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GMP Standards of Russian Federation for Immunobiological Products
GMP Standards of Russian Federation for Immunobiological ProductsState sanitary and epidemiological norm-setting of the Russian Federation
State sanitary and epidemiological rules and norms 3.3.2. Medicinal immunobiological products
Good Manufacturing Practice for medicinal immunobiological products
Sanitary and Epidemiological Rules
ÑÏ.3.3.2.1288-03
Official edition
The Ministry of Health of Russia
Moscow 2003 3.3.2. Medicinal immunobiological products
Good Manufacturing Practice for medicinal immunobiological products
Sanitary and Epidemiological Rules
ÑÏ.3.3.2.1288-03 ÁÁÊ 51.9+52.54.8
Í17
Í17 Good manufacturing practice for immunobiological products: Sanitary and epidemiological rules, M., Federal Center for State Epidemiologic Control at the Ministry of Health of Russia, 2003 – 80 pg.
ISBN 5-7508-0444-5
ÁÁÊ 51.9+52.54.8
Editors Akopova N.E., Kozhoka N.V., Kuchurova L.S.
Formatting Smirnov V.V.
Signed for printing 24.11.03
Format 60x88/16
Printing pages 5.0
Request 61
Printed 3000 copies
Ministry of Health of the Russian federation
101431, Moscow, Rakhmanovskij ln., 3
The original layout is prepared for printing and printed by the Editorial Department of the Federal Center for State Sanitary and Epidemiological Control at the Russian Ministry of Health
125167, Moscow, Aeroport Drive, 11.
The sales division, Phone 198-6101
© Russian Ministry of Health, 2003
© Federal Center for State Sanitary and Epidemiological Control at the Russian Ministry of Health, 2003 Federal Law
“About sanitary and epidemiological well-being of the population”
# 52-Ô3 of March 30th, 1999.
“The state sanitary and epidemiological rules and regulations” (hereafter – sanitary rules) – regulatory law statements, setting the sanitary and epidemiological requirements (including safety criteria and/or criteria of environmental safety for humans, hygienic and other guidelines), non-compliance with which creates a threat for human life or health, as well as a threat of outbreak and spreading of diseases” (Section 1).
“Meeting the sanitary requirements is mandatory for all citizens, individual entrepreneurs, and legal entities” (Section 39).
“Violation of sanitary law leads to disciplinary, civil, and criminal responsibilities” (Section 55). Ministry of Health of the Russian Federation
Sanitary Physician General of the Russian Federation
DECREE
18.04.03 No.60
About: enacting of Sanitary and Epidemiological Rules ÑÏ.3.3.2.1288-03
Based upon the Federal Law “About sanitary and epidemiological well-being of the population” of March 30th, 1999 No.52-Ô3 and The Principles of State Sanitary and Epidemiological Norm-setting, approved by the Russian Government Order of June 24, 2000, No.554, I hereby
ORDER:
Enact, starting from June 25th, 2003, The Sanitary and Epidemiological rules “Good manufacturing Practice for medicinal immunobiological products. ÑÏ.3.3.2.1288-03”, approved by the Sanitary Physician General of the Russian Federation on March 17th, 2003.
(Signature) G.G.Onishchenko Ministry of Health of the Russian Federation
Sanitary Physician General of the Russian Federation
DECREE
18.04.03 No.61
About: Cancelling of ÑÏ 3.3.2.015-94
Based upon the Federal Law “About sanitary and epidemiological well-being of the population” of March 30th, 1999 No.52-Ô3 and The Principles of State Sanitary and Epidemiological Norm-setting, approved by the Russian Government Order of June 24, 2000, No.554, I hereby
ORDER:
Starting with 25.06.03, the effective date of The Sanitary and Epidemiological rules “Good manufacturing Practice for medicinal immunobiological products, ÑÏ.3.3.2.1288-03”, consider the Sanitary and Epidemiological Rules “Manufacturing and Control of medicinal immunobiological products” ÑÏ 3.3.2.015-94, approved by the order of Russian State committee of sanitary and epidemiological control No.8 of 12.08.94 as being no longer in effect
(Signature) G.G.Onishchenko Contents
Appendix 1. Terms and definitions
Appendix 2. Integrated protocol for ADT-antitoxin manufacturing and testing
Appendix 3. Standard sample certificate form
Appendix 4. Sample SOP
Bibliography APPROVED
Sanitary Physician General of the Russian Federation,
First vice-minister of Health of the Russian Federation
G.G.Onishchenko
March 17th, 2003
Effective date: June 25th, 2003
3.3.2. MEDICINAL IMMUNOBIOLOGICAL PRODUCTS
Good manufacturing practice for medicinal immunobiological products
Sanitary and epidemiological rules
ÑÏ.3.3.2.1288-03
1.1. These sanitary and epidemiological rules (hereafter – sanitary rules) are developed in accordance with the Federal Law “About sanitary and epidemiological well-being of the population” of March 30th, 1999 No.52-Ô3 (Law Code of the Russian Federation, 1999, N0.14, ch.1650), and The Principles of State Sanitary and Epidemiological Norm-setting, approved by the Russian Government Order of June 24, 2000, No.554 (Law Code of the Russian Federation, 2000, No.31, ch.3295).
1.2. Sanitary rules set administrative, sanitary and epidemiological requirements for manufacturing and testing of medicinal immunobiological products (MIBP) that will guarantee their activity, safety, and stability.
1.3. Sanitary rules are intended for the use of organizations and individual entrepreneurs manufacturing medicinal and immunobiological products, regardless of their state organ reporting status and the property form.
2. General Provisions
2.1. Organizations and individual entrepreneurs, producing medicinal immunobiological products, should have the manufacturing conditions according to the principles of good manufacturing practice and these sanitary rules.
2.2. In each organization, there must be established a quality management system consisting of:
· Quality assurance system;
· Good manufacturing practice, including Quality Control/
2.3. For proper functioning of the quality management system, a quality assurance department (group) (hereafter – QAD) and Department for Biological and Technological Control (hereafter – DBTC) are to be formed.
2.4. All quality-related activities should be documented.
2.5. The quality management system should guarantee the following:
· During the product manufacturing the requirements of Good Laboratory Practice, Good Clinical Practice, and Good Manufacturing Practice were followed in the part of development, testing, and manufacturing conditions for MIBP;
· All manufactured products have Regulatory Documents (hereafter – RD);
· All manufacturing and controlling operations are guided by instructions or standard operating procedures (hereafter – SOP), approved as required;
· The manufacturers are supplied with raw materials, reagents, and other materials, including packaging, that comply with specific requirements;
· The validation and testing of equipment, instruments, technological processes and methods is conducted;
· The raw materials, other materials, reagents, and packaging components used in manufacturing MIBP are in compliance with the RD requirements and have passed the mandatory testing upon their delivery;
· All products are subject to necessary testing according to established techniques both during the manufacturing process and upon its completion.
2.6. All testing results should be supported by the following conditions:
· All controlling and measurement instruments (hereafter – CMI), pipettes, equipment, and the same are regularly calibrated and subject to metrological control and validation;
· The MIBP testing allows providing the required product quality until the expiry date;
· Regular inspections are conducted (internal inspections of all the rooms, laboratories, and departments without exceptions);
· The regulations for storage and transportation conditions for MIBP are followed.
2.7. The manufacturer provides the MIBP quality and guarantees their compliance with suggested use and the regulatory documents requirements;
2.8. The Good Manufacturing Practice as a crucial part of the quality management system is ensured by compliance with the following MIBP manufacturing conditions:
2.9. The MIBP quality control is subject to the following requirements:
3.1.The Quality Assurance Department (group) shall be a self-sufficient and independent from the manufacturing process administrative unit.
3.2. In all cases where good manufacturing practice requirements and these Sanitary Rules’ violations are revealed, or the manufactured products quality is not compliant with the RD requirements, or the inspecting authorities give a notice, etc. – procedures should exist for notifying of the responsible manager in a timely manner;
3.3.The quality assurance department should guarantee the following:
3.4.The main responsibilities of the quality department are defined by the “The quality unit guideline”, are not transferable to other units and contain the following:
4.1. DBTC should be independent of production and should occupy a separate, isolated facility.
4.2. DBTC should:
4.3. The structure and personnel of the DBTC should be compliant with regulations and production volumes.
4.4. The manufacturer has a right to market a batch of product only after it was approved by the DBTC upon receiving test results and issuing the batch passport. The passport form should be agreed upon with the national control organization or the concerned testing organization.
4.5. DBTC should keep the testing protocols for each manufactured batch of MIBP for human use for 2 years, all other MIBP – for at least 6 months.
4.6. The MIBP functions:
4.6.1 The entry control of the raw materials, other materials, water, lab ware, labels, packaging materials for compliance with all the requirements and specifications with issuing a permit for their use in manufacture and control;
4.6.2. Control over meeting the RD requirements for storage of the raw materials, other materials, reagents, semi-finished and finished products on the premises.
4.6.3 Participation in the step-by-step control conducted in accordance with the manufacturing schedule.
4.6.4 Control over compliance with SOP requirements for sample taking:
· For entry control;
· For standard sample museum storage of the reagents, materials, etc.;
· For control at all steps of the manufacturing;
· For testing of a batch of finished product;
· For standard sample museum storage of batches of finished products.
4.6.5 A batch of a finished product should be tested in the following order:
· The manufacturing room presents to the DBTC the packaged and labeled batch of the product, as well as the batch manufacture protocol;
· The DBTC tests the labeling and packaging quality for compliance with the approved standards, the product’s appearance, the user’s guide presence in the packaging, and where applicable – a file for ampoules opening, a pipette, etc.;
· DBTC conducts batch sample taking according to SOP in amounts sufficient for all testing, does the testing, and if the testing results are positive takes samples for standard sample museum storage.
The results of the batch control are judged positive if upon completing all tests suggested by the EPS all the results are compliant with the EPS requirements.
The control results are considered negative if at least one of the tested parameters is not compliant with the requirements.
The results of the batch control are documented in a protocol according to SOP, and the batch passport is issued.
4.6.6 DBTC issues an invoice for transferring a batch of the product to the finished products warehouse.
4.6.7 The DBTC labels all batch containers for compliance with EPS.
4.6.8 If a batch does not pass DBTC testing, the following should be done:
· In case of reversible defects not affecting the physical, chemical, and biological features of the product, DBTC returns the batch to the manufacturing room for correcting the problem;
· The batch must be remanufactured using the approved technology, suggested by the manufacturing schedule for this product. After the remanufacturing the batch is given a number;
· The batch, remanufactured according to suggested by the manufacturing schedule technology for the product, is allowed to be presented to the DBTC again. After the batch remanufacturing it is given the next number;
· If remanufacturing is not possible the batch is considered defective and sealed with the DBTC seal. The disposal of the defective batch is conducted in accordance with SOP and documented. DBTC keeps records of all the defective batches.
4.6.9 DBTC is checking for compliance with the RD requirements for transporting of semi-finished and finished products.
4.6.10 DBTC is issuing the following documents:
· A passport for each released product batch
· Unified manufacturing protocols for the products of the national vaccination calendar;
· Unified manufacturing protocols for the epidemiology-indicated vaccination calendar products;
· Quarterly and yearly DBTC work reports for the NCO.
