of November 3, 2016 No. 77
About approval of Rules of proper production practice of the Eurasian Economic Union
According to articles 30 and 56 of the Agreement on the Eurasian Economic Union of May 29, 2014, Item 14 of appendix No. 12 to the Agreement on the Eurasian Economic Union of May 29, 2014, article 9 of the Agreement on the single principles and rules of drug circulation within the Eurasian Economic Union of December 23, 2014, Items 57 and 82 of appendix No. 1 to the Regulations of work of the Eurasian economic commission approved by the Decision of the Supreme Eurasian economic council of December 23, 2014 No. 98, and the Decision of the Supreme Eurasian economic council of December 23, 2014 "About implementation of the Agreement on the single principles and rules of drug circulation within the Eurasian Economic Union" Council of the Eurasian economic commission solved No. 108:
1. Approve the enclosed Rules of proper production practice of the Eurasian Economic Union (further - Rules).
2. This Decision becomes effective after 10 calendar days from the effective date of the Protocol signed on December 2, 2015 on accession of the Republic of Armenia to the Agreement on the single principles and rules of drug circulation within the Eurasian Economic Union of December 23, 2014, but not earlier than after 10 calendar days from the date of official publication of this Decision, except for provisions of the Rules approved by this Decision concerning requirements to production of veterinary medicines.
The provisions of Rules concerning requirements to production of veterinary medicines become effective since January 1, 2021.
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Members of council of the Eurasian economic commission: From the Republic of Armenia |
V. Gabriyelyan |
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From the Republic of Belarus |
V. Matyushevsky |
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From the Republic of Kazakhstan |
A. Mamin |
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From the Kyrgyz Republic |
O. Pankratov |
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From the Russian Federation |
I. Shuvalov |
Approved by the Decision of Council of the Eurasian economic commission of November 3, 2016 No. 77
Pharmaceutical industry of state members of the Eurasian Economic Union (further respectively - state members, the Union) supports high standards of quality management in case of development, production and control of medicines. The system of state registration guarantees that all medicines are estimated by authorized body to ensure them compliance modern trebovanyam safety, quality and efficiency. The system of licensing of production guarantees that all products allowed for use in the territories of state members are made only by producers which have the corresponding permissions (licenses) and are regularly inspected by authorized bodies with use of the principles of risk management for quality. Permission (license) for production is obligatory for producer of medicines of state members irrespective of, these products in the territories of state members or beyond their limits are sold.
Compliance to these rules is considered in case of receipt of permissions (licenses) for production of medicines, and inspection of producers of medicines is based on it.
Requirements of these rules to production of veterinary medicines are same, as well as in case of production of medicines for medical application. Special requirements of these rules for veterinary medicines and immunobiological veterinary medicines are stated in annexes No. No. 4 and 5.
These rules are provided by 3 parts and number of appendices. Part I contains the principles applicable in case of production of medicines. Part II covers the principles applicable in case of production of the active pharmaceutical substances used as initial materials. Part III contains Sections in which the requirements of authorized bodies of state members connected with rules of proper production of medicines are explained.
In Chapter 1 of part I of these rules the fundamental management concept is in general stated by quality in case of production of medicines. Each of the following Chapters contains the principle sketching the quality management purposes within this Chapter, and the explanation which provide sufficient disaggregation that producers understood the main questions which need to be considered in case of realization of this principle.
In these rules detailed information on the principles of proper production concerning the active pharmaceutical substances used as initial materials is stated. Part II was developed on the basis of management of ICH published as the document ICH Q7A for active pharmaceutical substances. This part extends both to medicines for medical application, and to veterinary medicines.
In addition to the main content stated in parts I and II, these rules include number of the appendices providing disaggregation concerning separate types of activity. Various appendices will be applied to some production processes at the same time (for example, the appendices regulating production of sterile medicines and production of radio pharmaceutical medicines and (or) biological medicines).
Part III contains the Sections connected with rules of proper production which are not the detailed guidelines. Part III purpose - to explain requirements of regulatory bodies, it is necessary to consider it as information source concerning the best modern methods. Separately in each Section the details concerning its applicability are described.
After appendices to the main parts of Rules the dictionary of the terms used in these rules is provided.
These rules do not extend to questions of labor protection of the personnel occupied in production. These questions can be important in case of production of such medicines as highly active, biological and radioactive. They are regulated by the legislation of state members.
These rules provide that the holder of permission (license) for production systematically includes requirements of the registration file of medicine for safety, quality and efficiency of products in all actions for production, control and production in realization.
For many years production of medicines is carried out according to the guidelines of rules of proper production and not regulated by the CEN/ISO standards. In these rules the CEN/ISO standards were considered, but terminology of these standards was not applied.
There can be other acceptable methods, excellent from described in these rules by means of which it is possible to observe the principles of quality management. These rules are not directed to restriction of development of any new concepts or new technologies which underwent validation and provide quality management level, at least equivalent established by these rules.
These rules will be regularly reviewed for the purpose of reflection of continual improvement of practice in the field of quality.
Principle
The producer shall make medicines so that to guarantee their compliance to the appointment, requirements of the registration file and (or) to the protocol of clinical trial and to minimize the risk for patients connected with safety, quality and efficiency of medicines. Responsibility for accomplishment of these requirements is born by the top management, their accomplishment requires participation and responsibility of personnel of various divisions of the manufacturing company at all its levels, and also suppliers and the organizations of wholesale trade. For achievement of this purpose comprehensively developed and correctly functioning pharmaceutical quality system including proper production practice and risk management for quality is created. This system shall be drawn up documentary, and its efficiency - is checked. All elements of the pharmaceutical quality system shall be staffed by qualified personnel, are provided with necessary and proper rooms, the equipment and technical means. The holder of permission (license) for production of medicines and the authorized person (persons) bear responsibility according to the legislation of state members for functioning of the pharmaceutical quality system.
The basic principles of quality management, proper production practice and risk management for quality are interconnected. They are described below to emphasize their interrelation and paramount value for production and control of medicines.
Pharmaceutical quality system
1.1. Quality management - the comprehensive concept covering all questions which separately or in general influence product quality. It is set of the organizational measures undertaken for the purpose of ensuring compliance of quality of medicines to their purpose. Quality management includes proper production practice.
1.2. Rules of proper production and quality control are applied to all stages of product lifecycle: to production of medicines for clinical trials, to transfer of technology, industrial production, cessation of production of medicines. However the pharmaceutical quality system can extend also to such stage of product lifecycle as pharmaceutical development. It is described in part III of these rules in the Section "Pharmaceutical Quality System" which in spite of the fact that is referral, shall promote innovations and permanent improvement, and also hardening of communication between pharmaceutical development and productive activity. The Section "Pharmaceutical Quality System" can be used to add contents of this Chapter.
1.3. In case of development of the new pharmaceutical quality system or in case of change of the existing system it is necessary to consider amount and complexity of organization activity. The structure of the pharmaceutical quality system shall include the corresponding principles of risk management with use of suitable tools. While some aspects of the pharmaceutical quality system can be applied to activities of all organization in general, and others - only to certain production sites, efficiency of implementation of the pharmaceutical quality system is usually shown at the level of the production site.
