Years of hard work and research go into developing new APIs, so when it comes to developing one into a new formulation for mass production, careful attention must be paid to its physical and chemical properties. Thorough consideration must go into the excipients to be used, as these can affect how the active ingredient will be released, and they can also react with the API and thereby reduce the product’s shelf life. Additionally, the processing method, such as freeze drying, must be factored for as this can cause many physical and chemical changes to the API.
However, across the biopharmaceutical industry, there is often a disconnect between the API synthesis and formulation development stages. The API manufacturing process will frequently be almost complete when the formulators begin work on a final commercial formulation, with little or no prior communication between the two lines of work – leaving formulators with a drug substance that is less than optimal for product development. This is why it’s vital to characterise API properties early in order to produce the best possible final formulation.
The Importance Of Early Product Characterisation
The physical and chemical properties of an API have a direct impact on the formulation requirements, such as:
Solubility in physiological fluids
How it reacts with other components of the formulation
Dissolution rate in the body
Powder properties like particle size and distribution
Flow properties which can affect the manufacturing process
The cost and time involved in conducting these kinds of tests prior to formulation development is a legitimate concern. However, the modest costs involved in gaining these kinds of critical insights into the characteristics of your API early on will save you a lot of avoidable damage, liability, lost efficacy, costly interruptions, and, ultimately, will prevent risk to the patients whose lives you’re aiming to improve.
It might seem like an easier option to go back and redevelop the drug substance to fit with your final formulation, but the truth is that would be a much more time-consuming and laborious process. Even small changes to your API manufacturing process are likely to require a new clinical study to demonstrate that it is equally effective as the original substance in order to gain FDA approval.
There’s no doubt that it’s hard to break down existing organisation silos in order to create a more aligned approach to API synthesis and formulation development, but the benefits of shortening the development timeline by getting things ‘right first time round’ far outweigh the negatives. In addition, you’ll see a faster return on investment, and – most importantly – get your life saving medicine to patients sooner.
The Benefits Of Freeze Drying
Whether you’re already sold on the benefits of freeze drying as part of your manufacturing process, or just looking at moving on from cold chain to freeze dried chain for a new product, it’s worth noting all the benefits of freeze drying:
Your final product will be stable at room temperature for at least 2 years, removing the requirement for chilling equipment for transport and storage
Batches are more homogenous in structure and appearance, which is crucial for FDA approval
The drug can be rapidly reconstituted for fast release of the API
There are high levels of activity in the reconstituted product
Batch production is highly controllable
Before you get onto formulating your freeze dried product, there are several analytical techniques which you should employ to create an optimum freeze drying cycle for your formulation.
How To Ensure Your Freeze Dried Formulation Will Be Compatible With Your API
First and foremost, you need to identify the critical temperatures for the primary drying phase of your freeze drying cycle. This is (as the name suggests) one of the most important factors that will affect your final product.
If you freeze dry your formulation above its critical temperature it can lead to:
Loss of physical structure
Incomplete drying (high moisture content)
Decreased solubility
Reduced activity and/or stability.
If you freeze dry your formulation below its critical temperature it can lead to:
Poor efficiency
High running costs
Longer cycles than necessary.
There are two pieces of equipment which can be used to identify your product’s critical temperatures: a freeze dry microscope and an impedometer.
Freeze Dry Microscopy (FDM) is the only technique which can reliably identify collapse temperate (Tc) in amorphous products and eutectic temperatures (Teu) in crystalline solutions. It can also be used to identify crystallisation phenomena, the possibility of skin/crust formation, and the effects of annealing on ice crystal growth and structure.
An impedometer can conduct two kinds of analysis:
Impedance Analysis (Zsinφ) is a fixed frequency dielectric analysis which indicates the sample’s rigidity/molecular mobility, including events not picked up by thermal methods like DTA or DSC.
Differential Thermal Analysis (DTA) analyses the difference in temperature between a sample and a reference point, highlighting exothermic and endothermic events e.g. crystallisation, eutectic melting and glass transitions.
This instrument can therefore be used to calculate both the dry state glass transition temperature (Tg) and eutectic temperature (Teu) of a sample, as well as to observe crystal transitions, softening and changes in viscosity.
It is best to conduct these tests prior to developing the formulation for your API, but if that is not possible, the results will help you with reformulating with the addition of cryoprotectants or stabilisers.
Now you have a suitable formulation for your API, you can move onto developing a freeze drying cycle which provides reliable, safe processing in a financially efficient manner.
Post-Process Characterisation Analyses
It is also important to assess the effect of moisture on your product after it has been processed, as this could lead to cake collapse and therefore impact its long-term stability.
The best technique for assessing the effect of moisture is Dynamic Vapour Sorption (DVS) which determines the moisture content of a solid-state material as a function of temperature and humidity.
This testing will give useful information not just about which specific humidity level will cause cake collapse, but also which changes are irreversible, such as crystallisations and pore collapse, and which changes are reversible, such as hydrate formation. Once collapse behaviour has been determined for the freeze dried cake, you can produce accurate guidelines for its storage and stability.