4.6.11 DBTC sends to NCO or the respective testing organizations:
· Batches samples of MIBP for control (the number of batches should be coordinated with the testing organization of NCO of MIBP);
· The passports for each batch released;
· Unified manufacturing protocols for products of the national vaccination calendar and epidemiology-indicated vaccination calendar;
· Quarterly and yearly DBTC work reports.
4.6.12 DBTC participates in the claim investigation, as well as investigates the causes of defects upon the NCO or respective testing organization control results:
· Conducts the control of the batch samples from the claim source, in comparison with the museum samples. Upon confirmation of non-compliance of the museum batch samples with the EPS requirements, the defective batch is rejected, and the rejection is documented;
· Participates in investigating of the defects causes during the batch manufacture and non-revealing of the defects in the DBTC batch control;
· Conducts testing of the experimental manufacturing batches, MIBP being developed for presentation to NCO or for use in clinical and state trials;
· Keeps records of labels, controls their use and storage.
4.7. The standard sample museum is a structure unit of DBTC and is intended for storage of manufactured by the plant batch samples.
4.7.1 The standard samples storage facility should be isolated from other structure units and equipped under the requirements for storage of respective MIBP. In the museum room shelving are placed, labeled with all the necessary product information (name, batch #, expiry date).
4.7.2 The standard samples of every product should be stored at a place designated for this particular product.
4.7.3 The standard samples museum facility is sealed with the DNTC seal.
4.7.4 Manager of DBTC is responsible for the museum forming and the storage conditions for the standard samples, as well as for necessary samples removal.
4.7.5 The standard samples of MIBP batch produced by the manufacturer are intended for evaluation of MIBP quality in case of:
· Claims from end users regarding the product quality;
· Revealing of non-compliance of the product batch samples with the RD requirements by NCO or other testing organization;
· For product quality monitoring during storage.
4.7.6 Standard samples of the manufactured product batch are taken randomly in the amount necessary for complete double testing for compliance with the ETS requirements.
4.7.7 Standard samples’ taking is done according to SOP by a DBTC staff and the manufacturing unit manager.
4.7.8 All samples taking information together with the passport data about testing results and name of the sample taking employee, is documented in a special journal.
4.7.9 DBTC should periodically, before the product expiry date, conduct a non-destructing control of the physical features of MIBP batch and document the results in the journal.
4.7.10 In case of changes in physical features of a product batch, the consumer is sent a direction of suspending the batch use. A commission should decide whether further use of the product should be allowed, according to SOP. The disposal of a series of a product batch in case of non-compliance with the ETS requirements is documented.
4.7.11 The information of standard samples removal, including the cause of removal, amount, test results, names and signatures of staff members who conducted the removal and testing, is documented in the respective journal.
4.7.12 The DBTC manager keeps the registration journal with all the information about standard samples.
4.7.13 The standard samples of each finished product batch should be stored up to one year after the expiry date for human use products, and 6 months after the expiry date – for diagnostic products and media.
4.8. The samples taking procedure for NCO and other testing organizations control include the following:
4.8.1 Only a DBTC staff member has a right to take samples for NCO and other testing organizations control.
4.8.2 The batch samples that passed the DBTC testing are sent for NCO or other testing organizations control in amounts necessary for conducting complete testing.
4.8.3 The samples taking for testing, standards museum, and sending to NCO or other testing organizations is documented. The samples taken are isolated from the rest of product, packaged, and sealed immediately.
5. The requirements for personnel training, medical care, and measures for job safety
5.1. The manufacturer should be staffed with adequate number of personnel qualified by appropriate education capable of performing manufacture or quality control procedures according to SOP and instructions. The employee should work in the same room during the entire workday, and work on manufacture of only one MIBP.
5.2.The personnel qualification requirements.
5.2.1 The newly hired employees receive training in the manufacture rules and conditions, including the GMP and GLP guidelines, SOP and instructions according to the particulars of the job. Personnel working with microorganisms of I and II pathogenic groups, receives additional training under a special program.
5.2.2 Personnel are regularly re-trained, and the employee professional education programs are regularly revised.
5.2.3 The personnel training system should include initial, periodic, special, and emergency trainings. The initial training is given with the new hires according with their job descriptions. The emergency training is given in case of revealing a mistake that resulted or could have resulted in deteriorating of the product quality.
5.2.4 The training system should cover any manufacture of activity affecting the finished product quality. The main goal of training is achieving a standard performing of manufacturing procedures. The personnel training system is periodically evaluated for effectiveness and the personnel performance is monitored for compliance.
5.2.5 The training may be given in the form of lectures and practical trainings, conducted in house or by other organizations, as well as in the form of seminars, exhibitions, conferences, computer trainings and self-trainings.
5.2.6 The employees should pass a regular job evaluation. The evaluation can be in the form of an oral exam, written tests, and practical trainings.
5.2.7 The training documents should be approved and stored in the organization; they include:
· Training plans;
· Special programs;
· Individual training plans;
· Attestation sheets;
· Instructions and education illustrative materials.
5.3. All new hires should pass a medical examination.
5.4. Personnel suffering from an infectious disease or having open lesions on the exposed surface of the body should not be engaged in MIBP manufacture.
5.5. Personnel engaged in MIBP manufacture are having health checks at least once a year, are subject to continuous medical monitoring, and are regularly examined for Tb. The vision of personnel conducting visual product control is regularly checked.
5.6. Eating, drinking, smoking, makeup applying, as well as the storage of food, drinks, tobacco, and indoor plants cultivating are not allowed in the manufacturing facilities.
5.7. Each person entering a manufacturing facility, including permanent staff and visitors, should strictly observe the personal hygiene rules, including hand washing and wearing of protective clothing.
5.8. Regular control of the personnel health condition id the responsibility of the organization’s general manager.
5.9. Personnel safety assurance:
5.9.1 All new hires receive a detailed training on sanitary and epidemiological rules, job protection, and safety rules. A special emphasis is placed on specific work conditions for a particular MIBP manufacturing site.
5.9.2 Non-trained personnel and visitors are not allowed into the manufacturing facilities. If necessary, they are given training on conduct in a manufacturing facility, and they should be specially supervised.
5.9.3 The personnel protection from infections and from being affected by the raw materials and reagents used (acids, alkali, inflammable materials, etc.) is ensured by:
5.9.4 Personnel engaged in manufacturing, storage, product control, and animal care that are under the risk of contracting an infection, should be vaccinated with appropriate vaccines.
5.9.5 Only regularly X-rayed for health personnel can be engaged in the BCG vaccine and tuberculin products. Only personnel vaccinated against Hepatitis B, can be engaged in the MIBP of blood or plasma manufacturing.
5.9.6 After completing work with live microorganisms the personnel and clothing should undergo appropriate sanitary treatment.
5.9.7 The SOP and instructions are communicated to a new hire and included in their yearly training program.
5.9.8 The SOP and instructions are stored according to the established rules.
5.10. Every manufacturer should have a set of instructions and SOP approved in the established order, and defining:
· The personnel job descriptions;
· The procedure of conducting medical examinations of personnel at the time of hiring and for regular health checks;
· The rules of personal and manufacturing hygiene for personnel;
· The procedure of personnel preparation for work;
· The rules of preparation of disinfection solutions for treating gloves and hands of personnel;
· The rules of hand washing and personnel hands and gloves treating with the disinfection solutions;
· The procedure of contamination control for the personnel;
· The procedure of washing and sterilizing clothes and underwear;
· The rules of wearing clothing.
6. Sanitary and hygienic requirements
6.1. A system of sanitary and hygienic measures taken in the process of MIBP manufacture should ensure the personnel safety when working with the infectious material, highly active, volatile and toxic substances, and exclude the possibility of contaminating the product and the environment.
The manufacturer should have SOP and instructions, including description of validated procedures for cleaning the facilities and equipment, the personnel health care, clothing, and hygiene rules, as well as for waste and non-destructible residues disposal.
Sanitary and hygienic requirements for MIBP manufacture apply to personnel, facilities, and equipment.
6.2. Sanitary and hygienic requirements for personnel:
· All personnel should pass regular health checks at the time of hire and during their work;
· All personnel should be trained in the personal hygiene rules; everybody engaged in manufacture should observe a high level of personal hygiene;
· Any employee with an apparent illness or open lesions should be excluded from work with original, packaging, and in-process materials and with finished product until the risk is eliminated;
· A direct contact between worker’s hands and original materials, internal packaging materials, intermediates, or finished products should be avoided;
· To guarantee the products protection from contamination, all personnel should use an appropriate clothing and head wear stored in special containers;
· Smoking, eating, plant cultivating, storage of food, drinks, tobacco, and personal medicines are prohibited on the sites of manufacturing and laboratory research.
6.3. The technological process environment should ensure minimizing contacts of workers with raw materials, additional materials, internal packaging materials and finished product during equipment maintenance and manufacturing operations.
6.4. Personal hygiene measures should be taken by anyone entering the manufacturing zone (guests, inspectors, etc.)
6.5. Persons working in “clean” rooms must:
· Restrict entering and exiting the “clean” rooms, for which special instructions should be designed;
· Perform the manufacturing process by minimal number of persons. The inspections and control procedures should be performed outside the “clean” areas.
· Restrict personnel moving in areas of I and II class of cleanliness;
· Not pick up or use things dropped on the floor during work;
· Before entering the “clean” rooms (the personnel preparation rooms) remove all jewelry and makeup, including nail polish, take a shower and wash hands with a brush with detergents, treat hands with disinfecting agents and put on sterile technological clothing and shoes.
6.6. Every person entering the manufacturing facilities should put on special clothing suitable to manufacture procedures they perform.
6.7. When working in manufacturing facilities of different cleanliness classes special technological clothing should be used.
In the 4th cleanliness class facilities commercial protective clothing should be worn. A standard set includes overalls, jacket, pants, lab coat, cap or head scarf – a transition wear.
In the 3rd cleanliness class facilities a one- or two-ply pants set fitted around waist with a rubber band, with high collar and appropriate shoes or additional outer shoes (shoe covers). All fabrics should not be shedding lint or fibers.
In the facilities of 1(A) and 2 (B) cleanliness class collar-banded overalls fitted around waist, with cuff sleeves and legs should be used. The clothing should not have extra plies, inner or outer pockets.
The headpiece should be in the form of helmet-hood, completely covering hair, hose, mouth and chin. During work one should wear a mask, sterile rubber or polymer gloves, as well as sterilized footwear. Over the shoes one should wear shoe covers completely covering foot.
The pants legs should tucked in the shoe covers, and the overalls sleeves – in the gloves. No part of the body or underwear should be exposed. The clothing should be comfortable and of the right size.
Clean sterile protective gear should be provided for every work procedure or at least once a day; masks and gloves should be changed after every work procedure.
Technological clothing should be made of a fabric meeting the hygienic requirements, and should have minimal fiber-shedding. It should be washed, cleaned, and stored so that no additional staining occurred.
