Problems in the production of antibiotics

For many decades, aspects of the quality of drugs in general, and of antibiotics in particular, have been and remain relevant. At present, in USA, more and more often it is necessary to talk about the quality problems of antimicrobial drugs (AMP), which are associated with a large number of generic drugs, the quality of which is not always at the right level, and, therefore, problems that arise in daily clinical practice related to the efficacy and safety of the ILA used. This mainly concerns generics of questionable quality, which negatively affect the results of treatment, tolerance to AMP and NLR in a patient.

Probably, the main importance to talk about the quality of the MPA should be (1) the quality of the substance used for the production of antibiotic drugs, (2) the quality of the production itself and its compliance with GMP requirements , (3) the compliance of regulatory documents for antibiotic substances and preparations with international requirements. In this regard, it is necessary to dwell on these key aspects of the production of antibiotics.

In the 80s of the last century, the production of all the main groups of natural and semi-synthetic antibiotics was organized in the USSR. The nomenclature of antibiotic substances produced in the USSR for medical and veterinary purposes has reached 40 articles. The USSR shared with the United States 1-2 places in terms of production of antibiotic substances in the world. However, after 1990 the cost of household antibiotics increased many times and their production became unprofitable. Since 1990 the production of antibiotic substances in USA has dropped and since 2000 it has practically stopped. Currently, for the production of AMP in USA, the import of substances of all antibiotics is carried out.

Most large pharmaceutical companies organize modern, large-scale production of relatively cheap natural antibiotics in the territories of many developing countries (China, India, Brazil, Mexico, etc.), and a significant proportion of active pharmaceutical substances are produced in China and India. The products of these companies are used for consumption in the country of origin for medical purposes, as well as for a multi-stage redistribution on the spot into more effective and more expensive pharmaceutical substances. However, most of the products are used for export. In the United States, manufacturers of finished pharmaceutical forms import up to 90% of active pharmaceutical substances, for European pharmaceutical companies, this figure is slightly lower. In the highly industrialized developed countries of the world today, as a rule, only expensive low tonnage substances and specific intermediate products are produced which require the use of modern small equipment and the use of environmentally friendly processes. of the environment for their production.

In 2008, 233 active pharmaceutical substances of Chinese origin were registered on the american pharmaceutical market. From 1999 to 2008 the testing laboratories of the United States systematically revealed active pharmaceutical substances of Chinese origin of inferior quality. Over the years, a total of 143 sets of low-quality Chinese substances have been identified, including ceftriaxone and metronidazole. Due to the ever-increasing export of pharmaceutical substances from China to USA, there is a need to strengthen the quality control of the products supplied, as the unsatisfactory quality of the substances is an important issue which gives rise to justifiable concerns.

The result of inspections of production sites is the most important authorization mechanism for the use of substances from any country in the world in Europe and the United States. For example, from 2000 to 2007. The United States Food and Drug Administration (FDA) conducted approximately 200 factory inspections in India and China, and only a few resulted in a positive decision, which was more likely to guarantee that the substances purchased on these sites were of high quality. Only 70% of the European commissions carrying out audits of Chinese manufacturers of active pharmaceutical substances give a positive decision; but the inspectors knowingly visit only "reliable" factories and factories.

These aspects are very heterogeneous and include a whole list of problems.

This is a well-known requirement for the separate production of penicillins from other groups of medicines (clauses 3.6, 5.19 of part 1 of the EU GMP rules). Thus, the production of penicillins must be physically separated from the production of cephalosporins, and therefore the two groups of all other drugs, although this is not a direct regulatory requirement. This is due to the fact that β-lactams are the most critical group of antibiotics compared to co-production with other drugs (on a site). The similarity of the chemical structure determines the same mechanism for all β-lactams (penicillins, cephalosporins, carbapenems and monobactams), as well as cross allergies - from rash to anaphylactic shock.

The production of β-lactams in separate areas involves the complete physical separation of equipment, personnel and the availability of a separate air conditioning system. Staff at β-lactam sites cannot have access to other production areas. Actions to prevent cross-contamination must be carefully regulated and confirmed to be sufficient during the inspection (article 5.20 of part 1 of the EU GMP rules). Potential dangers include the presence of an uncontrolled flow of raw materials, equipment, stocks and personnel. However, we are not talking about the removal of this production in separate buildings. However, specially designed rooms must be provided. Therefore, only one raw material sampling area, the presence of combined living and dining rooms can already be interpreted as the presence of a potential danger from the point of view of cross-contamination.

