Masterstudiengang "Drug Regulatory Affairs"

Master-Thesis

How to define the acceptable evaluation threshold (AET) for large volume parenterals (LVPS): European regulatory requirements and their practical implementation outweighing patients` needs versus safety ***

Dr. Christiane Scherer (Abschlußjahr: 2013)

Summary

Language: English

Overall the establishment of safe drugs is directly correlated with the establishment of safe acceptable evaluation thresholds (AET-values) for impurities during the drug development process following the current state of the art of science and technology. This is what all drug products have in common. Nonetheless the challenge for large volume parenterals (LVPs) seems to be higher than for many other groups of products (e.g. for tablets) for diverse reasons. The officially required safety thresholds are set out as permitted daily exposures (PDE values in weight per day), and the very high doses of some lifesaving LVP-subgroups (e.g. doses of up to about 18-20 litres per day for peritoneal dialysis (PD) solutions (chronical) or up to about 75-135 litres per day for (acute) haemofiltration (HF) solutions do not seem to be considered adequately. This can be deduced from the analytical perspective, in that analytical action limits (AAL-values), which would be required for such high daily doses of LVPs, cannot be reached for diverse impurities with the currently available analytical technologies. For example, a commonly recognised PDE for a genotoxic impurity (with an anticipated threshold-related activity) of 0.15 µg/day might correspond to about 0.001 µg/l for 135 l of a HF solution applied in adults. (If used in children in cases of concern the concentration might even be lower.) Moreover it is noteworthy, that most of the data sets for the derivation of parenteral safety thresholds are exclusively based on orally applied drugs and on compounds with selected chemical structures (see Munro-databases or Cramer-classifications). This extrapolation from the oral to the parenteral pathway is justified with the assumption, that risks coming from parenterally applied drugs should generally be higher than the ones coming from perorally applied drugs, since the first group has an immediate bioavailability of 100 % in the systemic circulation (no first pass metabolism). However this extrapolation is not universally valid, and there should be a case-by-case evaluation, since first pass metabolism of chemical compounds applied via the peroral route, can also lead to a toxification. Vice versa the toxicity of parenterally applied compounds might even be lower compared to the peroral route, due to the immediate start of their metabolism / detoxification and their elimination from the systemic circulation. (That`s why pharmaceutical technologists and toxicologists must develop the optimal application routes and pharmaceutical forms for APIs.) In addition the influence of the large volumes and flow rates of PD- and HF-solutions are not considered, which also trigger the diffusion and convection of impurities out of the systemic circulation, in that the chance of accumulation of an impurity in the different compartments of the body will in most cases be quite low. Accordingly, following the theory of the concentration gradient for passive transport mechanisms of hydrophilic compounds representing the biggest part of the impurities probably present in the aqueous LVP-solutions, such compounds will rarely accumulate within the body of a patient. This is attributed to the facts, that active transport mechanisms are considered to be marginal for exogenous compounds, and that aqueous solutions (hydrophilic) for PD and HF will hardly contain lipophilic compounds in concentrations below the established AET-values for the respective finished products.

Accordingly, the question for LVP-adapted safety thresholds arises, in that experts should also take into account the exposure scenarios and consider empirical knowledge from lifesaving products being on the market since decades. However, currently the manufacturers of LVPs bear the main responsibility beyond official requirements to establish safe drugs. This is nonetheless possible if considering the current provisions, but it requires quite a huge effort

In summary the manufacturers must strictly follow the QbD-principle (“quality by design”) for the whole life cycle of a product starting with the development phase in order to minimise potential sources for impurities. Hence high quality raw materials for the finished product and its container closure system must be chosen including the qualification and monitoring of external suppliers. Besides the production process and related processes including analytical approaches and methods must follow GMP- and QbD-requirements, in that production lines are made of appropriate materials, critical and analytical processes are validated and operations are performed by trained staff. All these aspects must be based on expert opinions and the whole circuit development process of a drug should always be supported by overall experts for the diverse areas like analytics, pharmacology or toxicology. This is also crucial for the establishment of the drug-dependent AET, which is derived from the theoretical thresholds of toxicological concern of all impurities potentially present in the drug product, and which is set as a threshold for release of a drug during routine production as (virtually) safe. This value means that experts have considered for a specific drug and exposure scenario that the increase of the risks for patients treated with the respective drug is negligible if the AET-limit is met. Since it is never possible to reach a risk-level of zero (“you can never prove the evidence of absence”), it is also justifiable from the ethical perspective, to balance risks of patients versus their benefits for the decision about the approval of a drug for marketing authorisation. Last, but not least, one should also consider with regard to safety of LVPs, that they are generally quite simple solutions (mostly physiological saline-dextrose solutions) of high quality materials, and hence the risk for very harmful impurities coming from these sources is relatively low. Moreover one has to take into account the very exceptional exposure scenario for the acute or chronical lifesaving medications with LVPs. Besides, the only alternative to the lifesaving dialysis is organ transplantation, which is still a big problem including the waiting lists for the donation of a kidney, suppression of potential organ rejection by “harmful” drugs, potential rejection, limited number of re-transplants and donor organs, and reduced lifetime of a donor organ. In many cases, patients have to come back to dialysis even after organ transplantation for diverse reasons.
Hence overall risks coming from appropriately developed LVPs (with drug-depending safe AET-values) are relatively low if compared with many other drugs on the market, or with alternate options to dialysis. Moreover the benefit of patients` life extension is unambiguous.  


Pages: 65,
Annexes: 01, Pages: 02