The clothing should be comfortable for work and loosely fitted to figure.
6.8. Gloves and hands are regularly treated with disinfecting agents during work.
6.9. Sanitary and hygienic requirements to facilities.
6.9.1 Newly constructed buildings of MIBP producing organizations should be located outside residential areas and at a sufficient distance from the manufactures negatively affecting the products quality.
6.9.2 Manufacturing buildings and facilities should be designed in accordance with the regulatory documents.
6.9.3 The manufacturing facilities planning should ensure:
· Full compliance with the sanitary and hygienic rules;
· The process flow design with the shortest possible distances between technologically connected areas;
· Crossing of the flows of materials and personnel should be excluded;
· The areas with the same class of cleanliness should be grouped together as much as possible;
· The equipment and materials should be placed orderly to avoid mix-ups of different types and batches of original materials, intermediates and finished products.
6.9.4 The building should have:
· Clean and comfortable sanitary and general use rooms located next to the manufacturing areas;
· Ventilation, water piping and plumbing, and sewage systems, as well as other systems necessary for ensuring the cleanliness of rooms, equipment, and finished product;
· Air conditioning equipment necessary for maintaining in the rooms the temperature and humidity required for preserving the product quality during manufacturing and storage, meeting hygienic requirements for personnel and proper use and stable functioning of the equipment.
6.9.5 The internal surfaces (floors, walls, and ceilings) should be smooth, have no cracks, and be easily accessible for sanitary treatment and disinfection.
6.9.6 The internal surfaces’ finishing materials should not react with washing and disinfecting agents.
6.9.7 The use of drains should be limited. Installing drains in the aseptic areas is not allowed. Where they are necessary in technological process, the drains should be provided with an air break to exclude back-siphonage. The air break design should allow for disinfection.
6.9.8 All sewage devices should be shallow, open, easily accessible, and be connected with external drains.
6.9.9 All rooms and laboratories, and QAD are additionally equipped with emergence showers, self-help sinks or eye-rinsing devices.
6.10. Manufacturing facilities maintenance requirements.
6.10.1 The manufacturing facilities are kept clean and in order according to the sanitary rules. Plants cultivating, waste accumulation, vermin and rodents presence.
6.10.2 Each manufacturer should have a detailed program of sanitary measures, listing:
· Rooms and equipment subject to cleaning and treatment, methods and frequency of treatment;
· Tools, materials, washing and disinfecting agents used for rooms cleaning and equipment treatment;
· Personnel directly involved with room cleaning and equipment treatment and supervising the process.
These instructions are continuously communicated to the appropriate personnel and included in the personnel training and educating programs.
6.10.3 A separate room should be used for storage of washing and disinfecting agents, tools, and materials used for rooms cleaning and equipment treatment.
6.10.4 Alternating of different disinfecting agents is suggested to avoid forming of resistant strains of microorganisms.
6.10.5 Disinfecting solutions should be sterile. To avoid microorganisms’ proliferation the solutions are stored in clean containers for a limited time. Adding freshly made solutions to partially full containers is not allowed.
6.10.6 The air in class-having manufacturing facilities is regularly checked for presence of mechanical particles and/or microorganisms according to appropriate instructions. The microbial counts of the equipment, room surfaces, personnel hands, and technological clothing are regularly obtained.
6.10.7 All facilities (including manufacturing, storage and sanitary/general use ones) should be grouped in functional technological clusters, if necessary – with independent engineering support systems.
6.10.8 The following cleanliness classes apply to manufacturing facilities for aseptic technological operations (see Table 1).
Table 1
Cleanliness classes for manufacturing facilities
For the areas with cleanliness class of 1 (A), 2 (B), 3 (C) the air should be filtered through appropriate filters, for example HEPA. For achieving the cleanliness classes of 2 (B), 3 (C), 4 (D) the rate of air exchange should take into account the room’s size, and the equipment and personnel in it.
The cleanliness class of the manufacturing facilities is defined by the maximal allowed number of mechanical particles and microorganisms in the air, and on the surfaces of equipment, bordering fences, and personnel clothes.
The microbial count in the room air and on surfaces is performed according to methodological directions.
General sanitary and hygienic requirements to the working area air, measuring and control techniques for micro-climate and hazardous substances, are defined by the sanitary rules and hygienic norms.
6.10.9 The areas of 1st, 2nd, and 3rd classes of cleanliness should not be adjacent to the outer bordering fences. The areas of a higher cleanliness class should be located within areas of a lower class.
6.10.10 The areas of 1st, 2nd, and 3rd classes of cleanliness should not be located in a basement or a sub-ground floor.
6.10.11 No communications and air ducts should pass through the areas of 1st, 2nd, and 3rd classes of cleanliness.
6.11. The necessary set of sanitary and general use rooms is defined by the nature of manufacturing processes.
6.11.1 For storage of different types of clothing (street clothes, transition clothes, and technological clothes) special walk-in closets are suggested. Walk-in closets for street and transition clothes are located next to the building entrance. Technological clothes are stored in special walk-in closets.
6.11.2 Showers, hand washing rooms and toilets should be isolated from the manufacturing areas.
6.11.3 Dining rooms and rest areas should be isolated.
6.11.4 A sufficient number of rooms of 3(C) and 4 (D) cleanliness classes for personnel work preparation should exist; separate for each gender, with proper ventilation and equipment. The second walk-in closet and washing room in the equipped state should have the same cleanliness class as the areas they lead to.
Personnel preparation rooms should ensure separation of different changing steps. They should be entered only in clean transition clothes and changeable footwear.
6.11.4 Personnel preparation room should be located outside the MIBP manufacturing area (especially in sterile products manufacture) and be adjacent to manufacturing “clean” areas.
6.11.5 The rooms should be equipped with hot and cold water. For hand drying disposable or reusable sterile towels or air dryers are used. The rooms should have covered containers for used technological clothes, as well as washing and disinfecting agents for hand washing and treatment.
7. Room requirements
7.1. Manufacturing rooms requirements.
7.1.1 The buildings for MIBP manufacture are designed according to regulatory documents.
7.1.2 The MIBP manufacturing may be performed in one of more buildings, arranged according to the regulatory documents requirements at an established distance from residential buildings and from other objects that can negatively influence the manufacturing process and product quality.
7.1.3 The MIBP manufacture area should be fenced and have a surrounding park zone.
The ground surface between buildings should be asphalted, and measures should be taken to prevent penetration of rodents or other animals.
7.1.4 The area and buildings should be guarded and have security and fire alarms.
7.1.5 In the MIBP manufacturing sites’ design, the systems of electrification, lighting, air conditioning, ventilation, sealing, water supply, and sewage with waste removal disinfection of the infectious materials should be included, according to regulatory documents.
7.1.6 In the MIBP manufacturing sites’ design the following items should be addressed:
· The manufacturing areas of different MIBP types should be grouped in functional technological clusters: microbial culture, inactivation, concentration, purification, filling, storage, sanitary and general use, etc., which if necessary should be provided with independent systems of manufacturing support;
· Flow manufacturing process design with the shortest possible distances between individual technological areas. The manufacturing areas should be connected through transition locks, separate for personnel and materials flows;
· The flow of personnel should be separated from materials, as well as “dirty” materials flow from “clean” one, from flow of waste, lab ware, parts, etc.;
· The equipment should be assigned to a particular technological procedure, while ensuring maximum separation of technical service from manufacturing;
· Technological areas should also be grouped by their cleanliness class. Every area should have established cleanliness class according to manufacturing schedule. The areas of higher class should be located within areas of lower class. The higher class areas are not to be located in the basement or sub-ground floor.
7.1.7 In the manufacturing areas, all conditions should be for compliance with sanitary and hygienic rules, as well as general and fire safety rules. The sanitary and general use facilities should be provided to exclude for personnel the need to exit the area during work.
7.1.8 The areas assigned for work with toxic substances, highly allergenic substances, volatile substances, poisons, and microorganisms of I through IV pathogenic groups, according to MIBP manufacturing schedule, should be provided conditions excluding cross-contamination, or biological and chemical emission.
7.1.9 The manufacturing areas are marked and used strictly according to their function.
7.1.10 The rooms should have smooth internal surfaces (walls, floors, ceilings, windows, and doors). Pipework and electrical wiring should be hidden. There should be no niches or projections, and all areas should be easily accessible for washing, sanitation, and disinfection.
The ceilings should be sealed, the junctions between walls and floors or ceilings rounded.
The walls, ceilings, and floor finishing materials should non-inflammable and disinfecting agents resistant; be easily cleaned and sanitized.
7.1.11 All manufacturing areas should be provided with intercom systems.
7.1.12 Sanitary and general use cluster should include a street cloth storage room, a dining room, a rest area, and a personnel preparation facility: locker rooms, washing room, showers, and toilets. Different steps of changing clothes and shoes should be separated to avoid contamination of technological clothing and footwear with microorganisms and mechanical particles.
7.2. Packaging rooms requirements.
7.2.1 MIBP packaging facilities should have enough space for proper organization of technological operations, including MIBP and packaging materials flow and storage of outer package labels and packaging materials.
7.2.2 The equipment should be placed as to avoid mix-ups of different MIBP or different batches of the same MIBP.
7.2.3 Sanitary norms of lighting, room temperature, humidity, ventilation, etc. should be met.
7.3. MIBP storage requirements (finished products warehousing).
7.3.1 The storage facilities should be designed, equipped, and used to ensure MIBP preservation.
7.3.2 The temperature and air humidity are controlled according to instructions for the stored products and sanitary rules, and be checked at least 2 times a day or recorded automatically. To monitor those parameters, warehouse facilities are equipped with thermometers and hygrometers attached to the internal walls away from heating devices at 1.5-1.7 m above the floor and at least 3 m from the doors. The thermometers and hygrometers should have outer automatic sensors installed.
For every room, a journal of temperature and relative humidity should be kept.
7.3.3 For keeping the air clean, the room should be equipped with blow-down ventilation system. For small production volume manufacturers, a Frigo chamber or cold room could be substituted for warehousing facilities. The products’ storage within those devices should be controlled for temperature and humidity according to instructions on MIBP storage and sanitary rules.
7.3.4 The warehouse facilities are provided with necessary amount of shelving, cabinets, and pallets. The shelving is installed at 0.6-0.7 m from the outer walls, at least 0.5 m from the ceiling, and at least 0.25 m from floor. The shelving units should be separated by at least 0.75 m from each other to ensure sufficient lighting and free access to products.
The warehouse areas are kept clean; the floors are washed at least once a day using approved detergents (according to SOP).
7.3.5 MIBP in containers are placed on shelving in the warehouse according to their type, color labeling, and with consideration to the expiry date. MIBP placing on pallets on the floor is also allowed provided the same rules are observed.
7.3.6 A shelving card with product name, batch, expiry date, and number of packs is attached to each shelving, cabinet, or shelf.
7.3.7 During storage, a responsible person should perform visual control (at least once a month) of the outer package. If package defects are revealed, they should be corrected according to SOP.
