Scientific rationale for optimizing the provision of healthcare institutions of the Russian Federation with medicinal preparations from donor plasma. Guidance on plasma-derived medicinal products Fractionation of blood plasma

PHARMACOPOEIAL ARTICLE

Introduced to replace FS 42-0091-02

This pharmacopoeial monograph applies to plasma for fractionation, which is the liquid part of human blood remaining after separation of the cellular elements of blood prepared with an anticoagulant. Plasma for fractionation is obtained from whole human blood using centrifugation, apheresis, etc. Human plasma for fractionation should not contain antibacterial and antifungal agents.

Human plasma for fractionation is used as a substance for the production of human blood products.

Donors

To produce human blood plasma, plasma from healthy donors selected based on the results of a medical examination, medical history examination and laboratory blood testing can be used in accordance with the requirements of current regulations.

Recorded data must provide identification and traceability of the donor, each unit of plasma included in the pool, and associated laboratory samples.

Individual plasma unit

An individual unit of plasma is subject to mandatory testing for the absence of surface antigen of the hepatitis B virus, for antibodies to the hepatitis C virus, HIV p24 antigens, antibodies to HIV-1, HIV-2, and the causative agent of syphilis. Plasma samples with negative results of enzyme immunoassay tests are combined into minipools and tested for the presence of nucleic acids of human immunodeficiency viruses, hepatitis B and C viruses. If the test results are positive, the plasma of such donors is rejected and destroyed.

Plasma intended for the isolation of labile proteins (blood clotting factors) must be frozen to a temperature of minus 25°C or lower no later than 24 hours after donation.

Plasma intended for the isolation of stable proteins (albumin, immunoglobulins) obtained by apheresis must be frozen to a temperature of minus 20°C and below no later than 24 hours after donation, and obtained by other methods to a temperature of minus 20°C and below no later than 72 hours after donation .

To collect blood and its components, disposable polymer containers that meet established requirements are used. The packaging must be sealed to prevent contamination by microorganisms.

Quarantine

Individual plasma units are subject to quarantine in accordance with current regulations. If blood-borne infections are detected in a donor during the quarantine period or the presence of specific and non-specific markers of blood-borne infections in the donor's blood after the quarantine period has expired, frozen plasma collected from the donor must be isolated, disinfected and disposed of with mandatory registration of this procedure.

Before forming a production pool (load), individual plasma units are combined for performance testing. When producing blood products, the production pool (load) of plasma must be tested for the HIV p24 antigen and antibodies to HIV-1, HIV-2, for antibodies to the hepatitis C virus, the surface antigen of the hepatitis B virus, the causative agent of syphilis using enzyme immunoassay methods and for the presence of nucleic acids human immunodeficiency viruses, hepatitis B and C viruses using the polymerase chain reaction method.

The results of plasma viral safety testing of the production pool must be negative.

The number of individual plasma units to be combined is indicated in the pharmacopoeial monograph.

TESTS

Description

When frozen, it is a dense, solidified mass of yellowish color. Before freezing and after thawing (thawing) – a transparent or slightly opalescent liquid from light yellow to greenish. The presence of turbidity and flakes is not allowed.

Note

Thawing of individual plasma units is carried out at a temperature of (35-37) ° C for 15 minutes.

Authenticity (species specificity)

The authenticity of plasma for fractionation is confirmed by the presence of only human serum proteins. The test is carried out using sera against human, bovine, equine and porcine serum proteins by gel immunoelectrophoresis in accordance with or by gel immunodiffusion method in accordance with.

Impigments

The optical density of the test solution should be no more than 0.25. The determination is carried out in accordance with the General Pharmacopoeia Monograph “Spectrophotometry in the ultraviolet and visible regions” in cuvettes with a layer thickness of 10 mm at a wavelength of 403 nm relative to water.

Note

Preparation of the test sample. The test plasma sample for fractionation is diluted with 0.9% sodium chloride solution in a ratio of 1:4.

pH

From 6.5 to 7.5. The test is carried out by the potentiometric method in accordance with , using thawed plasma.

Sterility

Plasma must be sterile. The test is carried out in accordance with. The method of determination is indicated in the pharmacopoeial monograph.

Protein content

Not less than 5%. The determination is carried out using a suitable method in accordance with.

Specific activity

In human plasma for fractionation used for the production of normal human immunoglobulin preparations, the quantitative content of antibacterial antibodies (at least against one pathogen) and antiviral antibodies (at least against one pathogen) is indicated, for example, the content of anti-alphastaphylolysin should be at least 0.5 IU/ml; the content of anti-measles antibodies must be at least 1:80. The determination is carried out according to the method(s) specified in the regulatory documentation (for example, the content of anti-measles antibodies - in the passive hemagglutination reaction, the content of anti-alphastaphylolysin - in the reaction of neutralizing the hemolytic properties of staphylococcal alpha toxin) using standard samples.

In plasma for fractionation, used for the production of human immunoglobulin preparations for specific and special purposes, the quantitative content of specific antibodies is indicated. For example, in plasma for fractionation used for the production of human anti-staphylococcal immunoglobulin, the content of anti-alphastaphylolysin must be at least 3 IU/ml; in plasma for fractionation used for the production of human immunoglobulin against tick-borne encephalitis, the content of antibodies against tick-borne encephalitis virus must be at least 1:10; in human plasma for fractionation used for the production of human immunoglobulin against hepatitis B, the content of antibodies to the surface antigen (HBsAg) of the hepatitis B virus must be at least 5 IU/ml, etc. The determination is carried out according to the method(s) specified in the regulatory documentation using standard samples.

Fractionation plasma used for the production of coagulation factor preparations is tested for factor VIII activity according to . Factor VIII activity must be at least 0.7 IU/ml. The test is carried out on a pooled sample containing at least 10 individual units of plasma.

Virus safety

Surface antigen (HBsAg) and hepatitis B virus nucleic acid

Antibodies to human immunodeficiency virus (HIV-1, HIV-2) and human immunodeficiency virus nucleic acid

Must be missing. The determination is carried out using the enzyme immunoassay method and the polymerase chain reaction method with commercial test systems approved for use in the Russian Federation, in accordance with the instructions attached to them.

Antibodies to the virushepatitis C and hepatitis C virus nucleic acid

Antibodies to the causative agent of syphilis

Plasma should not contain antibodies to the causative agent of syphilis. The determination is carried out by the immunological method in a microprecipitation reaction with commercial diagnostic kits or by the enzyme immunoassay method with commercial test systems approved for use in the Russian Federation, in accordance with the instructions attached to them.

Packageand labeling

Primary packaging (polymer containers for disposable use) must be sealed, ensure the preservation of the declared properties of plasma during the regulated shelf life and are approved for use for packaging medicines.

The package label indicates the name and address of the organization for donating blood and its components, donation identification number, ABO blood group and Rh factor, date of donation, date of production of the plasma unit (in case it does not coincide with the date of donation), expiration date, name and volume of the anticoagulant and (or) additional solution, name of the blood component, volume or weight of blood or blood components, storage conditions, indication of additional processing (irradiation, filtration, inactivation), inscription: “Antibodies to HIV-1, HIV-2 , to the hepatitis C virus and the surface antigen of the hepatitis B virus are absent.”

X wound

Store at a temperature of minus 30°C and below.

Transportation

It is carried out at a temperature of minus 25 o C and below in special refrigerators (chambers, modules) equipped with sensors and temperature recording devices.

Guideline on plasma-derived medicinal products

Incorporation into the main text of the Guidance on Assessing the Risk of Viral Transmission - new Chapter 6 of the Guidance on Plasma-Derived Medicinal Products ( CPMP/BWP/5180/03);
Link to guidance on replacing the rabbit pyrogenicity test with an alternative for plasma-derived medicinal products ( EMEA/CHMP/BWP /452081/2007), test.

