Rules of proper production practice Ministry of Industry and Communist Party 916. Legal base of the Russian Federation

On approval of the rules for adequate production practice(Registered in the Ministry of Justice of Russia 09/10/2013 №29938)

• 
  Site Administration Note: We did not post the full text of the order, if you wish, it is easy to find a consultant on the website. About preparations for clinical studies we are talking only in Appendix 13.

Appendix N 13.

to the proper rules

industrial practice
Medicinal preparations for clinical studies
I. Principle
1. Medicinal preparations for clinical studies must be made in accordance with theseRules and taking into account the provisions of the relevant regulatory legal acts of the Russian Federation, depending on the development stage of the drug. Methods of work must be flexible to ensure the possibility of making changes as knowledge of the process is expanded, and must respond to the development stage of the drug.

2. In clinical studies, additional risks may arise for patients involved in them compared with risks for patients who take registered drugs.

3. Application of presentRules The production of the studied drugs is aimed at eliminating risks for patients, as well as to ensure that the results of clinical studies did not affect insufficient safety, the quality or efficacy of the drug, which are a consequence of its inappropriate production.

4. Inconsider, these requirements are intended to ensure constancy from the series to a series of one and the same studied drug used in one or in different clinical studies, as well as for documentary and justify changes in the process of developing such a drug.

5. The production of the studied drugs is associated with additional complexity compared with the production of registered drugs due to the lack of established procedures that exist differences in clinical research schemes and, as a result, different packaging requirements, the need for randomization and coding (masking, using "blind "Methods), as well as due to the risk of cross-contamination and the confusion of drugs. In addition, the data on the efficacy and toxicity of the drug may be incomplete, the process validation may be incomplete or registered drugs that were repaled or in some way modified. The manufacturer's staff should take preparation for the use of thisRules For the studied drugs. Cooperation should be established with sponsors of clinical studies, which are responsible for organizing clinical studies, including the quality of the studied drugs. The increased complexity of technological processes requires the use of a highly efficient pharmaceutical quality system.

6. This Annex also has established requirements for issuing orders, shipping, transportation and refund of drugs intended for clinical studies.
Medicinal preparations that are not studied
7. Patients may be provided with drugs that are not studied drugs, placebo or comparison drugs. Such drugs can be used as concomitant therapy or to provide medical care In order to prevent, diagnose or treatment, and (or), due to the need to provide patients with medical care. Such drugs are also allowed to be applied in accordance with the Clinical Study Protocol in order to stimulate the physiological response. These drugs are not under investigation drugs and can be provided by a sponsor or researcher. The sponsor must ensure that these drugs comply with the application for issuing a permit for clinical research and have the quality required for the purpose of the study. At the same time, he must take into account the source of drugs, whether such drugs are registered and whether they were repacked. It is recommended to attract an authorized person to this work and take into account his opinion.
Licensing of production and preparation for use
8. both full production and separate production stages of the studied drugs, as well as various processes of their separation, packaging, or transmission them are subject to licensing. The license for medicines is not required to prepare for the use of studied drugs in medical organizations.

9. As part of these provisions, a simple process is understood under the preparation for use, such as:

dissolution or dispersion of the drug test for its introduction to the patient or

dilution or mixing of the studied drugs (CO) preparations (A) with another substance (substances) used as a carrier in order to introduce a drug.

10. Mixing a few ingredients together, including the active ingredient, in order to obtain the examined drug is not a preparation for use.

11. The test drug must be in stock before the preparation process.

12. The preparation process is recommended immediately before administration.

13. Such a process should be set forth in a statement on issuing a permit for a clinical study and (or) the dossier of the drug under study and a clinical research protocol either in the relevant instructions available in a medical organization.
II. TERMS AND DEFINITIONS
14. For the purposes of this Annex, the following basic concepts are used:

dossier for a drug - a set of documents containing all the information (or references to the relevant documents) necessary to compile detailed instructions in production, packaging, quality control, issuing permission to issue a series and shipment of the drug under study;

order - Task for production, packaging and (or) delivery of a certain number of units of the studied drugs (CO) drugs (A);

the importer of the drug under study is a person who has the right to import the examined drug, decorated in accordance with the regulatory legal acts Russian Federation;

researcher - individualBecause of the responsibility for conducting a clinical study in a medical organization. In the case of a study in a medical organization by a group of persons, the researcher (also called the main researcher) is the leader of the Group;

the drug under study is a drug or placebo, studied or used as a preparation comparison during a clinical study. The underlying drugs also include already registered drugs, if the method of their use or production (dosage form or packaging) differs from the registered, as well as if they are not yet approved by testimony or for more information about the already registered dosage form;

a clinical study is any study conducted with the participation of a person as a subject to identify or confirm the clinical, pharmacological and (or) other pharmacodynamic effects of the studied drug (s) and (or) to identify unwanted reactions to it ( them), and (or) to study its (their) suction, distribution, metabolism and derivation in order to assess its (s) security and (or) efficiency;

shipment - packaging operations for shipment and transportation of ordered drugs;

the preparation of comparisons is the test drug or a registered drug (for active control) or placebo used for comparison when conducting clinical studies;

the randomization code is a list that allows you to establish what therapy with each patient receives, taking into account randomization;

randomization is the process of distribution of patients in groups of treatment or control randomly, allowing to minimize subjectivity;

"Blind" method ("masking") - method, when using one or more Parties involved in the study, are not informed about the (s) therapeutic (their) appointment (appointments). The simple "blind" method means the admission of the patient (s), and the double "blind" method is the ignorance of the patient (s), researchers (s), observers and in some cases), the researcher (s); analyzing the data obtained. With respect to the test drug "Blind", the method means a deliberate disguise to the identity of this drug in accordance with the directorials of the sponsor. Code disclosure (dismantling) means disclosure of information that allows you to identify a previously disguised drug;

sponsor - a legal entity that organizes a clinical study of the drug for medical use.
III. QUALITY CONTROL
15. (1) A pharmaceutical quality system developed and tested by the manufacturer must comply with the requirements of thisRules Related to the drugs under study should be documented and accessible by the sponsor.

16. (2) Specifications and technological instructions on the studied drugs may vary in the process of their development, but it is necessary to ensure their full control and traceability of all changes.
IV. STAFF
17. (3) All personnel whose activities are associated with the drugs under study must undergo appropriate training associated with the specifics of this type of product.

18. Even in cases where the staff is not a few, for the production of each series of studied drugs, a separate personnel responsible for production and quality control should be determined.

19. (4) The authorized person must ensure the availability of relevant systems that meet the requirements of this Annex. For this, an authorized person must have proper training in the development of drugs and clinical studies. Guide for authorized person According to the evaluation of the studied drugs, it is given inparagraphs 61 - 65 of this application.
V. Premises and equipment
20. (5) When working with drugs under study, information on toxicity, activity and sensitizing properties may be incomplete, in connection with this, the manufacturer should pay particular attention to minimizing the risks of cross-contamination. The design of equipment and premises, methods of testing and control, as well as the limits of permissible concentrations of residues after cleaning, should take into account the nature of the specified risks. In appropriate cases, the manufacturer should pay attention to the organization of work by production cycles (campaigns). When choosing a detergent, it is necessary to take into account the solubility of the drug for clinical studies.
Vi. DOCUMENTATION
Specifications and instructions
21. (6) Specifications (on source raw materials, primary packaging materials, intermediate products, non-Fasted and finished products), regulations, technological instructions and packaging instructions should be so complete as the existing level of product knowledge. In the course of the development of a drug, they must be periodically evaluated and updated (if necessary). Each new version must be taken into account the latest data currently used technology, requirementsState Pharmacopoeia Russian Federation and regulatory legal acts of the Russian Federation. A new version It should also contain a reference to the previous version to ensure the traceability of changes. The manufacturer must approve the procedure for making any changes that may affect the quality of the drug under study, in particular, on its stability and bioequivalence.

22. (7) Justles for making changes should be documented. The manufacturer must analyze the effect of changes made on the quality of the drug under study and on conducted clinical studies. The results of such an analysis must be documented.
Order
23. (8) The order must contain a requirement for production and (or) packaging of a certain number of products and (or) its shipment. The manufacturer is sent by the sponsor or face acting on his instructions. Order must be decorated on paper and (or) in in electronic format And be quite clear to avoid discrepancies. The order must be approved by a person who has appropriate authority, and have a reference to a dossier on a drug and on the protocol of clinical studies.
Drug dossier
24. (9) Dossier on the drug should be continuously updated as the drug is developed. At the same time, the manufacturer must ensure traceability of previous versions of the drug dossier.