1.4. The pharmaceutical quality system intended for production of medicines shall guarantee that:
i) production is provided by means of development, planning, implementation, maintenance and continuous enhancement of system which gives the chance constantly to deliver products with the corresponding indicators of quality;
ii) knowledge management about products and process of its production is performed throughout all stages of product lifecycle;
iii) medicines are developed and enhanced taking into account requirements of these rules;
iv) transactions are precisely determined by production and control and conform to requirements of these rules;
v) responsibility and obligations of heads are accurately determined;
vi) measures for production, delivery and use of the initial materials conforming to the established requirements and also for the choice and control of suppliers and for check that each delivery is received from approved suppliers (the approved supply chain) are taken;
vii) the processes providing management of the activities transferred to other organization for accomplishment (outsourcing activities) are implemented;
viii) the controlled condition by means of development and use of effective monitoring and control systems in respect of carrying out process and product quality is established and is supported;
ix) results of monitoring of processes and product quality are taken into account in case of release of series, in case of investigation of variations and for acceptance of the warning measures in order to avoid potential variations which can happen in the future;
x) necessary control of intermediate products, any other control in production process are carried out, and validation is performed;
xi) assistance is rendered permanent improvement by means of implementation of the enhancements based on urgent knowledge of process and products;
xii) measures for perspective assessment of the planned changes and their approval before implementation taking into account need to execute the notification of authorized bodies or to approve changes with them are taken if it is required;
xiii) assessment of any realized changes after their implementation for confirmation of the fact that the objectives of changes were achieved is carried out and that it not negatively affected product quality;
xiv) during investigation of variations, expected defects of products and other problems the appropriate level of the analysis of basic reasons of these discrepancies which can be determined with use of the principles of risk management for quality shall be applied. In cases when the actual basic reason (reasons) of discrepancy cannot be established, it is necessary to identify the most probable cause. In cases when as the reason it is suspected or the human error is identified, it shall be proved with special care to guarantee that the existing process, procedural or system errors or problems were not passed. By results of investigation the corresponding adjusting and warning actions shall be determined and taken. Efficiency of such actions shall be checked and estimated according to the principles of risk management for quality;
xv) medicines will not be released before the authorized person does not certify that each product series was made and checked according to requirements of the registration file and these rules;
xvi) the sufficient measures providing maintenance of quality of medicines during all expiration date in case of their storage and the subsequent address are taken;
xvii) there is procedure of conducting self-inspection and (or) audit of quality according to which efficiency and suitability of the pharmaceutical quality system are regularly estimated.
1.5. The top management bears the main responsibility for availability of the effective pharmaceutical quality system, that there are necessary resources and that obligations, responsibility and powers are determined, brought to the attention and are carried out, implemented in all divisions of the company. The leading role of the top management and its active participation in the pharmaceutical quality system is important. It shall guarantee support of the pharmaceutical quality system and interest of personnel at all levels and in divisions of the company.
1.6. Periodic reviews of functioning of the pharmaceutical quality system with involvement in this process of the top management shall be carried out to determine opportunities for permanent improvement of products, processes and the system.
1.7. The pharmaceutical quality system shall be determined and drawn up documentary. There shall be available quality manual or the document equivalent to it which shall contain the description of quality management system, including responsibility of management.
Proper production practice
1.8. Proper production practice is that part of quality management which guarantees that products are constantly made and controlled on the quality standards corresponding to its appointment and also according to requirements of the registration file, the protocol of clinical trials and specifications on these products.
Proper production practice is connected both with production, and with quality control. Main requirements of proper production practice:
i) all production processes are determined, systematically reviewed taking into account the accumulated experience and confirm capability constantly to make medicines of required quality according to specifications;
ii) critical stages of production process and essential changes of process shall undergo validation;
iii) all necessary conditions for fulfillment of requirements of these rules, including availability shall be provided:
properly trained personnel having necessary qualification;
respective rooms and areas;
corresponding equipment and servicing;
corresponding materials, containers and labels;
the approved procedures and instructions according to the pharmaceutical quality system;
corresponding storage conditions and transportation;
iv) instructions and procedures shall be stated in writing clearly and unambiguously, they shall be specifically applicable to available means;
v) procedures shall be observed precisely, and the personnel shall be trained in their correct accomplishment;
vii) in production process it is necessary to constitute the records (hand-written method and (or) using technical means) documenting the actual carrying out the stages provided by the established techniques and instructions and also the fact that the quantity and product quality meet the established standards;
viii) any essential variations shall be drawn completely up documentary and investigated for the purpose of determination of reason for rejection and implementation of the corresponding adjusting and warning actions;
ix) in clear and available form the records relating to series (for example, in the file on series), including documentation on realization which allow to trace complete history of series remain;
x) in case of wholesale of products it is necessary to minimize risks for its quality and to consider the rules of proper distributor practice approved by the Eurasian economic commission;
xi) there shall be available system of withdrawal of any product series from sale or delivery;
xii) the complaints for the delivered products shall be reviewed, be investigated the reasons of defects and be taken adequate measures both concerning poor-quality products, and for prevention of similar cases.
Quality control
1.9. Quality control is part of the proper production practice connected with sampling, specifications and carrying out testing, and also with the procedures of the organization, documentation and issue of permission to release guaranteeing that all necessary testing are carried actually out and that materials will not be resolved for use, and the finished goods will not be allowed to realization or delivery until their quality is not acknowledged satisfactory.
Main requirements to quality control:
i) there shall be available respective rooms and the equipment, the trained personnel and the approved techniques for sampling, control and testing of initial materials, intermediate, bulk and finished goods, and also (if necessary) for monitoring of conditions of the production circle for the purpose of fulfillment of requirements of these rules;
ii) carrying out sampling of initial and packaging materials, intermediate, bulk and finished goods the appointed personnel according to the approved techniques;
iii) test methods shall undergo validation;
iv) the records (hand-written method and (or) using technical means) documenting shall be constituted that all necessary actions for sampling, control and techniques of testing are really held. Any variations shall be drawn completely up documentary and investigated;
v) the finished goods shall contain the active pharmaceutical substances corresponding to the registration file on high-quality and quantitative structure, shall have required purity, shall be enclosed in suitable packing and are correctly marked;
vi) the records which are drawn up by results of control and material tests, intermediate, bulk and finished goods shall be officially compared with requirements of specifications. Assessment of products shall include the overview and assessment of the corresponding manufacturing documentation and assessment of variations from the established procedures;
vii) any product series cannot be resolved for realization or delivery before the authorized person according to appendix No. 16 does not certify its compliance to the requirements established in case of state registration;
viii) it is necessary to keep enough control samples of initial and packaging materials and finished goods which will allow to carry out testing in the future (if necessary) according to appendix No. 19. Samples of finished goods should be stored in final packaging.