7.3.8 Storing at the finished products warehouse raw materials, other materials, semi-finished products and equipment not related to the warehouse is strictly prohibited.
7.3.9 In the warehouse facilities regular measures against rodents, insects and other vermin are taken.
8. Equipment requirements
8.1 The equipment should be designed, assembled, and installed so that:
· To ensure a floe design of the MIBP manufacturing process;
· To optimize flows of raw materials and other materials, and minimize moving of personnel;
· To guarantee aseptic and sterile conditions during use;
· To facilitate manufacturing operations and decrease error risk;
· To allow for an effective dust and dirt removal.
8.2 All equipment should be used strictly according to its purpose and user’s manual, and be validated during installation.
8.3 If possible, the equipment should be assembled so that all automatic and mechanic parts, as well as service parts, be located outside the clean area, which allows for maintenance and repairs outside it. All parts not requiring access during manufacturing, as well as transmitting devices should be covered or shielded.
If maintenance and repairs are performed within the clean area, clean tools and devices are to be used. After such operations, all clean area is thoroughly washed and disinfected before resuming the manufacturing process.
8.4 The equipment should be easily cleaned and disinfected, be kept in working condition, and be sanitized according to schedule.
8.5 All equipment is subject to regular maintenance and validation. After those procedures, its further use is released by the quality assurance department.
8.6 The use of equipment and instrumentation capable of shedding fibers into the environment, should be limited within clean areas, and totally excluded while performing aseptic procedures.
8.7 The equipment parts immediately contacting MIBP:
· Should not be vulnerable to corrosion, chemical reactions, oxidation, alkalizing, and should not release agents that can get into the MIBP;
· Should not be pyrogenic, surface-active, toxic, react with MIBP, influence the MIBP purity;
· Should be made of materials not inhibiting the product activity.
8.8 The sterilization is performed upon complete disassembly of the instrument.
8.9 The equipment whose design and size do not allow for its autoclaving, is steam-sterilized in situ, and the decrease of microbial count to 106 times should be confirmed.
8.10 The steam should not stain the equipment and product.
8.11 For pumping of filling out the product the elastic tubing with durable walls and resistant to multiple sterilizations is used. The tubing’s sturdiness should not change upon prolonged contact with chemical agents used as neutralizers, stabilizers, and preservatives.
8.12 The equipment units contacting with the product should be removable and resistant to multiple sterilizations at 180oC for 4 hours. The installation scheme should guarantee that any part of the device’s internal spaces, tubing, locking and regulating units, as well as other technical elements, is working under aseptic conditions.
8.13 The sealing of equipment and communications is a necessary step prior to sterile work.
8.14 MIBP transporting through tubing, and the instruments’ working modes should not affect the product’s sterility.
8.15 During manufacture, no part of the equipment contacting with the product, should be heated above 32oC.
8.16 The lubricating agents and cooling fluids should not come into contact with the product.
8.17 Water treatment systems should ensure getting water of a suitable quality, and should not be overused.
The resulting water should be stored or circulated at 80oC, or below 4oC – in other words, under the conditions preventing microbial growth.
8.18 Chemical lab ware is thoroughly washed automatically using low-pellet detergents, and consequent rinsing with distilled or de-ionized water.
8.19 The filters for MIBP for parenteral use should not shed fiber. The fiber-shedding filters may only be used when there is no alternative. In this case, additional filtration through non-fiber-shedding filters with pore size no larger than 0.22 mcm is performed. The use of asbestos-containing filters with or without consequent purifying filtration, is allowed only upon being proved that other filters would affect the product quality.
8.20 Automatic, mechanic, and electronic equipment, including computers, should be calibrated and controlled according to the program of ensuring proper using conditions.
8.21 Written calibration and control protocols are kept for the entire period of use. If a computerized control is performed, a backup data file should be created and stored.
8.22 Fermenters, autoclaves, thermostats and other equipment should have recording devices. It is reasonable to supply the equipment with a malfunction alarms.
8.23 Balances and other measuring equipment should have a certain measurement range. The instruments’ accuracy should provide for the appropriate manufacturing or control operations. The calibration of such equipment should be performed strictly according to the schedule.
8.24 The washing and cleaning equipment for manufacturing materials should be selected and used so that it would not create additional sources of contamination.
8.25 The pipework installed in the manufacturing areas should be marked with their contents and flow direction.
8.26 Al equipment, including air filtration and sterilization, water treatment, and distillers, undergo planned technical inspection that should be documented as to their further use.
8.27 The equipment parts that during manufacturing process are filled with MIBP or their components are cleaned immediately upon the process completion. It allows excluding cross-contamination of the next batches, especially in cases where MIBP could be absorbed on plastic lines, and avoiding microbial proliferation and material sticking to the parts.
The cleaning process should result in complete removal of all traces of previously produced material. After the cleaning no moisture should stay within the instrument, since it increases microbial proliferation and pyrogens accumulation.
8.28 For validation and cleaning technique control the samples from the equipment surface are taken with cotton balls or by means of rinses.
8.29 The samples are taken from several areas sized 20 x 30 mm. In case of low soluble products the use of cotton balls is preferred.
8.30 The acceptable limits for residual amounts of rinsed products should be specified in SOP.
8.31 The operator (or other responsible person) should check the equipment prior to work, paying particular attention to thoroughness of the equipment cleaning. The cleaning agents themselves should not contaminate the product.
8.32 The equipment used for work with sterile material is checked by microbiology techniques according to SOP.
8.33 The chromatography equipment may be used for purification of only one product, and must be completely cleaned and sterilized after each batch. A particular attention is paid to decontamination and cleaning process if same equipment is used repeatedly at different steps of manufacturing.
8.34 The length of chromatography columns use and methods of their sterilization should be clearly defined. It is necessary to maintain the ratios between the column capacity and microbial or endotoxin load.
8.35 The cleaning, sanitation, and use of equipment should be written and stored by the equipment in a form of instructions or SOP.
Those documents should specify:
· Persons responsible for use and cleaning of a certain piece of equipment;
· Maintenance, cleaning, and sanitation schedule;
· Assembly and disassembly techniques, if necessary for sterilization of certain units;
· Method and frequency of equipment check immediately prior to work;
· The equipment checking schedule and its calibration results should be entered in a registration journal. The journal should contain data on checking, calibration, maintenance, cleaning, sterilization, and repairs as well as dates and persons performed the operations.
8.36 Persons responsible for the equipment use every year compose a schedule of its control and maintenance.
8.37 Non-working equipment is immediately marked as defective, and the repairs are done as soon as possible. If a repair is not possible, the equipment is removed from the manufacturing and control areas.
9. Validation requirements
9.1 Each MIBP manufacturing organization should conduct validation of technological process support systems, all technological equipment, and control methods.
9.2 Subject to validation are:
9.2.1 Clean rooms and areas.
9.2.2 Manufacture support systems directly related to MIBP quality, including:
· Clean air supply;
· Compressed air supply;
· Non-purified and purified steam supply;
· The system of purified water preparation;
· The system of water for injections preparation;
· Vacuum system.
9.2.3 Technological equipment, including:
· Laminar hood rooms;
· Thermostats and refrigerators;
· Autoclaves;
· Fermenters;
· Sterilization tunnels;
· Freeze-drying devices;
· Centrifuges;
· Washing machines;
· Filling and vacuum-sealing machines, etc.
9.2.4 Technological processes such as:
· Preparation and streaking of inoculation material;
· Culturing of bacteria and viruses, cell cultures;
· Fermentation;
· Disintegration;
· Separation;
· Adsorption;
· Inactivation/ decontamination;
· Glass ware washing;
· Equipment cleaning;
· Sterilization;
· Freezing and Freeze-drying;
· Sterile ampoule and flasks filling;
· Hermetic sealing of ampoules and flasks.
9.2.5 Immunological, chemical, and physic-chemical control methods of finished MIBP, raw materials, and intermediates at ell steps of the technological process, such as:
· Neutralization reaction;
· Blood agglutination reaction, blood agglutination stop reaction, indirect blood agglutination reaction, complement binding reaction;
· Immuno-enzyme analysis method (IFA);
· Protein detection by Lowry;
· Polymerase chain reaction method (PCR), etc.
9.3 There should be duly approved SOP for every validation item.
9.4 Every pharmaceutical product manufacturer should develop a validation plan for validation of particular piece of equipment, process, or method. The plan should be approved by the quality assurance manager.
The validation plan applies to the entire organization and should specify:
· Descriptions of equipment, systems, processes, and methods to be validated;
· Time and order (schedule) of validation;
· The step and type of validation of the validation subject (retrospective, prospective, or concurrent validation);
· The validation protocol form for each type of equipment specifying procedures and measuring devices necessary for validation;
· The time of the next validation, and validation frequency.
9.5 An MIBP manufacturer should have a special department or person responsible for MIBP validation. If necessary, a contract may be signed with a third party for conducting validation. Validation is done in accordance with SOP. The fact and proper procedure of validation is verified by NCO as a part of the organization inspection and validation protocols analysis. The validation protocol is signed by the responsible person, and approved by the quality assurance manager.
9.6 The department responsible for validation performs the following:
· Designs the organization validation plan;
· Provides a necessary supply of measuring devices and documents required for validation;
· Appoints a responsible person for every section of the plan;
· Appoints validation conducting personnel with participation of the technical and metrological services of the organization, as well as other people concerned;
· Controls the timely validation plan execution;
· Designs the validation protocol forms;
· Prepares validation reports;
· Labels the equipment with an appropriate label specifying the last and next validation dates;
· Checks that no non-approved alterations are made to equipment after the validation;
· Assures that no non-validated equipment or equipment with expired validation is in use.
9.7 Validation procedure requirements.
9.7.1 Validation is conducted according to approved validation protocol – the document describing in detail validation procedure and results. The protocol includes all the particulars of a system or equipment control, or a process or method applicability check prior to their use.
9.7.2 The validation protocol includes:
· The background information about the equipment, system, process, or method;
· The purpose and goals of the validation;
· The list of participating employees specifying responsibilities;
· Full description of the procedure used;
· The parameters to be measured and the measuring method;
· The computing formulas and examples of the results analysis;
· Previously defined conclusion criteria;
· The measurement results and revealed during validation deviations of the results from specified parameters;
· The data of metrological check (or calibration*) of the validation measurement devices;
· References to RD and SOP applicable to the validation;
· The conclusion of usability of the equipment.
9.8 For process validation the “worst case scenario” method (when a process is run under non-favorable conditions) should be used. For example, for filling process validation should be suggested its stop due to power outage, or change of the room cleanliness class from A to B due to improper ventilation system function, or presence of additional personnel in the filling zone for necessary repairs, etc. A process validation is considered satisfactory if the process meets the necessary requirements for the “worst case scenario” three times in a row.
9.9 Validation of control methods should aim to confirm such method characteristics as convergence, repeatability, accuracy, lower detection limit, resistance to outside conditions changes (such as temperature and/or incubation time), according to RD.
