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Prevent cross contamination. The problem of microbial contamination of medicines Risk of contamination

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Microbial contamination medicines and ways to reduce it

1. The influence of microorganisms on the quality of medicines. ANDsources of microbial contamination

Medicines contaminated (contaminated) with microorganisms pose a danger to the patient.

In the process of evolution, the adult human body, with the help various systems has adapted to protection from microflora (peeling of the epidermis, acidic environment of the stomach, lysozyme in tear fluid, etc.), but the most important organs and biological fluids (brain, heart, blood, cerebrospinal fluid) always remain sterile. The protective mechanisms of a newborn are imperfect, and those of a sick person are weakened, so the risk of infection increases sharply when using non-sterile external dosage forms (ointments, oils, etc.). There is a high risk of infection of the body when administering injection solutions, when treating injuries, burns, and frostbite.

Microorganisms contained in the dosage form can cause the decomposition of active and auxiliary substances. This leads to loss of the therapeutic effect of the drug and changes in appearance. dosage form, sometimes to the formation of toxic products. Unlike pathogenic microorganisms many saprophytes have a large set of enzymes and are capable of decomposing a wide variety of substances, proteins, lipids, etc.

The intensity of destruction of dosage forms and substances depends on their concentration, humidity, ambient temperature, as well as the nature and degree of initial contamination. The shelf life of medications is also important.

Sources of microbial contamination of medicines can be:

· indoor air. It is known that 1 liter of air in a big city contains from 1 thousand to 1 million. different particles, which are carriers of microflora - one microorganism per 1000 suspended particles;

· original medicinal and auxiliary substances of animal, plant and synthetic origin (for example, highly contaminated - pancreatin, pepsin, glucose, talc, starch, agar, etc.);

· dispersion media, including purified water, microbial contamination of which occurs during transportation and storage;

· auxiliary materials (filtering materials - cotton wool, paper, gauze; packaging materials - paper, bottles, jars, boxes, corks);

· Human. In a calm state, a person emits up to 200 thousand different particles (scales, epidermal cells, etc.) in 1 minute; when moving - up to 1 million, therefore the presence of a significant number of visitors in the pharmacy sales area, the introduction of dust and dirt from outside leads to an increase in microflora in the air, penetrating into production premises;

· pharmacy staff. Even in special clothes in clean rooms in environment employees isolate up to 2 million particles ranging in size from 0.5 microns to 5 microns, 300 thousand particles measuring 5 microns and more than 160 particles containing microorganisms.

· Sources of pollution are mainly the mouth and nose. When talking, the number of particles emitted by a person increases;

· process(equipment, devices, devices).

2 . The concept of microbial purity of drugs and sterilityness

There are four categories of microbiological purity of dosage forms and preparations:

· Injection, infusion, ophthalmic dosage forms, drugs administered into sterile body cavities, on open wounds, burns, sterile drugs for newborns;

· Preparations used topically, transdermally, intervaginally, for inhalation and administered into the cavities of the ear and nose;

· Dosage forms for oral administration;

· Preparations for rectal administration.

Non-sterile medicines (substances, various forms of preparations - tablets, capsules, granules, solutions, suspensions, syrups, ointments, suppositories, etc.) can be contaminated with microorganisms. They allow the presence of a limited number of microorganisms, in the absence of certain types of bacteria that pose a danger to human health.

There are various categories of medicinal products, according to which requirements for microbiological purity are imposed, for example: according to GPM 42-0067-07 XII GF

Preparations subject to the requirement of “sterility”

Preparations must be sterile

For use topically, externally, intravaginally

· For insertion into the cavities of the ear, nose

Respiratory

· Transdermal patches

· Total number aerobic bacteria and fungi (total) no more than 100 per 1 g or 1 ml, or per 1 patch (including the adhesive side and base)

· Absence of enterobacteriaceae and other gram-negative bacteria per 1 patch (including adhesive side and base)

· No more than 10 enterobacteria and other gram-negative bacteria in 1 g or 1 ml of other drugs

· Absence of Pseudomonas aeruginosa in 1 g or 1 ml, or per 1 patch (including adhesive side and base)

· Absence of Staphylococcus aureus in 1 g or 1 ml, or per 1 patch (including adhesive side and base)

The term “sterility” means the absence of viable microorganisms of any kind in the preparation.

Sterility testing was first proposed for vaccines, toxins, serums, adrenaline, and insulin. In the 1930s the sterility test was introduced into the UK and US pharmacopoeias.

