«Association  of  Engineers  for  microcontamination  control»  (ASENMCO)
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  Dr. Alexander Fedotov,
President of ASENMCO
(ASsociation of Engineers for Microcontamination Control,
All-Russia public organization)
Email: fedotov@invar-project.ru


In 2004 EU GMP Guideline was approved as Russian national standard GOST R 52249-2004 «Manufacturing and quality control of medicinal products». This is the direct translation of EU GMP with all 18 Annexes without any changes.
Different GMP-like guidelines existed in Russia earlier. They reflected need to improve quality of medicinal products but did not consider some key elements of GMP approach and sometimes set unnecessary rigid requirements.
ASENMCO started proving necessity to implement in Russia EU GMP in early 90-th. It was obvious that Russia should have the same normative basis as Europe.
Russia will join WTO in nearest future so harmonization of standards became a mandatory requirement.

Now we have to solve several tasks to provide implementation and control of GMP rules:

  • to create family of standards to support manufacturers in their GMP efforts;
  • to develop system of training;
  • to develop inspection, audit and certification institutions.

GMP Guideline is written mainly with general words. But for practice we need standards to explain key elements of GMP with more details.

For this we prepared at first stage following standards:

  • GOST R 52537-2006 «Manufacturing of medicinal products. System of quality assurance. General requirements»;
  • GOST R 52550-2006 «Manufacturing of medicinal products. Organizing and technological documentation»;
  • GOST R 52538-2006 «Cleanrooms. Garments. General requirements».

The first standard is the key document. It systematically summarizes requirements for quality assurance and introduces chapters on control of execution, proper arrangement of design and validation etc:
The paper discusses experience of work according to ISO 9000 standard and describes some myths around this system.

1. History of GMP in Russia

History of GMP in Russia is similar to development of standardization in general.
Until 1991 Russian economics was different from western world in principle. All property belonged to the state. All plants received plans and orders for manufacturing of products from the state. Supplying by all materials was centralized and controlled by the state. Management of plants did not care about marketing and had the only duty to fulfill state plans. Furthermore nobody had legal right to produce anything by direct negotiation with customers without a plan.

The state covered 100% of manufacturing capacities. And the state created standards that were mandatory. Under these circumstances the plants were interested only on what the state said and not on market. Better to say that the market was absent at all.
So the state had several roles:

  • it was the only customer,
  • it was the only supplier,
  • it was owner of plants,
  • it was authority that created standards and controlled compliance to them.

All this was controlled by huge bureaucratic system with many institutions that were not much interested on world level of production and quality standards. This system created many people who set standards only on basis of their own understanding. The system of so named «national specific standards» was established. This system actually did not reflect real national specific features but served for interests of bureaucracy.

In early 90th situation was changed dramatically. Three first roles of the state were eliminated. Only control of laws and normative documents remained for the state. Manufacturers were dropped onto market and it was their responsibility to select proper standards to reach success on the market. Not everybody understood it quickly.
The system was changed but many of old institutions and old people remained. They make resistance for implementation of new ideology of standards.

Implementing of GMP EC Rules in Russia should solve several tasks:

  • elimination of trade barriers,
  • setting in Russia the same standards as in Europe and giving normative basis for export of products,
  • upgrading national pharmaceutical industry,
  • setting barrier to import of poor quality drugs from some countries.

Movement towards implementation of GMP Rules in Russia started in early 90-th. Very soon two opposite approaches appeared:

  • The first of was to create something «national specific». It belonged to bureaucracy and institutions;
  • The second was to implement GMP EC guide in Russia directly without any changes. This approach belonged to ASENMCO.

ASENMCO was founded in 1991 as a non-profit independent society of professionals who were free of influence of bureaucracy. The core of ASENMCO included internationally oriented people who looked forward and set goal of upgrading national industry.
During 90th ASENMCO efforts had no success.
In 1991 and 1998 two industry «nationally oriented standards» were approved in Russia. In fact they were compilations of GMP EC text with some withdrawals, mixings, changes and adding new unnecessary requirements that were even more rigid then in GMP EC Guide. For ten years ASENMCO was proving that this way has no future and is harmful for industry and society. This was a frustrating period.