25. Dossier on the drug should include, in particular, the following documents (or contain links to them):

specifications and analytical techniques for feedstock and packaging materials;

specifications and analytical techniques for intermediate, non-fraud and finished products;

technological instructions;

control methods in the production process;

approved copy of the label;

protocols of clinical studies and, in appropriate cases, randomization codes;

contracts with performers specified inparagraphs 237 - 255 of these rules (if necessary);

stability data;

storage and transportation conditions.

26. The above list of documents may vary depending on the drug and the stage of its development. The information contained in the dossier should serve as a basis for evaluating the readiness for acceptance and issuing permission to issue a particular series by an authorized person who should have access to such information. If different stages of the production process are carried out on different siteswhere the responsibility carry different authorized persons is allowed to conduct separate files with limited informationrelated to activities in the respective sites.

federal Service for Veterinary and Phytosanitary Supervision

This section contains topical versions of regulatory acts (laws, orders, decrees, decisions. Supreme Court RF, etc.), of interest to specialists in the field of veterinary and phytosanitarian.

You can get more information by asking the question in the "Electronic Reception" section.

Order of the Ministry of Industry and Commission of Russia of June 14, 2013 No. 916

"On approval of the rules for organizing production and quality control of medicines"

The rules for organizing production and quality control of medicines come into force upon expiration of 10 days from the date of their official publication.

Drugs, Ministry of Industry

Order of the Ministry of Industry and Commission 916 from 14062013

• Order of the Ministry of Industry and Trade of the Russian Federation of June 14, 2013
  Order of the Ministry of Industry and Trade of the Russian Federation dated June 14, 2013 No. 916 "On approval of the rules for organizing production and quality control of medicines"
  Registered in the Ministry of Justice of the Russian Federation on September 10, 2013 Registration No. 29938

In accordance with Part 1 of Article 45 Federal Law dated April 12, 2010 No. 61-FZ "On the circulation of medicines" (meeting of the legislation of the Russian Federation, 2010, No. 16, Art. 1815, No. 26, Art. 3446) and subparagraph 5.2.18.31 of paragraph 5 of the Regulation on the Ministry of Industry and Trade of the Russian Federation, approved by Decree of the Government of the Russian Federation dated June 5, 2008 No. 438 (Meeting of the legislation of the Russian Federation, 2008, No. 42, Art. 4825; 2009, № 3, Art. 378, No. 6, Art. 738, No. 11 , Art. 1316, No. 25, Art. 3065, No. 26, Art. 3197, No. 33, Art. 4088; 2010, No. 6, Art. 649, No. 9, Art. 960, No. 26, Art. 3350, No. 31, Art. 4251, No. 35, Art. 4574, No. 45, Art. 5854; 2011, No. 43, Art. 6079, No. 46, Art. 6523, No. 47, Art. 6653, 6662; 2012, No. 1, Art. 192, No. 43, Art. 5874, 5886; 2013, No. 5, Art. 392) I order:
1. To approve the accompanying rules for organizing production and quality control of medicines.
2. Control over the execution of this order leaves for itself.

Denis Manturov: The demand for Russian weapons in the world is constantly growing

Denis Manturov: For most Russians, the quality of products is more important than the price

Software, man or "iron"? Interview with Denis Manturova According to the results of "Innoproma 2018"

Denis Manturov: enterprises will be expected by VAT in case of export of their products

On Amendments to the Commission on the Certification of the heads of federal state unitary enterprises under the jurisdiction of the Ministry of Industry and Trade of the Russian Federation, as well as the powers of the founder and the owner of the property of which the Federal State Budgetary Institution "National Research Center" Institute named after N.E. Zhukovsky ", approved by the Order of the Ministry of Industry and Trade of the Russian Federation of October 20, 2016 No. 3729

On Amendments to the Order of the Ministry of Industry and Trade of the Russian Federation of October 26, 2016 No. 3806

Legislative base of the Russian Federation

Free consultation

Federal legislation

• the main
• Order of the Ministry of Industry and Commission of the Russian Federation of 06/14/2013 N 916 "On approval of the rules for organizing production and quality control of medicines"
• At the time of inclusion in the database, the document was not published

Documentation and recording (6)

375. (6.10) All documents related to the production of intermediate products or FS must be compiled, check, assert and distribute in accordance with the procedures approved by the manufacturer. Such documents may be decorated both in writing and electronically.

376. (6.11) Issue, revision, replacement or removal of all documentation should be monitored with the preservation of information about their previous versions.

377. (6.12) The manufacturer must organize a storage system of all documents (for example, reports on the development, scaling reports, reporting reports, process validation reports, records for training, records for production, documents for monitoring and registering records) with By specifying the timing of storage of such documents.

378. (6.13) All records for production, control and implementation must be stored at least 1 year after the expiration date of the series. Entries containing FS repeat test data should be kept at least 3 years after the full implementation of the series.

379. (6.14) Records must be performed by indelible ink in the places specifically provided for this immediately after performing operations; The person who has made a record must be designated. Corrections in the records must be signed with the loss of the date. Such corrections should not prevent reading the recording in its original form.

380. (6.15) During the storage period, originals or copies of records must be easily accessible at the production site, where the works described in these records were carried out. It is also allowed to quickly receive entries from other storage sites using electronic or other means.

381. (6.16) Specifications, instructions, procedures and records can be stored either in the original or in the form of copies, such as photocopies, microfilms, microfosses, or other forms of accurate playback of original records. If the methods for reducing the original, for example, microfilming, or electronic records, must have appropriate reading equipment, as well as means for manufacturing printed copies.

382. (6.17) The manufacturer should develop and arrange documented specifications for feedstock, intermediate products (if necessary), FS and marking materials and packaging. Additionally, the specification may be needed on some other materials (for example, auxiliary materials, gaskets) used during the production of intermediate products or FS, which can be critical for quality. It is necessary to establish and document the sustainability criteria for control in the production process.

383. (6.18) if used electronic signatures On documents, they must be identified and protected.

384. (6.20) in the uses, cleaning, sanitary processing and (or) sterilization, and the maintenance of the main equipment must be indicated by the date, time (if necessary), the name of the product, the number of each series produced on this product equipment, as well as The person who conducted cleaning and maintenance.

385. (6.21) No compilation of individual cleaning and equipment cleaning records are required if it is specifically designed for the production of one name of the intermediate or FS and a series of this intermediate or FS are produced in a traceable sequence. In cases of using specially designed equipment for recording it, maintenance and operation can be either part of a series of dossier or a separate document.

386. (6.30) It is necessary to record on the feedstock, intermediate products, packaging materials, materials for marking FS, containing the following data:

the name of the manufacturer, identification and the amount of each delivery of each series of raw materials, intermediate products or packaging materials and materials for marking FS;

supplier name; Supplier Control Number (if known) or other identification number; the number assigned to the acceptance and acceptance date;

the results of all tests or checks and the conclusions made on their basis;

recordings in which the use of materials is monitored;

documentation for assessing and verifying packaging materials and materials for the marking of the FS for compliance with the established specifications;

the final decision relative to rejected raw materials, intermediate products or packaging materials and materials for marking FS.

387. (6.31) The manufacturer must store the approved label samples to compare with them of the manufactured labels.

388. (6.40) To ensure homogeneity from the series to the manufacturer's series, the manufacturer must develop industrial regulations for each type of FS, which are approved by the manufacturer's head, and are independently checked, signed by the person from the quality entrusal of the date. Based on industrial regulations, technological instructions are developed for each stage of the technological process and (or) for each type of intermediate products that are signed by one person with an affixation of the date, as well as are independently checked, signed by the person from the quality unit with an affilution of the date. Industrial Regulation includes a list of materials used indicating the number of each of them, data on the equipment used, a description of the technological process and control methods at all stages of FS production. General requirements for the structure and other requirements for the content of industrial regulations are established by the relevant regulatory legal acts of the Russian Federation.