1.Introduction (background information)

Human plasma contains many proteins that, once isolated, purified and incorporated into drugs, play a major role in medicine. Plasma-derived products are a life-saving therapy, but the amount of plasma available for fractionation is limited by the number of donors. Therefore, in order to ensure the best use of donated blood/plasma, the exchange of intermediate products between manufacturers or the use of a variant production process (see below) is possible.

Although the therapeutic use of blood transfusion dates back to the early 20th century, the widespread use of drugs isolated from human plasma did not begin until the 1940s. following the introduction of plasma fractionation technology invented by Cohn and colleagues.

Improvements in the technology of protein purification and molecular separation have made it possible to obtain a wide variety of drugs, the medical use of which covers a wide area; their therapeutic value is beyond doubt. However, the potential for viral transmission is well known, and due to the large number of donations being pooled, one contaminated batch of plasma-derived product, contamination of which may be due to a single donation, can transmit viral disease to a large number of recipients. Established in the mid-1980s. The discovery that plasma-derived drugs, particularly clotting factor concentrates, have been implicated in widespread transmission of human immunodeficiency virus (HIV) and hepatitis C (formerly called non-A, non-B hepatitis) has led to major changes in manufacturing processes, with the introduction of special stages of inactivation or elimination of these and other bloodborne viruses. In the 1990s and early 2000s. Infectious non-enveloped viruses have been detected in certain plasma-derived medicinal products. Therefore, recent process improvements have been aimed at further reducing non-enveloped viruses such as hepatitis A (HAV) and parvovirus B19 (B19V).

Measures taken to prevent infection include donor selection, screening of individual donations and plasma pools for infectious markers of known viruses, and validation of the manufacturing process for virus inactivation and elimination. Since the 1990s. Measures to minimize contamination of source plasma have been improved through improvements in serological test kits and the use of nucleic acid amplification technology (NAT) to detect viral DNA and RNA, thereby reducing the seronegative window during which infected donations are undetected.

Recent cases of confirmed iatrogenic variant Creutzfeldt-Jakob disease (vCJD) due to blood transfusion in humans in the United Kingdom provide strong evidence that vCJD is transmitted by blood transfusion. Since the identification of the first cases of vCJD in 1998, the CMLP has introduced precautionary measures to minimize the risk of transmission of infectivity through plasma-derived medicinal products, which are continually reviewed and updated as necessary.

In the EU, the legal basis for minimum quality and safety standards for the starting material of plasma-derived medicinal products was created in parallel with pharmaceutical legislation, therefore special norms were laid down in pharmaceutical legislation. This legislation provided for the possibility of centralized certification of the plasma master file.

In 2003, the European Parliament and Council adopted a framework “Establishing quality and safety standards for the collection, testing, processing, storage and distribution of human blood and blood components...”, also known as . Thus, starting from February 8, 2005, the amendment introduced requirements for the collection and testing of human blood and blood components, regardless of the purpose of their use. As a follow-up, this Commission adopted technical Directives 2005/61/EC and 2005/62/EC. In addition, the Council of Europe has compiled “Guidelines for the preparation, use and quality assurance of blood components”, which contains a set of measures aimed at ensuring the safety, effectiveness and quality of blood components.

This manual applies to:

medicinal products containing plasma-derived proteins as active ingredients;

investigational medicinal products containing plasma-derived proteins as active ingredients;

plasma-derived proteins used as excipients in medicinal products, including investigational medicinal products;

proteins derived from plasma used as additional substances in medical devices.

2.Scope of application

Medicinal products obtained from human blood and plasma fall within the definition of paragraph 10 of Article 1: “Medicines based on blood components, prepared industrially by public or private organizations, such medicinal products include, in particular, albumin, coagulation factors and immunoglobulins of human origin." Moreover, pharmaceutical legislation also applies to plasma prepared by a method involving an industrial process (Article 2(1)). An example of the latter category is solvent-detergent-treated plasma.

Many parts of this guidance may also apply to active substances isolated from cellular components, such as hemoglobin.

In accordance with paragraphs 1, 2 and 6 of Article 3, the scope of application does not include blood and blood components. Moreover, it does not cover medicinal products prepared on a non-industrial scale for individual patients in accordance with a medical prescription, however many parts contained in this document may be applicable to them. Directive 2001/83/EC together with the relevant Commission Directives. 2005/61/EC and 2005/62/EC, in essence, should ensure the implementation of minimum standards for the quality and safety of blood and blood components in EU Member States. These requirements also apply, where applicable, to blood/plasma and plasma-derived medicinal products imported from third countries.

In addition, it is a legal requirement for the manufacturer to confirm the consistency of the quality of batches of plasma-derived medicinal products before placing them on the market. In addition, it is necessary, as far as the current state of technology allows, to confirm the absence of certain viral contaminants.

European Pharmacopoeia standards for plasma-derived medicinal products are given in the article “Human plasma for fractionation” and the specific articles for medicinal products derived from plasma (Appendices II and III).

Since the free movement of goods applies to all medicinal products, Member States are free to apply stricter requirements to plasma-derived medicinal products. The Treaty on the Functioning of the EU (Article 168(4)(a), Section XIV) states that Member States may not be restricted in their right to maintain or introduce more stringent protective measures regarding quality and safety standards for blood and blood derivatives.

The authorized body has the right to require the DRU to submit samples of each bulk medicinal product or each batch of medicinal product for the purpose of testing by the state laboratory before releasing it to the market (Article 114 by email with the request.

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37. (6.6) The conditions for storage and transport of blood or plasma to the fractionation facility should be defined and documented at all stages of the supply chain. The fractionation facility must be notified of any deviations from the specified temperature. Equipment that has been qualified and procedures that have been validated must be used.

Evaluation and authorization for the release of plasma for fractionation used as feedstock

38. (6.7) Authorization for the release of plasma for fractionation (from quarantine) can only be done through systems and procedures that ensure the quality necessary for the production of the finished product. Plasma may only be supplied to a fractionator or manufacturer after it has been documented by the responsible person (or in the case of blood or plasma collection in third countries, a person with similar responsibilities and qualifications) that the plasma to be fractionated complies with the requirements and specifications set out in the relevant contracts, and also that all stages were carried out in accordance with these Rules.

39. (6.8) The use of all plasma containers for fractionation upon entering the fractionation facility must be authorized by an authorized person. The authorized person must confirm that the plasma meets all the requirements of the pharmacopoeial monographs of the State Pharmacopoeia of the Russian Federation, and also satisfies the conditions of the relevant registration dossier, including the main plasma dossier, or in the case of using plasma for fractionation programs under a contract for third countries, all the requirements provided for in paragraph 9 of this Appendix.

Plasma Processing for Fractionation

40. (6.9) The steps in the fractionation process vary depending on the product and manufacturer. They typically involve various fractionation steps, and some of these may help inactivate or remove possible contamination.

41. (6.10) Requirements for pooling, pooled plasma sampling, fractionation, and virus inactivation or removal processes should be established and must be followed.

42. (6.11) Methods used in the viral inactivation process must be applied in strict accordance with validated procedures. Such methods should be consistent with the methods that were used to validate viral inactivation procedures. All failed viral inactivation procedures should be thoroughly investigated. Adherence to a validated process is particularly important in virus reduction procedures, as any deviations may pose safety risks to the finished product. Procedures must be in place that address these risks.

43. (6.12) Any reprocessing or reprocessing may only be carried out after quality risk management measures have been carried out and only at certain stages of the process, as specified in the relevant industrial regulations.