Overview of product quality
1.10. It is regularly necessary to carry out reviews of quality of all registered made medicines, including medicines produced only for export for the purpose of confirmation of permanency of the available process, compliance to the existing specifications both on initial materials, and on finished goods to reveal any tendencies (trends) and to establish possibility of product improvement and process. Such reviews should be drawn up documentary and to carry out, as a rule, annually, in view of the previous reviews. They shall include, at least, the following:
i) the overview of the initial materials (including packaging materials) used in case of production especially noting those which are received from new suppliers, and the separate overview of traceability of supply chain of active pharmaceutical substances;
ii) the overview of critical points of control in production process and results of control of finished goods;
iii) the overview of all series which did not meet the established specifications, and results of the corresponding investigations;
iv) the overview of all essential variations or discrepancies, the related investigations, efficiency and effectiveness of actions taken adjusting and warning;
v) the overview of all changes made to processes or analytical techniques;
vi) the overview of the given, approved or rejected changes in the registration file, including in the file on the medicines intended only for export;
vii) overview of results of monitoring of stability and any unfortunate trends;
viii) the overview of all returns connected with product quality, claims and responses, and also investigations made at this time;
ix) the overview of sufficiency of any earlier carried out corrective actions concerning production or the equipment;
x) the overview of post-registration obligations in case of receipt of new registration certificates or modification of registration files;
xi) condition of qualification of the corresponding the equipment and technical means, for example, systems of heating, ventilation and air conditioning, systems of supply with water, the compressed gases, etc.;
xii) the overview of any contractual agreements specified in Chapter 7 of these rules for the purpose of confirmation of their compliance to the existing requirements.
1.11. The producer and the holder of the registration certificate (if they are the different organizations) shall estimate results of the overview of quality and draw conclusions about need of implementation of the adjusting and warning actions or carrying out repeated validation within the pharmaceutical quality system. There shall be available procedures for permanent management and the analysis of such actions. Efficiency of these procedures shall be confirmed during self-inspection. Reviews of quality can be grouped in products types (for example, firm dosage forms, liquid dosage forms, sterile medicines, etc.) in the presence of scientific reasons.
If the holder of the registration certificate is not producer, then the agreement between it and producer in which the corresponding obligations of the Parties concerning creation of the overview of quality are established shall be signed.
Risk management for quality
1.12. Risk management for quality is the systematized process of assessment, control, information transfer, and also the overview of risks for quality of medicine. This process can be carried out as it is perspective, and is retrospective.
1.13. The principles of risk management for quality:
the risks assessment for quality is based on scientific knowledge, work experience in the relation of process and eventually is connected with protection of the patient;
the scale of works, extent of formalization and documentary registration of risk management process for quality correspond to risk level.
Examples of processes and application of risk management for quality are also specified in Chapter II of part III of these rules.
Principle
Proper production of medicines depends on personnel. Therefore at the company there shall be enough qualified personnel for the solution of all tasks relating to the sphere of liability of the producer. Each employee shall understand individual responsibility which shall be drawn documentary up. All personnel shall know the principles of proper production practice concerning its activities and also to undergo primary and subsequent training according to its obligations, including instructing in accomplishment of hygienic requirements.
General requirements
2.1. The producer shall have enough employees with necessary qualification and practical experience of work. The top management shall determine and provide sufficient and proper resources (human, financial, material, and also rooms and the equipment) for implementation and maintenance of quality management system and permanent increase in its efficiency. Obligations of any employee shall not be excessive to exclude possibility of risks for product quality.
2.2. At the company there shall be scheme of organizational structure in which the relations between production managers, quality control and where it is applicable, the division manager of quality assurance or division on quality, specified in Item 2.5 of this Section, and line item of the authorized person (persons) are clearly designated in hierarchy of management.
2.3. Obligations and appropriate authority for their accomplishment shall be determined and stated in job descriptions. Obligations of managing personnel can be transferred to the appointed deputies having sufficient skill level. The duties of personnel shall cover all parties of proper production practice, however there shall not be unreasonable duplication of spheres of responsibility.
2.4. The top management bears the main responsibility for providing effective quality management system for goal achievement in the field of quality, and also for the fact that roles, obligations and powers are determined, brought to the attention personnel and are performed within all organization. The top management shall establish policy in the field of quality which determines the general intentions and activities of the company connected with quality and shall provide permanent suitability and system effectiveness of quality management and compliance of proper production practice by participation in the analysis from management.
Key personnel
2.5. The top management shall appoint key managing personnel, including the production manager and the division manager of quality control, and also sufficient number (but at least 1) authorized persons if the obligations provided for the authorized person do not enter obligations of the production manager and (or) division manager of quality control. The key managing personnel, as a rule, shall work full time. Production managers and divisions of quality control shall be independent from each other. In the big organizations there can be need to transfer to other employees the separate obligations specified in Items 2.7 - 2.9 presents of the Section.
Besides, depending on the size and structure of the organization the division manager of quality assurance or the division manager of quality can be separately appointed. In the presence of such divisions some of their obligations specified in Items 2.7 - 2.9 presents of the Section, will be general with obligations of the division manager of quality control and the production manager therefore the top management shall provide that their obligations and powers were accurately and are unambiguously determined.
2.6. Obligations of the authorized person:
for the medicines made in the territories of state members, the authorized person shall guarantee that each series was made and checked according to the legislation of these states and according to requirements of the registration file;
for medicines from the third countries irrespective of whether they were made in the territories of state members, the authorized person shall guarantee that each batch underwent in state member to complete qualitative and quantitative analysis at least of all active agents and to all other testing or checks necessary for quality assurance of medicines according to requirements of the registration file.
The authorized person (persons) before release of any series shall document that all necessary transactions are executed and that each series conforms to the established requirements.
Education, training and length of service of authorized persons shall conform to the requirements established by international treaties and decisions of bodies of the Union, constituting the right of the Union. They shall be constantly and continuously at the disposal of the owner of permission (license) for production for accomplishment of the obligations.
Obligations of the authorized person can be transferred only to other authorized person (persons).
The procedure for confirmation by the authorized person of compliance of product series is given in appendix No. 16.
2.7. Obligations of the production manager include, as a rule:
i) ensuring compliance of production and storage of products of the approved documentation for ensuring required quality;
ii) approval of the instructions relating to production operations and ensuring their strict accomplishment;
iii) providing assessment and signing of production documents with the personnel authorized on it;
iv) providing and guarantee of qualification, proper maintenance, operation and maintenance of rooms and the equipment in the division;
v) providing and guarantee of carrying out the corresponding validation;
vi) providing and guarantee of carrying out necessary primary and subsequent continuous personnel training of the division.
2.8. Obligations of the division manager of quality control include, as a rule:
i) approval or variation if he considers it necessary, initial raw materials and packaging materials, and also intermediate, bulk and finished goods;
ii) ensuring carrying out all necessary testing and assessment of the corresponding records;
iii) approval of specifications, procedures for sampling, techniques of testing and other procedures for quality control;
iv) approval of the experts involved to carrying out testing under the contract and control of them;
v) providing and guarantee of qualification, proper maintenance, operation and maintenance of rooms and the equipment in the division;
vi) providing and guarantee of carrying out the corresponding validation;
vii) providing and guarantee of carrying out necessary primary and subsequent continuous personnel training of the division.
Other obligations of personnel of division of quality control are specified in Chapter 6 of part I of these rules.
2.9. Production managers and divisions of quality control, and also the head of department of quality assurance or the head of qaulity (if necessary), as a rule, have some general or jointly the carried-out obligations relating to quality assurance of products, including, in particular, development, effective implementation, maintenance and monitoring of quality management system.