Little by little situation was changing. Manufactures started to understand that they need internationally recognized norms. Some new people came to authorities.
In 2004 special Technical Committee for standardization TC 458 «Manufacturing and quality control of medicinal products» was approved by National body for standardization (Gosstandart of Russia). ASENMCO was appointed to held secretariat of TC 458. President of ASENMCO Dr. A. Fedotov was appointed to be a convenor of TC 458.

The first result was achieved already in 2004. GMP EC Guide was approved as Russian national standard GOST R 52249 «Good Manufacturing Practice for Medicinal Products». This standard is identical to GMP EC including all 18 Annexes.
It was really a breakthrough.
Furthermore GOST R 52249 is the first Russian standard that sets main rules for the whole industry that are identical to European norms. Many ISO and CEN standards were approved in Russia earlier but GMP was the first one among key standards for the whole industry.

2. New problems

National standards are not mandatory documents according to Russian Law «On Technical Regulating» that is in force since 01.07.2003.
So GMP – GOST R 52249 is only recommendation.
Technical Regulation is a mandatory document (normally a Law). Standard can be a basis to prove compliance to Technical Regulation.
This system is similar to European Practice (Table 1).

Technical Regulation is analogue to European Directive.
So we need special Technical Regulation on GMP to form the complete basis for GMP norms in Russia.
Russia has the Law «Safety of medicinal products». This is a general law and has only note about manufacturing of medicinal products.

ASENMCO offered simple solution. This is to approve Russian version of European COMMISSION DIRECTIVE 2003/94 EC of 8 October 2003 laying down the principles and guidelines of good manufacturing practice in respect of medicinal products for human use and investigational medicinal products for human use.
ASENMCO prepared the draft of relevant Technical Regulation and submitted it to formal discussion.

We understand that approval of such key document is a slow process and we need to overcome resistance of some groups of people, for example, counterfeit makers.
Of course it is necessary to develop procedure how to upgrade national manufacturing sites to GMP Rules in full scale.

Table 1. System of GMP documents in different countries
DocumentsUSAEC Russian Federation
Mandatory 21 CFR- Part 211 «Current Good Manufacturing Practice for Finished Pharmaceuticals» (GMP) European Commission Directive 2003/94 EC of 8 October 2003 laying down GMP principles Law «Safety of medicinal products». Technical regulation «Manufacturing and Quality Control of Medicinal products. General requirements»
Recommended but approved by state authorities FDA guidelines, national and ISO standards GMP EC Guide ISO, CEN and other standards

PIC documents
GOST R 52249 «Good Manufacturing Practice for Medicinal Products» Other ISO, CEN and national standards,
Recommended Practices of professional Societies and others. ISPE, PDA, IEST and other Baselines and practices ISPE, PDA, IEST and other Baselines and practices др. ISPE, PDA and other Baselines and practices

3. Need for system of GMP related standards

GMP is a big and complicated field. To design plant, select equipment and to arrange manufacturing we must know how to do it. Normally standards should give necessary instructions.
But GMP is a general guide and has many instructions like «make it appropriate way» or «equipment should suit its intended purpose». These phrases have no technical sense. It is impossible to design anything according to them and to prove compliance. Real sense appears when general words are supported with detailed standards that have clear requirements for technical parameters. Such standards for pharmaceutical industry are almost absent. But without them we find ourselves in difficult and not clear area that is based on opinions, traditions etc.
Opinion is not a real argument for design, proving budgeting expenses and conducting audits and inspections.

Here we see difference between pharmaceutical world and military, space, railway and other similar industries. These industries have numerous good detailed standards. These standards describe every requirement for equipment, processes etc with details. They really leave nothing to chance and to opinions. They are really much closer to GMP sense then pharmaceutical industry. The reason is that the state invested a lot in development of standards for military and similar technologies. Pharmaceutical industry is in a worse position. Such picture is typical for most countries.