44. (6.13) A system should be in place to clearly separate and/or differentiate between medicinal products or intermediates that have and have not undergone viral load suppression.

45. (6.14) Depending on the outcome of a carefully conducted risk management process (taking into account possible differences in epidemiological data), production on a production cycle basis may be permitted where plasma or intermediates of different origins are processed at the same production site, including the necessary procedures clear separation and established validated cleaning procedures. Requirements for such events should be based on the relevant regulatory legal acts of the Russian Federation. The risk management process should address the need for special equipment in the event of fractionation programs under contract with third countries.

46. (6.15) The shelf life for intermediates intended for storage should be based on stability data.

47. (6.16) Requirements for the storage and transportation of intermediates and finished medicinal products at all stages of the supply chain should be established and documented. Equipment that has been qualified and procedures that have been validated must be used.

VIII.QUALITY CONTROL (7)

48. (7.1) Requirements for testing for viruses or other infectious agents should be established taking into account new knowledge about infectious agents and the availability of validated test methods.

49. (7.2) The first homogeneous pool of plasma (for example, after separation of cryoprecipitate from plasma) must be monitored using validated methods with appropriate sensitivity and specificity in accordance with the relevant pharmacopoeial monographs of the State Pharmacopoeia of the Russian Federation.

IX. ISSUANCE OF PERMISSION FOR RELEASE

INTERMEDIATEAND FINISHED PRODUCTS (8)

50. (8.1) The release of only those batches that are produced from plasma pools recognized as a result of control as negative in relation to markers of viral infections transmitted through blood, and also meeting the requirements of pharmacopoeial articles of the State Pharmacopoeia of the Russian Federation (including any special virus limits) and approved specifications (in particular the plasma master dossier).

51. (8.2) The issuance of permission for the release of intermediate products intended for further processing within the production site or delivery to another production site, as well as the issuance of permission for the release of finished medicinal products must be carried out by an authorized person in compliance with established requirements.

52. (8.3) The authorized person must issue authorization for the release of intermediate or finished products used for fractionation programs under a contract for third countries, on the basis of standards agreed with the customer, as well as in accordance with the requirements of these Regulations. If such medicinal products are not intended for use in the Russian Federation, the requirements of pharmacopoeial articles of the State Pharmacopoeia of the Russian Federation may not apply to them.

X. STORAGE OF PLASMA POOL SAMPLES (9)

53. (9.1) One pool of plasma can be used for the production of several series and (or) drugs. Control samples of each plasma pool, as well as corresponding records, must be retained for at least one year after the expiration of the medicinal product obtained from that pool with the longest shelf life of all medicinal products obtained from that plasma pool.

XI.WASTE DISPOSAL (10)

54. (10.1) Procedures for the safe storage and disposal of waste, disposable and discarded materials (e.g. contaminated items, items from infected donors, and expired blood, plasma, intermediates or finished medicinal products) should be established and documented. documented.

Appendix No. 15

to the Rules for Organization of Production

and quality control of medicines

QUALIFICATION AND VALIDATION

I. PRINCIPLE

1. This Annex sets out the qualification and validation requirements applicable to the manufacture of medicinal products. In order to demonstrate that the parameters of critical processes (equipment) meet specified requirements, manufacturers must validate the processes and equipment used in the production of medicinal products. Validation is also carried out when there are significant changes to premises, equipment and processes that may affect product quality. A risk-based approach should be used to determine the composition and scope of validation work.

II. PLANNING FOR VALIDATION

2. All validation activities must be planned. The key elements of the validation program should be clearly defined and documented in the validation master plan or similar documents.

3. The master validation plan should be a summary document written in a concise, precise and clear manner.

4. The master validation plan shall contain, in particular, the following information:

(a) the purpose of the validation;

(b) an organizational chart for the validation activities;

(d) the form of documentation to be used for minutes and reports;

(e) planning and scheduling of work;

5. For large projects, it may be necessary to develop separate master validation plans.

III.DOCUMENTATION

6. A written protocol should be developed specifying how qualification and validation will be carried out. Such a protocol must be reviewed and approved. The protocol should specify critical steps and acceptance criteria.

7. A report should be prepared, cross-referenced to the qualification and/or validation protocol, summarizing the results obtained, commenting on any observed deviations and conclusions, including recommended changes needed to correct the deviations. Any changes made to the plan, which is given in the protocol, must be documented with appropriate justification.

8. Upon successful completion of qualification, formal written approval must be issued to proceed to the next stage of qualification and validation.

IV.QUALIFICATION

Project qualification

9. The first element of validating new premises, systems or equipment is design qualification.

10. It is necessary to demonstrate and document the project’s compliance with the requirements of these Rules.

Installation qualification

11. Installation qualifications must be performed for new or modified facilities, systems and equipment.

12. The installation qualification must include (but not be limited to) the following elements:

(a) checking the installation of equipment, piping, auxiliary systems and instruments for compliance with the approved design, including technical documentation, drawings and specifications;

(b) assessing the completeness and collation of the supplier's operating and operating instructions and maintenance requirements;

(d) checking the materials used in the structures.

Operational qualification

13. Functional qualification must follow installation qualification.

14. Performance qualification should include (but not be limited to) the following elements:

(a) tests based on knowledge of processes, systems and equipment;

(b) testing the performance of the equipment at operating parameters equal to the upper and lower permissible limits, that is, under “worst case” conditions.

15. Successful completion of performance qualification should facilitate the finalization of calibration, operating and cleaning instructions, operator training, and preventative maintenance requirements. Only after this can the customer accept premises, systems and equipment.

Operation qualification

16. Operational qualification is carried out after successful completion of installation qualification and operation qualification.

17. The operational qualification must include (but not be limited to) the following elements:

(a) tests using materials used in production, selected substitutes with similar properties or a simulator, developed on the basis of knowledge of the process and of the facilities, systems or equipment;

(b) tests at operating conditions equal to the upper and lower permissible limits.

18. Despite the fact that the qualification of operation is considered as a separate stage of work, in some cases it is advisable to carry it out together with the qualification of operation.

Qualification of installed (used)

technical means, premises and equipment

19. It is necessary to have data justifying and confirming the compliance of critical operating parameters with the specified requirements. Instructions for calibration, cleaning, preventive maintenance and operation, as well as operator training and record keeping, must be documented.

V.PROCESS VALIDATION

General requirements

20. The requirements and principles set out in this Annex apply to the production of dosage forms. They cover the initial validation of new processes, subsequent validation of changed processes and revalidation.

21. Process validation should generally be completed before the medicinal product is marketed and sold (prospective validation). In exceptional cases where such validation is not possible, it may be necessary to carry out process validation during ongoing production (concurrent validation). Processes that have already been in place for some time are also subject to validation (retrospective validation).

22. Facilities, systems and equipment used must be qualified and analytical test procedures validated. Personnel involved in the validation must be appropriately trained.

23. Facilities, systems, equipment and processes should be periodically assessed to ensure they are operating in accordance with specified requirements.

Prospective Validation

24. Prospective validation should include (but not be limited to) the following elements:

(a) a brief description of the process;

(b) a list of critical process steps to be examined;

(c) a list of premises and equipment used (including measuring, control, recording equipment) indicating information about their calibration;

(d) specifications for finished products upon release;

(e) if necessary, a list of analytical procedures;

(f) proposed in-process control points and acceptance criteria;

(g) if necessary, additional tests to be carried out, together with acceptance criteria and validation of analytical methods;

(h) sampling plan;

(i) methods for recording and evaluating results;

(j) roles and responsibilities;

(k) the expected schedule for completing the work.