These obligations can include:
i) coordination and approval of written procedures and other documents, including introduction of changes in them;
ii) monitoring and control of the production circle;
iii) control of observance of hygienic requirements at the company;
iv) validation of processes;
v) personnel training;
vi) approval and monitoring of suppliers of initial and packaging materials;
vii) approval and monitoring of the organizations performing works on the contract, and suppliers of other outsourcing services connected with proper production practice;
viii) determination and monitoring of observance of storage conditions of materials and products;
ix) storage of records;
x) monitoring of observance of requirements of GMP;
xi) check, investigation and sampling it (is model) for the purpose of control of factors which can affect product quality;
xii) participation in the analysis from management of functioning of processes, product quality and quality management system and support of permanent improvement;
xiii) ensuring timely and effective exchange of information and finishing problematic issues on quality to administrative board of appropriate level.
Training
2.10. The producer shall provide personnel training which job responsibilities assume stay in production and warehouse areas or control laboratories (including technical and service personnel and the employees who are carrying out cleaning), and also other personnel which activities can exert impact on product quality.
2.11. Except the main training including the theory and practice of application of quality management system and GMP, each employed employee shall undergo primary training according to the job responsibilities. The producer shall provide the subsequent continuous personnel training, periodically estimating its efficiency in practice. Personnel training shall be provided according to the programs approved respectively by the production manager or the division manager of quality control. The producer shall store records about carrying out training.
2.12. The personnel working in zones where contamination constitutes danger (for example, in net zones or in zones where work with the highly active, toxic, infecting or sensibilizing substances) shall undergo special training.
2.13. Visitors and (or) not trained employees shall not be allowed in zones of production and quality control. If it is inevitable, they shall undergo previously instructing, in particular according to hygienic requirements to personnel and use of protective clothes. Their maintenance and observation of them shall be organized.
2.14. When training the principles of the pharmaceutical quality system, and also all measures improving their understanding and implementation shall be explained and be discussed in detail.
Hygienic requirements to personnel
2.15. At the company detailed programs for occupational health taking into account features of specific production shall be developed. These programs shall contain the procedures concerning health, observance of hygienic rules and requirements to personnel clothes. Each employee whose obligations assume stay in zones of production and control shall understand and precisely observe these procedures. The management of the company shall promote development of programs for hygiene which should be discussed when training.
2.16. Persons employed shall have medical examination. The producer shall approve the instructions providing its awareness on the state of health of personnel which can affect product quality. After primary medical examination regular subsequent medical examinations of personnel shall be performed.
2.17. The producer shall take the measures providing non-admission of persons with infectious diseases or open damages on open parts of the body to production of medicines.
2.18. Persons entering production zones shall wear the protective clothes corresponding to the transactions which are carried out in these zones.
2.19. In production and warehouse areas smoking, meal, drink, chewing, and also storage of foodstuff, drinks, tobacco products and personal medicines are forbidden. Any actions violating hygienic requirements in production rooms (zones) or other places which can exert adverse impact on product quality are not allowed.
2.20. It is necessary to avoid direct contact of hands of personnel with open products, and also with any part of the equipment contacting to products.
2.21. The personnel shall be trained in rules of washing of hands.
2.22. The special requirements relating to production of separate types of products (for example, sterile medicines), are given in appendices to these rules.
Consultants
2.23. Consultants shall have the corresponding education, preparation and experiment on the questions concerning activities for which consultation in the sphere they are attracted. It is necessary to keep their account with indication of personal data, residence address, qualification and the type of service provided by these consultants.
Principle
Rooms and the equipment should have, design, build, equip and to be operated so that they corresponded to the performed operations. Their arrangement and design shall minimize risk of mistakes and provide possibility of effective cleaning and servicing for the purpose of exception of cross contamination, accumulating of dust or dirt and any adverse factors for product quality.
Rooms. General requirements
3.1. The production circle of rooms, considering all measures for protection of production, shall represent minimum risk of contamination of materials or products.
3.2. It is necessary to carry out careful maintenance of rooms, guaranteeing that repair and servicing will not constitute any danger to product quality. Rooms should be cleaned and where it is applicable, to disinfect according to detailed written instructions.
3.3. Lighting, temperature, humidity and ventilation shall be corresponding and not make adverse effect (direct or indirect) on medicines during their production and storage, on proper functioning of the equipment.
3.4. Rooms shall be designed and equipped so that to provide the maximum protection against penetration in them of insects and (or) animals.
3.5. The measures preventing entrance to rooms of persons who do not have access rights in them shall be taken. Zones of production, storage and quality control shall not be used as checkpoints for personnel which in them do not work.
Production zone
3.6. Cross contamination shall be prevented for all medicines during the designing and operation of production rooms. Measures for prevention of cross contamination shall be commensurable with risks. For assessment and risk management it is necessary to use the principles of risk management for quality. Depending on risk level the allocated rooms and the equipment for production and (or) packaging operations can be required to control risk of possible cross contamination by some medicines.
It is necessary to allocate production sites if medicine represents risk:
i) which cannot be controlled by properly organizational and (or) technical measures, or
ii) the scientific estimates given toxicological do not confirm possibility of proper risk control (for example, the high-sensibilizing materials with allergenic potential, such as beta lactams), or
iii) the corresponding limits of residual quantities received by toxicological assessment cannot be well determined by means of validirovanny analytical method.
Further instructions are given in Chapter 5 of these rules and in appendices No. No. 2 - 6 to these rules.
3.7. It is preferable that planning solutions of rooms corresponded to the logical sequence of production operations and required levels of purity.
3.8. Planning solutions of working areas and intra production zones of storage shall provide the consecutive and logical placement of the equipment and materials minimizing risk of pereputyvaniye of various medicines or their components, providing lack of cross contamination and minimizing risk of the omission or the wrong implementation of any stage in case of production or control.
3.9. Where initial raw materials and primary packaging materials, intermediate or bulk products are subject to influence of the production circle, internal surfaces (walls, floors and ceilings) shall be smooth, without cracks and cracks on joints, shall not allocate particles, and also shall be cleared easily and effectively and, if necessary, be disinfected.
3.10. Pipelines, lighting instruments, ventilating installations and other systems of servicing shall be designed and located so that there were no deepenings complicating their cleaning. Whenever possible access to them for servicing shall be provided from the outside of production zones.
3.11. Points of connection to sewer drains shall be the corresponding sizes and are equipped with devices for prevention of the return flow. Whenever possible it is necessary to avoid open drain trenches, but if they are necessary, then they shall be superficial for simplification of cleaning and disinfection.
3.12. Production zones should be ventilated effectively; in them there shall be means for control of parameters of air (including temperature and, where is necessary, humidity and filtering) corresponding to the processed products to the performed operations and production zone.
3.13. Weighing of initial raw materials, as a rule, should be performed in the certain, intended for this purpose room.
3.14. When there is formation of dust (for example, during sampling, weighing, mixing and production operations, packaging of dry products), special measures of precaution for the purpose of the prevention of cross contamination and simplification of cleaning shall be taken.
3.15. Rooms for packaging of medicines shall be specially designed and located so that to avoid pereputyvaniye or cross contamination.
3.16. Production zones shall be well lit, especially where constant visual control is carried out.
3.17. Control in production process can be carried out in production zone if it does not create risk for engineering procedure.
Warehouse areas
3.18. Warehouse areas shall be rather capacious to provide the ordered storage of various material categories and products: initial raw materials and packaging materials, intermediate, bulk and finished goods, and also products which are in quarantine, products permitted for release, rejected, returned or withdrawn.
3.19. When designing and equipping warehouse areas it is necessary to provide proper storage conditions. In particular, they shall be net and dry, required temperature shall be maintained in them. If special storage conditions are required (for example, temperature, humidity), then it is necessary to provide and check such conditions, and also to perform their monitoring.
