Central Research

Quality of medicines

The quality of medicines is an issue of great importance in human health. At present, methodologies, disciplines and institutions have been generated whose objective is that the population has safe and effective medicines, with precise uses and in safe environments. The reason for this article is to recall the most important elements to guarantee the quality of medicines in three stages: Development, Approval and Marketing.

Development

When a pharmaceutical company or laboratory intends to search for new drugs, its main concerns are safety and efficacy, a quality drug during preclinical and clinical development will be the one with an acceptable degree of safety and efficacy. These two elements are analyzed during preclinical trials, usually in vitro cell cultures and in non-human animal models (mice, rabbits, monkeys, etc.). In these models, toxic doses of the molecules studied are calculated, as well as possible therapeutic doses. Only in the case that low toxicity is demonstrated, even at high doses, the study can continue with the Phase clinical studies.

Phase 1 studies primarily evaluate the safety of the drug, as well as potential therapeutic doses. These trials use a small number of individuals, usually healthy. If safety is demonstrated in Phase 1, we proceed to Phase 2, where the number of participants is increased, the doses with possible therapeutic effects are evaluated and the presence of adverse events of the drugs studied is thoroughly analyzed. It is important to note that all drugs have associated adverse events, this is natural when dealing with molecules with physiological effects, the important thing is that the adverse events of the compounds studied are not more serious than the disease that is trying to combat and that, in general, they occur with low frequency. Finally, Phase 3 is a large study, with a high number of research subjects and where the efficacy and safety of the drug will be tested at clinically relevant doses.

Approval

If a medicine has demonstrated its efficacy and safety in clinical trials, it can be submitted to the corresponding health authorities for approval in order to be marketed. The authorities that regulate the drugs are in charge of evaluating the existing scientific evidence on the drug to be approved, particularly the Phase 3 trials. In the United States this authority is the Food and Drug Administration, FDA, in Europe it is the European Medicines Agency, EMA for its acronym in English, and in Mexico the Federal Commission for the Protection against Sanitary Risks, COFEPRIS. It is very important to note that these agencies have as their main objective to protect the health of the population, so they particularly evaluate the safety of medicines.

In general, regulatory agencies have groups of experts that analyze, objectively and critically, the scientific information provided by the applicant for approval, which are usually the laboratories that developed the molecule or the company that will commercialize it. An important point of the approval process is that the applicant has to specify the dosage (how much and how to administer the drug) as well as the therapeutic indication to which it is directed. The role of the regulatory entity is to approve or reject the application; In the first case, sanitary registration is granted to the drug, which allows its manufacture and commercialization in the country.

Another important area where the health authority intervenes is in the manufacture of medicines, every manufacturing plant has to comply with a series of minimum standards and regulations for its operation. This is essential to ensure the quality of a drug, since, as we know, a drug not only contains the active substance, responsible for the therapeutic function, but also a number of other compounds that provide stability, release, taste, etc. Each of them must have the appropriate quality, purity and quantity, which guarantee the efficacy and safety of the drug. The manufacturing process of the drug is a key step in ensuring its quality.

Marketing

Although it seems that, by demonstrating safety and efficacy in clinical trials and obtaining sanitary registration and production approvals, the quality of a drug is already guaranteed, this is not true. Storage and distribution processes are critical steps, all medicines have to remain in specific conditions, temperature is a very relevant factor: below -15/-20 °C is frozen, between 2 °C and 8 °C refrigerated, between 8 °C and 15 °C is cold or cool and between 15 °C and 25 °C room temperature. Another important factor is exposure to sunlight, many chemical compounds are very sensitive to sunlight and have to be protected from it, for this manufacturers use dark packaging, amber jars or double packaging, however, this is not exempt from the need to store away from direct sunlight. The physical integrity of containers, packaging or bottles is something that always has to be corroborated, any medicine with damaged packaging (broken, wet, open, discolored, deformed, etc.) should not be used, there is a risk that the quality is compromised. Finally, storage time is essential, all medicines have an expiration date, after which their use is not recommended. At present the activity of surveillance of the quality and safety of medicines is known as pharmacovigilance, this is the responsibility of the companies that produce medicines, but also of health professionals and health institutions, when it is taken responsibly, pharmacovigilance in a powerful tool to ensure the quality of medicines.

It is true that sometimes the expiration or mishandling of medicines causes their lack of effectiveness and not directly new safety risks or adverse effects different from those known, however, in some cases, serious health risks may appear, such as contamination by bacteria or fungi. One of the potentially most serious cases in the quality of medicines is their falsification or alteration, unfortunately, it is not uncommon for altered or counterfeit medicines to be marketed clandestinely, which represents a serious health risk.

What about the quality of generics and biosimilars?

Generic drugs are those that contain the same active ingredient(s) as another medicine already registered. When a company obtains registration for a novel drug, that is, whose formulation of active ingredients was not previously used, this drug is known as a reference drug, which has a period of commercial exclusivity, usually about 10 years, from obtaining registration, in which only the company that owns the registration can produce the drug. Once this period expires, any other company can manufacture the medicine in question, as long as it meets the requirements of bioequivalence and manufacturing.

Bioequivalence is the key to ensuring that a generic drug (other than the reference drug) makes no significant difference in the rate and degree to which the active ingredient or active fraction is available at the site of action of the drug when administered at the same dose and under conditions similar to the reference dose. Therefore, when we talk about an equivalent generic, it is guaranteed that they have the same chemical-pharmaceutical quality, potency or concentration and safety. According to the legislation of each country, the parameters and definitions for bioequivalent generic medicines may vary, but in general, we can say that the use of generic medicines that have the appropriate permits is as safe and effective as the reference medicine.

On the other hand, biological drugs, also known as biotechnology, are subject to the regulations of the authorities, although the analysis and evaluation techniques may be different from chemical drugs; biologics need to guarantee safety, efficacy and quality. Like generics, in the case of biologics, there are biosimilars, non-original drugs that claim to have the same therapeutic effects and safety as reference biologics. In some cases, particularly with some monoclonal antibodies, this can be difficult to achieve, however, thanks to biotechnological advances, a large number of high-quality biological medicines are now available.

Rodrigo Martínez Espinosa

Medical Advisor - Medical Manager at Carnot Laboratorios. Specialist in Genetics and Molecular Biology of Complex Diseases.