Biotechnology - Yu.O. Sazykin 2006

General Biotechnology
GMP System for the Production and Quality Control of Medicines

Nowadays, the pharmaceutical market is international in the truest sense of the word. A medicine can be manufactured on one continent and consumed on another, separating the consumer from the manufacturer by thousands of miles. The variety of both drugs and dosage forms is steadily increasing, alongside growing competition among their manufacturers. Pharmaceuticals are produced in countries with diverse social systems, national traditions, and customs, and manufacturing plants may operate in vastly differing climate zones, and so forth.

Medicines belong to a category of products whose quality, efficacy, and safety are not always easy for the consumer to evaluate, as this requires specialized laboratories.

It is well known that the quality of a medicine is guaranteed by the pharmacopoeia, which has the force of law. However, as early as the mid-20th century, the need arose for yet another document. This document (or more precisely, set of documents)—GMP (Good Manufacturing Practice)—does not replace the pharmacopoeia; rather, it complements it to serve a single ultimate goal: guaranteeing the consumer high-quality medicines. While the pharmacopoeia applies directly to the medicinal product itself, the official Introduction/27.html">Translation of the document's title—"Rules for the Manufacture and Quality Control of Medicinal Products"—pertains to the facility where the medicine is produced.

GMP regulations set the standards for manufacturing operations to ensure high operational standards across all manufactured drugs and possess official status as a set of guiding regulatory documents. They are mandatory for all enterprises producing both finished medicinal products and active pharmaceutical ingredients (APIs)—BIOLOGICALLY ACTIVE SUBSTANCES intended for drug manufacturing. Non-compliance with these rules leads to sanctions against the facility, up to and including its closure.

GMP rules were first adopted in the USA in 1963. However, they gained true international significance in 1969 when, under the auspices of the WHO, about a hundred countries concluded a multilateral agreement by adopting a document known as the "Certification Scheme on the Quality of Pharmaceutical Products Moving in International Commerce." It was emphasized that the new document was introduced "to assist health authorities in importing countries in assessing the quality of imported pharmaceuticals and the standards of their production.">

The adoption of this document meant that relying solely on the pharmacopoeia as the sole barrier guaranteeing drug efficacy and safety was no longer sufficient, thereby necessitating stricter control over manufactured pharmaceutical products. The concluded agreement granted certain rights to drug exporters seeking to expand their sales markets; however, to exercise these rights, exporters had to fulfill three conditions:

✵ registration of medicinal products in the country of manufacture;

✵ governmental inspection of pharmaceutical manufacturing facilities;

✵ official adoption of GMP rules.

Subsequently, starting in 1975, this document was revised and improved on numerous occasions. Currently, In addition to the international GMP rules adopted by the WHO, there are national GMP rules adopted in more than 30 countries (including the USA, Great Britain, and Japan), as well as regional ones, such as the GMP rules of the European Community, the Association of Southeast Asian Nations, and the Arab Union of Manufacturers of Pharmaceuticals, among others.

For various reasons, these documents differ somewhat from one another. One reason for this is, for instance, the desire to facilitate product distribution on the domestic market (sometimes temporarily) in order to gain the opportunity to enter the international market later.

In Russia, as stated in the federal targeted program "Development of the Medical Industry in 1998–2000 and for the Period up to 2005," one of the most critical tasks associated with The Development of the pharmaceutical industry was "the development and Structure/175.html">Implementation of a national industry standard for GMP." This work was carried out taking into account the guiding regulatory document introduced in 1992 (RD 64-125-91) concerning GMP rules. In February 1998, this document was revised, supplemented with several sections, and approved by the Minister of Health of the Russian Federation (OST 42-510-98).

In their modern form, GMP rules have a similar structure regardless of whether they are national, regional, or international, and consist of eight sections.

The first section, "Terminology," defines the Key Concepts used in the document. To avoid unnecessary disputes, clarifying these Definitions is essential in the event of conflict situations.

The section begins with the definition of pharmaceutical manufacturing, followed by definitions of concepts such as manufacturing processes, operations, Materials, premises, etc.

The second section, "Quality Assurance," outlines mandatory measures, including adequate staffing with personnel responsible for product quality; documentation of manufacturing stages; the Procedure for recalling product batches in the event of quality failures; investigation of the causes of quality defects, and so on.

The third section (with several subsections) concerns the personnel of a pharmaceutical enterprise. It emphasizes the requirement for specialized education for the HEAD of the pharmaceutical facility (though not necessarily the owner), as well as a clear delineation of responsibilities among management staff. Specific provisions are made for staff training, personal hygiene, and behavior, particularly within cleanrooms. The rules for using and maintaining functional work garments are listed, followed by instructions for personnel, Procedures for communicating these to employees, and so forth.

As an example of the heightened attention given to personnel at pharmaceutical plants, It is worth noting that some national GMP rules even recommend pre-employment screening and Selection of cleanroom personnel based on temperament: in certain cases, phlegmatic individuals are preferred as they "make fewer unnecessary movements," while sanguine and choleric individuals are nonetheless fully eligible to be company owners, commercial directors, and the like.