25. Using an established process (using components that meet specifications), a number of batches of finished products can be produced under normal conditions. In theory, the number of production runs performed and observations made should be sufficient to allow the normal degree of variability and trends to be established, and to provide the necessary amount of data for evaluation. To validate a process, it is considered sufficient to perform three consecutive series or cycles in which the parameters are within specified limits.

26. The batch size for validation should be equal to the batch size for industrial production.

27. If the sale or supply of batches produced during validation is intended, then the conditions of their production must fully comply with the registration dossier and the requirements of these Rules, including a satisfactory result of the validation.

Related Validation

28. In exceptional cases, it is allowed to begin mass production before the completion of the validation program.

29. The decision to conduct associated validation must be justified, documented and approved by persons with appropriate authority.

30. Documentation requirements for concomitant validation are the same as those specified for prospective validation.

Retrospective Validation

31. Retrospective validation can only be carried out for well-established processes. Retrospective validation is not permitted if changes have recently been made to the product, process or equipment.

32. Retrospective validation of these processes is based on historical data. This requires the preparation of a special protocol and report, as well as a review of previous operation data with the issuance of a conclusion and recommendations.

33. Data sources for such validation should include, but are not limited to, batch production and packaging records, production control charts, maintenance logs, personnel change data, process capability studies, finished product data, including trend maps, as well as the results of studying its stability during storage.

34. Product batches selected for retrospective validation should be a representative sample of all batches produced during the review period, including all batches that did not meet specifications. The number of production batches must be sufficient to demonstrate the stability of the process. When conducting retrospective process validation, additional testing of historical samples may be necessary to obtain the required amount or type of data.

35. To assess the stability of the process when conducting retrospective validation, it is necessary to analyze data on 10-30 sequentially produced batches, however, if there is appropriate justification, the number of batches studied can be reduced.

VI. CLEANING VALIDATION

36. Cleaning validation should be carried out to confirm the effectiveness of the cleaning procedure. The rationale for the selected limits for carryover product residues, detergents, and microbial contamination should be based on the properties of the materials used. These limit values must be realistically achievable and verifiable.

37. Validated analytical techniques must be used to detect residues or contaminants. The detection limit for each analytical procedure must be sufficient to detect the specified acceptable level of the residue or contaminant.

38. In general, only cleaning procedures for product contact surfaces of equipment need to be validated. However, it is also necessary to pay attention to parts of the equipment that do not come into contact with the product. The length of time between the end of a process and cleaning, and between cleaning and the start of the next process, must be validated. Cleaning methods and time intervals between cleaning must be specified.

39. For cleaning procedures involving very similar products and processes, it is acceptable to select a representative range of similar products and processes. In such cases, a single validation study can be conducted using a “worst case” approach in which all critical factors are taken into account.

40. Successful completion of three consecutive cleaning cycles is sufficient to validate a cleaning procedure.

41. The “test until clean” method does not replace validation of the cleaning procedure.

42. If the substances to be removed are toxic or dangerous, then, as an exception, drugs that simulate the physicochemical properties of such substances can be used instead.

VII.CHANGE CONTROL

43. The manufacturer must establish procedures describing the actions that must be taken if there is to be a change in raw materials, product components, processing equipment, environmental conditions of the production (or site), method of production or control method, or any other change that may affect quality product or process reproducibility. Change control procedures must ensure that sufficient data is obtained to demonstrate that the changed process produces product of the required quality and conforms to the approved specifications.

44. All changes that may affect product quality or process reproducibility must be submitted to the pharmaceutical quality system. Such changes must be documented and approved. The potential impact of changes to premises, systems and equipment on the product must be assessed, including a risk analysis. The need and extent of requalification and revalidation should be determined.

VIII.RE-VALIDATION

45. Facilities, systems, equipment and processes, including cleaning procedures, should be periodically assessed to ensure they meet specified requirements. If there are no significant changes, then instead of revalidation, it is sufficient to produce a report indicating that the premises, systems, equipment and processes meet the specified requirements.

IX.TERMS AND DEFINITIONS

For the purposes of this Appendix, in addition to the terms and definitions provided for in Chapter II of these Rules, the following basic concepts are also used:

risk analysis– a method for assessing and describing critical parameters during the operation of equipment, systems or a process in connection with an identified hazard;

cleaning validation– documented evidence that the approved cleaning procedure ensures that the equipment is as clean as necessary for the production of medicinal products;

process validation– documented evidence that the process, carried out within established parameters, is carried out efficiently, reproducibly and results in the production of a medicinal product that meets pre-established specifications and quality characteristics;

installation qualification– documented confirmation that the installation of premises, systems and equipment (installed or modified) was carried out in accordance with the approved design and the recommendations of their manufacturer;

project qualification– documented confirmation that the proposed design of production premises, equipment or systems is suitable for its intended use;

performance qualification– documented evidence that premises, systems and equipment (installed or modified) function in accordance with specified requirements in all intended operating modes;

operating qualification– documented evidence that facilities, systems and equipment, when used together, operate efficiently and reproducibly in accordance with approved requirements and process characteristics;

change control– a documented process whereby qualified representatives from various disciplines review proposed or actual changes that may affect the validated condition of premises, equipment, systems or processes. The purpose of such control is to determine the need for measures that should ensure and document the maintenance of the system in a validated state;

modeling drug– a material that is similar in its physical and, if possible, chemical characteristics (e.g. viscosity, particle size, pH) to the product being validated. In many cases, a batch of a placebo drug (a product that does not contain a pharmaceutical substance) may have these characteristics;

worst case- Conditions or set of conditions defined by standard operating procedures that relate to the upper and lower limits of process operating parameters and associated factors that make a process failure or product defect more likely to occur than ideal conditions. Such conditions do not necessarily result in process failure or product defects;

prospective validation– validation performed before the start of mass production of products intended for sale;

revalidation– repeat process validation to ensure that changes to the process and/or equipment made in accordance with the change control procedure do not impair process performance and product quality;

retrospective validation– validation of the serial production process of the product being sold, based on the collected data on the production and control of product batches;

accompanying validation– validation performed during the current (serial) production of products intended for sale.

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Human plasma intended for fractionation is divided into 3 categories. Plasma of categories 1 and 2 is used for the production of factor VIII and factor IX, plasma of category 3 is used for albumin and immunoglobulins (Table 3). These categories of plasma differ in the characteristics of obtaining plasma and the period of freezing after donation of blood by donors, in the applied freezing and storage temperature, in its shelf life and shelf life, and in the time of delivery of plasma for processing. Plasma of the 3rd category may include not only plasma separated from whole blood, but plasma, during storage and transportation of which there was a violation of the temperature regime. Therefore, it is called recovered plasma and is suitable only for the production of stable protein components - immunoglobulins and albumin.

The quality, standard and safety of plasma for the production of drugs is determined by the pharmacopoeial standard. Most European countries have national pharmacopoeias. The European Pharmacopoeia is intended to create a single pharmacopoeial space for countries of the continent seeking mutual integration of economics, healthcare, and industry within the European Union. In 2002, the domestic Pharmacopoeial Article 42-0091-02 “Plasma for fractionation” was published for the first time, which is a national standard mandatory for all Russian manufacturers of plasma products. A comparison of the corresponding Pharmacopoeial Article (FS 42-0091-02) “Plasma for fractionation” with the European Pharmacopoeia revealed that it is advisable to introduce adjustments to the document in question.

