|«Association of Engineers for microcontamination control» (ASENMCO)|
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.
Now we have to solve several tasks to provide implementation and control of GMP rules:
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:
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:
1. History of GMP in Russia
History of GMP in Russia is similar to development of standardization in general.
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.
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.
Implementing of GMP EC Rules in Russia should solve several tasks:
Movement towards implementation of GMP Rules in Russia started in early 90-th. Very soon two opposite approaches appeared:
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.
Little by little situation was changing. Manufactures started to understand that they need internationally recognized norms. Some new people came to authorities.
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.
2. New problems
National standards are not mandatory documents according to Russian Law «On Technical Regulating» that is in force since 01.07.2003.
Technical Regulation is analogue to European Directive.
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.
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.
Table 1. System of GMP documents in different countries
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.
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.
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:
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.
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.
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 .
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».
Standard has 13 chapters and 9 Annexes:
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:
Standard gives also recommended list of instructions (SOP's).
Standard GOST R 52538-2006 «Cleanrooms. Technological garments. General requirements» describes following issues:
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.
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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