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Technological or production documentation within GMP in Russia and in the EAEU

The technological documentation is understood as the documents used in the pharmaceutical industry to produce and record the activities related to the development of specific product series, as well as the technology description included in the drug registration dossier. In this material, the concepts of technology, technological documentation include a recipe, i.e. qualitative and quantitative composition of the series, description of the technological process and equipment used, as well as all related types of quality control in the production of a particular medicinal product.

GMP Documentation - General Considerations

The introduction of GMP rules in some countries was accompanied by criticism of the very concept of GMP from individual experts. In this regard, it was often suggested that all the requirements in this area are to write documents, for the most part unnecessary. Hence the proliferation of humorous deciphering of the reduction of GMP: a great mountain of paper or give more paper [1].

However, the most prominent experts in the field of GMP expressed on this account the opposite opinion. Thus, J. Sharp, the author of the British standard for GMP (the so-called Orange Manual, 1971) later in his textbooks called the documentation a key factor in the work on GMP [2]. According to a number of specialists of the building, equipment, engineering systems, etc. reflect traits of  the production site, and not the work itself on GMP. Documentation is the visible part of the quality system of the enterprise, its supporting structure. The corresponding provisions are also reflected in the Russian GMP rules [3].

Familiarization with the documentation is an important, and sometimes the main part of the surveys according to GMP rules. According to available information, the inspectors of the US regulator (FDA) can spend on this work up to 80% of the time allotted for the inspection of the entire enterprise. In doing so, they are guided by the following principles:

  • Everything that is written down must be done.
  • Everything that's done must be recorded.
  • Undocumented information is just gossip.
  • Documented, but not signed, information on reliability can be compared with the inscription on the fence (graffiti).

Such approaches to inspection have spread to other countries.

Working within the Registration dossier

The most important principle of the modern rules of GMP, incl. Russian, is the conduct of production in accordance with the requirements of registration dossiers for specific drugs (Ch.1 Pharmaceutical Quality System). It should be borne in mind that in international practice, the terms registration dossier, application or materials of the application for registration of the drug, as well as permission to sell a new drug are often used as synonyms. The reason is that if the application is approved, all the materials attached to it (the registration dossier) are considered to be agreed with the regulatory body, otherwise approved by it [It should be clarified that the said above concerns only the final version of the dossier. As you know, during the registration process the applicant often has to supplement or refine the originally submitted materials. Hence, there are differences between the initial (original) dossier and its final version]. The situation with regard to the application for site licensing is similar. Accordingly, the applicant must comply with all the conditions of production and quality control, reflected in the materials of the application for registration of the drug and in the file on the enterprise (on the production site).

According to Ch. 4 Documentation of the EU GMP Guidance Document [4] must be in line with the relevant parts of the drug registration dossier, as well as with the application materials for the licensing of the enterprise. At the same time it is specified that the reproduction of texts in working documents based on the source documentation should be performed by the method excluding errors (Section 4.2). In the Russian GMP Rules, these requirements are reflected too (paragraph 100), but in less clear language.

The close connection of the GMP rules with the drug registration system noted above reflects the current trend of combining separate regulatory mechanisms into a single integrated quality system, the components of which support and strengthen each other. With this in mind, GMP inspections generally verify (on a selective basis) the compliance of the actual production conditions on the site with those described in the registration dossier of the medicinal product. In this case, the registration materials should be answered both by the general description of the technology used (on the industrial schedule, the production recipe and the technological instructions, the master copy of the technology document, etc.) and the documents reflecting the process of producing specific series (records, dossiers on the series).

Russian domestic rules of GMP for documentation contain both new and old benchmarks. On the one hand, in accordance with international experience, all types of documents should comply with registration dossiers (paragraphs 5, 13).

At the same time, in terms of production methods and quality control, the existence of industrial regulations is required (paragraphs 97, 115, 120). This provision, established in the Soviet period, is fixed in the current Russian legislation: 61-FZ, Ch. 45.