389. (6.41) Technological instructions should include:

the name of the output of intermediate products or the FS and the stage of the process, as well as, if applicable, the corresponding document code;

a complete list of initial raw materials and intermediate products with an indication of the names or codes, sufficiently specific in order to identify and identify any special quality characteristics;

accurate indication of the amount or ratio of each name of the source used raw materials or intermediate products with an indication of the measurement units. If such a quantity is not fixed, then it is necessary to calculate the calculation for each size of the series or the process mode. It is also necessary to indicate deviations from these quantities if they are justified;

the place of implementation of the technological process and the main technological equipmentwhich is used;

detailed technological actions, including:

the sequence that must be followed;

used range parameter ranges;

instructions on sampling and control in the production process with an indication of acceptability criteria when necessary;

the limit deadlines for the completion of individual stages of the technological process and (or) the whole process as a whole, when necessary;

expected product output ranges at the respective stages of the process or at a certain time;

special instructions and precautionary measures that must be followed, or corresponding cross references to them when necessary;

instructions for the storage of intermediate products or FS to ensure their suitability for use, including packaging material and marking material, as well as special conditions storage with the deadlines when it is advisable.

390. (6.50) For each intermediate and the FS, a dossier on a series of products must be prepared, which includes full information about the production and quality control of each series. The issued form for making registration records must comply with the technological instruction and be an urgent version. If the form for making records for the production of the series is compiled on the basis of a separate part of the technological instruction, this document must contain a reference to the current technological instruction.

391. (6.51) Molds for making entries should be numbered with a specific number of the series or identification number, as well as signed with the loss of the date when issuing. In case of continuous production, the product code, as well as the date and time of the release, can serve as unambiguous identifiers before assigning the final number of the series.

392. (6.52) In a series of products (records for the production and control of quality) of products, after completion of each important technological stage, the following information must be specified:

date and where applicable time;

basic equipment used (for example, reactors, dryers, mills);

specific identification of each series, including mass, units of measurement, number of episodes of raw materials, intermediate products, or any materials that have been repeated processed during production;

registered actual results of critical process parameters;

data on any sample selection;

signatures of persons who performed every critical stage during operation, as well as carried out direct supervision or verification;

test results in the process of production and laboratory testing;

actual output at the respective stages or at a certain time;

description of packaging and marking for intermediate products or FS;

sample label for FS or intermediate products if they are produced for sale;

any noticeable deviation, its assessment, information on the investigation carried out (if necessary) or reference to such an investigation, if the relevant documents are stored separately;

the results of control when issuing permission to issue.

393. (6.53) The manufacturer must develop and approve the procedures to comply with the investigation of critical deviations or in the inconsistency of the series of intermediate products or the FS of their specifications. Such an investigation should be distributed to other series to which the inconsistency or deviation data could be related.

394. (6.60) Laboratory control documents should include complete information about the data obtained during all tests conducted to confirm compliance with the established specifications and a general pharmacopoeial article, a pharmacopoeia article, regulatory documentation or regulatory document, including research and quantitative definitions, namely:

description of the samples obtained for testing, including the name of the source raw material, the sampling site, the number of the series or other characteristic code, the sampling date and, where applicable, the amount of the sample presented for testing and the date of its receipt;

description of each method of testing or reference to such a method;

specifying the mass of the sample or other units of measurement for the sample used for each test, in accordance with the method described; data on the preparation and testing of standard samples, reagents and standard solutions or corresponding cross references;

full records of all the source data obtained during each test, in addition to the graphs, tables and spectra obtained by laboratory devices, properly identified for a particular substance and series subjected to the test;

records of all calculations made in connection with testing, including units of measurement, recalculation coefficients and equivalence factors;

statement of test results and their compliance with the established acceptability criteria;

signature of the person who conducted each test, and the date (dates) of their conduct;

the date and signature of the person indicating that the originals of the records were tested for accuracy, completeness and compliance with the established requirements.

395. (6.61) It is also necessary to maintain full records indicating:

any changes to the established analytical techniques;

periodic calibration of laboratory equipment, devices, measuring instruments and registering devices;

all FS tests for stability;

investigations of deviations from specifications.

396. (6.70) To determine the conformity of intermediate products or FS, established specifications before issuing a resolution of the release of the series or before it is implemented, procedures must be developed to follow when reviewing and approving the production and laboratory control records, including packaging and labeling.

397. (6.71) Records for the production of episodes and laboratory control of critical stages of the process are subject to verification and confirmation by the unit (divisions) of quality before issuing permission to issue or before implementing each FS series. Records for the production and laboratory control for non-critical stages of the process can be checked by qualified personnel of the production unit or other units in accordance with the procedures approved by the Division (divisions) of quality.

398. (6.72) All deviations, reports on investigations and deviations of results from specifications should be assessed in the process of reviewing a dossier on a series before issuing permission to issue this series.

399. (6.73) Division (divisions) of quality may (may) transfer the production unit of obligations and authority regarding the issuance of permission to use intermediate products except when the products are intended for delivery beyond the scope of the manufacturer's control.

Adopted: June 14, 2013 (N 916 of 14.06.2013)

Reproduction of materials is allowed only if the restrictions established by the copyright holder, when specifying the author of the materials used and references to the "Pharmaceutical Bulletin" as a source of borrowing, with a mandatory hyperlink to the site www.pharmvestnik.ru.

Restrictions and prohibitions for playing site materials:

1. Materials posted on the website www.pharmvestnik.ru (hereinafter referred to as the "Site"), with respect to which the right holder has limited reproduction restrictions:

• access to which only subscribes are available on the site;
• any materials published in the printed version of the newspaper, and containing the mark "Published in the newspaper issue";
• all site materials reproduced in any way, in addition to distributing on the Internet.

On the use of materials in respect of which these restrictions are established, in obligatory The written consent of the copyright holder is required - Bionics Media LLC.

1. reproduction of materials of other copyright holders (the user must solve the issues of legitimate distribution of those without the involvement of Bionics Media LLC);
2. the use of extracts from the materials under which the context changes, the excerpts are acquired by an ambiguous character or intact shade, as well as any processing of material;
3. commercial use of materials, i.e. The use of a defined material selected on the site (its fragment) in order to commercially implement the right to access such material or the provision of rights to such to third parties.

Order of the Ministry of Industry and Commission of Russia F N 916 of 14.06.2013

Document Adoption Date: June 14, 2013

Props: N 916 dated 06/14/2013

Order of the Ministry of Industry and Commission of Russia F N 916 dated June 14, 2013 "On approval of the rules for organizing production and quality control of medicines".

4. Order of the Ministry of Justice of the Russian Federation of June 16, 2017 No. 108 "On Amendments to the Forms of Register Registry notarial action, notarial evidence, certificate inscriptions on transactions and evidence of documents and in the procedure for forming forms [...]
5. Order No. 477n dated 04.05.2012 Approval of the list of states under which the first assistance is provided and the list of first-aid activities is registered in the Ministry of Justice of the Russian Federation on May 16, 2012 Registration number 24183 in accordance with Article 31 [...]
6. Fines for violation of traffic rules In Armenia in June of this year, the opposition in Armenia presented its requirements in 12 points to the authorities, who mainly concerned the improvement of the social conditions of citizens. Among them, a separate item required to revise the current [...]
7. Order of the Ministry of Internal Affairs of the Russian Federation of April 27, 2012 N 373 "On approval of the administrative regulations of the Ministry of Internal Affairs of the Russian Federation on the provision of a state service for issuing a citizen of the Russian Federation for storage and wearing [...]
8. Certification of jobs Question: Good afternoon. In February 2013, the certification of jobs for companies that have only offices have been canceled. I have contradictory information: Some lawyers tell me that attestation of jobs to hold [...]
9. Decree of the Government of the Russian Federation of August 16, 2013. N 712 "On the procedure for conducting waste I - IV hazard classes" Decree of the Government of the Russian Federation of August 16, 2013 N 712 "On the procedure for conducting waste of waste I - IV hazard classes" O [...]
10. Bogorodsky-Shchelkovo.rf Forum inhabitants of the microdistrict "Bogorodsky", Shchelkovo return taxes when buying housing Go to page: Message Matvey »27 Mar 2015, 10:26 Re: Tax Return when buying housing Message SVV777» 12 May 2015, 21: 32 R2D2 [...]

