Biopharmaceuticals safety

Aranha, H. 2001. Viral clearance strategies for biopharmaceutical safety part 3, general considerations. Biopharm Int 14, 28-35. 

An overview of the general principles of filtration having specific appHcation to bacterial and viral removal is given herein. The emphasis is on ensuring that the sterility and/or safety of biologicals and biopharmaceuticals be maintained. 

Product Development Rationale Overview of Biopharmaceutics Overview of Clinical Pharmacology Overview of Efficacy Overview of Safety Benefits and Risks Conclusions Literature References... 

Summary of Biopharmaceutic Studies and Associated Analytical Methods Summary of Clinical Pharmacology Studies Summary of Clinical Efficacy Summary of Clinical Safety Literature References Synopses of Individual Studies... 

The principal considerations involved in design of a process-scale chromatographic purification include scalability, reproducibility, safety, and validatability. Cost factors, however, must by necessity enter into all industrial decisions. Due to the high value-added nature of most biopharmaceuticals, this cost factor is driven by throughput, rather than by capital investment cost. 

Clinical trials serve to assess the safety and efficacy of any potential new therapeutic intervention in its intended target species. In our context, an intervention represents the use of a new biopharmaceutical. Examples of other interventions could be, for example, a new surgical procedure or a novel medical device. Veterinary clinical trials are based upon the same principles, but this discussion is restricted to investigations in humans. Clinical trials are also prospective rather than retrospective in nature, i.e. participants receiving the intervention are followed forward with time. 

Once filed, an NDA undergoes several layers of review (Figure 4.12). A primary review panel generally consists of a chemist, microbiologist, pharmacologist, biostatistician, medical officer and biopharmaceutics scientist. Most hold PhDs in their relevant discipline. The team is organized by a project manager or consumer safety officer (CSO). The CSO initially forwards relevant portions of the NDA to the primary review panel member with the appropriate expertise. 

The physiological similarity and phylogenetic proximity of nonhuman primates to humans are often cited as rationale for primate selection for safety studies especially when mechanisms of toxicity or pharmacologic action are expected to be closely related to potential physiological reactions in humans. Likewise, species selection is often based on the demonstration of pharmacologic activity of the test article. Many biopharmaceuticals do not exhibit their intended activity in nonprimate species, whereas small molecules may have activity across all species. 

Biopharmaceuticals are subjected to strict regulations to monitor and quantitate impurities to maintain product safety, quality, integrity, and efficacy.4 The following are definitions that relate to purity ... 

Phase II studies encompass a detailed assessment of the compound s safety and efficacy in a larger patient population (a few-to-several hundreds of patients). It is important that any formulation selected for these studies must be based on sound biopharmaceutical and pharmaceutical technology principles. Phase III clinical studies, also referred to as pivotal studies, involve several thousands of patients in multiple clinical centers, which are often in multiple countries. The aim of these studies is to demonstrate long-term efficacy and safety of the drug. Since these studies are vital in the approval of the drug, the dosage form plays a very critical role. 

Although no biopharmaceutical product delivered to the bloodstream via the pulmonary route has been approved to date, several companies continue to pursue active research and development programmes in the area. Amongst the leading product candidates is Exubera , an inhalable dry powder insulin formulation currently being evaluated by Pfizer and Aventis Pharma in Phase III clinical studies. The inhaled insulin is actually more rapidly absorbed than if administered subcutaneously and appears to achieve equivalent glycaemic control. While promising, final approval or otherwise of this product also depends upon additional safety studies which are currently under way. 

While the majority of critical manufacturing operations of injectable pharmaceuticals (e.g. most biopharmaceuticals) occurs in specialized clean areas, proper design and maintenance of non-critical areas (e.g. storage, labelling and packing areas) is also vital to ensure overall product safety. Strict codes of hygiene also apply to these non-critical areas. 

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