Recall that the procedure for the conduct of technological documentation adopted in the USSR was adapted to the conditions of centralized state management of the creation and production of drugs. Industrial regulations, as well as forms used in the production of documents (technological instructions, route maps, operating sheets, etc.) "descended" to enterprises from above as mandatory requirements. The GMP rules were not taken into account, as the industry departments did not recognize them. Practically there was no procedure for registration of drugs in the modern sense of the term. In this regard, the order of admission of new medicines to patients was not linked to the conditions of their production.

As a result, the industrial regulations performed two functions. They described the mandatory procedure for performing all technological, supportive and controlling operations. They also served as source documents, on the basis of which other types of production documentation were compiled at enterprises.

It is obvious that the current situation in the domestic pharmaceutical industry is completely different. First, industrial regulations are not approved by the state. The description of the technology of a new, unregistered drug comes to the production from its developer [Normally, it must be accompanied by a development report or a Technical Transfer Report. Both materials are considered and evaluated by the producers. It is highly desirable that the future producer participate in the development of technology]. Secondly, the industry adopted the GMP rules, harmonized with international standards, in particular, with requirements for documentation.

Thirdly, registration materials of medicinal products compiled in the format of the General Technical Document recognized in Russia in 2013 (section 3.2.Р.3 of Module 3) should contain a sufficiently detailed description of the conditions of production. In accordance with the world practice, if the application is approved, this description acquires a legal status and becomes mandatory for the enterprise.

In other words, at present, the original documentation for the manufacturer is still a description of the conditions of production, obtained from developers in the form of regulations or in some other form, if necessary modified on the site. It is to this text that the description of the production conditions in the application and the documents reflecting the order of development of specific series should correspond. At the same time, from the standpoint of state supervision and control, the status of an official standard is no longer the text, but the section Production of the registration dossier of the preparation.

As noted earlier in the publications [5], the requirements for the content of the product used in the site to describe the production conditions of a particular preparation in the various GMP manuals are almost the same (in Russian rules, these are paragraphs 115 and 116). At the same time, this kind of documents did not receive a single generally accepted term either at the international level or in Russia. In foreign regulations, it can be referred to as the Master formula, Manufacturing formula and processing instructions, Master production and control records. [It should be clarified that the listed terms mean the documentation intended for use on a particular site, unlike the Soviet-style regulations that were often developed for the industry and, therefore, required adaptation in factories]. The Terms of the GMP in the EAEU use the term production recipe and process instructions. For Russian documents, you can suggest, for example, the designation "master file (or master copy) of the technology document."

Note that the term "industrial regulations", used in Order 916, is not suitable for this purpose, since its content is much wider. In accordance with OST 64-02-003-2002 [6] and GOST R 52550-2006 [7], the regulations contain sections that are not related to GMP: safe operation of production, environmental protection, processing and neutralization of industrial waste, economic standards, etc. In view of this, obviously, this term is not used in the rules of the GMP in the EAEU. It should be expected that references to obsolete categories of documents will be removed from domestic GMP standards during their revision and updating. The term instruction (industrial, technological) also can not be considered suitable because it, in accordance with industry standards and established practice, is applied, as a rule, not to the entire production process, but to its part carried out in one area (working place).

Description of technology in the Registration dossier

At first glance, it is not difficult for the manufacturer to fulfill the requirement to work according the registration dossier. To do this, it is sufficient to use the same text as the master file of the technology document and as the description of the Production section in the materials of the application. However, in accordance with the current practice at the world level, in most cases the technological section of the drug registration dossier contains a brief description of the conditions of production due to the exclusion of minor details. This approach has become widespread due to the fact that it meets the interests of both producers and registration authorities.

For the company, this facilitates the post-production changes in the production conditions, since changes relating to elements not reflected in the dossier cannot be coordinated with the regulator. The registration authorities, for their part, do not object by default against such practices. It is easier and more convenient for them to work with shortened applications, since only the main elements of the technology are important for them, allowing to assess its ability to ensure stable quality of products. This means that the principle of work in accordance with the requirements of the registration dossier should not be taken literally.

