PHARMACEUTICAL MICROBIOLOGY - V. A. Galynkin - 2015

PART III. MICROBIOLOGICAL ASPECTS OF PHARMACEUTICAL MANUFACTURING

CHAPTER 25. GMP AND GPP PRINCIPLES IN PHARMACEUTICAL ACTIVITIES

The pharmaceutical industry of the Russian Federation maintains high standards of quality management in the development, manufacturing, and control of medicines. The state registration system ensures that all medicinal products are evaluated by the competent authority to guarantee their compliance with modern safety, quality, and efficacy requirements [38, 39].

A drug manufacturer must produce medicinal products in a way that guarantees they are fit for their intended use, meet the requirements of the marketing authorization dossier or clinical trial protocol, and eliminate any risk to patients related to safety, substandard quality, or efficacy. The fundamental principles of quality management, Good Manufacturing Practice (GMP), quality control, and quality risk management are interrelated. Good Manufacturing Practice applies to all Stages of the product lifecycle: manufacturing of investigational medicinal products, technology transfer, commercial manufacturing, and discontinuation of production. The pharmaceutical quality system may also extend to such product lifecycle stages as pharmaceutical development.

25.1 GMP Rules in Ensuring Drug Quality

Every manufacturer of medicines and pharmacist bears an enormous responsibility towards consumers—namely, patients: medicinal products must strictly suit their intended purpose, and patients must not be exposed to risks resulting from compromised safety, quality, or efficacy. To meet these requirements, an enterprise must establish a quality assurance system. Quality assurance is a broad concept that encompasses all parameters

that individually or collectively influence product quality.

The pharmaceutical quality assurance system in drug manufacturing guarantees that:

1) drug development is conducted in accordance with the requirements of manufacturing rules and Good Laboratory Practice (GLP);

2) clear documentation is drawn up for all manufacturing and control operations;

3) the production, supply, and use of appropriate starting and packaging Materials are ensured;

4) finished products are manufactured and checked in accordance with approved instructions;

5) finished products are stored in a manner that does not compromise their quality level;

6) self-inspections and/or quality audits (by third-party organizations) are conducted to enhance the effectiveness of the quality assurance system.

GMP regulations are an integral part of the pharmaceutical quality assurance system, ensuring that products are consistently produced and controlled in accordance with quality standards.

25.2 General Concepts of the GMP System

One of the primary indicators of pharmaceutical product quality is safety for the patient. This principle is implemented at all stages of drug development, testing, manufacturing, and distribution (Fig. 82).

Class="center">Fig. 82. Stages of drug development, testing, manufacturing, and distribution—the medicinal product lifecycle.

GMP rules (literally meaning "rules of good and proper manufacturing") are aimed at achieving a dual objective: (1) they serve as guarantees of the quality of manufactured products, and (2) they aim to minimize the inherent risks associated with any pharmaceutical product that cannot be completely eliminated merely by testing against quality standards.

Substandard medicines not only pose a threat to human health but also cause financial losses to the state and individual consumers. Substandard drugs may contain unintended toxic substances. A product that lacks a sufficient amount of active ingredients will fail to deliver the expected therapeutic effect.

GMP regulations cover all aspects of new drug development, facility design, and manufacturing—starting from raw materials, premises, and equipment, down to personnel training and personal hygiene. Detailed instructions must be in place for every process capable of affecting the quality of the finished product.

GMP regulations facilitate the expansion of export opportunities for medicines. The majority of countries agree to import and distribute only those drugs that have been manufactured in compliance with GMP standards.

Currently, 140 countries have adhered to these rules, including Russia.

Key provisions of GMP:

1. Clear documentation of all manufacturing processes and their systematic evaluation.

2. Validation of all critical manufacturing steps and significant process modifications in accordance with HACCP principles.

3. Compliance with requirements concerning personnel, production conditions, premises, equipment, materials, containers, and labeling.

4. Instructions and standard operating Procedures must be written clearly, unambiguously, and tailored specifically to the installed equipment.

5. Maintenance of batch records detailing all production steps, along with the recording and investigation of any deviations.

6. Product distribution management designed to minimize any potential risk to quality.

7. Availability of an effective product recall system.

8. Investigation of Complaints and ROOT causes of quality defects to implement appropriate corrective and preventive actions.

The advantages of GMP include:

1) a proactive approach to quality assurance;

2) a comprehensive and systematic framework;

3) enhancement of the manufacturer's corporate image;

4) long-term economic benefits.