4. System of GMP standards

The next step is to develop a family of standards that will describe requirements for critical equipment, process, methods of validation etc.
The scheme of such family of standards is shown on Fig. 1.

Fig. 1. Proposed system of GMP standards

Some of them already exist, for example standards ISO 14644 for cleanrooms and ISO 13408-1 «Aseptic processing of healthcare products. Part 1. General requirements».

Some of them exist but are overloaded with theory and cannot be used directly. ISO 11134 «Sterilization of healthcare products. Requirements for validation and routine control. Industrial moist heat sterilization» is the example. Such standards are to be replaced or supported by standards with practical methods for validation or performing other actions.

Some important items are not covered by existing standards. Equipment for solid forms manufacturing, freeze-drying etc are examples. ISPE Baselines give good information but it is not enough. We decided to create a family of standards for equipment and processes. The first standard is «Manufacturing of Medicinal products. Processing equipment for manufacturing of solid forms. General requirements». The draft is to be ready in autumn 2006.

Three new standards were approved recently:

  • GOST R 52537-2006 «Manufacturing of medicinal products. Quality assurance system. General requirements»;
  • GOST R 52550-2006 «Manufacturing of medicinal products. Organizing and technological documentation»;
  • GOST R 52538-2006 «Cleanrooms. Technological garments. General requirements».

Of course, creating of whole family of GMP standards is a huge work. International co-operation can give good result.

5. Quality assurance standard

ISO 9000 family of standards came to Russia earlier then GMP.
GMP describes Quality assurance problem rather shortly and with general words.
So some manufactures of medicinal products started implementation of ISO 9000 and even received certificate on compliance to ISO 9000.
Soon it became evident that some holders of ISO 9000 certificate are leaders on product recalls from the market, i. e. they have poor quality of products.

We studied the problem from different sides and understood that it has common roots for any industry. We receive a lot of products with ISO certificates from different countries. And these products sometimes have poor quality. Devices may have faults because of cold welding of chips, materials may not match the orders etc.

ISO 9000 describes only Quality management system.
Quality management system according to ISO 9000 includes documentation, responsibilities, analysis, management of resources (human, infrastructure, process media – for process some 10 general words), life cycle processes etc.

All this is described very general way and in some artificial language that has no real sense and should be translated into normal language. Excellent analysis was done by Kit Sadgrove [1].
He made translation of ISO 9000 from artificial language into normal English language. The result was a very simple text that consisted of well-known recommendations like how to cross the road.

But the worst is that ISO 9000 does not focus attention on such key elements of Quality assurance as Good materials, Good equipment and processes and Good executive discipline. Documentation, responsibility, analysis etc are only words without this.

Many people trust ISO 9000 label. Many of us have seen label «ISO 9000 certified» on different products but almost nobody have paid attention to the note with small letters: «Quality management system». Sometimes such note is absent. People think that words «Compliance to ISO 9000» and «Good product» are equivalent. But it is not so!

There are several myths around ISO 9000.

Myth 1:  «If product has ISO certificate – this is a good product».
Comment: Compliance to ISO 9000 means that manufacturer has documented Quality management system that assures processing of products according to pre-determined requirements. But what if these requirements are old or simply bad? What if the manufacture has a perfect documented system but poor equipment and poor executive discipline? – ISO 9000 certification body will not see these substantial disadvantages and manufacture will obtain certificate.

Myth 2:  «Quality assurance system is complicated. Manufacturer cannot create it himself. It is necessary to invite experienced consultants who will write necessary documents».
Comment: It is not true. Only manufacturer can create really working and useful Quality system for himself, asking, if necessary consultants for advice. The reason of this myth is lack of good guideline for creating Quality management system.