However, if the description of technology is reduced, it is not always easy to assess the level of significance of the parts being lowered. In this regard, there is a risk of excessive reduction, which can lead to a refusal or delay in the approval of the application for the registration of the drug, and, consequently, the release of the drug on the market. On the other hand, the interests of the producer may be answered by the retention of some specific details of the technology in the registry, if they are objected to by GMP inspectors. In the case of drug registration, these details in the materials of the application will be considered approved by the regulatory body. The manufacturer will thereby be protected from criticism arising from the inspectors.

Taking into account the above, adequate filling of the section Production of the registration dossier seems to be a rather complicated operation. In Russian domestic standards, the mechanisms and degree of linkage of the technology used in the sections are not explained with regards neither to the registration dossier nor to the regulations. Abroad, there is also no harmonized explanation of global (for example, WHO) or interregional (for example, ICH) levels on this score. In this respect the revised Manual approved in July 2017 [The first version of the document (CPMP / QWP / 486/95) adopted in 1995 has, to date, largely lost relevance due to profound changes approaches to registration of drugs introduced worldwide over the past 20 years] represents considerable interest on the procedure for completing the section Production in the materials of the application for registration of medicines [8].

This document does not introduce new requirements for already registered drugs. It should be considered as a methodology that clarifies the expectations of registration authorities regarding the completion of section 3.2.Р.3 of Module 3 of the Common Technical Document (CTD). Based on this text, the EAEU standard is prepared for the Guidelines for the production of finished dosage forms, which, once approved by the Eurasian Economic Commission, will acquire an official character, incl. for Russia.

Below are the main provisions of this document. The full text of the original is available on the website of the European Medicines Agency. The draft of EAEU document is posted on the website of the Eurasian Economic Commission.

  • All participating sites, including control and analytical laboratories, as well as the place of release of the series are indicated.
  • The prescription (composition per series, production recipe) is indicated in terms of the set volume of the series. If several volumes of the series are proposed, this should be justified. In this case, the composition is given, as a minimum, for the largest and smallest series. All ingredients are indicated, incl. removed in the manufacturing process (solvents, etc.). If the boot data for any ingredient is specified as a limit, this should be justified.
  • The proposed volume of the series should correspond to the industrial equipment of scale and be sufficiently representative in terms of scale in relation to the planned batch production. For example, for solid dosage forms, a full-scale series should contain, as a rule, not less than 100 thousand items. Failure to comply with this guideline should be justified. It should be noted that in this manual there is no concept of "semi-industrial series".
  • If the bulk product is packaged in different packages (presentations), the volume of the production series must be determined before the separation.

If sub-series (sub-series, batches) are produced and then combined, this procedure should be justified. In this case, it is necessary to indicate the number of subscriptions and the number of subseries in the calculation for the series. In continuous production, it is necessary to explain the order of formation of series: by the time of the process, by the volume of the product produced, and so on.

In this regard, the document contains a reminder that, in principle, the series should be produced from one volume of source material, and should be homogeneous. It should be noted that these provisions fully comply with the requirements of the Russian domestic GMP Rules (Paragraph 916 section Terms and definitions).

  • It is necessary to consistently present the process in the form of text in accordance with the order of operations performed, with the application of the technological scheme in which all operations are indicated, including the addition of ingredients, in-process control points, and so on.  If necessary, there must be mentioned special production conditions (for example, air humidity), the duration of individual operations and the maximum shelf life of intermediate products.
  • It is necessary to indicate the type of apparatus, including data on their capacity. However, small parts (brand, serial number) should not be given.
  • In cases of production of the drug at two or more sites, some differences in the hardware design of processes at different sites are permissible. In some cases, this is allowed for one site. At the same time, however, homogeneity of the product must be ensured; compliance with the specifications of release and storage. Differences in equipment for performing operations are permissible: wet granulation, drying of granulate, dry granulation, compression of tablets.
  • However, the differences associated with the use of alternative processes based on different principles, such as wet or dry granulation, autoclaving or sterilizing filtration, are unacceptable.
  • In the section on internal control, it is necessary to indicate critical points, the order of determining criticality, controlled intermediates, control methods, the permissible limits of the monitored parameters. The procedures for managing deviations and making decisions on the release of series should also be reflected.
  • A control strategy should be set out. This relatively new term is understood to mean a planned set of control types based on knowledge of the process and product, which ensures the functionality of the process and the quality of the product. The control strategy covers the input, in-production and issuing controls, and also explains the interconnection of the types of control.