Manufacturing substandard preparations does not lead to cost savings. In the long run, troubleshooting and correcting errors demand significantly greater resources than preventing them.

The purpose of GMP is to prevent errors. Implementing GMP is an investment in high-quality Pharmaceuticals. The production and distribution of substandard medicines undermine trust in all stakeholders of the drug supply chain, including the manufacturer.

Russian GMP regulations are set forth in the sections of OST 42-510-98, "Good Manufacturing Practice Rules." They serve as general guidelines establishing the framework for organizing the manufacturing process and quality control, providing baseline practical instructions for proper production management. Compliance is mandatory for all pharmaceutical manufacturers.

25.3 Microbiological Requirements for Pharmaceutical Manufacturing

All pharmaceutical products are classified into sterile and non-sterile based on microbiological purity criteria.

Sterile preparations are manufactured under aseptic conditions designed to prevent contamination by microorganisms, pyrogens, and particulate matter.

Technological processes in The production of sterile preparations may involve terminal sterilization at The final stage of manufacturing or sterilization at intermediate stages. The latter group includes:

✵ thermolabile preparations sterilized by Membrane filtration followed by aseptic filling;

✵ eye ointments that cannot be sterilized in their final packaging (aluminum tubes);

✵ eye drops produced by aseptic filling of a sterile solution into dropper tubes (previously sterilized by ionizing radiation or chemical Methods).

Special requirements regarding the establishment of aseptic conditions are imposed on the manufacture of such products, as detailed in the Appendix to the rules.

Non-sterile products are manufactured under non-aseptic conditions closely approximating aseptic ones. The required level of microbiological cleanliness is ensured through appropriate measures, including the Organization of production facilities, equipment Selection and operation, MICROBIOLOGICAL CONTROL OF production and finished products, as well as personnel selection and hygienic training.

Personnel at pharmaceutical enterprises are one of the primary sources of contamination of FPPs and intermediates with particulate matter and microorganisms.

All personnel working at the facility must possess the knowledge and experience necessary to fulfill their respective duties and must be familiar with GMP regulations.

The health status of personnel is a critical factor in the FPP quality assurance system, as humans can act as a source of infection or contribute to its transmission. All production personnel must undergo regular medical examinations. Individuals suffering from allergic and Skin diseases, excessive dandruff shedding, as well as smokers, must not be permitted to work in cleanrooms. Persons with infectious diseases, sunburnt skin, or various skin lesions are temporarily barred from work until their health condition normalizes. Personnel must inform management of any indispositions (acute respiratory, skin conditions) that could adversely affect drug quality.

Personal hygiene of personnel. Personnel involved in the manufacture of sterile medicinal products must strictly adhere to personal hygiene rules: take showers regularly and wash their Hair at least twice a week. Personnel preparation for work must be carried out in a specific order. During work, appropriate cleanroom garments suitable for the manufacturing operations being performed must be worn (GOST R 52538-2006).

During work, The Use of cosmetics is prohibited, as is wearing watches and jewelry, bringing personal items into production areas, eating, storing food, and keeping personal medications.

Rules of conduct for personnel. In the manufacture of sterile medicinal products, the number of working personnel must be strictly limited to the minimum necessary level. Aimless wandering during work is prohibited. All movements must be slow and smooth. Conversations on irrelevant topics are forbidden; verbal communication with individuals outside the production areas must be conducted via telephone or intercom. Laughing and shouting are prohibited, as this increases the number of microorganisms expelled from the Mouth. Objects dropped on the floor during work must not be picked up or used. The use of pencils and fountain pens is prohibited; ballpoint pens or markers are permitted, provided they are wiped once per shift with a special fabric wipe moistened with ethanol.

Personnel must report all violations and adverse Changes in the sanitary regime to management.

Improper preparation and behavior of personnel lead to a sharp decline in microbiological cleanliness indicators.

25.4 Quality Risk Management

Risks are inherently present to a certain degree during the manufacture and use of a medicinal product, including its components [38, 39]. Quality risks represent just one component of overall risk. It is important to understand that product quality must be maintained throughout its lifecycle in such a way that the quality attributes critical to the medicinal product remain identical to those of the medicinal products used in clinical trials. An effective quality risk management approach can further guarantee the patient a high-quality medicinal product by establishing preventive methods during development and manufacturing to identify and control potential quality-related issues. Quality risk management is based on a scientific and practical approach to decision-making. It provides documented, understandable, and reproducible methods for implementing the stages of the quality risk management process based on existing knowledge regarding the assessment of probability, severity, and, where applicable, detectability of risks.