Medicines for injections and infusions, eye drops, ointments and films and other preparations and substances for which there are appropriate instructions in the documentation must be sterile, that is, do not contain microorganisms. (OFS 42-0066-07 XII State Pharmacopoeia)

Regulatory documents regulating the sanitary regime of pharmacy organizations and microbiological quality control of medicines are:

- “Guidelines for microbiological control in pharmacies”, 1985;

- Order of the Ministry of Health of the Russian Federation No. 53 of March 25, 1994 “On strengthening quality control of medicines”;

- Order No. 118 of June 14, 1994 “On the accreditation of regional (territorial) control and analytical laboratories (medicine quality control centers) and certification of medicines in the Russian Federation”;

- Order No. 309 of the Ministry of Health of the Russian Federation dated October 21, 1997 “On approval of instructions on the sanitary regime of pharmacy organizations (pharmacies).”

- State Pharmacopoeia

3 . Dosage forms requiring aceptic manufacturing conditions

3.1 Eye drops

Eye drops - by definition from the Global Fund - are the official dosage form intended for instillation into the eye. Use water or oil solutions, the finest suspensions or emulsions of medicinal substances, dosed in drops. They must be prepared under aseptic conditions. The drops should not contain substances such as essential oils, solutions with strong acidic or alkaline properties. Most often prepared in pharmacies aqueous solutions medicinal substances for eye drops, lotions, rinses, irrigations of the eye mucosa.

The protective function of the eye is performed by lysozyme, a natural antibiotic substance contained in the tear fluid, which lyses microorganisms that enter the conjunctiva. In case of eye diseases, the content of lysozyme in the tear fluid usually decreases, and the conjunctiva is unprotected from the effects of microorganisms. Infection of the eye with non-sterile solutions can cause serious consequences, sometimes leading to loss of vision.

The main method of sterilization of eye drops is thermal - saturated steam in a steam sterilizer at 120±2 degrees Celsius, a number of solutions (atropine sulfate, dicaine, potassium iodide, ascorbic acid, chloramphenicol, sodium iodide, sodium sulfacyl, novocaine, ethylmorphine hydrochloride, riboflavin drops complex composition, etc.) are sterilized with flowing steam at 100 degrees.

If the substances do not withstand even the sterilization regime described above, then eye drops are prepared under aseptic conditions in a sterile solvent (purified water, 0.9% sodium chloride solution or a solution of a heat-stable substance). The filter sterilization method is used.

Thermal methods are not used with solutions of resorcinol, alum, collargol, protargol, trypsin, lidase, antibiotics (except chloramphenicol), citral, adrenaline hydrochloride and some other substances.

3.2 Eye ointments

Eye ointments is a dosage form intended for application to the mucous membrane of the eye. Towards quality eye ointments high demands are made: they must not contain solid particles with sharp edges (which can injure the cornea of the eye) and irritants.

Eye ointments should be easily and best distributed spontaneously and evenly over the moist surface of the conjunctiva, and be sterile. Their production must be carried out under aseptic conditions. Particular attention should be paid to the choice of bases for eye ointments, if they are not specified in the recipe or in the ND.

Fats that easily go rancid and acquire irritating properties are unsuitable bases for eye ointments.

Vaseline grade “for eye ointments” is a product purified from reducing substances, subjected to hot filtration and sterilization. A mixture of 1 g of Vaseline, 5 ml of distilled water, 2 ml of diluted sulfuric acid and 0.1 ml of 0.1 N. Potassium permanganate solution is heated by shaking for 5 minutes in a boiling water bath. The pink color (reducing substances) should remain in the aqueous layer.

The mixture is fused, filtered in the molten state and sterilized as described in the article “Sterilization”. The prepared base must be stored in sterile, tightly sealed jars. Due to the presence of lanolin, the base is sufficiently hydrophilic and easily distributed over the mucous membrane.

Vaseline grade “for eye ointments” can be obtained in a pharmacy according to the followingmethodology: Vaseline is heated for 1-2 hours at a temperature of 150 ° C activated carbon(1-2% by weight of Vaseline). In this case, volatile impurities are removed and coloring matter is adsorbed. The Vaseline is then filtered through filter paper using a hot filter funnel.

As a basis for eye ointments, freshly prepared glycerin ointment (7% starch paste on glycerin) is used, which is characterized by sufficient resistance to the action of microflora, strong hydrophilicity and neutrality. Glycerin ointment has the disadvantage of a rather strong water-removing effect and an associated irritant effect. However, this disadvantage is somewhat mitigated by the enveloping effect of starch.

3.3 Dosage forms for injections

There are two forms of introducing liquids into the body - injection (injectio - injection) and infusion (infusio - infusion). The difference between them is that the former are relatively small volumes of liquid administered using a syringe, while the latter are large volumes administered by drip or jet.

Infusion solutions are able to support body functions without causing a shift in the physiological balance or bringing this balance back to normal. They, as a rule, contain macroelements characteristic of blood plasma, but can also be saturated with microelements that perform an important physiological function.

The widespread use of injectable dosage forms in medical practice became possible as a result of research effective ways sterilization, invention of special vessels (ampoules) for storing sterile dosage forms.

The idea of administering medicinal substances in violation of the skin belongs to the doctor A. Fourcroix (1785). For the first time, subcutaneous injection using a silver tip extended into a needle was used by the Russian doctor P. Lazarev (1851). In 1852, the Czech doctor S.G. Pravac proposed a syringe of modern design.