We will clarify that the use of this EAEU Guidelines for the production of finished dosage forms assumes that the future manufacturer of the drug has an adequate description of the technology, including a control strategy. At the same time, in the Russian domestic pharmaceutical industry, it can now be used for another purpose: as a check list in the process of assessing the technological documentation received from the developer. Indeed, the absence in the materials of the developer of any element provided for in the Guide will make it more difficult and slower to complete the registration dossier, and, consequently, to bring the drug to the market. For this reason, this standard is useful not only for the registration authorities, but also for the producers.

Series entries

Next, we should touch on the format and order of record keeping for the production of specific series (dossier on the series). The source text here is also the technological documentation received from the developers, most often specified on the site (conditionally the master file of the technological document). The general rule on avoiding errors when reproducing texts from source documents is the most relevant to the content of the dossier on the series. In the world practice there was a strict requirement: a record on the series should contain a facsimile, i.e. accurate reproduction of the available on-site description of the technology.

A common form of registration of production conditions for individual series abroad is the use of a single copy (electronic copy or printout on paper) of the master file of a technological document as a blank (a form to be filled) for recording a specific series. This copy simultaneously performs the functions of the route map [According to MU 64-04-003-2002 [9], the route map is an in-production document filled in the production of each product series and includes all the necessary information to obtain objective evidence of the work done and the results achieved on each production operation], disjointed technological instructions and operating sheets.

For convenience of drawing up of records on manufacture of concrete series in a text of the master file of the technological document windows are inserted which further are filled by registration of the necessary data. This includes the signatures of the operators performing the operations with the indication of the date and hour, the signature of the second employee in the performance of critical operations, the technological and control parameters of the process, etc., which are subject to registration. The practice of placing windows intended for filling with signatures, on the margins of the document, versus describing the corresponding actions is widespread (see Figure 1).

Figure 1. Source: J. Sharp. Quality in the Manufacture of Medicines and other Healthcare Products. Pharmaceutical Press. London, 2000.

From industrial regulations to the current format of technological documentation

The above-mentioned profound changes in the pharmaceutical industry that occurred over the last quarter of a century did not lead to a radical revision of the Russian domestic requirements for the content of regulations and the registration of production documents. Current requirements in this area [5, 7, 9] largely reflect the practice of the Soviet period [10] without due regard for contemporary foreign experience.

For this reason, in order to use the best foreign experience in the field of technological documentation, it is necessary to produce a transitional document on the basis of industrial regulations. It is an abbreviated copy of the regulation, from which sections that are not directly related to compliance with GMP rules have been deleted. The transitional document contains a description of the technological and control operations specific for this particular drug. It can be considered as a form of industrial regulation or as a single technological instruction for the whole process [According to § 3.2 of GOST R 52550-2006 [7], the industrial regulations, the technological instruction and the packing instruction are the documents determining all used raw materials and operations for the production and product packaging]. Since a successful Russian-language name has not yet been invented for such a document, we will conditionally designate it as a master file for a technology document.

Unlike the traditional maintenance of technological documentation, the text of this document accurately copies the contents of the relevant parts of the regulation. Any exceptions, explanations, etc. are inadmissible here. The only type of additions are inserted in the corresponding places in empty windows, which were discussed above. The master file is saved in one copy in the package of basic documents of the enterprise for work according to the rules of GMP, it cannot be replicated, cut into pieces or transferred to the plots in the cut form.

The procedure for using this document can be summarized as follows. After making a decision to start production of the next series of preparations from the master file, a copy in one copy is taken, the next serial number is placed on it, which is registered in a special journal in the usual way. After that, this copy becomes a record form for a series, i.e. in the form to be filled out, replacing the disparate operating sheets (transaction protocol forms).

This text accompanies the materials from which the series are produced, throughout the entire production cycle, moving along with the series itself from site to site, from shop to shop, from housing to housing, and in some cases from site to site. In view of this, this document can be considered as a route map. All operations performed on the line, as well as the results of all types of in-process control and process monitoring are documented by entering data in the corresponding window of the form.