Quality risk management is a systematic process for the comprehensive assessment, control, communication, and review of risks to the quality of a medicinal product across its lifecycle. The quality risk management model is presented in Fig. 82 of this document.

Fig. 83. General diagram of a typical quality risk management process.

Decision points are not indicated in the presented diagram, as decisions may be made at any point in the process. Such decisions may return the process to a previous stage to seek further information, adjust risk models, or even terminate the risk management process based on information justifying such action. Note: "unacceptable" in Fig. 83 of this document refers not only to statutory, administrative, or regulatory requirements, but also to the necessity of reviewing the overall risk assessment process. Comprehensive risk assessment consists of hazard identification, as well as the analysis and evaluation of risks associated with exposure to those hazards (as outlined below). Quality risk assessment begins with a clear Description of the problem or risk question. Once the risk in question is clearly defined, it becomes easier to select an appropriate risk tool. The outcome of a risk assessment is either a quantitative estimate of risk or a qualitative description of a range of risks. When risks are expressed quantitatively, a numerical probability expression is used. Quality risk management within the technological process must be carried out at critical control points determined using the HACCP system.

Hazard Analysis and Critical Control Points (HACCP) is a systematic, proactive, and preventive tool for ensuring product quality, reliability, and safety. It is a structured approach applying technical and scientific principles to analyze, evaluate, prevent, and control risks or adverse consequences of hazards resulting from product planning, development, manufacture, and use.

HACCP can be applied to identify and manage risks associated with physical, chemical, and biological hazards (including microbial contamination). HACCP is most useful when product and process understanding is sufficiently comprehensive to enable the identification of critical control points. The outcome of HACCP is risk management information that facilitates the monitoring of critical points not only during the manufacturing process, but also at other stages of the lifecycle.

HACCP consists of the following seven steps:

1. conducting a hazard analysis and determining preventive measures for each process stage;

2. identifying critical control points;

3. establishing critical limits;

4. establishing a system to monitor critical control points;

5. determining corrective actions to be taken when monitoring indicates that critical control points are out of control;

6. implementing a verification system to confirm that the HACCP system is working effectively;

7. Establishment of a records management system.

25.5 GPP Principles in Ensuring Medicinal Product Quality

Ensuring the quality of medicinal products (MPs) is one of the paramount tasks of modern pharmacy. To standardize and unify the quality assurance process at the stage of direct delivery to patients (i.e., in the retail drug distribution chain), it is deemed necessary to apply the principles and methods of Good Pharmacy Practice (GPP) standards.

A crucial indicator of MP quality is their compliance with Pharmacopoeial microbiological requirements. To this end, microbiological control is implemented in pharmacies where medicines are compounded according to medical prescriptions.

The objects of microbiological testing are:

1) distilled Water;

2) injection solutions prior to sterilization;

3) injection solutions after sterilization;

4) eye drops after sterilization;

5) eye drops prepared under aseptic conditions using sterile bases;

6) dry pharmaceutical substances used to prepare injection solutions;

7) pharmacy glassware, stoppers, liners, and other auxiliary materials;

8) equipment, utensils, and the personnel's hands and workwear;

9) air environment.

Sampling and microbiological analysis are performed by staff of licensed laboratories in relevant Sanitary and epidemiological institutions.

Microbiological quality indicators for distilled water and MPs must comply with Pharmacopoeial requirements.

Criteria for assessing microbial contamination of air are given in Table 62.

Table 62. Criteria for assessing microbial contamination of pharmacy premises air.

The appearance and behavior of pharmacy personnel are of great importance. Neatness and cleanliness of clothing, hands, hairstyle, and adherence to personal hygiene habits play a significant sanitary and educational role. Pharmacy staff serve as a personal role model of professional conduct for visitors with whom they constantly interact.

Every pharmacy employee must constantly wear a lab coat and headwear (a cap or kerchief) while at work, which must be changed at least twice a week. Upon arriving at work, staff should put on their lab coat, thoroughly wash their hands with soap, treat them with a disinfectant solution, and tuck all hair completely under the headwear. Personal and work clothing must be stored separately. Pharmacy personnel must have designated work shoes. Throughout the working day, they must monitor the cleanliness of their hands, workwear, and workstation, and change the hand towel daily.

Before visiting the restroom, a pharmacy employee must remove their lab coat, and upon returning, thoroughly wash their hands with soap and treat them with a disinfectant solution. All of this is done in the anteroom, which must be equipped with a sink supplied with hot and cold water, a container with a disinfectant solution,

an electric hand dryer, and hangers for towels and lab coats.