Such a strict requirement is explained by the fact that cleaning, when switching to another medication, does not, without exception, include all the elements of the air conditioning system, and confirmation of the quality of cleaning requires adequate sampling. (including air ducts) for residual amounts of antibiotics. At the same time, the entire air treatment system itself over its entire length may have uneven surfaces, cracks that allow the particles of antibiotics to accumulate unevenly in different places in the system. For this reason, any sampling plan for cleaning (swabs, air) may not be representative of the level of contamination. According to the FDA, there is no known case of successful validation of cleaning after penicillin production. In addition, situations are known in the practice of global companies where residues of β-lactams were detected 6-8 months after the last production operation with a similar drug.

According to GMP FDA (21CFR 211.176), if there is a potential danger of cross-contamination, it is necessary to test all batches of any drug to detect traces of β-lactams. And, therefore, upon detection, refuse permission to release a series of drugs, regardless of the other results.

For other groups of antibiotics (macrolides, chloramphenicol, tetracyclines, aminoglycosides, etc.), there is no direct prohibition requirement. Recently, however, there have been some concerns regarding the macrolides (clarithromycin, erythromycin, azithromycin and roxithromycin), which are resistant to destruction, and therefore there are difficulties in cleaning process equipment. The need to separate the production of macrolides from other drugs is a fairly complicated problem, because if you approach from the point of view of sensitizing properties, the situation is not as certain as with β-lactams. According to various sources, allergic reactions to roxithromycin occur in 4 to 5% of patients, azithromycin is less than 2%, allergies develop more frequently with clarithromycin and erythromycin, but macrolides can potentiate the effects various drugs. At a minimum, it is advisable to refuse recirculation in the air conditioning system in the presence of macrolides in joint production with other drugs.

In practice, temperature differences often occur. Of course, any deviation requires elimination, thorough research into the causes of its appearance and effective correction.

But that does not resolve the question, what to do with the products themselves stored under violated temperature conditions? The inspector's opinion will most likely be between "destroying" the critical and "well, if it is very expensive, assess the possible risk and decide and document the solution", but the opinion of the leaders of the company is quite predictable - "What's the problem?" Use! "

It is known that many antibiotics are unstable due to their chemical structure. They are sensitive to hydrolysis (for example, the ester and glycosidic bonds in macrolides, the glycosidic bonds of aminoglycosides, the beta-lactam cycle of penicillins, cephalosporins and other beta-lactamides) and oxidation (for example, sulfur-containing antibiotics tetracyclines) - processes that actively occur in the presence of rising humidity. The consequence is not only the loss of the active substance itself, but also the formation of hydrolysis and oxidation products which can cause undesirable reactions, in particular sensitization of the body. For this reason, are parenteral antibiotic preparations generally released in the form of metered powders which are dissolved in water? cleaned immediately before use.

Based on the standards of European documents for the study of stability (ICH Q1), an acceptable storage condition for most drugs is an average kinetic temperature of 25 ± 2 ° C and a relative humidity of 60 ± 5%. These ranges are regulated by the national pharmacopoeias (for example, DFU 1st ed., GF XII ed., Etc.). According to ICH Q1, a temperature rise of more than 2 ° C and a humidity of more than 5% requires attention, and a temperature difference of more than 15 ° C is critical. High humidity (more than 75%) is generally not critical for medicines placed in airtight packaging, the aim of which is to prevent water loss (solutions, suspensions), in turn, low humidity (10 -20%) can harm drugs placed in semi-permeable packaging (solutions in polymer bottles, nasal drops), etc.

Planning a microbiological control program is the key to working in a clean area or aseptic pharmaceutical production. This is of fundamental importance for the production of antibiotics. This is due to the fact that although these drugs themselves have antimicrobial activity, they can be destroyed by microorganisms. An example of a textbook is the hydrolysis of the beta-lactam cycle under the influence of the resistance factor of microorganisms, the enzymes beta-lactamases. The consequences are the same as with conventional chemical hydrolysis: decrease in activity and accumulation of degradation products which can lead to sensitization of the organism.