Another example is the emphasis on staff hygiene. Some national GMP rules even recommend taking showers exclusively after work, because hot Water can cause Skin flaking, which is contraindicated for working in cleanrooms.

The fourth section of the GMP rules addresses the suitability of buildings and premises for pharmaceutical production. It contains over forty requirements, although requirements such as locating the pharmaceutical facility outside residential zones and at a considerable distance from other industries that negatively affect pharmaceutical product quality (due to atmospheric pollution, etc.) are very difficult to fulfill.

GMP rules as applied to the specifics of biotechnological production are as follows. When working with recombinant producer strains, precautions specified in special instructions must be observed. This applies particularly to room ventilation systems, their isolation, and so on.

Special requirements for biotechnological production must be strictly observed in the antibiotic industry. Given the allergenic nature of beta-lactam structures, it is recommended that manufacturing processes related to penicillin and its derivatives be carried out in separate facilities. Compared to many other industrially produced Antibiotics, penicillin has low toxicity. However, allergenicity is known to manifest at exceptionally low concentrations; therefore, micro-quantities of penicillin, if introduced into other antibiotic preparations or general products, can cause undesirable consequences. It is recommended to use dedicated vessels, pipelines, and equipment when working with penicillin.

The fifth section of the GMP rules pertains to process equipment, starting from the Fermentation department, followed by the chemical purification department, and so forth. Equipment must be appropriate for the processes, and measuring instruments must be calibrated according to a schedule. A number of recommendations concern equipment design, placement, and operation. In particular, attention is drawn to ensuring that equipment surfaces coming into contact with raw materials, intermediates, and finished products do not react with them, are corrosion-resistant, can withstand contact with disinfecting solutions, and so on.

The sixth section of the GMP rules covers the manufacturing process as a whole. Considerable attention is devoted here to starting materials (documentation, storage conditions, control, etc.). For biotechnological production, raw materials such as complex nutrient medium components—corn steep liquor, cottonseed meal, pea flour, etc.—are of particular importance. In accordance with GMP requirements, raw materials of this type are tested for microbial contamination and stored in separate, non-production, above-ground rooms (i.e., not in damp basements). The issuance of batches (samples) of raw materials for use in the manufacturing process is recorded. All of this is especially important for biotechnological production, given the inherent difficulty of standardizing complex nutrient media.

This section also includes a vital clause stating that step-by-step in-process control is mandatory at the enterprise, carried out jointly by workshop personnel and the quality control department. This involves verifying that raw materials, auxiliary materials, and intermediates comply with regulatory and technical documentation requirements, checking the sanitary condition of workshops and workstations, and ensuring adherence to standardized technological operations. The results of in-process control are recorded. Records of test results must be retained for at least one year after the expiration date of the medicinal product for which the inspection was carried out. Thus, if the enterprise operates in accordance with GMP rules, it maintains all the necessary documentation to identify the causes of emergencies, even if they occurred long ago.

The seventh section of the GMP guidelines is dedicated to the Quality Control Department (QCD). It specifies that such a department is mandatory for any pharmaceutical enterprise. The QCD oversees not only the finished product but also raw materials and intermediates as they are transferred from one production shop to another. Furthermore, the QCD is responsible for monitoring the Stability of the final product and retaining samples of every finished product batch for at least three years.

The eighth section of the GMP guidelines is of particular importance and is entitled "Validation" (from the English *validation* — ratification, confirmation).

A detailed definition of this section's title is as follows: "The assessment and documented confirmation that a manufacturing process and product quality meet established requirements."

Validation provides data demonstrating that a technological process complies with standard operating procedures and that the quality of the final product conforms to regulatory and technical documentation. It evaluates the process itself, the equipment (ensuring it is fit for the intended purpose), and ultimately the final product, including the limits of permissible process deviations. Validation concludes with a report that serves as the basis for either approving or rejecting the technological process. Validation is performed for every new technological process prior to its implementation in production, for both sterile and non-sterile medicinal products.

Periodic validation is carried out according to a schedule, whereas revalidation is performed when there are partial modifications to the technology of an existing process (such as A change in raw materials or equipment). Biotechnology manufacturing has specific features in this regard that distinguish it from chemical manufacturing; for instance, a biotech enterprise may replace a producer strain. Frequently, this is a "daughter" strain generated by geneticists from a strain already in use by the enterprise, but one that yields more of the target product and is therefore more cost-effective.

The question arises: is it necessary to perform validation in such cases, given that it requires a certain investment of effort, time, and financial resources? The answer is unequivocal: validation is mandatory. The higher METABOLIC ACTIVITY OF a new producer implies alterations in its METABOLISM. These changes can lead not only to increased productivity but also to shifts in the profile and concentration of various metabolites produced. The Isolation and Purification scheme established by the enterprise's standard operating procedures may prove inadequate under these new conditions; consequently, both the process and the final product require validation. The same applies when the fermentation medium is replaced with a more productive one (or one containing less scarce components). Any potential change in the producer's metabolism necessitates validation.