It is strictly prohibited to wear lab coats outside the production areas and, all the more so, outside the pharmacy, to enter production areas without a lab coat, to carry personal items in its pockets (except for a clean handkerchief), or to store personal and work clothing in the same locker.

Skin care and maintaining cleanliness are fundamental personal hygiene requirements. Special attention should be paid to the condition of the subungual spaces.

Personnel manufacturing drugs under aseptic conditions must strictly adhere to personal hygiene rules. The production of sterile medications requires rigorous compliance with personal hygiene standards. Operators must wear specially closed-fitting (surgical) gowns, dedicated headwear and footwear, and sterile gauze face masks. Changing clothes must take place in the pre-aseptic airlock area.

Scrubbing and disinfection of personnel hands. Hand hygiene procedures must be carried out in specially designated areas. Washing hands in sinks intended for washing pharmacy glassware is strictly prohibited.

To mechanically remove contamination, hands should be washed with warm running water for 1-2 minutes using high-foaming soap (such as bath, baby, or household soap). Afterwards, hands are rinsed with water to remove soap residue and treated with disinfectant solutions.

In the aseptic unit, hands are washed with soap for 1-2 minutes, thoroughly rinsed, treated with a disinfectant solution, and wiped dry. Sterile operational workwear is then put on. Hand disinfection must be repeated if the work process exceeds 4 hours.

For hand disinfection, 70% ethyl alcohol or other alcohol-based preparations (such as AHD-2000, octeniderm, octenisept), 0,5% chlorhexidine bigluconate solution (in 70% ethanol), or iodophor solutions (iodopyrone, iodonate, povidone-iodine 1%) are used; in the absence of other agents, a 0,5% chloramine B solution may be used.

When sanitizing hands with alcohol-based products, the hands are rubbed with a gauze pad soaked in the solution. When using chlorhexidine or iodophor solutions, 5-8 ml of the preparation is applied to the palms and rubbed into the skin. When treating hands with chloramine solution, they are immersed in the 0,5% solution and washed for 2 minutes, after which the hands are allowed to air dry.

Upon completion of work, hands are washed with warm water and treated with emollient agents: a mixture consisting of equal parts glycerin, alcohol, 10% ammonia solution, and water, which is thoroughly shaken before use. Ready-made emollient creams may also be used.

25.6 Storage of Medicinal Products in Pharmacy Facilities

The storage procedures for medications and medical devices are regulated by Order of the Ministry of Health No. 337 dated November 13, 1996.

Compliance with established regulations ensures the preservation of high-grade drug quality and creates safe working conditions for pharmaceutical personnel handling these products.

Proper drug storage relies on correct and rational warehousing organization, rigorous inventory tracking, and regular monitoring of expiration dates.

Maintaining optimal Temperature and humidity levels, as well as protecting specific medications from light exposure, is crucial.

Failure to observe storage regulations can lead not only to a loss of therapeutic efficacy but also pose health hazards.

Excessively prolonged storage (even when guidelines are followed) is unacceptable due to potential shifts in the pharmacological activity of the preparations.

The guidelines for organizing the storage of medications and medical devices apply to all pharmacies and pharmaceutical warehouses.

Storage facility equipment must guarantee product integrity. These facilities must be equipped with fire-extinguishing systems and maintain required temperature and humidity levels.

Air purity within storage areas plays a vital role; therefore, facilities must be equipped with supply and exhaust ventilation systems or, at the very least, transom windows.

Pharmacies located in climate zones subject to extreme temperature and humidity fluctuations must be equipped with air conditioning systems. Storage areas must contain an adequate number of cabinets, shelving units, pallets, etc. Shelving units must be positioned at least 0.5-0.7 m away from outer walls, at least 0.25 m off the floor, and 0.5 m below the ceiling. The aisle width between shelving units must be at least 0.75 m, and passageways must be well lit. Cleanliness in pharmacy and warehouse premises is maintained through wet cleaning at least once a day using approved detergents.

Depending on the physical and Chemical properties of the medicinal products and their susceptibility to environmental factors, they are categorized into drugs requiring protection from moisture, light, drying out, high and low temperatures, as well as coloring and odoriferous substances, and disinfectants.

Medicines requiring protection from light—such as Antibiotics, tinctures, extracts, Vitamins, corticosteroids, herbal raw materials, nitro compounds, amino and amido compounds, phenol and phenothiazine derivatives—must be stored in containers made of light-resistant materials.