Firstly, the methods for obtaining plasma are unreasonably limited. It must be taken into account that in the Blood Service a significant part of the plasma (about 10%) is released after spontaneous cell sedimentation. In addition, the volumes of plasma remaining after the release of cryoprecipitate are very significant. It is fundamentally important to comply with the requirement of immediately freezing the plasma after separation from whole blood obtained by plasmapheresis, following the separation of the cryoprecipitate. The mode of plasma freezing and storage should be indicated in separate sections of the FS, since they depend on the purpose of the plasma - obtaining stable or labile plasma fractions.

An important condition is to indicate that plasma should be supplied for fractionation only in an individual primary glass or plastic container from one donor, which should be checked for integrity and the presence of a label. Identification of each individual plasma container is possible only on the basis of the label and accompanying document, duly executed and signed by the person legally responsible for plasma certification. The data indicated on the label should be sufficient to allow plasma to be processed before production or sent to medical institutions.

The quality and standard of the collected plasma is determined by conducting an appropriate set of studies, however, the set of studies provided for by FS 42-0091-02 is not advisable to carry out in full in relation to each portion of plasma, not only from a technical point of view, but it is not very rational from an economic point of view, since as it requires unreasonable and significant economic investments. A number of studies (tests for transparency, color, pH, protein) can be carried out after combining the plasma into a load (pool), especially since tests for viral safety should be carried out only after pooling the plasma. This also leads to a reduction in research time, since in the production of high-quality plasma preparations it is necessary to minimize the time from the moment of thawing the plasma to the start of the technological process.

The shelf life of frozen plasma in our country is 1 year, 2 times less than abroad, where the storage period for plasma is 2 years. Increasing the shelf life of plasma leads to a reduction in the cost of producing plasma products.

The European standard and other international documents indicate that the temperature at which plasma should be stored is 10 degrees lower and is –20° C or lower. This entails the need to purchase more expensive equipment and consume more electricity. Therefore, increasing the storage temperature by 10 degrees. will also help reduce the cost of procuring and storing fresh frozen plasma and reduce the cost of derived plasma products.

The data obtained and the listed recommendations made it possible to develop forms of information letter, contract, quality specification and application documents that are part of the contract, which is a legal document defining the responsibility of the supplier for the quality and safety of plasma and the recipient for the production of high-quality medicinal products.

Chapter Six“Ensuring the viral safety of donor plasma” revealed the role of carrying out activities aimed at disinfecting fresh frozen plasma. Blood products transfused to patients can transmit a variety of life-threatening infections, the most serious of which are HIV infection, hepatitis caused by hepatitis B virus (HBV), hepatitis C virus (HCV) and hepatitis A virus.

In order to ensure the viral safety of donor blood, its components and preparations, proposals were developed that included a set of measures for the examination of donors and blood included in the Order of the Moscow Department of Health No. 513 of November 29, 2007 “On strengthening measures aimed at reducing the risk of developing post-transfusion infectious complications”, which is mandatory when working with donors at blood transfusion stations.

Despite the fact that when collecting plasma, a mandatory condition is the examination of the donor and the collected material, there is no complete confidence in viral safety, therefore, a prerequisite for further use of the collected plasma for fractionation is its storage for at least 3 months. at a temperature of –30°C, which makes it possible to remove plasma samples upon receipt of information about the disease of donors who were in the seronegative period of viral infection at the time of donation.

However, donors called for re-examination do not always come for re-examination. The data obtained indicate that annually, due to the failure of donors to appear for re-examination, an average of 1,605 liters of plasma, obtained from an average of 3,500 - 3,600 donors and quarantined, is destroyed. Considering that this number of liters is equivalent to 12,485 doses of plasma, then, provided that 1 patient needs an average of 3-5 doses of plasma, approximately 2,497 - 4,162 patients do not receive the plasma and its preparations they need for therapeutic purposes.

Freezing collected plasma and storing it requires significant costs. Considering this circumstance, it is advisable and justified to send quarantined plasma from donors who did not come for re-examination for inactivation and removal of viruses by any of the approved methods. Currently, quite a lot of methods for inactivating viruses are known, but only a few of them are approved for use. For these purposes, heat treatment, treatment with solvents and detergents, and the photochemical method are used. The most suitable method for inactivating fresh frozen plasma is the S/D method (solvent-detergent treatment of plasma). There is extensive practical experience in its use for processing large quantities of plasma and reliable data on the effectiveness of the effect on HIV infection and hepatitis B and C viruses. The need for inactivation of plasma for transfusions is obvious, since fresh frozen plasma continues to occupy a significant place in medical practice.

It should be remembered that inactivation of viruses is a responsible procedure, the effectiveness and harmlessness of which for plasma must be convincingly proven. The effectiveness of removing or inactivating viruses has its limitations and, in any case, these procedures represent a compromise between the ability to destroy the virus and the need to avoid negative consequences. Therefore, all these methods complement the donor selection and screening process, but do not replace them.

The quality, standard and safety of donor plasma can be achieved by unconditional compliance with regulatory documents during its procurement from a donor and storage.

IN seventh chapter“The concept of reforming the domestic production of plasma preparations” reflected such issues as structural and managerial approaches to organizing the production of preparations from fresh frozen plasma, optimization of the algorithm for the procurement of fresh frozen plasma for fractionation and the economic justification of the modern production of plasma preparations.

An analysis of published materials shows that the production of donor blood products in our country lags significantly behind the world level; the production of blood products is ineffective in technological and economic terms. Donor blood plasma is used for processing to 30-40% of its therapeutic capabilities due to the lack of modern technologies and equipment at enterprises. On the one hand, for every liter of processed plasma, about 6,000 rubles are lost due to its incomplete use and lost products. calculated at world prices, and on the other hand, the country annually spends hundreds of millions of dollars on the import of vital blood products, which are not enough for effective treatment.

In the Russian Federation there are currently small institutions with a plasma processing capacity of 200 liters or more. up to 30,000 l. in year. They are part of blood transfusion stations or operate as independent enterprises. Their operation requires significant funds. At the same time, achieving profitability of such production is impossible, since they cannot provide the technological process with standard equipment and equipment, and do not have modern technology or qualified personnel.

All over the world, there is a concentration of drug production, which makes it possible to achieve high economic efficiency with minimal technological losses and high quality and viral safety of products. In order to scientifically substantiate investments and organize an enterprise of appropriate capacity, it was necessary to conduct a study to prove that in order for the country to be self-sufficient in plasma and blood products, to achieve the required level of quality, high efficiency of industrial processing of plasma, and the profitability of manufacturing and selling medical products, it is necessary to create large production enterprises with modern technology of plasma protein fractionation.

The dissertation research used the “Methodology for the commercial evaluation of investment projects” of UNIDO (UNIDO - United Nations Industrial Development Organization - a specialized agency of the UN whose goal is to promote industrial development in developing countries). This methodology became the first in Russia to systematically present the concepts and tools for assessing investment projects that have developed in world practice, as well as the key issues of their application in the Russian macroeconomic situation.

To make a decision on a long-term investment (investment) of capital, it is necessary to have information that, to one degree or another, confirms two fundamental assumptions:

the invested funds must be fully reimbursed;
the profit must be large enough to compensate for the temporary refusal to use funds, as well as the risk arising from the uncertainty of the final result.

To make a decision on investment, you should evaluate the plan for the expected development of events from the point of view of how well the content of the project and the likely consequences of its implementation correspond to the expected result.

According to the methodology, the effectiveness of investments was assessed according to the following criteria:

investment attractiveness of the project,
simple methods for assessing effectiveness,
discounting methods,
net present value of the project,
internal rate of return,
accounting for uncertainty and risk assessment

The feasibility study of investments made it possible to establish the healthcare needs of the Russian Federation and Moscow for drugs and determine the volume of plasma processing to obtain them. It has been established that it is necessary to construct 4-5 modern production enterprises with a capacity of at least 200,000 liters of plasma fractionation per year each (Table 4).