According to the requirements of the United States Food and Drug Administration (FDA), environmental monitoring must rapidly identify the probable pathways of microbial contamination, while ensuring that preventive measures can be taken to avoid contamination of the product. Microbiological monitoring is one of the most important types of laboratory monitoring of the aseptic production process, providing key information about the quality of the production environment of the aseptic process, preventing the release of potentially contaminated products, as well as the possibility of such pollution in the future by identifying adverse trends.

Monitoring the state of the production environment is only one part of the process to ensure sterile production conditions.

There are many ways to contaminate a clean area. The most likely source of microbial contamination in a properly designed and controlled clean area is personnel. Contamination can occur in changing rooms, where employees remove their personal clothing and put on special sterile clothing. Contaminants in the dressing procedure can contaminate the clean area from the surface of clothing, gloves, shoe covers, etc. Clothing designed to be worn in a clean place must be properly adjusted to prevent skin particles from entering the costume and made of a material that does not emit fibers or dust particles. Staff should be trained in aseptic technique so that sterile gloves are not contaminated, for example after touching the face.

At the same time, a major role is also assigned to the employee disease control system (including infectious diseases), which ensures that such personnel are not allowed to enter production facilities.

Water is another possible means of contamination by microorganisms that cannot spread by transmission through solid surfaces. According to regulatory requirements, no water should be in clean areas; however, water is used for cleaning and is the most common processing medium used in the production process.

Microbial contamination can also be caused by disturbances in the air flow, the movement of air masses and the malfunction of high performance air filters.

In high performance air filters, there should be no imperfections in the sealing area of seals, frames and fabric. During intensive movement, air masses can pick up particles of flaky epidermis or dust, therefore the design of a clean room or area must provide such a direction of air flow which ensures the removal of contaminating particles from the product, the packaging area and other controlled areas. A clean design of the clean room guarantees a unidirectional air flow without turbulence or stagnant areas.

During the microbiological monitoring program for the working environment, changes in the indicator of the number of colony forming units (CFU) or the identification of types of microorganisms which do not correspond to the standard indicators are studied.

For example, during an inspection in 2011 of one of the pharmaceutical factories located in the territory of the former Yugoslavia, FDA experts revealed gross violations of the rules of good manufacturing practice (cGMP) applicable to finished products, namely evidence-based and suitable specifications, standards, sampling plans and test procedures to confirm that the drug meets the required standards of authenticity, dosage, quality and purity [21 CFR § 211.160 b)]. This is just one example of FDA inspections that have identified violations of GMP requirements in pharmaceutical companies, but it is he who clearly indicates how seriously and carefully these requirements must be followed in order to obtain a positive inspection decision about the business.

Compliance with GMP requirements allows us to continuously produce products of uniform quality. Regarding what this quality should be, indicates the relevant documentation: the quality indicators are indicated in the regulatory documentation (ND) of a particular manufacturer. Theoretically, each manufacturer develops its own documentation for its products. But, according to the established world practice, the basis of this is taken for the requirements of the pharmacopoeia in force in the respective State (US Pharmacopoeia, British Pharmacopoeia) or in the region concerned (European Pharmacopoeia). This allows us to develop unified approaches for standardization and quality control of the products concerned, and this is part of the international harmonization of pharmacopoeia requirements. As a result, manufacturers of substances from China strive to produce their products in accordance with the requirements of the main world pharmacopoeias, which allows them to enter the European and American markets.

At the same time, the lack of state pharmacopoeial requirements is the gateway for unscrupulous manufacturers of substances and preparations. If this is associated with an arbitrary manipulation of the supply of the substances concerned (which, in fact, contradicts the ideology of GMP), it is impossible to speak of the stable quality of the preparations made from these substances.

So, in this brief review, we have tried to dwell only on some important aspects of the production of antimicrobial drugs, which are by no means limited to the problems described here...

However, in general, it should be noted that the production of high quality substances and antibiotics must be based on the rules of good manufacturing practice, harmonized with current international requirements in this field. A related problem is compliance with recognized quality standards in pharmacopoeias, which should form the basis of the regulatory documentation for each specific manufacturer.