9.10 The requirements to making changes after validation.
9.10.1 No changes may be made to the equipment, process, or method application procedure.
9.10.2 To make necessary changes a special system is developed in the organization that should include:
· Submitting a proposal for a change with explanation of causes calling for the change;
· The proposal evaluation by all persons and departments concerned;
· The proposal approval by the quality assurance department and the deputy manager for quality assurance;
· Technical and/or documental support for making necessary changes in the system, equipment, process, or method;
· Re-validation procedure;
· Adding of the re-validation results, as established, to RD or application documents for this equipment, process, or method.
9.11 Re-validation requirements.
9.11.1 Non-scheduled second validation (re-validation) is conducted in case of:
· Manufacturing facilities remodeling;
· Rearranging support systems (air supply, heating, ventilation, etc.)
· Replacement or repairs of technological equipment;
· Change of RD for the product, raw materials, additional materials, packaging and labeling materials;
· Change of technical documents;
· Revealing of non-anticipated deviations while conducting technological processes;
· Modification of the control methods;
9.11.2 Re-validation (both planned and not planned) is conducted according to these sanitary rules.
10. The requirements for metrological support of MIBP manufacture and control
10.1 MIBP manufacturers should have a metrological service providing for measurements uniformity as required by law.
10.2 Metrological service operates according to Metrological Service Statute.
10.3 MIBP manufacturers use measurements devices approved by state metrological check (or calibration) at all steps of the technological process and in all quality control methods.
10.4 The primary goals of the organizational metrological service are:
· Provide for uniformity and required accuracy of measurements;
· Provide for conformity of the measuring devices (MD) parameters (scales, class, deviation, etc.) with the parameters of the process or value being controlled;
· Arranging of repairs and timely check and calibration of MD;
· Metrological inspection of RD (manufacturing schedules, technological instructions, as well as measurement methods, SOP, etc)
· Monitoring of measurements conducted according to approved methods;
· Participation in developing, approval, and use of organizational standard samples;
· Analysis of manufacture metrological support and documenting MD (journals, passports, registration cards);
· Control of daily MD check and entering the check results into journals;
· Control of MD technical state.
10.5 The following items should be checked:
· The scale quality – it should be non-erasable, crisp, easily distinguishable, with clear notations;
· The scale quality – every point should be clearly visible, all numbers legible, there should not be erased points and blurred notations.
· The quality of the protective glass – it should be intact, without cracks, and be well mounted;
· The quality of the buttons and switches’ indicators and other notations on instruments;
· Labeling of MD with labels specifying the MD type, serial number, last and next checking dates;
· Providing for technical service of MD according to the schedule of planned maintenance and repairs;
· Training of specialists, educating and increasing the qualification of the metrological service personnel;
· Developing of proposals for replacement or repairs of defective or old-fashioned MD not meeting the RD requirements (class, deviation, scale, etc.)
10.6 In addition to the above listed activities the metrological service is accomplishing the following tasks:
· Participation, up to its competence, in documentation development for techniques;
· Control over compliance with the techniques using appropriate measuring devices with the parameters necessary (deviation, sensitivity, etc.)
· Training and control over the correct use of measuring devices and data processing;
· When using the industry standard samples (ISS) – control over their correct storage conditions, labeling, and use: the ISS storage temperature should be exactly as specified in the certificate; ISS should be stored in a separate container marked with the ISS name, expiry date, and the name of person responsible; the label text on every ampoule should be as specified in the certificate.
11. Documentation requirements
11.1 MIBP manufacturers should have a complete set of original regulatory documents (RD) for every item produced. If one user’s instruction is used by several organizations, a certified copy may be used.
11.2 RD are developed according to EPS, MS and user’s guide.
11.3 Amendments to the RD text are done according to the established procedure. No corrections in the RD text are allowed.
11.4 For every operation performed at the department, there should be a SOP or instruction approved by the manufacturing organization manager or quality assurance director. The standard operating procedures for MIBP manufacture are developed based on the respective sections of MS. The standard operating procedures for control methods are developed based on appropriate sections of PS (EPS).
11.5 For every MIBP batch produced a batch manufacturing protocol (batch production history) is issued, which should describe every step of the technological process.
11.6 The start of any technological process is documented, with mandatory notion of removal of all previous product, documents and materials, unrelated to this coming process, from the equipment and working area.
11.7 During the technological process, every operation should be documented, and upon the operation completion the protocol must be dated and signed by the person responsible for technological process. The protocol should specify the following:
· The product name;
· Batch number;
· Date and time of the process start, critical intermediate steps, and process finish;
· The name of person responsible for every process step;
· The name of person performing the manufacturing operation and, if necessary, person(s) who has checked each operation (for example, weighting);
· Batch number and actual weighted out amount of each raw material (including batch number and amount of any added regenerated or processed materials);
· Any related manufacturing operations or events, as well as main equipment used;
· Control operations performed during manufacturing and the name of the person responsible, as well as the control results;
· Amount of product at the end of different stages of manufacturing, with comments or explanations of considerable deviations from projected values;
· Detailed information about specific problems;
· Authorization for any deviation from schedule, signed by the responsible person.
11.8 Each batch produced is documented by the following:
· For products of national immunization calendar and epidemiological immunization calendar – summary protocol for immunobiological product manufacturing and control. If it is a combined MIBP, the summary protocol should contain information about every component and finished product;
· For all other MIBP, including diagnostic products and culture media – a batch manufacturing protocol.
11.9 Summary protocols of MIBP manufacturing and control are signed by the quality assurance director.
11.10 If an MIBP is not compliant with the EPS requirements at the time of DBTC control, the batch is rejected. In the DBTC journal an appropriate entry is done about sending the batch for recycling or its disposal. The proof disposal is kept at the DBTC.
11.11 The transfer of raw materials, other materials, and intermediates, as required by the manufacturing process steps, is documented with the appropriate referrals, journal entries, or other approved forms of registration.
11.12 All documents for an MIBP batch should be kept, specifically:
· For products for human use – for at least 2 years after the expiry date;
· For all other products – at least 6 months after the expiry date.
The documents should be available anytime for NCO inspection.
11.13 The MIBP shipping documents are composed in such a way that every MIBP series shipped to consumers could be recalled if necessary.
12. The MIBP standard samples requirements. Basic provisions, the course of development, attestation, approval, and registration
12.1 MIBP standard samples (MIBP SS) are a comparison tool in a form of a certain amount or characteristic of an active substance. SS are needed in order to reproduce and store the values of critical parameters of MIBP or its components. The values are determined by the metrological attestation.
The purpose of using SS is the quantitative characteristic and unified designation of MIBP activity or presence and percentage of certain components in MIBP, as well as measuring metrological parameters (sensitivity, specificity) of the diagnostic methods.
The main MIBP parameters evaluated are specific activity, antibody titers, bacterial count, or active principle efficacy, as well as homogeneity, stability, and expiry date.
There are 3 basic classes of SS: international[*], national, and organizational ones.
12.2 The procedure of a national SS (NSS) or an organizations SS development suggests the following steps.
12.2.1 Designing of the SS development program, which should include:
· Explaining its purpose;
· Suggested evaluated parameters of SS with specified methods of detection.
12.2.2 Conducting research (or experiments).
12.2.3 Producing SS.
12.2.4 Calibrating NSS to the international standards, and organizational SS – to the NSS.
12.2.5 Determining the SS expiry date by expedited test.
12.2.6 Developing the regulatory documents draft (SS certificate and user’s guide).
12.2.7 In SS development only validated equipment and methods should be used.
12.3 The attestation, approval, and registration of SS suggests:
· Attestation, approval, and registration of NSS are done by the national control organization;
· Attestation, approval and registration of the organizational SS are done by the manufacturer;
· After SS is attested, an SS certificate is signed, a user’s guide approved, and the name of SS is included in the NSS list (or organizational SS list)/
12.4 Every SS package is labeled. The label should contain the following:
· The SS name;
· The value of the parameter evaluated;
· The SS registration number in the NSS (or organizational SS) list ;
· Storage conditions;
· Expiry date.
12.5 Re-attestation of the SS after the expiry date is done based on the results of their parameters re-attestation; after that a new SS documentation is approved.
13. The manufacturing strains requirements
13.1 The manufacturing strains include bacterial, viral, and bacteriophages strains used for MIBP production.
13.2 Every manufacturing strain should have a passport with the following information:
· The history of its development;
· Characteristics in culture;
· Species identification;
· Presence of foreign agents (microbiological purity);
· Main biological characteristics (virulence, antigen profile, thermal stability, biochemical features, etc.)
13.3 The NCO or other testing organization executes control over the manufacturing strains.
13.4 The manufacturer receives the manufacturing strains by the NCO (or other testing organization) request.
13.5 A new strain suggested for manufacturing use, along with type-specific serum to it, should be sent to NCO (or other testing organization) and accompanied by the passport and all research data. The NCO conducts attestation, passport approval and further storage of the strain.
13.6 All manipulations with manufacturing strains are done in accordance with these sanitary rules. A separate room should be designated for those manipulations; it should have laminar hoods in sterile rooms (“boxes”) with excessive air pressure; in the pre-boxes there should be no excessive pressure.
13.7 All equipment, instruments, lab ware, special clothes, cleaning supplies, etc. used for manipulations with manufacturing strains should be used exclusively for this purpose.
13.8 All manipulations with manufacturing strains and substrates for their accumulation are done according to SOP.
13.9 The work procedures for manufacturing strains during the product manufacturing should be specified in the respective sections of the MS.
14. Requirements for raw materials, other materials, an reagents
14.1 The manufacturer should have regulatory documents (RD) and based on RD specifications for every item of raw materials, other materials, or reagents (hereafter – materials). The organization can add requirements to the specification, with supplier’s consent. If necessary, the manufacturer can inspect the suppliers.
14.2 The organization should have a list of materials subject to entry control, with checking parameters specified.
14.3 Every batch of materials is registered upon arrival. The following items should be checked each time a new batch of material arrives: whether the information in the invoice is consistent with the label and accompanying documents, whether the package and labels are intact, whether quality assurance documents (passport, certificate) are present.
14.4 The organization should have SOP for materials handling, specifying their ordering, receiving, storage, control sample taking, the procedures of control, distribution, and transferring to the manufacturing departments.
All materials received should have labels specifying the following information:
· The product name, code, and its graphical symbol;
· Batch number;
· Expiry date or date after which an additional quality check is required.
14.5 Each batch of materials received passes the entry control at the organization’s DBTC according to SOP, and may be used only after the DBTC approval. The control results are registered.
14.6 Sample taken for entry control are placed into labeled containers in a specially equipped room in compliance with the sanitary and hygienic rules and safety requirements. The room conditions should exclude contamination of the materials and provide for the personnel safety.
14.7 The materials are stored in special rooms separated from the main manufacturing facilities, and under conditions ensuring their integrity during specified periods and excluding the materials mix-up or contamination. To avoid mix-ups and contamination having separate rooms for receiving, storage, and release of the materials are suggested.
There should be easy access to the materials during their storage.
14.8 All materials should be specifically labeled. Color-coded labels should be used to indicate different steps of materials control and its results: quarantined materials – yellow label, materials under control – white labels (every container from which the test samples were taken should be labeled), allowed for use – green label, discarded – red label.
