Grasping Lyophilization Product and Process Parameters for Biopharma

A clear understanding of product and process parameters is essential if freeze drying is not to remain a “trial and error” process. This excerpt from an authoritative book* summarizes the basics.

By Felix Franks, PhD, BioUpdate Foundation

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Editor’s Note: This is an excerpt from Chapter 3 of Dr. Franks’ latest book, “Freeze Drying of Pharmaceutical and Biopharmaceuticals: Principles and Practices,” published last year by the Royal Society of Chemistry (copyright reserved). Dr. Franks, founder and director of the BioUpdate Foundation, has long been an advocate of understanding the physical, chemical and biological properties involved in freeze drying. His early research focused on the vitrification of aqueous media, which led to the development of new ways to stabilize biomolecules in vitro. He established Pafra Biopreservation to develop these processes commercially and apply principles of materials science to the process.

Nektar Therapeutics later applied that know-how in the inhalable insulin drug form that would become Exubera. In his book, Dr. Franks recalls being invited to help a company specializing in human blood derivatives, which had been achieving highly variable results in its freezedrying processes. He writes: “During a roundtable discussion, it became apparent that those pharmaceutical chemists who were responsible for formulation development had never met or spoken to their engineering colleagues, who were responsible for the freeze-drying process. Indeed, for ‘security’ reasons, the latter were not informed of the nature of the products that were to be freeze-dried. This was a scenario that our technologists also encountered in a number of other mega-pharma companies. Usually, even the mention of glass transition or its measured value met with blank stares.

The complexities were not appreciated, the freeze-drying operation being regarded as a push-button affair.” hardly a recipe for success Later in his book, Dr. Franks discusses some case studies with specific lyophilization processes. For one bioactive substance, a client found that the process stopped working entirely. It was later discovered that the company had changed to a different set of narrower vials, in order to increase loading capacity, but they did not take into account the increased fill depth. Dr. Franks writes, “Process development staff [often] knew little or nothing of glass transitions or the materials science approaches to the formulation of amorphous pharmaceutical solids. Even where the knowledge exists within a company, its significance does not generally reach the thinking of marketing or senior management. “Too often the author has been invited by departments to make presentations to senior managers, with the sole purpose of convincing them of modern thinking on freezedrying. Unless this lack is remedied, freeze-drying will continue to be practiced as a trial-and-error technique.” Chapter 3 presents an overview of the basic product and process parameters essential to biopharmaceutical freeze drying. To order the book, visit www.rsc.org/shop/books.

The physics and chemistry of freezing show many complex and often surprising features, but the industrial freeze-drying process is limited to very few operational degrees of freedom. Thus, for a given solution composition and a given container and closure system, only three process variables exist by which direct control over the drying cycle can be maintained and which, therefore, determine the quality of the final dried product. They are:

  • shelf temperature
  • chamber pressure
  • time

On the other hand, the most important factor is of course the product temperature and its change throughout the duration of the process.

Formulation Parameters

In the manufacture of a therapeutic product, the initial stage requires the purification of the biologically active component, the drug substance. Purification methods for ‘‘conventional’’ drugs are well established. They are based on synthetic organic chemistry and standard analytical techniques.

The situation is more complex for biopharmaceutical products, in particular those based on proteins. The drug substance may then be of animal, plant or microbial origin; it may be obtained from the natural source materials or by recombinant DNA (rDNA) methods. The extraction and purification strategy depends to some extent on the source of the protein. Possible impurities are many. The downstream processing always requires several stages and, depending on the source material, may involve a combination of physical and chemical methods.

The total yield of purified protein is related to the number of stages required and their individual yields. For instance, in an isolation and purification process consisting of n steps, each one of which can be carried out with a 90% efficiency (highly idealised!), the final percentage yield of product is given by:

Yield (%) = 9n x 10(2-n)

Thus, for a process consisting of five stages, each of which can be performed with a 90% recovery, the yield of the final product cannot exceed 60%, which is reduced to 53% for a six-stage purification procedure. Since biopharmaceutical drug substances, whatever their origin, are usually expensive, a loss of 40% during the purification process is a serious factor. A minimization of the number of stages is therefore aimed at, but it has to be judged against other economic considerations and an acceptable degree of purity.

For biochemical and therapeutic uses, purity and longterm stability are the overriding requirements. Fractionation, purification and stabilization by freeze-drying then generally account for 50% of the total production costs, but since such products command high premiums in the marketplace, production hardly figures in the cost equation. Examples of typical production cost breakdowns for two product/process scenarios are shown in Table 1.

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