Suspensions cannot be injected into the blood; emulsions can be used, but only with particle diameters not exceeding the diameter of red blood cells (no more than 1 micron). These are emulsions for parenteral nutrition and emulsions that act as oxygen carriers.

Compared to other dosage forms manufactured in pharmacies - solutions for internal and external use, powders, ointments, for which only in some cases there are pharmacopoeial monographs, the compositions of almost all solutions for injections and infusions are regulated. Consequently, methods for ensuring their sterility and stability are regulated.

To ensure minimal contamination by microorganisms, solutions are prepared under aseptic conditions. Sterile solutions must be prepared in special clean rooms with a multi-stage system supply and exhaust ventilation. Indoor air must meet national cleanliness standards.

Manufactured injection solutions must be transparent, stable, sterile and pyrogen-free, and in some cases, meet special requirements.

3.4 Dosage forms for newborns and children under 1 year

All medications for newborns (for internal and external use, eye drops, oils for treating the skin) must be sterile. Internal solutions for newborns are prepared under aseptic conditions, by weight-volume method, using distilled water without adding stabilizers or preservatives. The reason for these requirements is the specific features child's body, namely the immaturity of all organ systems of the child, especially the central nervous system.

Medicines for children of the first year of life for oral administration should contain no more than 50 fungi and bacteria in total per 1 g or 1 ml in the absence of Enterobacteriaceae. Pseudomonas aeruginosa, Staphylococcus aureus.

3.5 Dosage forms with antibiotics

Antibiotics are very effective medicines modern medicine. The priority of their discovery belongs to the English microbiologist A. Fleming (1928), who received the Nobel Prize for this. L. Pasteur and I.I. Mechnikov predicted the discovery of antibiotics, but the first one appeared only in 1939-1940. In our country, for the first time, research on penicillin was started by Z.V. Ermolyeva (1942). The term “antibiotic” was proposed in 1942 by the American scientist S.A. Waksman to designate substances obtained from microorganisms and having a direct antimicrobial effect, i.e. directly on the causative agent of the disease. Currently, antibiotics are obtained not only from microorganisms, but also from other natural sources (including biotechnology methods), as well as synthetically and semi-synthetically. Can now be used not only to suppress the pathogen in the body, but also to delay development malignant neoplasms infective endocarditis, etc.

Reasons for the need to manufacture antibiotics under aseptic conditions:

· Destruction under the influence of microorganisms in non-sterile preparations (destruction of penicillins under the action of enzymes produced by bacteria, for example β-lactamase);

· Increased pyrogenicity, the possibility of intoxication of the body;

· Destruction of other substances of the drug by the products of the antagonistic struggle between the antibiotic and microorganisms.

References

microorganism medicinal injection aseptic

1. State Pharmacopoeia XII issue 1 - 150, 160 - 162, 216.

2. Technology of dosage forms. Krasnyuk I.I. 2004. - 27-42, 75, 187 - 194, 382, 396 p.

3. Order of October 21, 1997 No. 309 “On approval of instructions on the sanitary regime of pharmacy organizations (pharmacies)”

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Question #1: Are Health Based Exposure Limits (HBELs) mandatory for all medicinal products?

Answer: Yes, HBELs must be set for all medications.

The toxicological or pharmacological data on which the HBEL calculation is based must be re-evaluated periodically throughout the product's life cycle.

Question #2: Is there any framework that can be used to determine the significance of HBEL that provides broad guidance on the required quality risk management (QRM) coverage and controls required?

Answer: First, it must be recognized that hazards vary on a continuous scale, with no reliable cut-off points, so risks must be controlled on a proportionate basis. However, as a broad hypothetical model, consider the figure below, which shows an increase in the level of drug hazard (red represents the highest hazard) that should be accompanied by a proportionate increase in the level of controls to prevent potential cross-contamination in shared manufacturing facilities. In order to determine the effective control measures needed, QRM studies should use current HBEL values.

The diagram is based on an original concept published by ISPE. Source: ISPE Baseline® Pharmaceutical Engineering Guide, Volume 7 – Risk-Based Manufacture of Pharmaceutical Products, International Society for Pharmaceutical Engineering (ISPE), second edition, July 2017.

Question #3: How should manufacturers use HBEL values?

Answer: The role of HBEL values in determining clearance limits is explained in the answer to question #6. However, the purpose of the resulting HBELs goes beyond justification of clearance limits.

Once the health impact assessment and confirmation of the HBEL are completed, the resulting data should be used in the quality risk management process to determine the controls that need to be implemented, and to evaluate the suitability of existing organizational and technical controls or the need to supplement them. When determining the necessary control measures for a new equipment/production facility, this quality risk management process should be carried out prospectively.