The results obtained during the development of the business plan indicate that the costs of creating initial working capital can be covered through budget financing on a non-repayable basis. In general, the total amount of government support for the project will be 62% of the total project cost.

Table 4. Demand for plasma preparations of residents of Moscow, the Moscow region and the Russian Federation and the expected yield of finished products when processing 200,000 liters. plasma per year

Need	Fresh frozen plasma products
	Albumen	Immunoglobulin	Factor VIII		Factor IX
			max	min	max		min
	kg	kg	million IU		million IU
for Moscow, 10 million inhabitants	2000	90	7,8	20	1,5		4,0
for the Moscow region 7 million inhabitants	1400	63	5,5	14,0	1,9		2,8
for the Russian Federation without Moscow and the Moscow region, 126 million inhabitants	25 200	1 134	252	1 000	34,6		50,0
Total requirement for the Russian Federation	28 600	1 287	265,3	1 034	38		56,8
Yield of the finished product when processing 200,000 plasma per year	5 500	740	40			60

5. If the responsible person or persons specified in paragraph 3 above are replaced on a permanent or temporary basis, the blood collection/testing institution must immediately notify the authorized body of the name of the new responsible person and the date of his appointment.

Plasma for fractionation(plasma for fractionation): The liquid portion of donated blood that remains after separation of blood cells, collected in a container with an anticoagulant, or that remains after separation by continuous filtration or centrifugation of blood with an anticoagulant during an apheresis procedure. It is intended for the production of drugs obtained from plasma, which are described in the State Pharmacopoeia of the Russian Federation, in particular, albumin, blood clotting factors and human immunoglobulin.

Blood products(blood products): therapeutic drugs obtained from donated blood or plasma.

Contract fractionation program for third countries(third countries contract fractionation program): Contract fractionation at an enterprise for fractionation or production of drugs from donated plasma, which is located in the Russian Federation, using feedstock from other countries; Moreover, the manufactured products are not intended for use in the Russian Federation.

Authorized person(Qualified Person): This is a person appointed by the manufacturer of medicinal products who confirms the compliance of medicinal products with the requirements established during their state registration and guarantees that the medicinal products are manufactured in accordance with the requirements of these Rules. The responsibilities of the authorized person are described in detail in Section 2 of Part I and Appendix 16 of these Rules.

Blood collection/testing facility blood establishment: An establishment that is responsible for any aspect of the collection and testing of donated blood or blood components, regardless of their intended purpose, and for their processing, storage and delivery when they are intended for transfusion. This term does not apply to hospital blood banks, but does apply to facilities that perform plasmapheresis.

Fractionation, fractionation plant(fractionation, fractionation plant): Fractionation is a technological process in an enterprise (fractionation plant) during which plasma components are separated/purified using various physical and chemical methods, for example, precipitation, chromatography.

1 area of use

1.1. The provisions of this Annex apply to medicinal products obtained from donor blood or plasma fractionated in the Russian Federation or imported into the Russian Federation. The Annex also applies to the raw materials for such medicinal products (for example, donor plasma). These requirements also apply to stable fractions of donated blood or plasma (for example, albumin) that are included in medical devices.

1.2. This Annex establishes special requirements of these Rules regarding the production, storage and transportation of donor plasma used for fractionation and for the production of medicinal products obtained from donated blood or plasma.

1.3. This Annex makes special provisions in cases where feedstocks are imported from third countries and in cases of contract fractionation programs for third countries.

1.4. This Annex does not apply to blood components intended for transfusion.

2. Principle

2.1. Medicines obtained from donor blood or plasma (as well as their active (pharmaceutical) substances used as starting materials) must comply with the requirements of these Rules, as well as the registration dossier for the medicine. They are considered biological medicinal products and starting materials that contain biological substances such as human cells or fluids (including blood or plasma). Due to the biological nature of the raw material sources, the latter have certain characteristic features. For example, raw materials may be contaminated with infectious agents, especially viruses. Therefore, the quality and safety of such medicinal products depends on control of the starting materials and their source of origin, as well as on further technological procedures, including testing for infectious markers, removal and inactivation of viruses.

2.2. All active (pharmaceutical) substances used as starting materials for medicinal products must meet the requirements of these Rules (see paragraph 2.1 of this Appendix). With regard to the collection and testing of raw materials obtained from donated blood or plasma, the following established requirements must be adhered to. Collection and inspection should be carried out in accordance with an appropriate quality system, relevant standards and specifications. In addition, current requirements regarding traceability from donor to recipient and notification of side effects and adverse reactions must be met. In addition, one should be guided by the State Pharmacopoeia of the Russian Federation.

2.3. Raw materials imported from third countries for the production of medicinal products obtained from donated blood or plasma, if these medicinal products are intended for use or distribution in the Russian Federation, must meet standards equivalent to those in force in the Russian Federation regarding the quality systems of blood collection/testing institutions . Established requirements for traceability from donor to recipient and for notification of side effects and adverse reactions must also be met, as well as compliance with current requirements for blood and blood components.

2.4. When carrying out fractionation programs under contract with third countries, feedstock imported from other countries must comply with the requirements in force in the Russian Federation. Work carried out in the Russian Federation must fully comply with these Rules. The requirements in force in the Russian Federation regarding the quality systems of blood collection/testing institutions should be met. Established requirements for traceability from donor to recipient and for notification of side effects and adverse reactions must also be met, as well as compliance with current requirements for blood and blood components.

2.5. These Rules apply to all stages after blood collection and testing (for example, processing (including separation), freezing, storage and transport to the manufacturer). As a rule, these activities should be the responsibility of an authorized person of the enterprise that is licensed to manufacture medicinal products. funds. If specific processing steps for plasma fractionation are carried out at a blood collection/testing facility, a designated person may be designated there, but the presence and responsibilities may not be the same as those of the responsible person. To resolve this specific situation and to ensure that the authorized person's legal responsibilities are properly met, the fractionator (drug manufacturer) must have an agreement with the blood collection/processing facility. The contract must meet the requirements described in Section 7 of Part I of these Rules and establish the relevant responsibilities and detailed requirements for quality assurance. The person in charge of the blood collection/testing facility and the authorized person of the fractionation company (medicinal product manufacturer) must participate in the preparation of such an agreement. To confirm that the blood collection/testing facility is complying with the terms of such agreement, the authorized person must ensure that appropriate audits are carried out.

2.6. Special documentation requirements and other arrangements for starting materials for plasma-derived medicinal products are indicated in the main plasma dossier.

3. Quality management

3.1. Quality management should cover all stages from donor selection to delivery of finished products. Applicable traceability requirements should be met prior to delivery of plasma to the fractionation facility and during delivery itself, as well as all stages associated with the collection and testing of donated blood or plasma intended for the production of medicinal products.

3.2. The collection of blood or plasma that is used as a raw material for the production of medicinal products should be carried out in blood collection/testing facilities, and testing should be carried out in laboratories that implement quality systems that meet current requirements, are appropriately authorized by an authorized body, and are subject to regular inspection in accordance with current legislation. If the manufacturer has fractionation programs under contracts for third countries, he is obliged to notify the authorized body about this.

3.3. If plasma is imported from third countries, it should only be supplied by approved suppliers (e.g. blood collection/testing facilities, including external warehouses). These suppliers must be specified in the feedstock specifications established by the fractionation/manufacturing facility and approved by the competent authority (for example, after inspection), as well as by the authorized person of the fractionation facility in the Russian Federation. Section 6.8 of this Annex describes the evaluation and authorization of plasma (fractionation plasma) as a feedstock.

