 18). This dried layer creates an increasing impediment to the sublimated water vapour trying to escape from below. The thicker the layer of dried product, the more difficult it is for the vapour to escape. Drying slows, the effect of sublimation cooling decreases, and product temperature rises, risking collapse.

Even if the fill volume is kept constant, the product depth will be different for each vial size, meaning that each vial type will have different drying characteristics. Where conditions allow, maximum product depth should be in the region of 12-15mm. This is relevant both for product in vials and bulk product.

4. Any vacuum pump will do

“I have a vacuum pump in the lab that works fine. I’ll use that one and put it at the other end of the bench.”

Many pumps commonly found in the lab – central vacuum systems, single stage pumps or diaphragm pumps – are not suitable for freeze-drying as they cannot achieve the required vacuum and maintain that performance, having no pumping speed capability at typical freeze-drying operating vacuum. Two-stage, oil-sealed, rotary vane vacuum pumps are sufficient for most freeze-drying applications.

In all vacuum applications, it is useful to site the pump as close as possible to where performance is required. Long length, small bore tubes have a significant effect on reducing vacuum pump performance.

5. Shelf spacing recommendations are only there to make sure my vials will fit in the drier

“I have 10ml vials with a height of 45mm plus stopper at 8mm for a total height of 53mm – why can’t I select your dryer with an indicated shelf spacing of 55mm to maximise my batch capacity?”

Shelf spacing calculations are made to ensure that not only can vials be easily loaded onto shelves in a tray, but that there is also sufficient space above the drying vials to allow unhindered vapour escape (see Figure 2). Vapour can leave the drying vials at a high rate. If there is insufficient space for that vapour to escape above the vials, it is possible to end up with local drying conditions in the centre of a shelf and different drying conditions nearer the edge of a shelf.

There are various formulas available for determining the shelf spacing required. In the example given above, a basic calculation suggests that a spacing of around 65mm would be more acceptable. In practice, the dimensions of the shelf and vial shoulder design should also be considered when making recommendations. It is possible to complete drying with reduced spacing, but a slower, more extended cycle is likely to be required to reduce the vapour load and ensure consistent dryness across the batch.

6. A colder condenser means faster and better freeze-drying

“I need a colder condenser to improve my freeze-drying. A colder condenser will suck the water out faster.”

It is often thought that a colder condenser will improve freeze-drying by speeding up the process. However, it is the difference in vapour pressure between product and condenser that drives the process, not the condenser temperature alone.

Increasing the pressure differential between product and condenser will certainly hasten the end result. However, lowering the temperature of the condenser is actually less efficient than raising the temperature of the product. Table 1 shows that the pressure differential decreases as temperature drops; for example, the pressure differential between -70°C and -80°C is just 0.0021mbar, whereas the differential between 0°C and -10°C is 3.505mbar.

Of course, the product temperature cannot be forced above its collapse point without causing damage to the product during primary drying. However, a more favourable thermal profile might be generated via reformulation, which would then allow the freeze-drying process to be driven more quickly.

Colder condensers are designed to process non-aqueous solvents which have a low freezing point. Unnecessarily cold condensers will increase the cost and complexity of the equipment and also increase running costs.

7. A higher vacuum means faster and better freeze-drying

“I need a higher vacuum to create lower pressure to suck the water out faster.”

With lyophilisation, it is not the case that the vacuum sucks the moisture out of the product; this only occurs during vacuum drying. The vacuum is generated in order to create the conditions necessary for the ice to sublimate (see Figure 3). Once the chamber pressure is below the vapour pressure of ice for the product, a higher vacuum (lower pressure) will not affect the speed of sublimation. In fact, a higher vacuum during primary drying slows the drying process.

During primary drying, it is imperative that sufficient heat energy is put back into the product to counteract the effects of sublimation cooling, otherwise the rate of sublimation will drop and drying will slow. While heat is input from the shelf, convection from the remaining air particles is also an important source of heat energy. Dropping the chamber pressure too low will therefore slow the rate of drying.

As noted above in point 6, the driving force of freeze-drying is the vapour pressure differential between the condenser and the product in the drying chamber, not the pressure or flow of gas created by a vacuum pump.

8. Eutectic temperature and collapse temperature are the same thing

“Eutectic temperature is just another term for collapse temperature.”

Collapse is the failure of a frozen product to maintain its structure. The temperature at which collapse occurs is the most important critical temperature in lyophilisation.

Eutectic freezing is a complete mix of ice and solute crystals and occurs in the case of frozen crystalline materials, such as a salt solution. For frozen eutectic solutions the collapse and eutectic temperatures will be the same, and ‘eutectic temperature’ is often used as a synonym for ‘collapse temperature’. However, in other products the solute may persist in a partly crystalline, partly amorphous mix over a range of temperatures. In these cases, there will be no clearly defined eutectic temperature, and instead the term ‘glass transition’ is used to describe the gradual shift from brittle solid to soft solid.

Most freeze-dried products are complex mixes of excipients with different thermal characteristics and different freezing behaviour. The collapse temperature of any given formulation is a result of the precise combination of ingredients and may or may not be distinct. Where there is no clear point of overall collapse, cycle development can become extremely challenging.

9. If the dried product looks fine, it is fine

“There is no visible collapse so the product must be alright.”

A serious and complete collapse is visually obvious: the product will shrink, distort or, in the worst case, only a sticky residue will remain. However, aesthetic acceptability is not a guarantee of successful freeze-drying.

Formulations contain many ingredients which in combination exhibit complex freezing and drying behaviour. While the product may appear solidly frozen, if one of the elements within it has not been properly frozen, collapse can occur unseen within the structure.

A thorough analysis of the dried product is the best way to ensure the product is correctly processed and stable. Karl Fisher is the standard moisture measurement technique, although this is a destructive method and therefore cannot be run on every vial. Frequency Modulated Spectroscopy (FMS), on the other hand, is a non-destructive moisture analysis method that can be used in conjunction with Karl Fisher to provide in-line or long-term moisture determination studies. Differential Scanning Calorimetry (DSC) is also used to investigate the dried product’s properties in order to evaluate storage conditions.

All these techniques should be used in conjunction with stability and activity studies during development to ensure that the product is shelf-stable for the required amount of time.

10. Drier is always better

“The lower the final moisture content, the better the product will be preserved.”

Lyophilisation increases the stability of a product by reducing the moisture levels, so it is easy to assume that the drier the product, the better the result. However, many products can be damaged by over-drying. Live cells lose viability and the molecular structure of complex proteins can be damaged when moisture levels fall too low.

It is also important to note that secondary drying is an increasingly slow process and that obtaining an extra one or two per cent reduction in moisture content may add many hours to process time (see Figure 4). A product with zero per cent moisture will never be achieved, so a balance must be struck between product stability and realistic final moisture content.


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Katriona Scoffin is a freelance Science Writer working for the freeze-drying company Biopharma Technology Ltd (BTL), which is based in Winchester, UK. BTL are experienced in all aspects of freeze-drying technology, from pre-formulation through to full-scale production and dried product analysis. They have successfully processed over 1,000 substances on behalf of clients.
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