It is expected that more complex organizational and technical control measures will be required for drugs with potentially greater harm to humans/animals. Therefore, using a structured quality risk management process, manufacturers must consider the risks of cross-contamination up to the level established on the basis of the HBEL. During the QRM study, manufacturers should evaluate how easily this amount of contamination can be encountered and undetected, both at the batch and dosage unit level.

The level of detail in the QRM process must be commensurate with the potential harm demonstrated by the HBEL and the suitability of control measures supported by practical and scientific evidence.

Manufacturers should be aware that cross-contamination controls previously implemented may not adequately control cross-contamination risks in the context of an HBEL approach.

To provide truly complete confidence in the effectiveness of controls, additional study of work practices, investigations and analysis may be required.

Where control measures cannot adequately ensure that potential contamination is consistently controlled to below the HBEL, the products concerned should be manufactured in dedicated manufacturing facilities.

Question #4: What qualifications does the person involved in determining Health Impact Limits (HBEL) have?

Answer: Health assessment exposure limits should be determined by a person who has sufficient experience and knowledge of toxicology/pharmacology, knowledge of pharmaceuticals, and experience in determining health assessment exposure limits such as occupational exposure limits. factors (OEL) or permissible daily intake (PDE).

Where experts are subcontracted to determine HBEL, contracts must be in place in accordance with the requirements of section 7 before work commences. It is not acceptable for manufacturers to “purchase” an HBEL assessment without considering the suitability of the provider of such services (including individual technical experts) as a qualified contractor.

Question #5: What responsibilities do customers have to contract manufacturers with respect to data in support of the HBEL assessment?

Answer: Customers must provide contract manufacturers with either a complete HBEL assessment or data that allows the contract manufacturer to conduct its own HBEL assessment. In any case, the HBEL assessment, including data sources and information about relevant experts, must be provided upon request during the manufacturer's inspection.

Question #6: How can cleaning limits be set?

Answer: despite the fact that to justify the purification limits (according to third paragraph of the Introduction) EMA guidance (EMA/CHMP/CVMP/SWP/169430/2012) can be used, it is not intended to be used in setting treatment limits at the calculated HBEL.

For existing products, the purification limits that have historically been used by the manufacturer should be retained, and the introduction of precautionary limits may be considered where purification process capabilities are taken into account, as they provide sufficient assurance that deviations above the HBEL limits will be prevented. A similar process should be used when establishing purification warning levels for products introduced into a given manufacturing facility for the first time.

If results exceed the cleaning warning limit, then an investigation and, where appropriate, corrective action should be initiated to bring the cleaning process performance within its warning limits. Repeated deviations above the cleaning warning limit will be considered unacceptable as they indicate that the cleaning method is uncontrolled. Suitable recognized statistical methods can be used to determine whether a cleaning process is controllable or not.

Question No. 7: When changing a product produced in shared production facilities, is it necessary to conduct analytical testing followed by purification validation?

Answer: It is assumed that analytical testing will be performed at each product change unless otherwise justified by an appropriately documented quality risk management (QRM) process. The QRM process should consider, at a minimum, each of the following aspects:

reproducibility of the cleaning process (manual cleaning is generally less reproducible than automatic cleaning);
danger arising from the drug;
whether visual inspection can be relied upon to determine the cleanliness of equipment at the residual contamination limit justified by the HBEL.

Question No. 8: What are the requirements for performing the visual inspection identified in Question No. 7?

Answer: When using visual inspection equipment to determine cleanliness, manufacturers must establish a threshold at which the product is readily identifiable as a residue. Consideration should also be given to the possibility of visual inspection of the equipment, for example under lighting conditions and at distances specified in the area.

Visual inspection must include all product contact surfaces on which contamination may remain, including those that require disassembly of the equipment to gain access for inspection directly and/or using tools (e.g. mirror, light source, borescope), if these areas cannot be inspected in any other way. Also included in the visual inspection are non-contact surfaces where product may become trapped when it is unloaded or transferred for use in subsequent batches.

Written instructions must be available that identify all areas requiring visual inspection, and appropriate records must clearly demonstrate that all inspections have been completed.

Operators performing visual inspections must receive specific training in the process, including periodic vision testing. Their competence must be confirmed through practical assessment.

Question No. 9: Is it acceptable to simply separate general therapeutic classification drugs into a designated area as a measure to control the risk of cross-contamination?

Answer: Manufacturers cannot simply separate drugs as a measure to prevent risks to the safety of people and animals general group from other types of drugs. Although this may prevent contamination of other classes of drugs, this approach does not eliminate the possibility of cross-contamination within those drug classes. The approach used to control cross-contamination between individual products within the same class produced in the same designated area should follow the principles set out in question No. 3. It should include the implementation of suitable organizational and technical controls to prevent contamination between such drugs within the drug-specific HBEL.

Question No. 10. Is it acceptable to use the LD 50 indicator to determine the HBEL of drugs?