This text is edited in the admin in the section "Texts"

Order of the Ministry of Industry and Trade of the Russian Federation of June 14, 2013 N 916

• Order of the Ministry of Industry and Trade of the Russian Federation of June 14, 2013 N 916 "On approval of the rules for organizing production and quality control of medicines"
  Registered in the Ministry of Justice of the Russian Federation on September 10, 2013 Registration N 29938

  In accordance with part 1 of Article 45 of the Federal Law of April 12, 2010 N 61-FZ "On the treatment of medicines" (Meeting of the legislation of the Russian Federation, 2010, N 16, Art. 1815, N 26, Art. 3446) and subparagraph 5.2 .18.31 of paragraph 5 of the Regulation on the Ministry of Industry and Trade of the Russian Federation, approved by the Decree of the Government of the Russian Federation of June 5, 2008 N 438 (Meeting of the Legislation of the Russian Federation, 2008, N 42, Art. 4825; 2009, N 3, Art. 378, N 6, Art. 738, N 11, Art. 1316, N 25, Art. 3065, N 26, Art. 3197, N 33, Art. 4088; 2010, N 6, Art. 649, N 9, Art. 960 , N 26, Art. 3350, N 31, Art. 4251, N 35, Art. 4574, N 45, Art. 5854; 2011, N 43, Art. 6079, N 46, Art. 6523, N 47, Art. 6653, 6662; 2012, N 1, Art. 192, N 43, Art. 5874, 5886; 2013, N 5, Art. 392) Orders:
  1. To approve the accompanying rules for organizing production and quality control of medicines.
  2. Control over the execution of this order leaves for itself.

Rules of organization of production and quality control of medicines (appliance. Order of the Ministry of Industry and Trade of the Russian Federation of June 14, 2013 N 916)

I. General provisions

II. Terms and Definitions

III. Basic requirements for the organization of production and quality control of medicines

IV. Basic requirements for pharmaceutical substances used as feedstock

• Introduction (1)
• Quality management (2)
• Personnel (3)
• Buildings and premises (4)
• Technological equipment (5)
• Documentation and recording (6)
• Work with baseline raw materials (7)
• Technological process and control in the production process (8)
• Packaging and Identifying Marking pharmaceutical substances and intermediate products (9)
• Storage and implementation (10)
• Laboratory control (11)
• Validation (12)
• Monitoring changes (13)
• Deviation and reuse of materials (14)
• Claims and reviews (15)
• Production under the contract (including laboratories) (16)
• Organizations carrying out repacking and (or) stirring (17)
• Special Guide for Pharmaceutical Substances, produced by cultivating cells or fermentation (18)
• Pharmaceutical substances intended for clinical studies (19)
• Terms and definitions (20)

Annexes to the rules of the organization of production and quality control of medicines

Appendix No. 1 Production of sterile drugs

• I. Principle
• II. General requirements
• III. Classification of clean rooms and clean zones
• IV. Monitor clean premises and clean zones
• V. Insulating technology
• Vi. Technology "blowing - filling - sealing"
• VII. Products subjected to finishing sterilization
• VIII. Aseptic production
• IX. Staff
• X. Premises
• Xi. Equipment / XII. Sanitary treatment
• XIII. Technological process
• XIV. Sterilization
• XV Thermal sterilization / XVI. Steam sterilization
• XVII. Drake sterilization / XVIII. Radiation sterilization
• XIX. Sterilization of ethylene oxide
• XX. Filtering drugs that cannot be sterilized in the final packaging
• XXI. Ending the process of production of sterile products
• XXII. Quality control

Appendix No. 2 Production of biological (including immunobiological) pharmaceutical substances and drugs

• I. Scope
• II. Principle
• III. General Guide (Part A)
• IV. Special guide for individual types of products (part B)
• V. Terms and definitions

Appendix №3 Production of radiopharmaceutical drugs

• I. Principle
• II. Introduction
• III. Quality assurance / IV. Staff
• V. Premises and equipment
• Vi. Documentation / VII. Production
• VIII. Quality control
• IX. Control and archive samples / X. Implementation / XI. Terms and Definitions

Appendix No. 4 Features of the production of medicines for veterinary use (except immunobiological medicines for veterinary use)

Appendix No. 5 Features of the production of immunobiological medicines for veterinary use

Appendix No. 6 Medical Gas Production

• I. Principle
• II. Gas production as pharmaceutical substances
• III. Production of medical gases
• IV. Terms and Definitions

Appendix No. 7 Production of medicinal plant preparations

• I. Principle
• II. Rooms and equipment
• III. Documentation
• IV. Quality control

Appendix №8 Sampling of samples of raw materials and packaging materials

• Application text

Appendix No. 9 Production of liquids, creams and ointments

• Application text

Appendix No. 10 Production of dosage aerosol drugs under pressure for inhalations

• Application text

Appendix No. 11 Computerized Systems

• I. Principle
• II. General requirements
• III. Stage of the Project
• IV. Stage of operation
• V. Terms and definitions

Appendix №12 The use of ionizing radiation in the manufacture of drugs

• I. Introduction
• II. Responsibility / III. Dosimetry
• IV. Process validation
• V. Entering commissioning
• Vi. Premises
• VII. Technological process
• VIII. Documentation
• IX. Microbiological control

Appendix №13 Medicinal preparations for clinical studies

• I. Principle
• II. Terms and Definitions
• III. Quality management / IV. Personnel / V. Premises and equipment
• Vi. Documentation
• VII. Production
• VIII. Quality control
• IX. Issuance of the release permit
• X. Transportation / XI. Claims
• XII. Reviews and returns / XIII. Destruction

Appendix №14 Production of drugs obtained from donor blood or plasma

• I. Terms and definitions
• II. Scope (1)
• III. Principles (2)
• IV. Quality management (3)
• V. Traceability and events held after taking blood (4)
• Vi. Premises and equipment (5)
• VII. Production (6)
• VIII. Quality control (7) / IX. Issue permission to release intermediate and finished products (8) / X. Storage of plasma pool samples (9) / xi. Waste Removal (10)

Appendix №15 Qualification and Validation

• I. Principle / II. Validation planning
• III. Documentation / IV. Qualification
• V. Process validation
• Vi. Cleaning Validation / VII. Control of change
• VIII. Repeated Validation / IX. Terms and Definitions

Appendix №16 Confirmation by an authorized face of compliance with a series of products to issue it

• I. Scope / II. Principle
• III. Introduction
• IV. General requirements
• V. Conducting tests and release of a series of products produced in the Russian Federation
• Vi. Responsibilities of an authorized person
• VII. Terms and Definitions

Appendix number 17 issue by parameters

• I. Principle / II. Release by parameters / III. Release by parameters for sterile products
• IV. Terms and Definitions

Appendix №18 Control and Archive Samples

• I. Scope
• II. Principle
• III. Storage duration / IV. Number of control and archival samples
• V. Storage conditions / VI. Agreements
• VII. Control samples. General provisions
• VIII. Archive samples. General provisions

not entered into force Editorial 14.06.2013

Order of the Ministry of Industry and Commission of the Russian Federation of 06/14/2013 N 916 "On approval of the rules for organizing production and quality control of medicines"

Appendix 1. Production of sterile drugs

I. Principle

1. Special requirements are made to the production of sterile drugs in order to minimize the risk of contamination with microorganisms, particles and pyrogens. These provisions depend on the qualifications of production personnel, its training and attitudes towards work. To ensure quality in the production of sterile preparations, it is necessary to adhere to the carefully developed and validated methods of production and procedures. The final stage of production or control of finished products is not the only means of providing sterility or other product quality indicators.

2. Detailed methods for determining the purity of air, surfaces and other monitoring facilities over microorganisms and particles are determined by the regulatory legal acts of the Russian Federation.

3. (1) Sterile products must be made in pure zones, access to personnel and (or) flow of equipment, source raw materials and packaging materials should be carried out through air gateways. In clean rooms (zones), the level of cleanliness corresponding to the corresponding level of purity must be maintained, they must be supplied to air, which passed through the filters of the corresponding efficacy.

4. (2) Different operations for the preparation of components, preparation of products and filling should be carried out in separate areas (rooms) inside the net zone (premises). Technological operations are divided into two categories: the first when the products are subjected to finish sterilization (in the primary packaging), and the second when operations on several or all stages are performed in aseptic conditions.

5. (3) Clean zones (rooms) for the production of sterile products are classified in accordance with the required characteristics of the production environment. Each production operation requires a certain level of purity of the production environment in an exploited state in order to minimize the risk of contamination by particles or microorganisms of the product or processed raw materials and materials.

6. To ensure compliance with the requirements in the "exploited" state, pure zones (premises) must be designed to ensure exactly a certain level of air purity in a "equipped" condition.

7. "Equipped" condition is a condition in which the clean room is built and functions, the technological equipment is fully equipped, but the staff is absent.

8. "Operated" condition is a condition in which the clean room and technological equipment function in the required mode with a given number of working personnel.