3.20. In places of acceptance and shipment protection of raw materials, materials and products from impact of weather conditions shall be provided. Receipt areas shall be designed and equipped so that the container with the arriving raw materials and materials before warehousing if necessary could be cleared.
3.21. If the mode of quarantine is provided with storage of products in separate zones, then these zones shall be accurately designated, and access to them is resolved the personnel having appropriate authority. Any other system replacing physical quarantine shall provide equivalent reliability.
3.22. As a rule, there shall be separate zone for sampling of initial raw materials. If sampling is performed in storage zone, then it shall be carried out so that to prevent contamination or cross contamination.
3.23. For storage rejected, withdrawn or returned raw materials, materials or products the isolated zones shall be provided.
3.24. Highly active substances and medicines shall be stored in the safe and protected zones.
3.25. It is necessary to pay special attention to safe and reliable storage of printed packaging materials as they are considered critical for ensuring compliance of medicine to the established requirements.
Quality control zones
3.26. As a rule, laboratories of quality control shall be separated from production zones. It is especially important for laboratories on control of biological and microbiological medicines and radioisotopes which shall be also separated from each other.
3.27. Control laboratories shall be designed so that to conform to requirements to the works which are carried out to them. In order to avoid mistakes and cross contamination they shall have the sufficient area. It is necessary to allocate the respective and suitable areas for storage of samples and records.
3.28. For the sensitive devices needing protection against vibration, electromagnetic fields, air humidity, etc. certain rooms can be provided.
3.29. Special requirements are imposed to laboratories in which works with specific to substances are carried out (for example, biological or radioactive materials).
Auxiliary zones
3.30. Recreation room and meal shall be separated other zones.
3.31. Rooms for disguise, toilets and shower cabins shall have convenient access, their layout and the sizes shall correspond to personnel number. It is not allowed that toilets were directly reported with production or warehouse areas.
3.32. Workshops shall be whenever possible separated production zones. If storage of spare parts and tools is performed in production zone, they should be contained in the rooms or the locked boxes provided for this purpose.
3.33. Vivariums shall be isolated from other zones, have separate entrance (access to animals) and separate systems of airpreparation.
Equipment
3.34. The design, installation and procedure for maintenance of production equipment shall correspond to its appointment.
3.35. Works on repair and maintenance of the equipment shall not constitute any danger to product quality.
3.36. The design of production equipment shall be such that it was possible to clear it easily and carefully. Cleaning should be carried out according to detailed written instructions. The equipment should be stored only in net and dry condition.
3.37. The stock for washing and cleaning should be chosen and used so that it did not become contamination source.
3.38. The equipment shall be installed so that not to allow emergence of any risk of mistakes or contamination.
3.39. The production equipment shall not constitute any danger to products. The parts of production equipment contacting to products shall not react with it, allocate or absorb substances in such degree that it could affect product quality and create thus any danger.
3.40. Accuracy and operating range of scales and other measuring instruments shall correspond to production and control operations in which they are used.
3.41. Calibration and checking of the scales and other measuring instruments registering and survey meters shall be carried out with certain frequency by the corresponding methods. It is necessary to draw up and keep records of such testing.
3.42. Stationary pipelines shall have accurate marking with indication of the substances passing on them and if it is required, the directions of flow.
3.43. Water pipelines cleared, waters for the injections (distilled, deionized) and, if necessary, other water should be subjected to sanitary processing according to written instructions in which limits of microbic contamination and the taken measures in case of their excess are specified.
3.44. The defective equipment shall be removed from production zones and zones of quality control or is marked as defective.
Principle
Proper documentation constitutes integral part of system of quality assurance and is crucial element of work according to these rules. In quality management system of the producer different types of the used documentation and data carriers shall be accurately established. Documentation can exist in various forms, including on the paper, electronic or photographic medium. Creation, management, control and registration of all activities which can directly shall be main goal of the applied system of documentation or is mediated to influence all aspects of quality of medicines. In addition to proper documentary registration of various processes and assessment of any observations the quality management system shall contain rather detailed instructions. These instructions promote general understanding of requirements so that it was possible to show their permanent observance.
There are 2 main types of documentation for fulfillment of requirements of these rules and registration of their observance: regulating - instructions (instructions, requirements) and registering - records (reports). It is necessary to apply the corresponding proper practice of documentary registration depending on document type.
The corresponding control for ensuring accuracy, integrity, availability and clearness of documents shall be implemented. The regulating documents shall be available in writing and shall not contain mistakes. The concept "in writing" is used in "the data which are written down or documented on data carriers, with which can be obtained in readable form" value.
Documentation required by proper production practice
File of the production site: the document in which the activities of the producer concerning these rules are described.
Types of the regulating documents (management and the requirement):
specifications - the documents containing detailed requirements to which there shall correspond the initial and packaging materials and products which are used or received in case of production. They are basis for quality evaluation of medicines;
production compoundings, technological instructions, instructions for packaging, techniques of testing - the documents containing the detailed information about all used initial raw materials, the equipment and the computerized systems (in case of their availability). These documents shall contain all instructions for implementation of engineering procedures, packaging, sampling and carrying out testing. Where it is applicable, it is necessary to specify all points of control in production process, and also the used process and analytical technologies together with eligibility criterions;
procedures (standard operational procedures (further - SOP)) - the documents containing requirements to accomplishment of certain transactions;
protocols - the documents containing requirements to carrying out and registration of separate transactions;
technical agreements - the agreements signed between customers and contractors concerning works which are performed by third parties (outsourcing).
Types of the registering documents (record (reports)):
records - the certificates confirming accomplishment of various actions for the proof of compliance to instructions (for example, actions, incidents, investigations). For the made series also contain history of each product series, including information about its realization. Records contain the basic data used for forming of other records. In case of use of electronic records to determine what data should be used as initial, shall the established users. All data on which decisions on quality are based shall be determined as basic data. The records relating to specific series can be collected in the file on series;
certificates of the analysis - the documents (passports, analytical leaves, other documents) containing the summary of results of testing of product samples or materials together with assessment of conformity of the established specification. Assessment of conformity of series to the approved registration file can be also based (entirely or partially) on data analysis, the parameters and results received in real time (the summary and variance reports). Such approach is applicable if in case of production of series the process and analytical technology (PAT) is used;
reports - the documents reflecting accomplishment of specific tasks, projects or investigations together with results, conclusions and recommendations.
Management of documentation
4.1. Requirements to all document types shall be established, and they should be observed. Requirements are applied equally to all document forms on different types of data carriers. Difficult systems require well documented explanation, validation and adequate control. Documents can be mixed in form, for example, some elements in electronic form, and others - on paper. It is necessary to establish interrelations and controls concerning originals of documents, official copies, data processing and records, both for mixed, and for the same systems of documentation. It is necessary to implement appropriate means of management concerning such electronic documents as templates, forms and source documents. There shall be adequate measures of control for ensuring integrity of records during the storage duration.
4.2. Documents shall be developed, be prepared, be approved and be distributed carefully. Depending on type they shall meet the requirements of the meeting parts of specifications of the researched medicine, the registration file, and also documents filed for receipt of the license for production. Copying of original documents for the purpose of receipt of working documents origin shall not make any mistakes when copying.