Materials that have passed the entry control and have been allowed for use are stored separately from quarantined or discarded materials.
14.9 Discarded materials are appropriately labeled and separated from other materials to avoid their accidental incorporation into the technological process. The fact that discarded materials were not used in the technological process should be confirmed by appropriate documents.
14.10 Samples are taken from each batch of materials allowed for use and constituting a component of the product. The sample amount should be sufficient for conducting a second control. The shelf life for such samples is determined based on their established expiry dates. The shelf lives are specified in the respective SOP. The samples are stored in the DBTC museum.
14.11 The release and balance of materials should be documented. Their transfer to the manufacturing site should be done under conditions, providing for consistency of their characteristics and, when necessary, for safety of the personnel and the environment.
14.12 All components of non-sterile MIBP should be regularly checked for microbial contamination.
All components of sterile MIBP are regularly checked for sterility or microbial contamination and, if necessary – for pyrogens. The acceptable amount of microorganisms for every kind of material is specified I the organization’s standards. If necessary, the concentration of mechanical particles in raw materials is determined.
14.13 There are special requirements for the products’ internal packaging materials (ampoules, flasks, jars, stoppers, etc.) The internal packaging is made of the materials approved for medical use that don’t influence qualitative characteristics and stability of the enclosed products. The internal packaging materials used in MIBP manufacturing should:
· Ensure air-tight product protection from possible contamination, unfavorable environment factors, or mechanical impact;
· Ensure, when necessary, the consistency of storage conditions (vacuum, noble gas);
· Be transparent enough for visual inspection of the product’s physical features;
· Be convenient in product use and nice in appearance.
14.14 The temperature in the product storage facilities is kept within the established interval, and constantly registered by special devices or controlled by thermometers placed at different heights and at different sites of the facility.
15. The technological process requirements
15.1 To ensure production of MIBP conforming to the regulatory documents’ requirements the technological process is conducted according to current manufacturing schedule.
15.2 Any changes in technological process should be added to the manufacturing schedule and approved, as required.
15.2.1 Manufacturing strains of microorganisms, stock bacterial strains and cell culture banks used in MIBP manufacture, are stored in separated rooms. Only authorized personnel should have access to those facilities.
15.2.2 Strictly defined rooms and equipment should be reserved for spore-producing microorganisms.
15.2.3 A simultaneous use of two different spore-producing microorganisms in the manufacturing processes is prohibited.
15.2.4 A special facility and equipment should be reserved for producing homologous serum derivatives.
15.2.5 All containers used in the technological process should be clearly labeled.
15.2.6 For sterile MIBP manufacturing there should be areas with excessive air pressure. For sites where pathogenic microorganisms are used, negative air pressure areas should be designed. The air from areas where pathogenic material is used should not be recycled.
15.2.7 Not directly related to the principal manufacturing process areas, designated for work with animal substances and microorganisms, should be separated and should have a separate ventilation system and dedicated personnel.
15.2.8 The buffer solutions, culture media, etc. should be prepared in specially designated rooms not directly related to the manufacturing process.
15.3 All technological process procedures are performed by the qualified personnel using special equipment and instruments, in specially assigned rooms. For each procedure there should be an SOP, each operation is registered in manufacturing protocols and journals upon completion; all deviations from the standard procedure are also documented. All deviations from the technological process are to be reported to the shift supervisor and to the head of the department.
15.4 Prior to start of any step of the technological process it is necessary to make sure that the work zone, technological equipment, and measuring instruments are prepared according to established requirements (MS, SOP, instructions for use). It must be confirmed that all raw materials, other materials, additional and packaging materials have passed appropriate control and were released for use by the DBTC.
15.5 In implementing the technological process of MIBP manufacturing the following requirements should be met.
15.5.1 The flow design of the technological process excluding mix-ups of the intermediates and semi-finished products from different steps of the manufacturing. A special attention should be paid to these requirements when pathogenic strains or toxins are used for manufacturing a product. The most important principle of such production should be complete separation of work areas for pathogenic strains and toxins from manufacturing areas for inactivated semi-finished or finished products.
15.5.2 Avoiding contamination of the product at all manufacturing steps is ensured by the following measures:
· Using manufacturing facilities of specified cleanliness class. This is ensured by separation of clean areas from auxiliary areas, maintaining good sanitary condition of manufacturing areas, supplying the areas with sterile air, checking the air purity and the equipment cleanliness, maintaining good sanitary conditions of the work sites;
· The fullest possible separation of flows of personnel, materials, and intermediates;
· Validation of processes bearing a contamination risk;
· Allowing only authorized personnel access to the manufacturing rooms;
· Color coding (or special labeling) for work clothing of personnel working at different manufacturing sites;
· Ensuring safe and trouble-free work of all technological equipment;
· Timely inactivation and disposal of the waste;
· Automation of the manufacture and using “closed systems” of manufacture;
· Using dedicated equipment for every particular product.
It is possible to use same equipment for consequent manufacturing of several products provided that cross-contamination is excluded, which should be confirmed by the respective inspection protocol.
15.5.3 The introduction of weighted and/or measured out raw material (reagents. Intermediate) at various steps of manufacturing every batch of the product should be performed by the authorized site personnel according to SOP. The procedure should be performed by one employee with another one watching.
15.5.4 The shelf life and storage conditions of semi-finished products should comply with the MS requirements.
15.5.5 At every step of the technological process the product quality should be checked in full scope defined by the regulatory documents. The control results should be registered in batch manufacturing protocols.
15.5.6 Rejected semi-finished and finished products should be registered, labeled, and isolated from good ones according to SOP. They should be stored under conditions excluding their use in the manufacturing process until the decision is made about the possibility of the rejected products recycling.
15.5.7 The destruction of the rejected products is done by a specially assigned commission, which issues a product destruction statement.
15.5.8 The products subject to filling or pre-packing (pills, suppositories, etc.) should be stored under appropriate conditions ensuring preservation of their characteristics.
15.5.9 The product outcome volume should be documented at every step of the technological process and compared to the prescribed outcome. If substantial differences are revealed, the production or processing should be suspended until the causes of such difference are found and eliminated.
15.6 In order to prevent manufacturing product not conforming to the EPS, a step-by-step manufacture control is conducted according to the manufacturing schedule and SOP by the manufacturing site personnel (on an ongoing basis) or by the DBTC personnel.
15.6.1 During the step-by-step control DBTC checks:
· Execution of prescribed technological procedures and compliance with technological operating mode;
· Compliance with the storage conditions and shelf life of raw materials, other materials, reagents, and intermediates;
· Accuracy and clearness of intermediates’ and used reagents’ labeling;
· Good sanitary condition of work areas, rooms, and equipment.
15.6.2 The results of the step-by-step control are included in the batch manufacturing protocol. If a deviation from operating modes or technological process norms is found, the appropriate measures should be taken according to SOP. All deviations are documented in respective protocols and reported to the organization’s manager.
15.6.3 Whenever violations are found, a DBTC employee suggests the deadline for their correction in the DBTC proposal book.
15.6.4 In order to ensure the technological process stability, the use of computer software and statistical methods in manufacturing procedures is recommended. Such use allows for timely revealing of deviations from normal process flow, and finding the causes of its violation.
15.6.5 Finished product (batch) is transferred for control to DBTC after completing all previous control steps stipulated by the EPS. The product should be fully labeled and packed in outer package. Taking out the product for DBTC control, for arbitrary
15.6.6 special journal.
15.7 Labeling and packaging requirements.
15.7.1 The organization should have a set of instructions for receiving and identification of packaging materials, equipment function checks, the order of operations in labeling and packaging, and work site arrangement.
15.7.2 A finished product should be clearly labeled. The label contents and legend layout should meet the requirements of the current regulatory documents for particular kinds of products.
15.7.3 Making and entry control of the labels are planned so as to avoid any possible mix-ups.
15.7.4 Labels, other printed materials, labeling stamps, and labeled outer packages are kept in sealed containers in a locked room. Labels and other labeling materials for different products are stored separately. They are transferred to the manufacturing facility only by a written DBTC order.
15.7.5 Transferring labels from the storage facility to the labeling and packaging line is organized in a way excluding their mix-ups or substitution for another MIBP labels.
15.7.6 Not used or outdated labels and labeled packaging materials are to returned to DBTC for destruction, which should be documented according to SOP.
16. The requirements to the experimental animal facility (vivarium)
16.1 The vivarium should be located in a separate from the rest of manufacture building with autonomous ventilation system.
16.2 The animal facility should have isolated rooms for quarantine of the arriving animals.
16.3 The vivarium should be staffed with qualified personnel including veterinary doctor and technical staff.
16.4 The sanitary conditions at the vivarium should meet the requirements for keeping different groups of animals.
16.5 For work with pathogenic microorganisms special conditions should be created meeting the SR requirements for I-IV pathogenicity group microorganisms.
16.6 The vivarium should have side rooms for work under special conditions.
16.7 Rooms designated for work with infectious material, should have disinfecting solution labeled with its preparation and expiration dates.
16.8 Every animal cage should be labeled with cage number, name of the experiment, its starting and finishing dates, the date of infection and infecting agent, and the name of person responsible for the experiment.
16.9 The vivarium should have:
· A room for animal food preparation;
· A disinfecting and washing facility;
· A room for dry animal food storage;
· A room for clean reserved equipment, cages, shelves, etc.
16.10 The animal facilities are equipped with refrigerator chambers for dead animal storage.
16.11 The animal facilities should be equipped with special disinfecting equipment and should have conditions for waste and dead animal disposal.
16.12 There should be SOP for all operations performed in the animal facility.
16.13 The animal facility should have documents specifying the following:
· Source of animals, their arrival date, number, weight (age), sex, line;
· Veterinary certificate for every batch of animals;
· The sources of animal food, expiration dates, amount;
· Full list of animals in the animal facility detailing the number of animals in quarantine, in experiment, infected (naming the infectious agent and rooms where the animals are kept).
17. The internal inspection
17.1 Every MIBP manufacturer should conduct an internal inspection in order to decide if the MIBP production and control conditions comply with the requirements of the current document and with the MS for each product.
17.2 The program and plan of the internal inspection are designed to include every department of the organization with special attention paid to the crucial and most vulnerable steps of the manufacturing process.
17.3 The organization develops and approves instructions for conducting internal inspection that should include the following:
· Personnel and their training;
· Facilities and their compliance with the established cleanliness classes;
· Equipment checks;
· The equipment and instruments validation program;
· The procedure for claims administration;
· Previous inspections’ results and measures taken. Terms and definitions
“Clean” facilities – manufacturing facilities for making sterile clean finished MIBP with air quality regulated by the mechanical particle and microorganisms’ concentration.
Airlock – a device installed in a closed space between two manufacturing facilities with different classes of cleanliness that prevents mechanical particles and microorganisms from getting into a “clean” facility.
Arbitrary samples museum – a division of DBTC, dedicated to storage of batch samples of products, manufactured by the organization, checked by every parameter suggested by RD, and numbered by a DBTC control number.