3.4. The fractionator/finished product manufacturer must qualify suppliers, including auditing them, in accordance with written procedures. Suppliers should be regularly requalified using a risk-based approach.

3.5. The fractionator/finished product manufacturer must enter into written agreements with the blood collection/testing facilities that are suppliers.

Each such agreement must reflect, at a minimum, the following aspects:

Definition of duties and responsibilities;

Requirements for the quality system and documentation;

Donor selection criteria and testing;

Requirements for blood separation into blood components and plasma;

Plasma freezing;

Plasma storage and transportation;

Traceability and information after blood donation/collection (including side effects).

The drug fractionator/manufacturer must have test results available for all raw material units supplied by the blood collection/testing facility. In addition, any stage performed under subcontract must be provided for in a written contract.

3.6. An appropriate change control system must be established to plan, evaluate and document all changes that may have an impact on product quality, safety or traceability. The potential impact of proposed changes must be assessed. The need for additional testing or validation should be determined, particularly during the virus inactivation and removal steps.

3.7. To minimize the risks associated with infectious agents and new infectious agents, adequate security measures must be implemented. Such a system should include a risk assessment to:

Determine the holding time for production stock (internal quarantine time) before processing plasma to remove doses that are in doubt (doses taken during the period specified by law before it is determined that doses taken from high-risk donors should have been excluded from processing, for example due to a positive test result);

Consider all aspects related to virus reduction and/or testing for infectious agents or their analogues;

Determine virus reduction opportunities, feedstock batch sizes, and other significant aspects of the manufacturing process.

4. Ptraceabilityand activities after blood collection

4.1. There should be a system in place that allows traceability from the donor to the dose collected at the blood collection/testing facility and onwards to the batch of the medicinal product and vice versa.

4.2. Responsibility for product traceability must be defined (the absence of any stage is not allowed):

From the donor and the dose taken at the blood collection/testing facility to the fractionation facility (this is the responsibility of the person in charge at the blood collection/testing facility);

From the fractionator to the manufacturer of the medicinal product and any subcontractor, regardless of whether it is the manufacturer of the medicinal product or medical device (this is the responsibility of the authorized person).

4.3. Data required for full traceability must be stored for at least 30 years, unless otherwise provided by law.

4.4. The agreements specified in paragraph 3.5 of this Annex between blood collection/testing facilities (including reference laboratories) and the fractionator/manufacturer must ensure that traceability and post-collection activities cover the entire chain from plasma collection to all manufacturers responsible for issuing permission to produce finished products.

4.5. Blood collection/testing facilities must notify the fractionator/manufacturer of any incident that may affect the quality or safety of the product, as well as other important information obtained after accepting a donor or authorizing the release of plasma, such as feedback information (information obtained after blood collection). If the fractionator/manufacturer is located in another country, the information should be reported to the manufacturer located in the Russian Federation responsible for issuing the drug product authorization. In both cases, such information, if relevant to the quality and safety of the finished product, must be brought to the attention of the authorized body in charge of the fractionator/manufacturer of medicinal products.

4.6. In the event that the result of the inspection by the authorized body of the blood collection/testing facility is the cancellation of the existing license/certificate/permit, notification must also be given as specified in paragraph 4.5 of this Appendix.

4.7. Standard operating procedures should describe the management of information obtained after blood collection, and should take into account licensing requirements and procedures for reporting to competent authorities. It is necessary to take appropriate measures after blood collection, which are established by legal requirements.

5. Premises and equipment

5.1. To minimize microbial contamination or the introduction of foreign material into the plasma batch, thawing and pooling of plasma units should be carried out in areas that meet the minimum cleanliness class D requirements set out in Appendix 1 of these Regulations. Appropriate clothing, including face masks and gloves, should be worn . All other operations with open products during the technological process should be carried out under conditions that satisfy the relevant requirements of Appendix 1 of these Rules.

5.2. In accordance with the requirements of Annex 1 of these Regulations, regular monitoring of the production environment should be carried out, especially during the opening of plasma containers, as well as during the thawing and combining processes. Acceptance criteria must be established.

5.3. When manufacturing medicinal products derived from donated plasma, appropriate methods for inactivating or removing viruses must be used and appropriate measures must be taken to prevent contamination of processed products with unprocessed products. For process steps that occur after viral inactivation, dedicated separate rooms and equipment should be used.

5.4. To avoid introducing risks of contamination of ongoing production with viruses used during validation tests, validation of virus reduction methods should not be performed using production technology. Validation in this case should be carried out in accordance with the relevant regulations.

6. Production

Feedstock

6.1. The starting raw materials must comply with the requirements of the State Pharmacopoeia of the Russian Federation, as well as satisfy the conditions contained in the relevant registration dossier, including the main plasma dossier. These requirements must be set out in a written agreement (see paragraph 3.5 of this Appendix) between the blood collection/testing facility and the fractionator/manufacturer. They should be controlled through a quality system.

6.2. Feedstock for fractionation programs under contract for third countries must meet the requirements specified in paragraph 2.4 of this Appendix.

6.3. Depending on the type of collection (eg, whole blood collection or automated apheresis), different processing steps may be required. All processing steps (eg, centrifugation and/or separation, sampling, labeling, freezing) must be specified in written instructions.

6.4. Any mix-up of units and specimens should be avoided, especially during labeling, as well as any contamination, such as when cutting off tubing segments/capping containers.

6.5. Freezing is a critical step in the release of proteins that are labile in plasma, such as clotting factors. Therefore, freezing should be performed using validated methods as soon as possible after blood collection. In this case, it is necessary to adhere to the requirements of the State Pharmacopoeia of the Russian Federation.

6.6. The conditions for storing and transporting blood or plasma to the fractionation facility must be defined and documented at all stages of the supply chain. Any deviations from the specified temperature should be notified to the fractionation facility. Equipment that has been qualified and procedures that have been validated must be used.

Evaluation/authorization for release of fractionation plasma used as feedstock

6.7. Authorization for the release of plasma for fractionation (from quarantine) can only be done through systems and procedures that ensure the quality necessary for the production of the finished product. Plasma may only be supplied to the fractionator/manufacturer upon documentation by the responsible person (or, in the case of blood/plasma collection in third countries, a person with equivalent responsibilities and qualifications) that the plasma to be fractionated complies with the requirements and specifications set out in the relevant written contracts, and also that all stages were carried out in accordance with these Rules.

6.8. The use of all plasma containers for fractionation upon entry into the fractionation facility must be authorized by an authorized person. The authorized person must confirm that the plasma complies with all the requirements of the pharmacopoeial monographs of the State Pharmacopoeia of the Russian Federation, and also satisfies the conditions of the relevant registration dossier, including the main dossier of the plasma, or, in the case of using plasma for fractionation programs under a contract for third countries, all the requirements, specified in paragraph 2.4 of this Appendix.

Plasma Processing for Fractionation

6.9. The stages of the fractionation process vary depending on the product and manufacturer. They typically involve various fractionation/purification steps, and some of these may assist in inactivation and/or removal of possible contamination.

6.10. Requirements for pooling, pooled plasma sampling, fractionation/purification and virus inactivation/removal processes should be established and strictly adhered to.

6.11. Methods used in the viral inactivation process should be performed in strict adherence to validated procedures. These methods should be consistent with the methods that were used to validate viral inactivation procedures. A thorough investigation of all failed viral inactivation procedures should be performed. Adherence to a validated process is particularly important in virus reduction procedures, as any deviations may pose safety risks to the finished product. Procedures must be in place to address these risks.

6.12. Any reprocessing or reprocessing may only be carried out after quality risk management measures have been carried out and only at certain stages of the process, as specified in the relevant registration dossier.