4.3. The regulating documents shall be approved and signed persons having right to sign with indication of date. Contents of documents shall be unambiguous, documents shall have unique identification. Date of Introduction in action shall be determined.
4.4. The regulating documents shall have the logical structure providing simplicity of their check. Style of statement of documents shall correspond to their intended use. Standard operational procedures, work instructions and techniques shall be written in the form assuming obligation of their accomplishment.
4.5. Documents within quality management system should be reviewed and staticized regularly, it is necessary to exclude use of obsolete versions.
4.6. Documents shall not be processed in hand-written type, however if hand-written entering into documents of data is provided, then there shall be enough place for such records.
Rules of proper documentary registration
4.7. Manuscript records shall be made accurately, is legible and so that the entered data could not be removed.
4.8. Records should be kept in case of accomplishment of each action and so that it was possible to trace all significant activities concerning production of medicines.
4.9. Any change made to the document shall be signed and dated. Change shall give the chance of reading of initial information. Where it is applicable, the change reason shall be specified.
Document storage
4.10. It shall be accurately determined what record belongs to each type of productive activity and where it is. Reliable control measures, validated in appropriate cases, for ensuring integrity of record throughout storage duration shall be provided.
4.11. Special requirements are imposed to documentation of series which should be stored during 1 year after the termination of expiration date of this series or at least 5 years after issue of permission to realization of series by the authorized person depending on what term longer. For the medicines intended for clinical trials, it is necessary to store documentation of series at least 5 years after the termination or the official termination of the last clinical trials in which used this series. In requirements of the legislation of state members and the rights of the Union to specific types of medicines (for example, high-technology medicines for the most modern types of treatment) can be established longer storage periods of certain documents.
4.12. For other types of documentation the storage duration depends on types of activity which this documentation accompanies. Critical documentation, including the basic data (for example, the concerning validations or stability) confirming information of the registration file it is necessary to store throughout effective period of the registration certificate. It is admissible to delete certain documentation (for example, the basic data accompanying reports on validation or stability) if data were replaced with complete set of new data. Reasons for such actions shall be drawn up documentary. At the same time it is necessary to consider requirements to storage of documentation of series (for example, in case of data on process validation the accompanying basic data it is necessary to store at least the same time, as well as documentation for all series for which permission to release is confirmed with data of these validation researches).
In the following Sections examples of necessary documents are given. In quality management system all documents necessary for quality assurance of products and safety of patients shall be described.
Specifications
4.13. It is necessary to have available appropriately approved specifications on initial and packaging materials and finished goods with indication of approval date.
Specifications on initial and packaging materials
4.14. Specifications on initial materials, primary or printed packaging materials shall contain the following information (the corresponding references to information where it is applicable):
a) the description of materials including:
name and internal code;
the reference to pharmakopeyny Article or to other regulating documentation or the regulating document (in case of their availability);
the name of approved suppliers and if it is possible, the producer of initial and packaging materials;
sample of printed materials;
b) instructions for sampling and carrying out testing;
c) qualitative and quantitative indices with indication of admissible limits;
d) storage conditions and precautionary measures;
e) expiration date or the maximum storage duration before repeated control.
Specifications on intermediate and bulk products
4.15. Specifications on intermediate and bulk products shall be available for critical stages or in case of its acquisition and shipment. These specifications shall be similar to specifications respectively on initial raw materials or finished goods.
Specifications on finished goods
4.16. Specifications on finished goods shall contain the following data:
a) name of medicine and code (if necessary);
b) structure or reference to the relevant document;
c) description of dosage form and detailed data on packaging;
d) instructions for sampling and carrying out testing or reference to the relevant document;
e) qualitative and quantitative indices with indication of admissible limits;
f) storage conditions and special precautionary measures when using (if necessary);
g) expiration date.
Production compounding and technological instructions
On each made medicine and each size of series it is necessary to have the approved written production compoundings and technological instructions.
4.17. The production compounding shall include:
a) the name of medicine with reference to code according to the specification;
b) description of dosage form, dosage of medicine and size of series;
c) the list of all initial materials which will be used, with indication of the number of everyone. Also all substances which can disappear during engineering procedure shall be specified;
d) the expected exit of finished goods with indication of admissible limits and exits of the corresponding intermediate products where it is possible.
4.18. Technological instructions shall contain:
a) data on the place of implementation of process and on the capital equipment which shall be used at the same time;
b) methods or references to methods which shall be used for preparation of the critical equipment (for example, cleaning, installation, calibration, sterilization);
c) instructions for check that the equipment and workplace are free from the previous products, unnecessary for the planned process of documents and materials, and also on check of purity of the equipment and its readiness for the following process;
d) detailed postadiyny technological instructions (for example, check of materials, preliminary processing, procedure for loading of raw materials, critical process parameters (time, temperature, etc.));
e) instructions on all types of control in production process with indication of admissible limits;
f) requirements to storage of bulk products if necessary, including requirements to container, marking and special storage conditions where it is required;
g) all subjects to observance special precautionary measures.
Instructions for packaging
4.19. For each medicine, the size and type of packaging there shall be available instructions for packaging. As a rule, they shall include the following data (the reference to them):
a) the name of medicine, including number of series of bulk products and ready-made product;
b) the description of its dosage form and dosage (where it is applicable);
c) the amount of medicine in final packaging expressed in pieces, units of mass or amount;
d) the complete list of all required packaging materials, including their quantities, the sizes and types with indication of the code or number relating to specifications on each packaging material;
e) where it is applicable, the sample or the copy of the corresponding printed packaging materials and samples specifying the place of drawing number of series and expiration date of products;
f) requirements for check that the equipment and workplace are free from the previous products, documents or materials unnecessary for planned activities on packaging (cleaning of the line), and also on check of purity of the equipment and its readiness for the following process;
g) data on the special measures of precaution which are subject to observance (including careful check of zone of packaging and the equipment) guaranteeing cleaning of the packaging line before work;
h) packaging process description with all main auxillary operations and the used equipment;
i) the description of control in production process with instructions for sampling and admissible limits.
Other documents concretizing provisions of production compounding and technological instructions can be in addition developed.
Records on production of series
4.20. On each made series it is necessary to keep records on production of series.
They shall be based on the corresponding parts of the approved documents (production compounding and technological instructions) and to contain the following information:
a) name and number of product series;
b) dates and time of the beginning and completion of engineering procedure, and also main intermediate stages;
c) surname and initials of the operator (operators) of each main technological transaction, and also person which checked each of these transactions, if necessary;
d) number of series and (or) number of analytical control, and also actually given amount of initial materials of each type (including number of series and amount of any material added regenerated or processed);
e) data on any relevant technological transaction or any action, and also on the capital used equipment;
f) records on control in production process with indication of contractors and the received results;
g) production yield on various production stages;
h) data on special problems with the signed authorization on any variation from technological instructions;
i) the signature of person responsible for engineering procedure, with indication of date.
If validirovanny process is exposed to permanent monitoring and control, the reports automatically created can be limited to the short summary about compliance and variance reports (departures) from the specification.
Records on packaging of series
4.21. On each made series or part of series it is necessary to keep records on packaging of series. They shall be based on the corresponding parts of instructions for packaging.