Answer: No, LD 50 is not a suitable starting point for determining the HBEL of drugs.

Question No. 12. What must be taken into account when producing veterinary drugs for different types of animals at the same production facility?

Answer: Guidance for establishing health-based exposure limits states that the transfer limit value is usually derived from the human HBEL value.

However, where there is concern related to the known susceptibility of a particular animal species (e.g., as with monensin in horses), knowledge of its specific toxicity in animals.

Question #13: Should HBEL be re-evaluated throughout all phases of investigational medicinal product (IMD) development?

Answer: Health-based exposure limits should be established using all available evidence, in particular since the knowledge base for IMPs used as the basic reference in establishing HBELs is continually evolving, it should be regularly reviewed to take into account any relevant new evidence.

Introduction….3

1. Microbiological requirements for medicinal products and ensuring their quality…5

1.1 Sterile and non-sterile medicinal products…5

1.2 Principles of microbiological control of medicinal products….7

1.3 Antimicrobial preservatives in medicinal products....9

2.Sources and methods for reducing microbial contamination….18

2.1. Sources of microbial contamination of drugs...18

2.2 Methods for reducing microbial contamination….24

2.3 Survival of microscopic fungi in non-sterile medicinal products and excipients for their production...26

Conclusion….33

References….….35

Introduction (excerpt)

In recent years, soft dosage forms - ointments, pastes, liniments, suppositories, etc. are increasingly used in drug therapy. Due to the general deterioration of the environmental situation (in particular, in a number of areas exposed to radioactive contamination as a result of the accident at the Chernobyl nuclear power plant), there has been an increase in dermatological, gynecological diseases, malignant skin tumors, etc., in the treatment of which soft dosage forms are most often used. In areas of military conflicts in the CIS republics, large-scale accidents have occurred recently, there is also a great need among the population for drugs for local use (including soft dosage forms) for the treatment of wounds, burns and inflammatory processes. In addition, in the recipes of cosmetologists medical institutions about 70% of drugs are soft dosage forms.

Main part (excerpt)

Active pharmaceutical substance (API) or drug substance is any substance or mixture of substances intended for the production of medicines and being their active component. Such substances exhibit pharmacological activity in the treatment, prevention or diagnosis of diseases. Raw materials - starting materials intended for the manufacture of API. Auxiliary products are materials used as additives in the production of API. APIs are obtained by chemical synthesis and biosynthesis using producer cells (bacteria, fungi) or isolated from raw materials of natural origin (animal, plant, mineral).

Conclusion (excerpt)

Microbes living on medicinal plant materials may include representatives of normal epiphytic and phytopathogenic microflora. Microbial contamination of plant medicinal raw materials depends on the initial contamination, but can increase at the stages of primary processing, grinding, and bringing to a standard state. Damage to raw materials occurs mainly at high humidity, which promotes the proliferation of putrefactive microorganisms.

Epiphytic microflora [from Greek. epi, on + phyton, plant] is represented by microorganisms that live on the surface of plants. Epiphyte microorganisms do not harm the plant, and in some cases they compete with phytopathogenic microbes. As sources of nutrition, epiphytic microflora utilizes plant secretions and various surface contaminants.

Literature

1. Antimicrobial preservatives in finished medicinal products \\ N.A. Lyapunov, E.G. Zhemrova, E.P. Bezuglaya, E.V. Dunay \\Pharmacy - 2004 - No. 1\

2. L. A. Bochkareva, E. V. Gritsevskaya, I. T. Gilmutdinov et al., Express information "Advanced experience in the chemical and pharmaceutical industry", No. 1, 14 - 17 (1979).

3. Gunar O.V. Survival of microscopic fungi in non-sterile medicines and auxiliary substances for their production // - 2006 - No. 1 - pp. 54-56

4. Study of the suitability of the membrane filtration method using a pre-filter for monitoring the microbiological purity of non-sterile drugs Zhemerova E. G., Derkach N. Z., Dunay E. V., Litkevich S. A., Miroshnichenko A. P., Shermukhamedova O. G. ., Poddubnaya T. L. (State Scientific Center for Medicines, State Enterprise "Scientific Expert Pharmacopoeial Center") Farmak. 2002, No. 4, p. 22–30. Bible 12. Russian; res. Ukrainian, English

5. Medical microbiology, Pozdeev O.K. Pokrovsky V.I.

6. Microbiology and immunology / Edited by A.A. Vorobyov. - M.: Medicine, 2001.

7. Methodical recommendations“phytopathogenic microflora. microbiological methods for studying medicinal raw materials and finished dosage forms" for students Faculty of Pharmacy in the subject "microbiology" (Omsk State Medical Academy 2005)

Preventing Cross Contamination

during production

5.18. Contamination of raw materials or products with other raw materials or products must be excluded. This risk of accidental cross-contamination arises from the uncontrolled spread of dust, gases, vapors, aerosols or microorganisms from the handling of materials and products, from residues on equipment and on personnel clothing. The degree of risk depends on the type of contaminant and the contaminated product. The most dangerous contaminants include highly sensitizing substances, biological drugs containing live microorganisms, certain hormones, cytotoxic drugs and other highly active substances. The most dangerous is the contamination of drugs intended for injection, as well as drugs taken in large doses and/or for a long time.