9. Requirements for "equipped" and "exploited" states must be established for each clean room or complex clean rooms.

10. Pure zones (premises) in the production of sterile drugs are divided into four classes:

Class A - Local Area for conducting operations representing a high risk for product quality, in particular, zones of filling, capping, zones, where ampoules and vials are in the open state and compounds of equipment parts in aseptic conditions are performed. As a rule, such conditions are provided with a laminar air flow in the workplace. Laminar air flow systems should ensure uniform air velocity in the range of 0.36 - 0.54 m / s ( regulatory value) On the working surface located in an open pure zone. Maintaining laminarity should be proven and raised. In closed insulators and boxes with gloves, it is allowed to use a unidirectional air flow with lower speeds;

Class B - zone directly surrounding the class A zone, intended for aseptic preparation and filling;

classes C and D - Clean zones for performing less critical stages of production of sterile products.

11. (4) Clean rooms and clean zones are classified<*>. Confirmation of the purity class must be clearly separated from the monitoring of the production environment during the process. The maximum allowable concentration of aerosol particles for each class is shown in Table N 1.

Table N 1.

12. (5) For classification purposes in class A zones, the minimum amount of the selected air sample must be at least 1 m3 for each sampling point. Class A corresponds to the ISO 4.8 class in terms of the maximum number of particles in the air of 5.0 μm.

Class B (in the equipped state) by the number of aerosol particles corresponds to the ISO 5 class by the number of particles of both dimensions.

The C (in the equipped and operated states) in the number of aerosol particles corresponds to the ISO 7 and ISO 8 class, respectively.

The class D (in the equipped state) by the number of aerosol particles corresponds to the ISO 8 class.

To confirm the class of cleanliness, the technique is applied<*>in which the minimum number of sampling points are regulated and the size of the samples, taking into account the limits of this class, for the number of particles of the largest of these sizes, as well as the method of evaluating the data obtained.

<*> Reference: GOST R ISO 14644-1 (EN ISO 14644-1).

13. (6) To confirm class, it is necessary to use portable particle counters with short tubes for sampling due to a relatively high level of particle sedimentation with a size of 5.0 μm in remote systems for sampling with long tubes. In the case of unidirectional air flow systems, isokinetic nozzles for sampling should be used.

14. (7) Class confirmation in the exploited state is permissible to carry out during operation or in modeling operating operations, or when filling with nutritional environments, as required by modeling the situation in which the extremely mimic permissible parameters conducting the technological process with the most adverse factors and conditions (hereinafter - the worst case)<*>.

<*> Reference: Instructions for conducting tests To confirm the permanent compliance with the specified class of cleanliness, are given in the standard GOST R ISO 14644-2 (EN ISO 14644-2).

15. (8) It is necessary to carry out the current monitoring of clean rooms and clean zones during their operation. Sampling points for current monitoring are chosen based on the analysis of risks and results obtained in the classification of clean rooms and (or) clean zones.

16. (9) For class A zones, particle monitoring should be carried out continuously throughout the critical process, including equipment assembly. With proper justification, the exclusion is processes using pollutants that may damage the particle counter or constitute a danger, in particular, living organisms or radiological hazards. In such cases, monitoring should be carried out during the usual operations to set up equipment until the risk appear. It is also necessary to monitor during modeling operations. In class A zones, monitoring should be carried out at such a frequency and with this volume of the parameters of the samples, so that all interventions can be fixed, random events and any damage to the system, and in the event of a warning limit, lift the alarm. Directly at the fill site it is not always possible to demonstrate low levels of particles of 5.0 μm in the filling process due to the formation of particles or droplets from the product itself.

17. (10) It is recommended that the same system be used for class B zones, although the sampling rate may be less. The importance of the particle monitoring system should be determined by the separation efficiency between the ranges of classes A and B. In class B zones, monitoring should be carried out at such a frequency and the corresponding volume of the samples, so that you can fix the changes in the level of contamination and any deterioration in the system operation, and in the case Alarm levels could be taken by emergency measures.

18. (11) Systems for monitoring aerosol particles may consist of independent particle counters, from a system of sequentially located sampling points attached by pipeline to one particle counter, or combine these two approaches. When choosing control systems, the requirements for particle size should be taken into account. When using remote sampling systems, it is necessary to consider the length of the tubes and the bending radii of the tubes, taking into account the possibility of sedimentation of particles in the tubes. When choosing a monitoring system, it is also necessary to consider any risk emanating from the materials used in the process, for example, the presence of living microorganisms or radioactive drugs.

19. (12) when used automated system The current monitoring of the size of the samples depends, as a rule, from the sampling rate of the system used. The volume of samples at the current monitoring may differ from the sample volume when qualifying clean rooms and clean zones.

20. (13) In class A and b zones, monitoring of particles 5.0 μm particle concentration is of particular importance, since it is an important diagnostic tool for early detection of inconsistencies. Sometimes indicators of the number of particles of 5.0 μm particles may be erroneous due to electron noise, extraneous light, a random coating of circumstances and other factors. However, if the meter sequentially and systematically registers a small number of particles, this indicates the possibility of contamination, which requires an investigation. Such cases can be in advance to indicate the malfunction of the ventilation and air conditioning system, installation of filling or indicate a violation of the rules during equipment setup or its operation.

21. (14) The permissible amount of particles for the equipped state specified in the table must be achieved after a short period of purification of 15 to 20 minutes (regulatory value) in the absence of personnel after completing the work.

22. (15) Monitoring the C and D zones in the exploited state should be carried out in accordance with the principles of risk management for quality. The requirements for the level of anxiety and the level of action will depend on the nature of the operations performed, but in any case the recommended value of the "cleaning period" should be reached.

23. (16) Other indicators, such as temperature and relative humidity, depend on the production and nature of the operations performed. These parameters should not affect the set of purity standards.

24. (17) Examples of operations that should be performed in zones with different purity classes are shown in Table N 2, as well as in paragraphs 35 - 42 of this Annex.

Table N 2.

25. (18) When performing aseptic processes, microbiological monitoring should be constantly carried out using sedimentation and aspiration methods of air sampling, sampling from the surfaces with a wash with a tampon and with the use of contact plates. Sampling methods used in the exploited state should not harm the protection of the zone. The monitoring results should be taken into account when reviewing a series of a series for issuing permits for the production of finished products. After performing critical operations it is necessary to monitor surfaces and personnel. Additional microbiological monitoring is also carried out outside the technological process, in particular, after validation of systems, cleaning and disinfection.

Table N 3.

27. (20) The corresponding limits must be installed on the results of monitoring of particles and microorganisms: the level of anxiety and the level of action. In operating procedures, corrective actions should be described in case of exceeding these limits.

28. (21) The use of insulating technology minimizes human intervention in production zones, as a result of which the risk of microbial contamination of products produced in aseptic conditions is significantly reduced from the production environment. There are many types of insulators and transfer devices. The insulator and its components must be designed in such a way that in the appropriate zone the necessary air quality was provided. Insulators made from different materials are largely or less susceptible to insulation and depressurization. Transmission devices can be different: from structures with a single or double door to completely sealed systems, including devices for sterilization.

29. (22) The transfer of materials inside and outward isolator is one of the largest potential sources of contamination. Typically, the space inside the insulator is a limited area for conducting operations representing high risks for product quality. At the same time, it is assumed that in the working area of \u200b\u200ball such devices there may be no laminar flow of air.

30. (23) Requirements for air purity in the environment surrounding the insulator depend on the design of the insulator and its purpose. The purity of this medium must be controlled, and for aseptic production, it must correspond to at least a class of purity D.

31. (24) Insulators can be put into operation only after carrying out the appropriate validation. Validation should take into account all the critical factors of insulating technology, in particular, the quality of air inside and outside the insulator, the order of disinfection of the insulator, the transmission processes and the integrity of the insulator.

32. (25) It is necessary to conduct continuous monitoring, which includes frequent tests of the seal of the insulator and the nodes of the Gloves - Sleeves.

33. (26) The device "blowing - filling - sealing" is a device of a special design, where in the same automatic complex for one continuous technological cycle of thermoplastic granulate, packaging is formed, which are filled with the product and sealed. The device "blowing - filling - sealing" used in aseptic production and having a class A zone with an effective air flow can be established at least in the class C zone, subject to the use of clothing used in zones for classes a and (or) B. The production environment in the equipped state must comply with the established standards for particles and microorganisms, and in the exploited state - only in microorganisms. The device "blowing - filling - sealing" used in the production of products to be finished sterilization must be installed at least in the class D Class D.