A completed form is a record for the series. After the addition of documents reflecting the implementation of off-line activities (ancillary operations that produce laboratory quality control, environmental monitoring results, release decisions, etc.), a dossier is created for the series. If necessary, it makes notes on deviations from the established process, on decisions to continue the process, etc.

We summarize the differences of this approach to the maintenance of technological documentation from the traditional. In this case, the same text is used as:

  • a basic description of the production recipe and production technology;
  • a consolidated technological instruction for all operations used in the workplace;
  • Joint operating sheets;
  • Route map for the series.

The advantages of this form of documentation are obvious. Practically eliminates the risk of errors in the preparation of technological instructions and operating lists based on industrial regulations. The production personnel of the enterprise have the opportunity to see the whole process in aggregate, and not just its individual fragments related to specific workplaces (sites). In cases of changes in technology, they are reflected in one document. Accordingly, there is no need to remove old versions of technological instructions and operating sheets stored in the workplace for replacement with new ones. Such a procedure for documenting the data greatly facilitates and speeds up the procedure for reviewing the dossier for the series by an authorized person of the enterprise. This approach facilitates the transition to paperless workflow in order to get rid of the "huge mountain of papers".

It should be emphasized that this approach does not contradict the current Russian regulatory legal acts and does not require implementation costs.

According to available data, this procedure for maintaining production documentation is used by most of the world's leading enterprises in the industry. In this regard, it is reflected in the WHO recommendations [11].

In the last 15-20 years, this approach has been described in textbooks (see Fig. 1) and in periodicals, incl. in Russian [5]. In 2003, this order was introduced as mandatory in Ukraine [12]. At the same time, some large producers of remedies, for example, in Central Europe, adhere to the traditional order of forming a dossier for a series based on the completion of transaction sheets for individual transactions.


  1. И.А. Осмоловская, О.В. Зарочинская, М.О. Емельянова. Система документации – управление рисками. Новости GMP 2(13)/лето 2017, с. 142-149.
  2. J. Sharp. Quality in the Manufacture of Medicines and other Healthcare Products. Pharmaceutical Press. London, 2000.
  3. Приказ Министерства промышленности и торговли РФ от 14 июля 2013 г. № 916 «Об утверждении Правил организации производства и контроля качества лекарственных средств».
  4. EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use. The Rules Governing Medicinal Products in the European Union. Volume 4. EudaLex.
  5. Безуглая Е.П., Ляпунов Н.А., Кричевская Е.А. Технологическая документация по требованиям GMP. Технология чистоты №2/2003, с. 19-24.
  6. ОСТ 64-02-003-2002. Стандарт отрасли. Продукция медицинской промышленности. Технологические регламенты производства. Содержание, порядок разработки, согласования и утверждения. Министерство промышленности, науки и технологий РФ, 2002 г.
  7. ГОСТ Р 52550-2006. Производство лекарственных средств. Организационно-технологическая документация. Федеральное агентство по техническому регулированию и метрологии. 2006.
  8. Note for Guidance on Manufacture of the Finished Dosage Form. EMA/CHMP/QWP/245074/2015, 04.07. 2017.
  9. МУ 64-04-003-2002. Производство лекарственных средств. Документация. Общие требования. Примерные формы и рекомендации по их заполнению. Методические указания. Министерство промышленности, науки и технологий РФ, 2002 г.
  10. ОСТ 64-002-86. Продукция медицинской и микробиологической промышленности. Технологические регламенты производства. Содержание, порядок разработки, согласования и утверждения. Министерство медицинской и микробиологической промышленности CCCР. 1986 г.
  11. A WHO guide to good manufacturing practice (GMP) requirements. Part 1: Standard operating procedures and master formulae. Department of vaccines and other biologicals. WHO Geneva 1997 (WHO/VSO/97.01).
  12. Настанова 42-01-2003. Руководство. Лекарственные средства. Технологический процесс. Минiстерство охорони здоров’я Украïни. 2003.

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