5.19. Appropriate technical and/or organizational measures should be in place to prevent cross-contamination, for example:

production in dedicated areas (mandatory for products such as penicillins, live vaccines, medicinal products containing live bacteria and some other biological medicinal products) or production in batches (time-separated campaigns) followed by appropriate purification;

availability and organization of airlocks and exhaust devices;

minimizing the risk of contamination caused by recirculation or re-introduction of untreated or insufficiently treated air;

storing protective clothing inside areas where products that pose a particularly high risk of cross-contamination are processed;

the use of cleaning and decontamination methods of known effectiveness, since ineffectively cleaned equipment is usually a source of cross-contamination;

use of “closed systems” of production;

monitoring the presence of residues and applying labels indicating the cleaning status of equipment.

5.20. Measures to prevent cross-contamination and their effectiveness should be reviewed periodically in accordance with approved procedures.

Validation

5.21. Validation activities must support these Rules; they should be carried out in accordance with established procedures. Results and conclusions must be documented.

5.22. When introducing a new industrial regulation or a new production method, it is necessary to prove its suitability for mass production. It must be demonstrated that the process, using the specified materials and equipment, can consistently produce products of the required quality.

5.23. Significant changes to the manufacturing process, including any change to equipment or inputs that may affect product quality and/or process reproducibility, must be validated.

5.24. Processes and procedures should be subject to periodic revalidation (re-validation) to ensure that they remain suitable for achieving specified results.

Originalraw materials

5.25. The purchase of raw materials is a responsible operation that must involve personnel who have detailed and complete information about suppliers.

5.26. Starting materials should only be purchased from approved suppliers identified in the relevant specification and, where possible, directly from the manufacturer. It is recommended that the manufacturer's specifications for raw materials be agreed upon with suppliers. All aspects of the production and control of raw materials with respect to handling requirements, labeling, packaging, rejection procedures, and complaints handling must be agreed upon between the manufacturer and supplier.

5.27. For each delivery, the integrity of the packaging and seals should be checked, and the information specified in the delivery note corresponds to the supplier’s labels.

5.28. If a single supply of raw materials consists of different batches, each batch must be treated as separate with regard to sampling, testing and authorization of use.

5.29. The raw materials located in the warehouse area must be labeled accordingly (see paragraph 5.13 of Part I of these Rules). Labels must contain at least the following information:

product name and, if necessary, in-plant code;

manufacturer's batch number and/or batch number assigned upon acceptance;

where applicable, the status of the contents (eg: quarantined, testing, authorized, rejected);

expiration date or, where applicable, the date after which re-inspection is required.

If fully computerized storage systems are used, it is not necessary to include all this information on the label.

5.30. There must be appropriate procedures or measures to ensure the authenticity of the contents of each container of raw materials. The containers from which samples were taken must be marked (see paragraph 6.13 of Part I of these Rules).

5.31. Only those raw materials that are approved by the quality control department and have not expired should be used.

5.32. Raw materials must be issued only by designated persons in accordance with a written procedure to ensure that the required raw materials are accurately weighed or measured into clean and properly labeled containers.

5.33. Each feedstock issued and its weight or volume should be independently verified; this verification must be documented.

5.34. Starting materials issued for each batch should be kept together and clearly labeled.

Technological operations:

intermediate and bulk products

5.35. Before commencing any process operation, measures must be taken to ensure that the work area and equipment are cleared and free of any raw materials, products, product residues or documentation not relevant to the planned operation.

5.36. Intermediate and bulk products should be stored under appropriate conditions.

5.37. Critical processes must undergo validation (see paragraphs 5.21 5.24 - “Validation” - Part I of these Rules).

5.38. All necessary controls during the production process and control of the production environment must be carried out and documented.

5.39. Any significant deviation from expected product yield must be documented and investigated.

Packaging materials

5.40. The procurement, control and handling of virgin and printed packaging materials should be given the same care as raw materials.

5.41. Particular attention should be paid to printed materials. They should be stored in adequately secure conditions that prevent access by unauthorized persons. Cut labels and other loose printed materials must be stored and transported separately in closed containers to prevent them from being mixed up. Permission to use packaging materials must only be issued by designated persons in accordance with an approved and documented procedure.

5.42. Each shipment or lot of primary or printed packaging materials must be assigned an identification number or identification mark.

5.43. Expired or unusable printed or primary packaging materials must be destroyed and documented.

Packaging operations

5.44. When planning packaging operations, particular attention should be paid to minimizing the risk of cross-contamination, mix-ups or substitution. It is not allowed to package products various types in close proximity to each other, except in cases requiring physical separation.