Protection from moisture is essential for hygroscopic substances and preparations such as dry extracts, herbal raw materials, salts of nitrous, nitric, and phosphoric acids, antibiotics, and Enzymes. These products must be stored in dry rooms within tightly sealed Glass, metal, aluminum foil, or plastic containers.

Protection against drying out and volatilization is required for substances such as alcoholic tinctures, thick extracts, liquid alcohol concentrates, Essential Oils, solutions of ammonia, hydrogen chloride, formaldehyde, carbolic acid, ethyl alcohol, hydrogen peroxide, sodium bicarbonate, and chloramine B. Such preparations must be stored in airtight glass, metal, or aluminum foil containers in a cool place.

Many medications require protection from elevated temperatures (including antibiotics, hormonal agents, Glycosides, vitamins, fat-based ointments, and IMMUNOBIOLOGICAL PRODUCTS). Product package inserts specify storage temperatures: room temperature (+18-20°C) or cool (+12-15°C). Occasionally, low-temperature storage is required (e.g., +3-5°C for ATP).

Immunobiological products must be stored separately by name, batch, and taking into account their expiration

date. Storage temperatures for these agents are indicated in the instructions. Immunobiological products must undergo visual inspection at least once a month.

Antibiotics are generally stored at room temperature in their industrial packaging, unless otherwise specified in the instructions.

Organotherapy preparations should be stored in a dry, cool, and dark place at temperatures ranging from 0 to ±15°С (unless otherwise indicated on the label).

Coloring and aromatic medicinal agents as well as parapharmaceutical products (such as brilliant green, indocyanine green, and methylene blue) must be stored in a special cabinet in tightly sealed containers, segregated by item name. Dedicated scales, spatulas, mortars, and other equipment are allocated for handling each specific substance.

The storage of finished medicinal products is carried out taking into account The properties of their constituent ingredients.

Medicinal products with an expired shelf life are stored separately and are subject to re-examination (upon receipt of analytical results).

Tablets and dragees must be stored separately from other agents in their original manufacturer packaging, in a dry place and, if necessary, protected from light.

Injectable preparations are stored in a cool, dark place within a cabinet or a designated isolated room.

Liquid dosage forms (tinctures, syrups, etc.) are stored in tightly sealed containers filled to the brim in a dark and cool place. If sediment precipitates, tinctures may be filtered. They are considered suitable for use after quality verification.

Plasma-substituting and detoxification solutions are stored separately in a dark place at temperatures from 0 to +14°С.

Extracts must be stored in glass containers with screw caps and gasketed stoppers in a dark place at a temperature of +12-15 °С.

Liniments, ointments, and suppositories must be stored in a dark and cool place in well-sealed containers.

Medicinal plant raw materials are stored in dry, well-ventilated rooms in securely closed containers.

Cut raw materials should be kept in fabric bags, while powders must be stored in double bags (a multi-layer paper inner bag and a fabric outer bag) or in cardboard packaging. Packaging made of polymeric materials is sometimes permitted.

Digitalis leaves, Kidney tea, and other hygroscopic herbs and fruits are stored in tightly sealed glass containers.

Plant-based medicinal raw materials are periodically inspected in accordance with Pharmacopeia requirements.

If raw materials are affected by mold, pests, or lose their normal color and odor, they are either discarded or (after Processing) utilized, depending on the degree of damage.

Stricter storage and control periods apply to plant raw materials containing cardiac glycosides.

Disinfectants are stored in a cool, dark place in hermetically sealed containers, away from storage areas for plastic, metal, and rubber products, and away from distilled water production facilities.

Specific regulations govern the storage of narcotic and highly toxic medicinal products, medical equipment, as well as flammable and explosive substances, which are not covered here.

Conclusion

The safety of a medicinal product (MP) for the patient is ensured by a system of requirements and controls at all stages of MP development, testing, manufacturing, and distribution.

Good Manufacturing Practice (GMP) standards guarantee product quality and aim to mitigate risks that cannot be entirely eliminated through compliance testing alone. GMP regulations encompass the entire manufacturing sphere, including microbiological requirements for the production of sterile and non-sterile MPs: the design of production facilities, equipment selection and operation, production and finished product control, as well as personnel recruitment and hygienic training.

The principles and methods of Good Pharmacy Practice (GPP) standards are employed to standardize and unify the quality assurance process of MPs at the stage of their delivery to patients, i.e., within the retail distribution tier.

In pharmacies where medicinal products are compounded according to medical prescriptions, microbiological control is mandatory for distilled water, injectable solutions, eye drops, compounding ingredients, glassware, equipment, and ambient air.