Powder technology in the pharmaceutical industry: the need to catch up fast

Abstract

Pharmaceutical product development and manufacturing, which is largely an exercise in particle technology, is in serious need of technical upgrading. In this article, an overview of the current state of the art is provided, along with a discussion of expected research trends and their economic and societal impacts. In particular, the anticipated role of nanotechnology is discussed in some detail.

Introduction

The picture is entirely familiar. It is late at night, time for your child's medication. You open a small container, take a pill, and give it to your daughter or son. You go to sleep. You know that everything will be fine.

Astounding advances in medicine (beginning with the advent of modern antibiotics), reinforced by more than 50 billion dollars per year in worldwide advertising by drug companies, have led us to think of drugs as perfect products. We routinely consume tablets and capsules, expecting them to contain precisely what they are supposed to and to perform exactly as intended. If anything, we might be concerned about allergic reactions, i.e., our body experiencing the “wrong” reaction to the medicine, but questions such as “Is this pill OK? Does it contain the specified dose of drug? Has it been properly manufactured? Will it perform as intended?” rarely cross our minds. This is striking, considering that drug substances are highly toxic compounds. In some sense, they cure disease because they are toxic; i.e., because they have the ability to dramatically affect human physiology. In fact, the more potent the drug, the more toxic. Thus, health risks are an intrinsic, unavoidable component of pharmacological therapies. When we take medications, we are consuming potentially dangerous substances, and we can only hope that the processes used to make them are sufficiently well understood and controlled to make those risks as small as possible.

Is our faith in drug products justified? The answer is yes, but with qualifications. As part of the process of introducing new drugs to the market, industry and government go through tremendous efforts involving multiple stages of clinical trials to determine drug therapeutic benefits, optimum dose, and incidence of side effects. However, as discussed below, the technology used to manufacture drug products can at best be described as primitive. We only have a partial understanding of the materials and processes involved in pharmaceutical product development and manufacturing, which are carried out largely by empirical methods. Thus, the inherent reliability of pharmaceutical manufacturing is highly questionable, and is likely to be increasingly challenged in the near future. In the past, economics often led pharmaceutical companies to emphasize discovery, or mere advertising, at the expense of technology research. However, in the future the relative priorities will change as manufacturing challenges become substantial enough to have significant impact on the ability of companies to make certain products at all.

Early in clinical trials, companies determine the target concentration of drug in the bloodstream as a function of time. Subsequently, through a process termed “formulation”, they develop a dosage form (a tablet, a capsule, an aerosol, an injectable product, etc.) that will express the desired amount of drug as a function of time in the bloodstream of the “average person”. Thus, a drug product involves much more than a package containing the right amount of a compound; it is also a delivery system intended to interact with the human body in a specific manner. For example, many drugs are sensitive to pH and therefore must be engineered to be absorbed in the environment of the intestine, but not the stomach, or vice versa. Likewise, long chain proteins become degraded in the gut and must be delivered as inhalants, in which case, ensuring transport to the deep lung becomes important.

Increasingly, companies devote substantial efforts to understanding and controlling the factors that affect the delivery of the drug substance to the desired point of action. In fact, effective drug delivery is rapidly becoming a decisive factor in determining drug product effectiveness. Recent advances in molecular genetics are accelerating the discovery of much more potent and specifically targeted molecules that also tend to be larger, less soluble, less permeable, and more vulnerable to the body's enzymatic circuit. Increasingly, these compounds need to be quantitatively delivered at a precise location within the body at a carefully controlled rate in order to be safe and effective.

As a result, most major pharmaceutical companies have developed extensive research programs in drug delivery, both in-house and at academic institutions. However, much less effort is devoted to the technology used to manufacture drug products. Once a dosage form is designed, companies develop a batch manufacturing process in order to make a large number (typically millions) of units with properties (drug content, tablet hardness, dissolution, stability) within certain tolerance margins. This process is typically performed using empirical scale-up methods to translate formulation information into large-scale routine manufacturing. Given our limited understanding of human physiology, material science, and the interactions between the body and drug substances in the presence of other ingredients, the design and timely manufacture of millions of units of a drug product all having the same composition and physicochemical attributes is, both in principle and in practice, an increasingly daunting task, pregnant with enormous potential for both human and economic disaster.

At its core, the US FDA drug approval process challenges companies to manufacture a few (typically three) production-scale batches according to specifications that sometimes are set by the companies themselves. Once this is accomplished, the process is deemed “validated” and is intended to be repeated, without changes, indefinitely. In other words, once a drug product is developed, a method for its manufacture is determined, and it is reproduced three times within specifications, both industry and government are loath to introduce the slightest change in the manufacturing method, because of the numerous uncertainties involved. Simply put, neither industry nor governmental agencies know what would happen, and any changes might necessitate onerous testing and retesting to ensure that in vivo performance has not been adversely affected.

In order to protect the public from potential risks, companies are required (to a varying degree, depending on the type of product) to develop monitoring methods intended to control materials and processes and minimize undesirable changes. Unfortunately, as it is the case in most human enterprises, change is unavoidable, especially when we do not know the impact of many variables that go unmonitored, or even further, that cannot be monitored given the state of available technology.

It is thus clear that a much better understanding of pharmaceutical products, ingredients, and manufacturing processes is sorely needed. Much of the work to be done is in the area of powder technology. To make this point clear, let us briefly review how drugs are made.