34. (27) Given the features of this technology, it is necessary to pay special attention to:

construction and qualifications of equipment;

validation and reproducibility of "cleaning in place" and "sterilization in place";

Pure room space, which is an industrial environment for equipment placed there;

training operators and their clothing;

Actions in the critical zone of equipment, including the execution of connections and assembly in aseptic conditions before starting.

35. (28) Preparation of primary packaging components and other materials and the production of most types of products should be carried out in production environmentAt least class D to ensure a sufficiently low level of contamination risks by particles and microorganisms suitable for filtering and sterilization. If microbial contamination represents high or special risks for products (in particular, when the products are a good nutrient medium for the growth of microorganisms or its sterilization precedes a long period of time, or the process is carried out for the most part in open containers), preparation should be carried out in the class production environment C.

36. (29) Filling products to be finished sterilization should be carried out in a production environment for at least C.

37. (30) With an increased risk of product contamination from the production environment, in particular, if the filling operations pass slowly or packaging are widely throat, or they must be kept open more than a few seconds before sealing, the filling should be carried out in the class A area with the environment, At least class C. Preparation and packaging of ointments, creams, suspensions and emulsions Before finishing sterilization, it is usually necessary to implement in the Class C production environment.

38. (31) Operations with primary packaging components and other materials after washing should be carried out in an industrial environment, at least class D. Processing of sterile raw materials and components, if there is no sterilization or sterilizing filtering, it is necessary to exercise in the working area Class A with a class B production medium.

39. (32) Preparation of solutions that are subject to sterilizing filtering during the technological process, should be carried out in the Class C production environment. If the sterilizing filtering is not carried out, the preparation of materials and production of products should be carried out in the class A working area with the class A production medium.

40. (33) The processing and filling of products prepared in aseptic conditions must be carried out in the class A working area with the class B production medium.

41. (34) Transfer (transportation) not finally clapped primary packaging with products, for example, lyophilized, until the closure process is completed, it is necessary to carry out or in the class A zone located in the class B production environment, or in sealed gear containers in the class B industrial environment .

42. (35) Preparation and filling of sterile ointments, creams, suspensions and emulsions must be carried out in the class A zone in a class B production environment if the products are in open containers and is not subjected to sterilizing filtering.

43. (36) In pure zones, it is allowed to find only the minimum needed number of personnel, which is especially important for aseptic production. Checks and control operations, subject to availability, should be carried out by being beyond clean zones.

44. (37) All personnel (including personnel engaged in cleaning and maintenance), working in such zones, should be regularly trained on the proper production of sterile products, including hygiene issues and microbiology bases. If there is a need for extraneous persons who have not passed such training (for example, the construction workers or equipment approvals) were in a clean room, then the specified persons must undergo detailed instructions and the strict observation should be established for them.

45. (38) Entrance to the area of \u200b\u200bsterile production of personnel working with raw materials from animal tissues or cultures of microorganisms, which are not used in the current technological process, is allowed only if the personnel complies with the established entry procedures.

46. \u200b\u200b(39) It is necessary to comply with personal hygiene and purity. Personnel engaged in the production of sterile drugs should be instructed that it is obliged to report any circumstances that may be the reason for the dissemination of unacceptable quantities or types of contaminants; If such circumstances occur, periodic medical inspections employees. The actions that need to be taken with respect to personnel, which can be a source of microbial contamination, should be determined by a specially appointed person with the necessary powers.

47. (40) In pure zones, it is forbidden to wear wristwatches and jewelry, as well as use cosmetics.

48. (41) Change and wash in accordance with the instructions approved by the manufacturer developed in such a way as to minimize the risk of contamination of clothing to work in pure zones or the contribution of contaminants into pure zones.

49. (42) Clothing and its quality must match technological process and class of the working area. It must be worn so as to ensure the protection of products from contamination.

50. (43) Description of the necessary clothing for each class of cleanliness of the room is shown below:

Class D: Hair, as well as beard and mustache (if any) must be closed. It is necessary to wear an ordinary protective suit and appropriate shoes or bootings. Appropriate measures should be taken to prevent any contamination of the net zone from the outside;

class C: Hair, as well as beard and mustache (if available) must be closed. It is necessary to wear a jumpsuit or a trouser suit, a tightly fitting wrist and having a high collar, as well as appropriate shoes or bootings. Fibers or particles should not be separated from clothing and shoes;

Class A / B: The headpiece must completely close the hair, as well as the beard and mustache (if available), and should be inserted into the collar of the costume, on the face it is necessary to wear a mask to prevent the distribution of droplets. It is also necessary to carry appropriately sterilized and non-federated rubber or plastic gloves and sterilized or disinfected shoes. The lower edges of the pantian must be filled with inside the shoes, and the sleeves of the clothes are in the gloves. Protective clothing should not be distinguished by fibers or particles and must delay the particles separated from the body.

51. (44) Street clothing are prohibited to enter into rooms for dressing, which lead to the premises of classes B and C. Each employee in the class A / B region should be provided with a clean sterile (sterilized or appropriate sanitary processing) protective clothing for each working shift . Gloves during operation must be regularly disinfected. Masks and gloves need to be changed at least every shift.

52. (45) Clothes for clean rooms must be cleaned and process in such a way that it subsequently has caused the cause of contamination. These operations must be performed in accordance with the approved instructions. To prepare such clothes, it is desirable to have separate laundries. Incorrect clothing processing damages fabric fibers, which increases the risk of separation of particles.

53. (46) In pure zones, all open surfaces should be smooth, impermeable and intact to minimize the formation and accumulation of particles or microorganisms, and also allow the detergent and, if necessary, disinfectants.

54. (47) To reduce the accumulation of dust and facilitate cleaning in the premises, there should be no deepening cleaning and should be as few as possible edges, shelves, cabinets and equipment. Doors must be designed without rewards, inaccessible to clean, use sliding doors undesirable.

55. (48) Dropped ceilings Must be sealed in order to prevent contaminants from entering over them.

56. (49) Installation of pipelines, air ducts and other equipment must be carried out so that there are no recesses and unlocked holes, as well as there were no surfaces that are not available for cleaning.

57. (50) It is forbidden to install sinks and plums in class A and B zones used for aseptic production. In other zones, it is necessary to provide a break between the equipment and the sewer pipe (funnel). Streams in the floor in clean rooms with a lower class of purity should be provided with siphons or hydraulic assets to prevent reverse stream.

58. (51) Dressing rooms must be designed as air gateways and should be used to ensure physical separation. different stages Changes of clothing and, thus, to minimize the contamination of protective clothing with microorganisms and particles. They should effectively lie with filtered air. The zone before going out of the room (room) for dressing in the equipped state should have the same class of purity as the zone in which it leads. In some cases, it is advisable to have separate rooms (premises) to enter clean zones and exit. As a rule, hand washing devices should only be at the beginning of the dressing room.

59. (52) Both air gateway doors cannot be opened at the same time. To prevent simultaneous opening more than one door, a blocking system or a visual and (or) sound warning system should operate.

60. (53) The filtering air supply must maintain a positive drop of pressure on production zones with a lower class under all operating conditions, and the airflow should effectively contend the zone. Related premises with different classes of purity should have a difference in a pressure of 10 - 15 Pa (regulatory value). Special attention should be paid to the protection of the area of \u200b\u200bthe greatest risks for product quality, that is, a production environment, the direct influence of which products or purified components in contact with the products are subjected. Different options are allowed for air supply and pressure drops that may be required due to the presence of some materials, in particular, pathogenic, highly toxic, radioactive or living viruses or bacterial materials, or drugs from them. For some operations, decontamination of premises and equipment and air treatment, removed from the pure zone, may be needed.

61. (54) It is necessary to confirm that the direction of air flows does not represent risks for the contamination of the product, including it is necessary to make sure that the area representing the greatest risks for the quality of the product, the particles are not received with air flow, the sources of allocation of which are attendants, Performed operation or equipment.

62. (55) A emergency alert system should be provided to failure a ventilation system. If the pressure difference between two rooms is critical, it is necessary to establish pressure drop sensors. Pressure drop values \u200b\u200bmust be recorded regularly or decompat in a documenor.

63. (56) It is not allowed that through a septum separating the class A or b from the production zone with a lower purity of the air condition, the conveyor tape, except when the tape itself is subjected to continuous sterilization (for example, in a sterilization tunnel).