5.45. Before packaging operations begin, steps must be taken to ensure that the work area, packaging lines, printing machines and other equipment are clean and free of any previously used drugs, materials or documents unless they are required for the planned operation. Line cleaning should be carried out according to the appropriate procedure.

5.46. The name and batch number of the packaged product must be indicated on each packaging unit or line.

5.47. When products and packaging materials arrive at the packaging area, their quantity, identity and compliance with packaging instructions should be checked.

5.48. The primary packaging materials must be clean before starting the filling operation. Care should be taken to prevent and remove any contamination such as glass shards and metal particles.

5.49. As a general rule, labeling should be carried out as soon as possible after filling and capping. If this does not occur, then necessary measures should be taken to ensure that no mix-ups or mislabelings occur.

5.50. The correctness of any printing operations (for example, applying batch numbers, expiration dates), carried out either as a separate technological operation or during the packaging process, should be carefully monitored and documented. Particular attention should be paid to manual markings, which should be rechecked regularly.

5.51. Special precautions must be taken when using cut labels and applying off-line stamps. To prevent tangling of the printed material, it is preferable to use roll labels instead of cut labels.

5.52. Tests should be carried out to ensure that all electronic code readers, label counters and similar devices are operating correctly.

5.53. Printed or embossed markings on packaging materials must be legible and resistant to fading or erasing.

5.54. When monitoring the product packaging process on line, the following should be checked as a minimum:

general appearance packages;

completeness of packaging;

use of appropriate products and packaging materials;

correct application of any markings;

correct operation of control devices on the line.

Samples taken from the packaging line should not be returned to the line.

5.55. If unforeseen circumstances arise during packaging of the product, it may be returned to production only after special inspection, investigation and with the permission of a person having the appropriate authority. These actions must be documented in the form of a protocol, which should be stored in the prescribed manner.

5.56. If a significant or unusual discrepancy is identified during the balance sheet between the quantities of bulk product, printed packaging material and the number of finished product units produced, an investigation should be conducted to determine the cause of the discrepancy before release is issued.

5.57. Upon completion of packaging operations, any remaining packaging materials bearing the batch number must be destroyed and documented. Return of unmarked packaging materials to the warehouse is carried out in accordance with the approved procedure.

Finished products

5.58. Before a release permit is issued, finished products must be kept in quarantine under the conditions established by the manufacturer.

5.59. Before obtaining permission to release, an assessment of the finished product and documentation must be carried out, the procedure for which is given in Chapter 6 (“Quality Control”) of these Rules.

5.60. After release approval is issued, finished products must be stored as salable stock under the conditions established by the manufacturer.

Rejected, reused

and returned materials and products

5.61. Rejected materials and products must be clearly labeled and stored separately in restricted areas. They must be returned to the supplier, recycled (if permitted) or destroyed. Any actions performed must be documented and approved by persons with appropriate authority.

5.62. Reprocessing of rejected products is permitted in exceptional cases, provided there is no deterioration in the quality of the finished product and all specification requirements are met. Processing is carried out in accordance with approved industrial regulations after assessing the possible risk with subsequent documentation.

5.63. The reuse of all or part of previously produced batches of appropriate quality by combining with a batch of the same product at a certain stage of production prescribed by industrial regulations must be authorized in advance, taking into account an assessment of the risks involved, including any possible impact on shelf life. Reuse activities should be documented.

5.64. The need for additional control of any finished product that has undergone processing or products in which reused products have been included will be determined by the quality control department.

5.65 Products returned from the market over which control by the manufacturer has been lost must be destroyed unless their quality is confirmed to meet established requirements. A decision to resell, relabel or reuse can only be made after specific analysis by the Quality Control Department in accordance with a written procedure. In this case, it is necessary to take into account the nature of the product, its background and condition, compliance with special storage conditions and the time that has passed since the date of release. If there is any doubt about the quality of the product, it must not be reused or re-released, but chemical processing to recover the active ingredients is permitted. All actions performed must be documented.

Chapter6. QUALITY CONTROL

Principle

Quality control includes sampling, testing and checking for compliance with specifications, instructions and other documents, organizing work, documenting and issuing release permits. The purpose of quality control is to prevent materials or products that do not meet established requirements from being used or sold. Quality control is not limited to laboratory work, but must be involved in all decisions regarding product quality. The fundamental principle for the satisfactory operation of the quality control department is its independence from the production departments (see also Chapter 1 of Part I of these Rules).

General requirements

6.1. Every drug manufacturer must have a quality control department. This department should be independent from other departments. The head of this department must have the appropriate qualifications and experience, and he must have one or more control laboratories at his disposal. The department must be provided with sufficient resources to ensure that all quality control activities are carried out effectively and reliably.