Records on packaging of series shall include the following data:
a) name and number of series of medicine;
b) date (dates) and time of carrying out transactions on packaging;
c) surname and initials of the operator (operators) of each main technological transaction, and also person which checked each of these transactions, if necessary;
d) records of checks of identity and compliance to instructions for packaging, including results of control in production process;
e) detailed data on the performed transactions on packaging, including references to the used equipment and packaging lines;
f) samples of the used printed packaging material, including samples with put with number of series, expiration date and other additional marking data where it is applicable;
g) data on special problems or unusual incidents with the signed authorization on any variation from instructions for packaging;
h) quantity and the reference to number or the name of all printed packaging materials and bulk products issued, used, destroyed or returned on warehouse, and also quantity of ready-made product for creation of the corresponding balance. Electronic control in the course of packaging is the basis for non-inclusion of such information;
i) the signature of person responsible for packaging process, with indication of date.
Procedures and records. Acceptance
4.22. On acceptance of each delivery of each type of initial materials (including bulk, intermediate or finished goods), and also primary, secondary and printed packaging materials there shall be available written procedures and confirmatory records.
4.23. Records on acceptance shall contain:
a) the name of material in delivery note and on container;
b) the intra factory name (if it differs from the name specified in the subitem "an" of this Item) and (or) material code (if necessary);
c) date of acceptance;
d) name of the supplier and name of the producer;
e) number of series of the producer or code number;
f) total quantity of the received materials and number of units of packagings;
h) number of series assigned after acceptance;
i) any essential notes.
4.24. There shall be available written procedures for intra factory marking, quarantine and storage initial, packaging and if it is necessary, other materials.
Sampling
4.25. There shall be available written procedures for sampling containing data on the used methods and the equipment, quantities which shall be selected, and any subjects to observance precautionary measures in order to avoid contamination of material or any deterioration in its quality.
Carrying out testing
4.26. There shall be available written techniques of testing of samples of materials and products on various production stages with indication of the used methods and the equipment. The carried-out testing shall be drawn documentary up.
Other
4.27. There shall be available written procedures establishing procedure for release and variation of materials and products, in particular issue by the authorized person (persons) of permission to finished product output. All records shall be available to the authorized person. The system for designation of special observations and any changes in the relation of critical data shall be implemented.
4.28. It is necessary to conduct and keep records on realization of each product series for the purpose of simplification of withdrawal of this series in case of need.
4.29. There shall be available in writing stated politicians, the principles, procedures, plans, protocols, reports and records of activity undertakens or the made conclusions relating to them where it is applicable, in the relation:
validations and qualifications of processes, equipment and systems;
installation and calibration of the equipment;
transfer of technologies;
maintenance, cleaning and disinfection;
personnel, including lists of persons with specimen signatures, training in these rules and technical issues, disguise and hygienic requirements, and also learning efficiency check;
monitoring of the production circle;
the actions directed to control of emergence and distribution of wreckers;
claims;
withdrawals of products;
returns of products;
control of changes;
investigations of variations and discrepancies;
internal audit of quality (compliance to requirements of these rules);
generalization of records (for example, overview of product quality) if necessary;
audit of suppliers.
4.30. There shall be available accurate operating manuals of the main units of the production and control and analytical equipment.
4.31. It is necessary to keep registers for the most important or critical processing and control and analytical equipment, and also for rooms where products were made. In these magazines it is necessary to register in chronological procedure any use of these rooms, the equipment and methods, carrying out calibration, maintenance, cleaning or repair with indication of the dates and persons who performed these works.
4.32. It is necessary to record documents within quality management system.
Principle
Technological transactions shall be performed on accurately established procedures, they shall answer these rules for product receipt of required quality and correspond to permission (license) for production and the registration file.
General requirements
5.1. Production process shall be performed and controlled by qualified personnel.
5.2. All actions which are carried out with materials and products such as acceptance and quarantine, sampling, storage, marking, issue in production, engineering procedure, packaging and realization, it is necessary to perform according to written procedures or instructions and to draw up documentary.
5.3. All arriving materials shall be checked to guarantee that delivery corresponds to the order. The container shall be cleared (if necessary) and marked with indication of the information required.
5.4. The facts of damage of container and packaging and any other problems which can adversely affect quality of materials shall be investigated, drawn up documentary, and information on them shall be reported in divisions of quality control.
5.5. The arriving materials and the made finished goods shall be located immediately in the quarantine organized by the principle of separate storage or at the expense of organizational measures and to contain in it before receipt of permission to their use or realization.
5.6. Acceptance purchased intermediate and bulk products is carried out according to the rules existing for initial materials.
5.7. All materials and products should be stored in the corresponding conditions established by their producer in the certain procedure providing separation on series and the established priority of use of warehouse stocks.
5.8. It is necessary to perform exits and material balance to be convinced of lack of discrepancies with admissible extreme values.
5.9. Simultaneous or consecutive carrying out transactions with various products in the same room, except as specified, is not allowed if there is no risk of pereputyvaniye or cross contamination.
5.10. Products and materials shall be protected from microbic and other contamination on all production stages.
5.11. During the work with dry materials and products it is necessary to take special precautionary measures on prevention of education and distribution of dust. It is especially important during the work with highly active and sensibilizing substances.
5.12. During all production process all used materials, container for bulk products, the main units of equipment and in need of the room shall be marked by labels or different way with indication of the made products or the processed materials, and also their dosage (where it is applicable) and number of series. Where it is acceptable, such marking shall specify stage of engineering procedure also.
5.13. The labels attached to containers, the equipment or rooms shall be accurate, unambiguous, and also correspond to the form established at the company. It is recommended in addition to information on labels for specifying of the status (for example, "in quarantine", "is accepted", "rejected", "net", etc.) to use color marking.
5.14. It is necessary to control correctness of connection of the pipelines and other parts of the equipment applied to transportation of products from one zone in another.
5.15. Any variations from instructions or procedures are not allowed. If there is variation, it shall be previously in writing authorized by person having appropriate authority with involvement (if necessary) of division of quality control.
5.16. Production rooms can include only the personnel having right of access in them.
Prevention of cross contamination in case of production
5.17. Production of not medicinal appointment shall not be performed in rooms and on the equipment, the medicines intended for production, but if it is proved, it can be authorized if measures for prevention of cross contamination of medicines according to the measures provided below and in Chapter 3 of these rules are taken.
Production and (or) storage of such technical poisons as pesticides (except cases when they are used for production of medicines) and herbicides, is inadmissible in the rooms used for production and (or) storage of medicines.
5.18. Contamination of initial materials or products shall be prevented by other initial materials or products. Such risk of accidental cross contamination resulting from uncontrollable distribution of dust, gases, vapors, aerosols, genetic material or organisms from active agents, other initial materials and products in processing from remaining balance on the equipment and from clothes of operators, shall be estimated. The risk degree depends by nature kontaminiruyushchy material and kontaminiruyemy products.
The most dangerous is contamination of the medicines intended for injections, and also accepted for a long time.
Nevertheless contamination of any products represents risk for safety of patients depending on nature and extent of contamination.
5.19. Cross contamination needs to be prevented, first of all due to proper designing of rooms and the equipment as it is specified in Chapter 3 of these rules. It shall be supported with the corresponding design of process and implementation of any adequate technical or organizational measures, including the effective and reproduced processes of cleaning for risk control of cross contamination.