64. (57) Equipment, fittings (connections) and service areas are recommended to design and install in such a way that work with equipment, its maintenance and repair can be carried out outside the clean zone. If sterilization is needed, it must be carried out after the maximum full of equipment assembly.

65. (58) If the maintenance of the equipment was carried out inside the net zone and the necessary requirements of purity and (or) asepsis were broken during this work, the zone must be cleared, disinfected and (or) is sterilized (depending on what is suitable ) Before renewing the process.

66. (59) Installations for the preparation of water and the distribution system should be design, design and operate so as to ensure reliable provision of appropriate quality water. They cannot be operated in excess of design power. Water for injections should be made, stored and distributed in such a way as to prevent the growth of microorganisms, for example, due to its constant circulation at temperatures above 70 ° C.

67. (60) All equipment, such as sterilizers, air processing and filtering systems, air and gas filters, processing systems, obtain, storage and water distribution must be subject to validation and planned maintenanceAnd on their reinstalling commissioning should be issued permission to the person with the appropriate authority.

68. (61) Sanitary treatment of clean areas has especially important. Zones must be carefully cleaned in accordance with the manual approved by the manufacturer. In the case of disinfection, several types of disinfectants should be applied. To identify the development of resistant strains of microorganisms it is necessary to carry out regular control.

69. (62) Detergents and disinfectants must be monitored with respect to microbiological purity. Their solutions must be kept in pre-purified containers (containers) and stored only throughout the deadlines, with the exception of those solutions that are sterilized. Detergents and disinfectants used in classes zones A and B must be sterile before use.

70. (63) Fuligation of pure zones may be useful to reduce microbial contamination in inaccessible places.

71. (64) At all stages of production, including in the stages preceding sterilization, it is necessary to take measures to minimize contamination.

72. (65) The production of medicines of microbiological origin or filling them in the zones used for the production of other medicines is not allowed. Vaccines containing killed microorganisms or bacterial extracts, after inactivation can be packaged in the same rooms as other sterile medicinal products.

73. (66) The validation of the processes carried out under aseptic conditions should include modeling of the process using a nutrient medium (filling with nutrient media). The nutrient medium must be selected taking into account the dosage form of the drug, as well as the selectivity, transparency, concentration and suitability of the nutrient medium for sterilization.

74. (67) Process modeling should most accurately imitate the serial process of aseptic production and include its consecutive critical stages. It is also necessary to take into account various interventions that may arise during a conventional production process, as well as the situation of the "worst case".

75. (68) Process modeling at initial validation should include three consecutive satisfactory tests for each change of operators. In the future, they must be repeated through the established intervals, as well as after any significant change in the ventilation system and air conditioning, in the equipment, process or number of shifts. Modeling testing process must be repeated twice a year for each change of operators and each process.

76. (69) The number of containers (primary packages) intended for the packaging of nutrient media should be sufficient to ensure a reliable assessment. In the case of small series, the number of containers for packing nutrient media should, at a minimum, correspond to the size of the product series. It is necessary to strive for the lack of growth of microorganisms, and the following norms are subject to use:

A) if less than 5,000 units of products were filled, there should be no contaminated unit;

B) if filled from 5,000 to 10,000 units of products, then:

one (1) The contaminated unit is the basis for investigating the causes and re-packing of nutrient media;

two (2) contaminated units - the investigation of the causes and re-validation is carried out;

c) if more than 10,000 units were filled, then:

one (1) The contaminated unit is the basis for investigating causes;

two (2) Contamined units - the investigation of the causes and re-validation is carried out.

77. (70) With any number of primary packages with a nutrient medium, periodic cases of microbial contamination detection may indicate the presence of small levels of contaminants, which should be investigated. When a significant microbial contamination is detected, it is necessary to consider the possible effect on the sterility of the series released after the last successful tested with nutritional media.

78. (71) It is necessary to ensure the conditions under which any validation does not create a risk for technological processes.

79. (72) Sources of water supply, equipment for water preparation and prepared water are subject to regular monitoring for the presence of chemical and biological contaminants and necessary cases on endotoxins. The results of monitoring and any actions undertake must be documenting.

80. (73) In pure zones, especially during the process of aseptic production, staff activities should be minimal, and its movement should be measured and controlled to avoid excessive separation of particles and microorganisms caused by increased motor activity. The temperature and humidity of the environment should be not very high to not create discomfort, taking into account the properties of the clothing used.

81. (74) The microbial contamination of the initial raw materials and materials should be minimal. Specifications on them should include requirements for microbiological cleanliness.

82. (75) In pure zones, it is necessary to minimize the availability of containers and materials, from which the separation of fibers is possible.

83. (76) It is necessary to take measures to prevent the contamination of finished products by particles.

84. (77) At the end of the process of cleaning components, containers and equipment with them, it is necessary to do so that there is no re-contamination.

85. (78) The time intervals between the washing, drying and sterilization of components, containers and equipment, as well as between their sterilization and subsequent use must be minimal and have a time limit corresponding to storage conditions.

86. (79) The time between the beginning of the preparation of the solution and its sterilization or sterilizing filtering should be minimal. For each type of products, it is necessary to establish the maximum time-allowed time, taking into account its composition and the established storage order.

87. (80) Before sterilization, it is necessary to control the level of microbial contamination. The working boundaries of contamination should be installed immediately before sterilization that correlate with the efficiency of the method used. The level of microbial contamination must be quantified for each series of both products filled in aseptic conditions and products subjected to finish sterilization. If for drugs subjected to finish sterilization, more stringent sterilization parameters are installed, the microbial contamination level can be monitored only at the corresponding time intervals according to the graph. When using output systems by parameters, the determination of microbial contamination must be carried out for each series and viewed as a test in the production process. If necessary, the level of endotoxins should be monitored. All solutions, especially large-volume infusion fluids, must be subjected to sterilizing filtering as well as possible before filling.

88. (81) Components, containers, equipment and any other items necessary in a clean zone, especially when working in aseptic conditions, must be schecked and transmitted there through the passage sterilizer mounted in the wall to the wall with bilateral access or otherwise preventing contamination. Non-combustible gases should pass through filters, delaying microorganisms.

89. (82) The effectiveness of any new process must be confirmed when validation, which must be repeated regularly in accordance with the plan that takes into account the operation schedule, as well as with any significant change in the process or equipment.

90. (83) All sterilization processes must undergo validation. Special attention is necessary if the applied sterilization method is not described in State Pharmacopee Of the Russian Federation or is used for a product that is not a simple aquatic or oil solution. The thermal sterilization method is preferred. In any case, the sterilization method must comply with production licenses and a registration dossier.

91. (84) Before choosing any sterilization process, it is necessary to demonstrate with physical measurements and, if possible, biological indicators that it is suitable for this product and is effective for achieving required conditions Sterilization in all parts of each type of loading. The validation of the process must be repeated through the intervals established by the schedule, but at least once a year, and also in the case of significant changes in equipment. It is necessary to store entries with results.

92. (85) For effective sterilization, the entire material as a whole should be subjected to the necessary processing, and the process is organized in such a way as to ensure that due efficiency will be achieved.

93. (86) All sterilization processes should be developed and must undergo validation of the boot methods.

94. (87) The use of biological indicators should be considered only as an additional method of controlling sterilization. Biological indicators must be stored and used in accordance with the manufacturer's instructions, and their quality is controlled by the methods of positive control. In the case of using biological indicators, it is necessary to take strict measures to prevent microbial contamination from the indicators themselves.

95. (88) Measures must be clearly defined, ensuring the separation of products that have passed and not lasting sterilization. On each basket, a tray or other capacity for products or components should be a clear label with the name of the material, the number of the series and the indication, it passed sterilization or not. If necessary, such indicators as an autoclave tape can be used to indicate whether the series (or part of the series) was sterilized, but they do not provide reliable confirmation of whether the series is really sterile.

96. (89) For each sterilization cycle, it is necessary to constitute entries to be approved as part of the issuance of the issue permit.

97. (90) Each thermal sterilization cycle must be recorded as a diagram in the coordinates of the time-temperature at a fairly large scale or be registered using other relevant equipment that has the necessary correctness and accuracy. The location of the temperature sensors used to control and (or) record must be determined during validation and, if necessary, also verified using another independent temperature sensor, located in the same place.

98. (91) It is allowed to use chemical and biological indicators, but they should not replace physical measurement.

99. (92) A sufficient time must be provided for the entire loading amount reached the required temperature before the sterilization time is started. This period should be defined for each type of sterilized loading.