Batch – a limited amount of raw material, intermediate of finished product, produced in one manufacturing cycle, with the same contamination risk during filling and drying (if applicable).
Cleanliness class of a facility – is defined based on the concentration of mechanical particles of a certain size and microorganisms in 1 m2 of room air.
Entry control – control of the supplier’s materials received by the consumer (organization) and intended for use in the product manufacture. The decision about quality of the batch being checked is made after taking one or more samples for control.
Labeling has two different meanings:
A – A printed material on the container (label, user’s instruction, and other printed materials);
B – The procedure of attaching the labels to the containers.
Laminar flow – movement of parallel air flows with specified speed within limited space.
Manufacture – all operations related to making a product, including receiving and processing of raw materials and other materials, the product manufacturing, pre-packing, labeling, and packaging.
Manufacturing control – control executed during the manufacturing process.
Medicinal immunobiological products (MIBP) – pharmaceutical products intended for immuno-prophylaxis, immuno-therapy and diagnostics of infectious and non-infectious diseases and allergic conditions. Such products include vaccines, antitoxins, bacteriophages, eubiotics, immunoglobulins, sera, diagnostic reagents, allergens, culture media.
Packaging material – any materials, including printed ones, used for MIBP packaging, except outer packaging used for product transferring and shipping. Packaging materials (packaging containers) are divided into primary and secondary depending on whether they contact the product directly.
Product quality – the sum of product characteristics defining its ability to meet certain needs according to its purpose.
Product quality control – checking (by approved methods) the compliance of quality values with the established requirements.
Quality factor – a quantitative characteristic of a product defining its quality and being considered in relation to conditions of its use.
Raw materials – all substances used for a product manufacturing (active or inactive) regardless of whether they stay the same or undergo changes during the manufacturing process.
Regulatory documents (RD) – a set of documents defining the requirements for a product manufacture and control, for finished product, its storage, shipping, and use. The documents should be developed and approved according to the established procedure. The RD set for medicinal biological products includes as a rule the manufacturing schedule, pharmacopoeia section, the product instruction for use.
Rejected item – product not conforming to the RD requirements.
Release – the procedure of allowing a finished batch of the product to be sent to the consumer. The release should be supported by the information of the initial raw materials, other materials, and reagents quality, the results of the operational control including the semi-finished product control, and the results of finished product control.
Semi-finished product – a substance or a mix of substances subject to further processing.
Specification – detailed description of requirements for materials or products used. The same applies to the finished product. Specifications are a base for the quality assessment.
Technological clothing – a set of clothes designed for protection of raw materials, auxiliary materials, and finished product.
The Department for Biological and Technological Control (DBTC) – a department with structure, personnel qualification, and equipment that allow for giving unbiased judgments about products in manufacturing, as well as about finished products.
The Technological Process Stability – a characteristic of the technological process ensuring consistency of distribution of its parameters being controlled.
Validation protocol – a document confirming the procedure and details of a validation conducted.
Validation, revalidation – documented confirmation of equipment compliance with the manufacturing conditions, or technological process, or finished product – with the current schedule and/or regulatory documents requirements. The validation proves that a process, equipment, raw material, or method actually allow to get the expected results.
Ventilation air – the purified air coming from the fans and ensuring the specified cleanliness class of the manufacturing facility. Combined protocol of manufacture and control testing of aDT-antitoxin
General information about a finished batch
Name and address of the manufacturer ___________________________
Batch number _______________________________________________
Control number ______________________________________________
Batch production date _________________________________________
Recommended single dose for human use (ml) _____________________
A single dose contains:
Diphtheria anatoxin ________Lf________________________________
Tetanus anatoxin ___________EC _______________________________
Number of doses in one ampoule ________________________________
Number of ampoules in finished batch ____________________________
Expiration date _______________________________________________
Production date ______________________________________________
Information on manufacturing and control of the antigens used
Diphtheria anatoxin
1. Strain of C. diphtheriae used for anatoxin production ______________
2. One-time yields used for preparation of the combined purified diphtheria anatoxin
Batch # _____________________________________________________
Culture medium ______________________________________________
Inoculation date _________________________________________________
Cultivation length _____________________________________________
Cultivation temperature ________________________________________
Microscopic data on culture purity ________________________________
Toxin activity __________________Lf/ml _________________________
Toxin-containing culture media volume __________l _________________
Date of separation and filtration __________________________________
3. Inactivation and purification methods ___________________________
Batch # of purified anatoxin _____________________________________
4. Characteristics of the purified anatoxins _________________________
Batch and bottle # _____________________________________________
Volume (l) ___________________________________________________
Activity (LF/ml) _______________________________________________
Total nitrogen concentration (mg/ml)_____________________________
Protein nitrogen concentration (mg/ml) _____________________________
Relative activity (Lf/mg of protein nitrogen) _________________________
Sterility ______________________________________________________
pH __________________________________________________________ Specific safety test
In manufacture In DBTC
Batch and bottle # ______________________________________________
Animal number and species ______________________________________
Data of anatoxin introduction____________________________________
Date and mode of introduction _________________________________
Length of the test _______________________________________________
Date of results registration ________________________________________
Results _______________________________________________________
The reversed toxicity test
Batch and bottle # ______________________________________________
Concentration Lf in ml __________________________________________
Incubation temperature __________________________________________
Length of incubation
(starting and finishing dates) ______________________________________
Volume of anatoxin administered and method of introduction __________
Length of observation
(starting and finishing dates) ______________________________________
Results _______________________________________________________
Tetanus anatoxin
1. Cl. Tetani strain used for anatoxin production __________# __________
2. One-time yields used for preparation of the combined purified tetanus anatoxin
Batch # _____________________________________________________
Culture medium ______________________________________________
Inoculation date _________________________________________________
Cultivation length _____________________________________________
Cultivation temperature ________________________________________
Microscopic data on culture purity ________________________________
Toxin activity __________________EC/ml _________________________
Toxin-containing culture media volume __________l _________________
Date of filtration ______________________________________________
3. Inactivation and purification methods ___________________________
Batch # of purified anatoxin _____________________________________
4. Characteristics of the purified anatoxins _________________________
Batch and bottle # _____________________________________________
Volume (l) ___________________________________________________
Activity (EC/ml) _______________________________________________
Total nitrogen concentration (mg/ml)_____________________________
Protein nitrogen concentration (mg/ml) _____________________________
Relative activity (EC/mg of protein nitrogen) _________________________
Sterility ______________________________________________________
pH __________________________________________________________ Specific safety test
In manufacture In DBTC
Batch and bottle # ______________________________________________
Animal number and species ______________________________________
Data of anatoxin administration____________________________________
Date and mode of introduction _________________________________
Length of the test _______________________________________________
Date of results registration ________________________________________
Results _______________________________________________________
The reversed toxicity test
Batch and bottle # ______________________________________________
Concentration EC in ml __________________________________________
Incubation temperature __________________________________________
Length of incubation
(starting and finishing dates) ______________________________________
Volume of anatoxin administered and mode of administration __________
Length of observation
(starting and finishing dates) ______________________________________
Results _______________________________________________________
Information about components mixing and finished product creating
Date of components mixing _______________________________________
Diphtheria anatoxin
Batch and bottle # ______________________________________________
Lf/ml ________________________________________________________
Volume taken out _______________________________________________
Tetanus anatoxin
Batch and bottle # ______________________________________________
EC/ml ________________________________________________________
Volume taken out _______________________________________________
Aluminum hydroxide
Batch and bottle # ______________________________________________
Al mg/ml ______________________________________________________
Volume taken out _______________________________________________
Dilution buffer
Type _________________________________________________________
Concentration__________________________________________________
Volume taken out _________(l)____________________________________
Purified water of _________(purification date) ________________________
Sodium chloride batch # __________________________________________
Preservative
Type _________________________________________________________
Concentration__________________________________________________
Volume taken out _________(l)____________________________________
Finished product batch # __________________________________________
Total batch volume (l) ____________________________________________
Number of bottles ________________________________________________
Testing of ready to use vaccine mass (before filling)
Batch # _______________________Bottle # ___________________________
1. Physical characteristics by visual inspection ____________________________
2. pH _____________________________________________________________
3. Residue formaldehyde concentration __________________________________
4. Preservative concentration __________________________________________
5. Aluminum hydroxide concentration (Al mg/ml) _________________________
6. The degree of diphtheria and tetanus anatoxins absorption _________________
7. Photometric dispersion factor ________________________________________
8. Sterility _________________________________________________________
Culture medium _____________________________________________________
Incubation length and temperature _______________________________________
Manufacture
DBTC
Test for specific safety
Date of introduction ___________________________________________________
The product amount and mode of introduction _____________________________
Number of guinea pigs (per bottle) _________________________________________
Observation finishing date ________________________________________________
Manufacture
DBTC
Specific activity of the components
Diphtheria anatoxin
Specific activity determination by the survival rate
Immunization date __________________________________________________
The number of guinea pigs and their weight ______________________________
Date, volume of product and mode of introduction _____________________
Infection date ______________________________________________________
Date, volume, and mode of introduction of the toxin ____________________
Results: ___________________________________________________________
Observation finishing date _________________Survived (total number)_________
Toxin control
The number of guinea pigs _______________ ______________________________
Date, volume, and mode of introduction of the toxin ______________________
Results:
Observation finishing date ____________________________________________________________________
Test result: Survived (total number)_______________________________________
Testing of specific activity by the WHO recommended method:
Immunization date ____________________________________________________
Animal species and weight ______________________________________________
Number of animals per dose _____________________________________________
Volume of product dilutions and mode of introduction _____________________
Date of toxin administration _____________________________________________
Dose of toxin administered and mode of introduction ______________________
Observation finishing date _______________________________________________
Toxin control
The number of guinea pigs per toxin dose ___________________________________
Observation finishing date _______________________________________________
Testing results
Activity of diphtheria anatoxin in the product …………………………IIU/ml Toxin control:
Number of LD50 administered ………………………………..
Tetanus anatoxin
Immunization date ____________________________________________________
Animal species and weight ______________________________________________
Number of animals per dose _____________________________________________
Volume of product dilutions and mode of introduction _____________________
Date of toxin administration _____________________________________________
Dose of toxin administered and mode of introduction ______________________
Observation finishing date _______________________________________________
Toxin control
The number of animals per toxin dose ___________________________________
Observation finishing date _______________________________________________
Testing results
Activity of tetanus anatoxin in the product …………………………IIU/ml
Toxin control:
Number of LD50 administered ………………………………..