5.20. For assessment and risk control of cross contamination of the made products risk management process for quality, including assessment of activity and toxicological assessment shall be used. Also it is necessary to take into account such factors as design (project) and use of rooms and the equipment, flows of personnel and materials, microbiological control, physical and chemical characteristics of active agents, process parameters, possibilities of processes of cleaning and analytical opportunities concerning the corresponding limits set proceeding from assessment of the made products. The result of risk management process for quality shall be the basis for determination of need and level to which rooms and the equipment shall be allocated for specific medicine or group of medicines. Level of allocation can vary from specially allocated parts contacting to product before allocation of all production. Localization of productive activity in the allocated autonomous production zones on the multi-purpose site where it is justified can be acceptable.
5.21. Results of risk management process for quality shall become basis for determination of level of the technical and organizational measures necessary for risk control of cross contamination. These measures can include, without being limited to it, the following.
Technical measures:
i) the allocated productions (rooms and the equipment);
ii) the autonomous floor spaces having separate processing equipment and separate systems of ventilation and air conditioning (HVAC). Also can be desirable to isolate certain auxiliary systems from those which are used in other zones;
iii) the design of production process, rooms and the equipment allowing to minimize possibility of cross contamination in processing, operation, maintenance and cleaning;
iv) use of "the closed systems" for processing and transfer of material (product) between the equipment;
v) use of systems with physical barrier, including insulators, as measures for localization;
vi) controlled removal of dust near pollution source, for example via local exhaust devices;
vii) allocation of processing equipment, the parts contacting to product or separate parts which are the most difficult for clearing (for example, filters), tools for servicing;
viii) use of disposable technologies;
ix) use of the equipment designed taking into account cleaning simplification;
x) proper use of air locks and the cascade of pressure for localization of the potential contaminant containing in air within certain zone;
xi) minimizing of the contamination hazard caused by recirculation or reuse of the crude or insufficiently purified air;
xii) use of systems of automatic cleaning on the place with validirovanny effectiveness;
xiii) separation of zones of wash of the equipment, drying and storage for general zones of cleaning.
Organizational measures:
i) allocation of all production or autonomous floor spaces on the basis of campaigns (allocation with separation in time) with the subsequent cleaning with validirovanny effectiveness;
ii) storage of special protective clothes in zones where products with high risk of cross contamination are processed;
iii) verification of cleaning after release of each product for the purpose of maintenance of efficiency of approach of risk management for quality concerning products of high risk;
iv) verification of cleaning of the surfaces which are not contacting to products and monitoring of air in production zone and (or) adjacent zones depending on risk of contamination for confirmation of efficiency of measures against contamination the weighed particles or in the way of mechanical transfer;
v) special measures according to the address with the waste polluted by washing waters and the polluted clothes;
vi) registration of cases of spilling and dispersal, incidents or variations from procedures;
vii) development of processes of cleaning for rooms and the equipment so that cleaning processes in itself did not represent risk of cross contamination;
viii) development of detailed forms for records in the course of cleaning for ensuring accomplishment of cleaning according to the approved procedures and use of labels of the status of cleaning of the equipment and production zones;
ix) use of general zones of cleaning in case of compatibility of processes;
x) supervision of behavior of personnel for ensuring learning efficiency and compliance to proper actions of procedural control.
5.22. Actions for prevention of cross contamination and their efficiency should be checked periodically according to the established procedures.
Validation
5.23. Actions for validation shall promote accomplishment of these rules and shall be held according to the established procedures. Results of the held events and the conclusion on them shall be drawn up documentary.
5.24. In case of introduction of new production compounding or new production method it is necessary to prove their suitability for serial production. It shall be proved that this process when using of the provided materials and the equipment allows to make products of required quality constantly.
5.25. Essential changes of production process, including any change of the equipment or initial and packaging materials which can affect product quality and (or) reproducibility of process, shall undergo validation.
5.26. Processes and procedures should be subjected to periodic revalidation (repeated validation) for guarantee that they remain suitable for achievement of certain results.
Initial materials
5.27. Within the pharmaceutical quality system the choice, qualification, approval and maintenance of the status of suppliers of initial materials along with purchases and acceptance shall be documented. Level of control shall be pro rata to the risks connected with specific materials taking into account source of their origin, production process, complexity of supply chain and final purpose of material in medicine. For each approved supplier or material there shall be available confirmatory certificates. The personnel involved in these activities need to have urgent knowledge of suppliers, supply chains and the related risks. Whenever possible initial materials should be acquired directly at their producer.
5.28. The quality requirements of initial materials established by producer of medicine shall be approved with suppliers. The corresponding aspects of production, testing and control, including the requirement to processing, marking, packing and realization, procedures for consideration of claims, response and withdrawal, shall be fixed in official agreements on quality or in specifications.
5.29. Approval and maintenance of the status of suppliers of active pharmaceutical substances and excipients requires the following.
For active pharmaceutical substances:
the traceable supply chain shall be established. The risks connected with supply chain (from initial materials for active pharmaceutical substance to ready medicine) shall be exposed to formal assessment and recurring inspection. There shall be adequate measures on decrease in risk degree concerning quality of pharmaceutical substance;
shall be available and remain records about traceability of each supply chain;
audits of producers and distributors of pharmaceutical substances, for the purpose of confirmation of conformity to requirements of proper production practice and proper distributor practice shall be booked. The holder of the license for production of medicine shall check observance of such requirements independently or through person acting from his name under the contract;
for providing assessment of observance of these rules audits shall have the corresponding duration and audit area. It is necessary to pay attention to sources of potential cross contamination from other materials used on the production site. The report shall reflect completely all information, including any shortcomings found as a result of audit. All necessary adjusting and warning actions shall be performed;
the subsequent audits shall be booked with the frequency established on the basis of risk analysis for ensuring compliance with standards and further use of the approved supply chain.
For excipients:
excipients and suppliers of excipients shall be controlled on the basis of results of the formalized system of risks assessment for quality.
5.30. In each supply of initial materials the container shall be checked for integrity of packaging, including integrity of seals, and also for compliance of the data specified in delivery note, to labels of the supplier and the approved producer and the supplier of information approved by producer of medicine. Acceptance checks shall be documented.
5.31. If one supply of material consists of various series, then each series needs to be considered as separate concerning sampling, carrying out testing and issue of permission to use.
5.32. The initial materials which are in the warehouse area shall be appropriately marked according to subitem 5.13 of part I of these rules. Labels shall contain the following information:
the appropriated product name and if necessary intra factory code;
number of series assigned when obtaining;
the status of content where it is applicable (for example, in quarantine, on testing, it is authorized, rejected);
expiration date or date after which repeated control where it is applicable is required.
If completely computerized storage systems are used, then the specified information shall not contain on the label in readable form.
5.33. The corresponding procedures or measures guaranteeing authenticity of content of each unit of container of initial materials shall be determined. The container from which tests were selected shall be marked according to subitem 6.13 of part I of these rules.
5.34. It is necessary to use only those initial materials which use is authorized division of quality control and which expiration date did not expire yet.
5.35. Producers of finished goods bear responsibility for all testing of initial materials which are specified in the registration file <1>. Producers of finished goods can use in parts or in full results of testing of the approved producer of initial materials, but shall execute at least testing for authenticity of each series according to appendix No. 8 <2>.
<1> Similar approach should be applied to packaging materials as it is specified in Item 5.42 of these rules.
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