100. (93) After completion of the high-temperature phase of the thermal sterilization cycle, precautions should be taken, preventing contamination of sterilized loading during cooling. Any cooling fluid or gas in contact with the products must be schecked, except when the possibility of using non-grid packages is excluded and appropriate evidence.

101. (94) When sterilizing steam, it is necessary to control the temperature and pressure. It is recommended that the controls are independent of controls and recording devices. If automatic control and control systems are used for this purpose, they must pass validation to ensure their compliance with the requirements for the critical process. Violations during the process should be registered by the system and be under the supervision of the operator. During the process of sterilizing the readings of an independent temperature sensor, it is necessary to constantly check with the data of the recorder diagram. For sterilizers that have stock in the bottom of the chamber, it may be necessary to register temperature at this point during the entire sterilization cycle. If the sterilization cycle includes the evaporation stage, then it is necessary to regularly check the chamber for tightness.

102. (95) Sterilized items that are not in hermetic packages should be wrapped in air and steam material, but preventing these items preventing these objects after sterilization. It is necessary to ensure the contact of all parts of the load with a sterilizing agent at a given temperature and time.

103. (96) It is necessary to ensure that the sterilization is applied for a proper quality pairs that do not contain such a number of impurities that could cause contamination of products or equipment.

104. (97) In case of dry sterilization, air circulation should be provided inside the chamber and maintaining an overpressure to prevent non-sterile air into it. Any air coming inside should pass through high efficiency filters (HEPA filter). If sterilization provides for the elimination of pyrogens, then as part of the validation must be carried out with the deliberate use of endotoxins.

105. (98) Radiation sterilization is mainly used for sterilizing heat-sensitive materials and products. Many drugs and some packaging materials are sensitive to ionizing radiation, therefore, this method is permissible only when it was experimentally confirmed by the absence of harmful effects on products. As a rule, irradiation with ultraviolet radiation is not an acceptable method of sterilization.

106. (99) During the sterilization process, the absorbed dose of ionizing radiation should be measured. To do this, use dosimeters whose readings do not depend on the radiation dose power used, but which provide a quantitative registration of the radiation dose absorbed by the products itself. Dosimeters must be placed among the download in sufficient quantities and at sufficiently close range from each other to ensure the presence of dosimeters in all places exposed to irradiation. Plastic dosimeters should be applied only within the validity period of their calibration. Dosimeter readings must be removed for a short period of time after irradiation.

107. (100) as a means additional control Biological indicators can be used.

108. (101) Validation procedures should ensure that the influence of different density of stacking sterilized products is taken into account.

109. (102) The procedures for handling materials should prevent confusion between irradiated and unwired materials. Each packaging should be caused by radiation-sensitive color indicators in order to distinguish the packages that have passed and past exposure.

110. (103) The total absorbed dose of radiation should be typed over the time allotted to the sterilization process.

111. (104) This method can be used only when it is impossible to use another method. During the validation of the process, there should be proven that there is no damaging effect on the products, and the conditions provided for the degassing and the time are such that the amount of residual gas and the reaction products will be in the permissible limits set for this type of product or material.

112. (105) Immediate contact between gas and microorganisms is essential. Precautions must be taken from the inclusion of microorganisms into the material (for example, in crystals or dried protein). The view and number of packaging materials can significantly affect the process.

113. (106) Before processing gas, the compliance of humidity and temperature of materials should be ensured by the process requirements. The time required for this should be, if possible, minimal.

114. (107) Each sterilization cycle should be monitored using appropriate biological indicators, the required amount of which should be evenly distributed throughout the download. The information obtained at the same time should be part of the dossier on a series of finished products.

115. (108) For each sterilization cycle, records should be decorated with an indication of the time of the full cycle, pressure, temperature and humidity in the chamber during the process, as well as the concentration and total amount of gas used. Pressure and temperature must be registered throughout the entire cycle on the diagram. These entries should be part of the dossier on a series of finished products.

116. (109) The load after sterilization must be stored under control under ventilation conditions in order to reduce the residual gas content and reaction products to a set limit. This process must pass validation.

117. (110) Conducting sterilizing filtering is not a sufficient condition for sterilization, if it is possible to carry out the sterilization of products in the final packaging. Preferred is the ferry sterilization method. If the products cannot be sterilized in the final packaging, then solutions or liquids can be filtered through a sterile filter with a nominal pore size of 0.22 μm (or less) or through a filter with a similar ability to delay the microorganisms into pre-sterilized containers (packaging). Such filters can delete most bacteria and mold mushrooms, but not all viruses or mycoplasm. Therefore, the possibility of adding the filtering process to the heat treatment of a certain extent should be considered.

118. (111) Due to the fact that during sterilizing filtering compared to other sterilization processes, there is a potential additional risk, immediately before the packaging, re-filtering is recommended via an additional sterilizing filter, which delaying microorganisms. The last sterilizing filtering is necessary to carry out as close as possible to the place of packing.

119. (112) It is necessary to use filters with a minimum separation of fibers.

120. (113) Before using the sterilizing filter and immediately after its use, it is necessary to check its integrity as such as the "point of the bubble" method, by the method of diffusion flow or pressure test. At validation, the time required to filter the solution of the specified volume, and the pressure drop on the filter should be determined. Any significant deviations from the specified parameters during the current production it is necessary to register and explore. The results of these checks must be included in the dossier on a series of products. Immediately after use, it is necessary to confirm the integrity of critical gas and air filters. The integrity of other filters must be confirmed at the appropriate time intervals.

121. (114) It is not allowed to use the same filter for more than one working day, except in cases where the possibility of a longer use is confirmed by validation.

122. (115) The filter should not affect the products, delaying its ingredients or highlighting any substances into it.

123. (116) Partially unpaid vials after the completion of the lyophilic drying should be in the class A zone to their final slapping.

124. (117) Containers (primary packaging) must be evacuated by the relevant ways that have been validated. When using a selection method, for example, glass or plastic ampoules, all products are subject to 100% integrity control. In other cases, product integrity control should be carried out by established methods.

125. (118) The system of slapping bottles filled in aseptic conditions is not completely complete until the bottleneck of the bottle does not compress (sunset) aluminum cap (cover). In this regard, the crimping cap after slapping the plug must be performed as early as possible.

126. (119) Because when burning caps, a large number of mechanical particles may be distinguished, the crimping equipment must be placed separately and equip the air exhaust system.

127. (120) Coupling caps on vials can be carried out as part of aseptic process using sterilized caps or under clean space outside the aseptic zone. In the latter case, the vials must be protected by the class A zone until the aseptic zone is still abandoned, and in the future, the vials baked by traffic jams should be protected by supplying clean air of class A until the caps are fascinated.

128. (121) Bottles without a plug or with a displaced plug, it is necessary to delete before the cap clamp. In the event that a person's intervention is needed when firing a cap, to eliminate direct contact with vials and minimizing microbial contamination, the corresponding technology should be used.

129. (122) Effective tool Protection can be barriers or insulators that limit access to the working area providing the required conditions and minimize direct access to the crimping operation.

130. (123) Primary packages, sealed under vacuum (vacuum packaging), should be checked for preserving a vacuum after a predetermined period of time.

131. (124) Primary packaging with products for parenteral administration must be checked individually (individually) for extraneous inclusions or other quality inconsistencies. Visual control should be carried out at the set levels of illumination and the background of the work field. It is necessary to regularly check the vision of operators performing visual control (if the operators use glasses, then the vision check is carried out in glasses). In the course of visual control of products, it is recommended to quickly organize breaks in the operation of operators. When using other control methods, the control process must be validated, the state of the equipment must be periodically verified. The results of visual control must be documented.

132. (125) Testing ready-made sterility products must be considered only as the final stage in a series of control measures that guarantee sterility. Sterility test technique should be validated for each product.

133. (126) In cases where permission was obtained for the release of sterile products according to the parameters (Appendix N 17 to this Regulation), special attention should be paid to validation and control of the entire technological process.

134. (127) Sampling of products that were selected for testing for sterility must be representative for the entire series and must include samples selected from those parts of the series for which the greatest risk of contamination is expected, in particular:

A) (a) for products filled in aseptic conditions, samples should include containers (primary packaging), which occurred at the beginning and at the end of the production of the series, as well as after any significant intervention;

b) (b) For products that have undergone thermal sterilization in the final packaging, attention should be paid to the selection of samples from the potentially coldest parts of the download.

Appendix N 2.
to the rules of the organization
production and quality control
medicines