6.13. There should be a system for clearly separating/distinguishing between medicinal products or intermediates that have undergone virus inactivation/removal procedures and those that have not.

6.14. Depending on the outcome of a thorough risk management process (taking into account possible differences in epidemiological data), production on a production cycle basis may be permitted where plasma/intermediates of different origins are processed in the same facility, including the necessary clear segregation procedures and the availability of established validated cleaning procedures. Requirements for such activities should be based on relevant regulations. The risk management process should decide whether special equipment needs to be used in the case of fractionation programs contracted to third countries.

6.15. For intermediates intended for storage, a shelf life should be established based on stability data.

6.16. Requirements for the storage and transportation of intermediates and finished medicinal products at all stages of the supply chain must be established and documented. Equipment that has been qualified and procedures that have been validated should be used.

7. Quality control

7.1. Requirements for testing for viruses or other infectious agents should be established taking into account new knowledge about infectious agents and the availability of validated test methods.

7.2. The first homogeneous pool of plasma (for example, after separation of cryoprecipitate from the plasma pool) should be monitored using validated methods with appropriate sensitivity and specificity in accordance with the relevant pharmacopoeial monographs of the State Pharmacopoeia of the Russian Federation.

8. Issuance of permission to release intermediate

and finished products

8.1. The release of only batches produced from plasma pools that were found to be negative for virus markers/antibodies as a result of control and also found to comply with the requirements of pharmacopoeial articles of the State Pharmacopoeia of the Russian Federation (including any special limits limiting the content of viruses) and approved specifications (eg plasma master dossier).

8.2. The issuance of permission for the release of intermediate products intended for further processing within the enterprise or delivery to another enterprise, as well as the issuance of permission for the release of finished medicinal products must be carried out by an authorized person in compliance with the requirements of the approved registration dossier.

8.3. The authorized person must issue a permit for the release of intermediate or finished products used for fractionation programs under contract for third countries, based on the standards agreed with the customer, as well as in accordance with the requirements of these Rules. If such medicinal products are not intended for use in the Russian Federation, the requirements of pharmacopoeial articles of the State Pharmacopoeia of the Russian Federation may not apply to them.

9. Storage of plasma pool samples

9.1. One pool of plasma can be used for the production of several batches and/or drugs. Control samples of each plasma pool and associated records should be retained for less than one year beyond the expiration date of the medicinal product obtained from that pool with the longest shelf life of all medicinal products obtained from that plasma pool.

10. Waste disposal

10.1. There should be written procedures for the safe storage and disposal of waste, disposable and discarded materials (e.g., contaminated items, items from infected donors, and expired blood, plasma, intermediates, or finished medicinal products), which should be documented.

Appendix 15

QUALIFICATION AND VALIDATION

Principle

1. This Annex describes the qualification and validation principles applicable to the manufacture of medicinal products. This Regulation requires manufacturers to determine what validation work is necessary to demonstrate control of critical aspects of their specific operations. Significant changes made to premises, equipment and processes that may affect product quality must be validated. A risk-based approach should be used to determine the scope and scope of validation.

Validation planning

2. All validation activities should be planned. The key elements of the validation program should be clearly defined and documented in the master validation plan or equivalent documents.

3. The master validation plan should be a summary document written in a concise, precise and clear manner.

4. The master validation plan should contain, as a minimum, the following information:

a) the purpose of the validation;

b) an organizational chart for the validation activities;

c) a list of all facilities, systems, equipment and processes to be validated;

d) documentation form: the form to be used for minutes and reports;

5. For large projects, it may be necessary to develop separate master validation plans.

Documentation

8. Upon successful completion of qualification, formal written approval must be issued to proceed to the next stage of qualification and validation.

Qualification

Project qualification

9. The first element of validating new premises, systems or equipment is design qualification.

10. It is necessary to demonstrate and document the project’s compliance with the requirements of these Rules.

Installation qualification

11. Installation qualifications should be performed for new or modified facilities, systems and equipment.

12. The installation qualification must include (but not be limited to) the following elements:

a) checking the installation of equipment, piping, auxiliary systems and instruments for compliance with applicable technical drawings and specifications;

b) assessing the completeness and collation of the supplier's operating and operating instructions and maintenance requirements;

c) assessment of calibration requirements;

d) checking the materials used in the structures.

Operational qualification

13. Functional qualification must follow installation qualification.

14. Performance qualification should include (but not be limited to) the following elements:

a) tests based on knowledge of processes, systems and equipment;

b) testing the operation of the equipment at operating parameters equal to the upper and lower permissible limits, that is, under “worst case” conditions.

15. Successful completion of performance qualification should facilitate the finalization of calibration, operating and cleaning instructions, operator training, and preventative maintenance requirements. This will allow for formal acceptance of premises, systems and equipment.

Performance Qualification

16. Performance qualification is carried out after successful completion of installation qualification and operation qualification.

17. Performance qualifications should include (but not be limited to) the following elements:

a) tests using actual starting materials and materials used in production, selected substitutes with similar properties or a simulator, developed on the basis of knowledge of the process, and of technical means, systems or equipment;

b) tests at operating parameters equal to the upper and lower permissible limits.

18. Although performance qualification is considered as a separate stage of work, in some cases it is advisable to carry it out together with performance qualification.

Qualification of installed (used) technical means, premises and equipment

19. It is necessary to have data justifying and confirming the compliance of critical operating parameters with the specified requirements. In addition, instructions for calibration, cleaning, preventive maintenance and operation, as well as operator training and reporting, should be documented.

Process Validation

General requirements

20. The requirements and principles summarized in this Annex apply to the production of dosage forms. They cover the initial validation of new processes, subsequent validation of changed processes and revalidation.

22. Facilities, systems and equipment used must be qualified and analytical test procedures validated. Personnel involved in the validation must be appropriately trained.

23. Periodic assessments of premises, systems, equipment and processes should be carried out to ensure they are operating in accordance with specified requirements.

Prospective Validation

24. Prospective validation should include (but not be limited to) the following elements:

a) a brief description of the process;

b) a list of critical process steps to be examined;

c) a list of premises/equipment used (including measuring/control/recording equipment) with information on their calibration;

d) specifications for finished products upon release;

e) if necessary, a list of analytical procedures;

f) proposed production process control points and acceptance criteria;

g) if necessary, additional tests to be performed, together with acceptance criteria and validation of analytical methods;

h) sampling plan;

i) methods for recording and evaluating results;

j) roles and responsibilities;

k) expected work schedule.

25. Using an established process (using components that meet specifications), a number of batches of finished products can be produced under normal conditions. In theory, the number of production runs performed and observations made should be sufficient to allow the normal degree of variability and trends to be established and the necessary amount of data to be obtained for evaluation. To validate a process, it is considered sufficient to perform three consecutive series/cycles in which the parameters are within specified limits.

26. The batch size for validation should be equal to the batch size for industrial production.

Related Validation

28. In exceptional cases, it is allowed to begin mass production before the completion of the validation program.

29. The decision to conduct accompanying validation must be justified, documented and approved by persons entitled to do so.

30. Documentation requirements for concomitant validation are the same as those specified for prospective validation.

Retrospective Validation

31. Retrospective validation can only be carried out for well-established processes. It is not permitted if changes have recently been made to the composition of the product, technological process or equipment.

32. Retrospective validation of such processes is based on historical data. This requires the preparation of a special protocol and report and a review of previous operation data with the issuance of a conclusion and recommendations.

33. Data sources for such validation should include, but are not limited to: batch production and packaging records, production control charts, maintenance logs, personnel change data, process capability studies, finished product data, including including a trend map, as well as the results of studying its stability during storage.