Myth 3:  «Quality management system requires great mounts of paper, including big quality manual».
Comment: It is not true. Nobody reads great mounts of paper. Quality management system has several levels. Upper level is Quality manual (or Information about the plant). This document should not exceed 20 pages. All other levels are to be user oriented and include only necessary information with references.

Myth 4:  «ISO 9000 system is an achievement of progress. It is necessary to study it for a long time».
Comment: Actually ISO 9000 is a set of well known and simple rules, but they were written unclear way.

Industry needs special standard that should cover all key elements of Quality assurance. This standard should be detailed enough to understand the matter, to provide quality and to give criteria for estimation of quality system. It should be written in simple and clear way by people who really know manufacturing process and have personal experience of work in industry.

For this we prepared Russian standard «Manufacturing of medicinal products. System of quality assurance. General requirements».
It covers main topics of the problem and offers practical recommendation how to arrange and check Quality assurance system.

Standard has 13 chapters and 9 Annexes:

2Normative references
3Terms and definitions
4Quality assurance system
4.2Principles of Quality assurance
4.3Structure of Quality assurance system
4.4Information about the plant
4.5Organizational chart
4.6Management of the plant
4.7Quality assurance and quality control
4.8Quality policy
7Quality control and release of finished product
8Quality assurance at the creation stage of facility
8.2Design qualification
8.3Installation qualification
8.4Operational qualification
8.5Performance qualification
8.6Premises, equipment and processes that are subject for qualification
9.2Requirements for personal
9.3Training of personal
9.4Qualification of personal
9.5Responsibilities of personal
9.6Requirements for health
10Execution Control
11Risk analysis at critical control points
12Stages of creating Quality assurance system
13Auditing and inspections
Annex AInformation about the plant
Annex BQuality policy (example)
Annex CMaterials
Annex DPreparing and execution of orders (contracts)
Annex EManagement of production process
Annex FManagement of execution control
Annex GStages of creating Quality assurance system (example)
Annex HRecommendations for Auditing and Inspection to meet GMP requirements
Annex IChecklist for Auditing and Inspections

6. Documentation

The next standard is GOST R 52550-2006 «Manufacturing of medicinal products. Organizing and technological documentation».

It describes organizational and technological documents and offers examples of documents:

  • specifications for materials,
  • specifications for intermediate and finished products,
  • in-process labels,
  • instructions or procedures (SOP's),
  • batch records.

Standard gives also recommended list of instructions (SOP's).

7. Garments

Standard GOST R 52538-2006 «Cleanrooms. Technological garments. General requirements» describes following issues:

  • Classification of garments depending on area of use,
  • Requirements for different items of garments,
  • Requirements for marking, packaging and storage,
  • Handling of garments,
  • Laundries,
  • Repair of garments,
  • Testing.

8. Terms and definitions

GMP standards use several terms with one and the same meaning, for example such terms as validation, verification, qualification, testing. All these terms really mean «confirmation of compliance to specified requirements». One can hardly find technically clear differences in these terms. Such non-clear differences (or absence of differences) create difficulties when translating terms into other languages. Sometimes people try to find hidden sense that is actually absent in these terms. Probably it is time to suggest one term and to add additives to it depending on circumstances.

Discussion on terms is out of scope of this presentation.
But it is worth to discuss term «quality». This is really a key term.
Important point of departure is that term «quality» has different senses for market and for manufacture. For market and customers quality means somewhat like «degree of excellence» or «product must fit for intended use».
The sense of these definitions is more lyrical and philosophical then technical.
For purpose of manufacturing «fitting for intended use» must be described by technical parameters with numbers or words that can be implemented into technology and tested.

Requirements are to be specified clearly and in full and must be included in specification. It is possible to arrange proper production process and prove that product has expected quality only in this case. So for purpose of manufacturing term «quality» means compliance to specification. Considering this point Quality assurance system can be constructed in clear and comprehensive way.

9. List of reference

1.  ISO 9000 BS5750. MADE EASY. A PRACTICAL GUIDE TO QUALITY, Kit Sadgrove, England, 1994.

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