6.2. The main responsibilities of the head of the quality control department are summarized in Chapter 2 of Part I of these Rules. The quality control department as a whole may also have other responsibilities, such as the creation, validation and implementation of all quality control procedures, storage of control samples of raw materials, materials and products, ensuring correct labeling of packages with raw materials and products, monitoring product stability , participation in the investigation of claims regarding product quality, etc. All of these responsibilities should be performed in accordance with approved procedures and documented as necessary.

6.3. When assessing the quality of finished products, all relevant factors should be considered, including manufacturing conditions, in-process controls, review of manufacturing documentation (including packaging documentation), compliance with finished product specifications, and inspection of final finished product packaging.

6.4. Quality control personnel must have access to production areas to take samples and conduct necessary tests.

Rules for Good Laboratory Quality Control

6.5. The premises and equipment of control laboratories must comply with the general and special requirements for quality control areas given in Chapter 3 of Part I of these Rules.

6.6. Personnel, premises and equipment of laboratories must correspond to the type and volume of production. In some cases, the use of third-party laboratories is permitted, provided that they comply with the requirements set out in Chapter 7 (“Activities transferred to another organization (outsourcing)”), Part I of these Rules, and make appropriate entries in the quality control documents.

Documentation

6.7. Documentation of control laboratories must comply with the principles set out in Chapter 4 of Part I of these Rules. An important part of this documentation relates to quality control. The following documentation should be readily available to the quality control department:

specifications;

sampling procedures;

methods and documents on the tests performed (including analytical operating sheets and/or laboratory journals);

analytical reports and/or certificates;

results of monitoring the production environment, where required;

test method validation protocols, where applicable;

procedures and protocols for instrument calibration and maintenance equipment.

6.8. Any quality control documentation related to production records of product batches must be stored for one year after the expiration date of the batch and for at least five years after assessment of the conformity of the batch by an authorized person in the prescribed manner (clause 2.4, subclause c of Part I of these Rules).

6.9. For some types of data (for example, results of analytical tests, yield of finished products, parameters of the production environment, etc.), it is advisable to store records in a form that allows one to evaluate trends in changes in parameters.

6.10. In addition to the information that is part of the batch dossier, other source data, such as laboratory notebooks and/or records, should be maintained and readily accessible.

Sampling

6.11. Sampling should be carried out in accordance with approved written procedures that specify:

sampling method;

equipment used;

the amount of sample to be collected;

procedures for dividing the selected sample into parts (if necessary);

the type and condition of the container used for sampling;

identification of the container with the samples taken and the container from which the samples were taken;

any special precautions that must be observed, especially when collecting samples of sterile and hazardous substances;

storage conditions;

procedures for cleaning and storing sampling equipment.

6.12. The control samples selected should be representative of a batch of starting raw materials, packaging materials or finished products. Additional samples may also be collected to monitor the most important stages of the process (eg start or end).

6.13. The label of the container with the selected samples must indicate its contents, batch number, date of sampling, as well as the designation of the package from which the samples were taken.

6.14. Additional requirements for control and archival samples are given in Appendix 19 of these Rules.

Carrying out tests

6.15. Quality control methods must be validated, with the exception of methods established by pharmacopoeial quality standards. All tests given in the registration dossier must be carried out in accordance with approved methods.

6.16. The test results obtained must be recorded and checked to ensure their consistency with each other. All calculations should be checked carefully.

6.17. Tests carried out should be recorded and documented with at least the following information:

name of the starting raw materials, packaging materials or products and, if necessary, dosage form;

the batch number assigned upon acceptance and, where applicable, the manufacturer's batch number, and the name of the manufacturer and/or supplier;

test results, including observations, calculations and links to all documents containing the results of the analyzes performed;

test dates;

surnames and initials of the persons conducting the test;

names and initials of persons who verified the testing and calculation results, where applicable;

a clear conclusion on the issuance of permission or rejection of the product (or other decision on the status of the product), date and signature of the responsible person.

6.18. All controls during the production process, including those performed in the production area by production personnel, must be carried out in accordance with methods approved by the quality control department, and the results must be documented.

6.19. Particular attention should be paid to the quality of laboratory reagents, volumetric laboratory glassware and titrated solutions, standard samples and culture media. Their preparation and preparation must comply with the requirements of the instructions approved in the prescribed manner.

6.20. Laboratory reagent solutions must be marked with the date of preparation and with the signatures of the performers. The label must indicate the expiration date of unstable reagents and culture media and the specific conditions for their storage. For titrated solutions, the date of last titration and the corresponding correction factor should be indicated.

6.21. Where appropriate, the container should indicate the date of receipt of each substance used for testing (for example, reagents and reference materials), with appropriate instructions for its use and storage. In some cases, after receipt or before use of a reagent, it may be necessary to perform an identity test and/or other testing.

6.22. Animals used to control components, raw materials or products should, if necessary, be quarantined before being handled. Animals must be cared for and controlled to ensure they are fit for their intended purpose. Animals must be marked, and information about previous work with them must be documented.

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