The terms "prospective validation" (conducted prior to the Introduction of a technological process into production) and "retrospective validation" (an analysis of data collected over a specified period resulting in relevant Conclusions) are widely used.

Validation allows for experimentation—simulating process conditions by pushing them toward extremes, such as elevating room temperatures (within defined limits), and so forth. This helps determine the deviation boundaries within which the technological process will not adversely affect product quality. Sometimes such experiments are combined with more frequent sampling for analysis than what is normally specified in the standard operating procedures.

In Conclusion, it should be noted that the WHO has published a "Guidelines for Validation."

GMP standards are gradually being applied to virtually all aspects of pharmaceutical operations and continue to evolve constantly. Recently, in addition to the previously mentioned sections, new ones have been introduced: "Waste," "Contract Work," "Complaints and Product Recall," "Improving Enterprise Work Culture," and "Competitiveness."

Currently, GMP rules have been adopted in 140 countries worldwide. Examples of compliance with GMP standards in our country include the tablet production lines at the Akrikhin enterprise, injectable drug manufacturing at Ferein, and the pharmaceutical production lines at the Cardiology Institute.

GLP (Good Laboratory Practice) rules—properly or appropriately organized Laboratory tests (more accurately translated not as laboratory tests, but as preclinical or non-clinical trials of a new drug)—require not only strict adherence to a set of tests but also the highest possible standardization of conditions during drug testing. The reliability of results when working with laboratory animals relies on meeting numerous requirements, such as selecting inbred strains, maintaining them on a standard diet, and so on. Additionally, animals in the vivarium must be housed in a manner that minimizes various stress factors to avoid distorting test results.

New substances, whether discovered intentionally or by chance, may be investigated in any direction based on their biological activity profile. However, conducting preclinical trials of these substances and subsequent clinical studies in human volunteers (with eventual introduction into medical practice) requires strict compliance with GLP guidelines. This provides the highest possible guarantee of safety when the new substance is subsequently administered to humans.

New medicinal products may exhibit species Specificity and, despite positive results in animal testing, can lead to fatal outcomes during clinical trials in human volunteers.

Currently, attempts are being made to replace animal (mammalian) experiments with various biochemical and biophysical assays utilizing enzyme systems, Tissues, and invertebrate Organs. Such efforts are primarily aimed at the humanization of experiments.

Overall, GLP regulations constitute an extensive body of documents with an established history, and their development and refinement across various directions are ongoing.

The acronym GCP stands for Good Clinical Practice and refers to the proper and appropriate conduct of clinical trials (for a new medicinal product). Upon the successful completion of preclinical trials of a new biologically active substance, the relevant regulatory authorities issue authorization for clinical testing.

When discussing GCP guidelines, two main aspects must be emphasized: ensuring maximum safety for trial subjects and achieving the highest reliability of results obtained from human volunteers. It is mandatory that individuals receiving the new drug are fully informed and provide their consent to participate. They are also entitled to receive additional information, including their right to compensation for health-related harm in emergency situations. Except under specifically stipulated circumstances, clinical trials of new drugs in children are prohibited.

In recent years, a new mechanism for protecting patient rights has been implemented abroad and in Russia. So-called ethics (institutional review) committees are established, independent of the administration of the healthcare facilities where the trials are conducted. These committees include physicians, legal experts, clergy, government representatives, and others. Their Functions are limited to monitoring the rights of human volunteers participating in clinical trials of new drugs (in accordance with GCP guidelines). Ethics committees do not provide recommendations regarding prescribed Treatment regimens and therapeutic schemes.

The issue of the reliability of clinical trial results is quite complex. One of the challenges is eliminating The Influence of personal interests among those conducting the trials. The reasons for such biases can vary, such as "pressure" from drug developers, the pharmaceutical companies owning the data, and others.

One way to enhance the reliability of clinical trial findings is to pool data obtained by independent research teams. Data gathered, for instance, from five clinical sites (with one hundred cases each) allow for more robust conclusions regarding a drug's efficacy and safety than data derived from the same number of patients at a single institution. Naturally, this is just one example of conducting clinical trials in compliance with GCP standards.

Overall, the conduct of clinical trials for pharmaceutical products is regulated by a vast array of interconnected documents.

The study, testing, and manufacturing of pharmaceutical products are strictly regulated, and new drugs pass through all these stages under the direct oversight first of GLP, then GCP, and finally GMP standards.

Review Questions

1. What are the reasons for introducing international standards into pharmaceutical practice?

2. What is the scope and content of the GMP rules?

3. What is the difference between the Pharmacopoeia and GMP guidelines?

4. What do GCP and GLP standards encompass?

5. Why does quality testing of an investigational medicinal product (drug) according to GMP rules yield more reliable results?

6. What are the reasons for performing validation when replacing producer strains in manufacturing?

7. What are the specific GMP requirements for biotechnological production?

8. What special GMP requirements apply to the manufacture of beta-lactam antibiotics?