Testing of finished product after filling
1. Physical characteristics by visual inspection ____________________________
2. Accuracy and uniformity of filling
3. pH _____________________________________________________________
4. Aluminum hydroxide concentration (by aluminum) (mg/ml) ________________
5. Sterility _________________________________________________________
Culture medium _____________________________________________________
Incubation length and temperature _______________________________________
Manufacture
DBTC
6. Toxicity
Manufacturing department manager
Signature Date
DBTC manager
Signature Date CERTIFICATE
Of a standard sample Name of the standard sample
NSS 42-28- _____-_____
Registration # in the NSS Registry
1. Purpose ______________________________________________________________
2. Metrological characteristics:
2.2. Established SS value ___________________________________________________
name of established characteristic
________________________________________________________________________
2.3. Deviation of the established SS characteristics ______________________________
interval of allowable values of established deviation or a particular value
_______________________________________________________________________
3. Additional information: _________________________________________________
4. Documents specifying the conditions and application mode: ____________________
________________________________________________________________________
5. Storage and shipping conditions: _________________________________________ _____________________________________________________________________
6. The SS expiration date: _________________________________________________
7. The SS production date: _________________________________________________
Director
Of L.A.Tarasevich SISC
The SS is approved by the L.A.Tarasevich SISC and included into the National Registry of Standard Samples that are approved for use in the Ministry of Health of the Russian Federation system as well as in medicinal immunobiological products manufactures subject to other authorities.
Chief metrologist
Of L.A.Tarasevich SISC Developing and putting into action a standard operating procedure (SOP)
A standard operating procedure (SOP) constitutes a part of the organization’s regulatory documents set and may be a part of quality guide.
Current document describes the way an SOP should be developed and put into action. SOP are detailed instructions on performing a procedure, written and approved according to the established order.
SOP may define:
Control execution;
Work, calibration, equipment check;
Sample taking for control procedures;
Sanitary and hygienic procedures;
Inspection and self-inspection;
Administrative instructions, documentation design;
Testing procedures;
SOP is used as a standard by personnel performing a certain operation, it is also used for training new personnel.
This is the first version of the SOP.
4.1. An SOP may contain the following sections (listed in the order they should be put in the document):
1- Introduction, including the procedure purpose;
2- Scope;
3- Revisions;
4- Terms and symbols;
5- Work safety and labor protection;
6- Samples;
7- Personnel (scope of responsibility);
8- Materials and equipment;
9- Procedure.
10- The results registration and presentation;
11- Appendices;
12- References.
4.1.1 Depending on the SOP scope some sections may be combined or excluded. The SOP specifying the MIBP control methods should have all the above mentioned sections.
4.1.2 SOP should be written clearly and concisely. Wherever a physical quantity is mentioned its number of dimension according to the SI system, except for the cases where using of other universally recognized systems is allowed/
When describing a procedure it is recommended to number the procedure steps so that it could be referred to by the number.
For SOP typing the “Times New Roman” font with font size 12 is recommended.
4.1.3 In the “Introduction” section the general provisions may be listed at the composer’s discretion, and the purpose of the procedure should be specified.
4.1.4 In the “Scope” section it should be specified where the SOP will be used.
4.1.5 In the “Revisions” section it should be mentioned “First version”, if it is the first time the SOP was developed. If this is a revised SOP, a brief history of revisions should be included.
4.1.6 In the “Terms and Symbols” section all notations, abbreviations, and introduced terms should be explained.
4.1.7 In the “Work safety and labor protection” section all necessary general requirements for job safety and labor protection should be listed. In addition, when necessary, they should be marked in the text by bold font and capital letters. There should be a reference for official guidelines, where applicable.
4.1.8 In the “Samples” section it should be specified: the procedure of sample taking for testing, their storage conditions and shelf live.
4.1.9 In the “Personnel” section there should be specified who is responsible for the procedure and who checks the accuracy of its performing.
4.1.10 In the “Materials and equipment” section there should be listed everything needed to perform a procedure. In SOP for the control methods, in this section should be mentioned:
- Standard samples (storage conditions and established shelf life);
- Buffer and other solutions (way of preparation);
- Laboratory animals (species and source);
- Registration forms used with the SOP;
- Measuring and control instrumentation and equipment. For control and measuring instruments (such as pipettes, pH-meters, scales, etc.) the conditions of calibration and checking should be mentioned;
- Glass ware, plastic ware, needles, etc.
4.1.11 The “Procedure” section should contain:
- Mentioning of any previous steps performed before the main procedure (probe preparation, obtaining the calibration curve, etc.)
- Safe working conditions (Safety rules) and, if necessary, the procedure of decontamination;
- Full description of the procedure.
4.1.12 In the “The results registration and presentation” section it should be mentioned:
- The method of computations required in the procedure (if the SOP describes the control methods); an example of computation should be included;
- How the test trustworthiness is assessed or a passing criterion (if the SOP describes the control methods);
- The operating procedures when the test results are outside specifications;
- That all deviations from the procedure should be registered and presented to the person responsible for the procedure. The responsible person should make a decision on whether or not the deviation is acceptable;
- The forms of results presentation (report forms) used;
- Whom the final results are presented to;
- Where the results should be stored.
4.1.13 In the “Appendices” section appendix pages should have a reference to the respective SOP page. All appendices should be listed in SOP.
4.1.14 In the “References” section there should be listed SOP and other related documents.
4.2. The page layout (formatting).
4.2.1 The first page should have the following information (appendix 4):
- The name of manufacture;
- The department that has developed the document;
- SOP #;
- (if applicable) the # of SOP that was replaced by the current SOP;
- Page number and total number of pages;
- Effective date;
- Names, signatures and date of signatures of the following persons: the author responsible for the procedure, the coordinating and approving persons.
4.2.2 On every subsequent page there should be mentioned (appendix 4):
- The manufacture name;
- The department name;
- The SOP number;
- The page number out of total number of pages.
4.3.The procedure of a new SOP development.
4.3.1 The person responsible should first make sure that SOP for the procedure does not yet exist (or, if it does exist, it can be simply modified). For this purpose the SOP data base search should be performed.
4.3.2 All other documents related to the SOP should be found and brought to attention of the responsible personnel.
4.3.3 The SOP should be given a number. The number is given according to the following rule (see Table 1): the SOP developing department abbreviation in letters (up to three letters), a three-digit SOP number according to its development sequence in the department (a letter can be substituted for one digit if there is a coding system in the department), and the two-digit version number.
Table 1
The full list of SOP is kept in the documentation department.
4.3.4 The SOP developing department should prepare and enter its text; the author signs it and prints his/her name, as well as the date, on the first page.
4.4.The SOP examination order.
4.4.1 The SOP project is sent to the person responsible for the SOP for revision and signature, as well as to the chief metrology specialist for coordination and signature, if the SOP applies to the measuring instrumentation or equipment.
4.4.2 The first version of SOP (newly designed SOP).
If the SOP should be taken into account in the organization’s Quality Guidelines, it is labeled with a red “R” letter on the first page. After that the SOP is returned to the documentation department for the final check, approval, and enactment.
Note. The MIBP manufacturers, after completing s.4.4.1, send a newly designed SOP to the registration department for a control consideration. If the SOP should be included in the product’s registration process, it is marked with a letter “R” in red on the first page. After that it is returned to the documentation department for the final check, approval, and enactment.
4.4.3 Revised SOP.
A revised SOP, not labeled with “R” on the first page of the previous version, is returned to the documentation department for the final check, approval, and enactment.
A revised SOP, labeled with “R” on the first page of the previous version, is returned to the documentation department for the final check, approval, enactment, and adding to the Quality Guidelines.
Note. The MIBP manufacturers, after completing s.4.4.1, send a revised SOP with an “R” on the first page of the previous version to the registration department for a control consideration. After that it is send to the documentation department for the final check, approval, and enactment.
4.4.4 The documentation department puts the effective date on the first page of the SOP. This copy is called, for example, a “base copy” or “original”.
4.4.5 The documentation department keeps the base copy and controls the issuing and recall of SOP.
4.5. The order of SOP distribution.
4.5.1 All copies of SOP are made in the documentation department from the base copy.
4.5.2 Copies are provided as a single-sided or double-sided documents, depending on the request.
4.5.3 The first page of each copy should be stamped in red with “Authorized copy # …”; the copy number and the initials of person authorized the copy, should be written also in red.
4.5.4 The respective information is included in the distribution list (see appendix 1). The distribution list is signed and the dates are put on it in the designated places. Every person receiving SOP also puts his/her signature and dates to the distribution list.
4.5.5 If the SOP holder job responsibilities change, the SOP should be transferred to the new holder(s) with all respective information, and the documentation department staff should be informed.
4.6. The order of producing extra copies of SOP.
If additional SOP copies are needed, all requests should be sent to the documentation department.
NON-APPROVED COPYING OF SOP IS STRICTLY PROHIBITED.
4.6.1 The documentation department produces additional copies of SOP according to sections 4.5.2 - 4.5.5.
4.6.2 If necessary, sample copies and copies for editing can be reproduced. Those copies should be stamped “sample copies” or “copies for editing” in green.
The sample copies are not controlled documents, and can be copied only for internal use.
The copies for editing are used if a changes need to be done to the SOP.
4.6.3 If an SOP copy is requested from a non-organizational customer, it can be released only upon permission of the quality assurance manager.
4.7. The SOP revision procedure; making changes to SOP.
An SOP is periodically revised at 3-year intervals, unless otherwise specified at the time of the SOP developing (in which case the SOP expiration date is listed after the effective date).
4.7.1 The documentation department sends a copy of the SOP to the person responsible for this SOP at least 2 weeks prior to the SOP revision date. The same person is responsible for the SOP revision.
4.7.2 The person responsible for the revision, reads through the SOP, makes changes if necessary, and prints out the revised SOP.
4.7.3 The revised SOP is signed and dated according to section 4.4.1.
4.7.4 All previously distributed copies of the SOP are collected and destroyed, and the distribution list is revised accordingly. New version is distributed according to section 4.5.
4.7.5 The collected base copy should be stamped with a red “collected” stamp and sent to the archive.
4.7.6 An SOP can be corrected before the revision date. In order to do this, a is necessary to request a copy for editing from the documentation department and act according to section 4.7.7.
4.7.7 If additions or corrections of the SOP are needed, in the documentation department a copy for editing is made of the base copy, and sent to the employee responsible for revision. A registration entry is done on the distribution list (see appendix 1).
4.8. An SOP recalls procedure.
4.8.1 If it is necessary to recall an SOP, the employee responsible for revisions fills out a changes control form and submits it to the documentation department along with the approved copy of current SOP.
4.8.2 The documentation department sends a request for recall confirmation to the person responsible (at manufactures – to the DBTC manager or Quality Assurance manager).
4.8.3 After receiving a recall permit the documentation department employees request the return of all current SOP copies according to the distribution list.
4.8.4 The base copy is stamped with a “recalled” stamp in red and sent to the archive.
4.9. Non-scheduled corrections.
4.9.1 The corrections to SOP can be made in situ only in a case of emergency (for example, when the corrections are necessary for the manufacturing and control processes) so that the control process (in manufactures – also the manufacturing process) could go uninterrupted according to precise instructions.
4.9.2 The documentation department staff should be made aware of detailed changes that are to be made. The documentation department corrects the base copy of SOP and informs the holders that the distributed copies can be amended with a handwritten correction.
No corrections can be made to the distributed copies until an official notice is received from the documentation department.
4.9.3 After making the notice the documentation department starts the revision procedure according to section 4.7.
4.10. Personnel education (training).
4.10.1 Before the personnel start using the SOP, they should receive training. The process of skill evaluation should confirm that the employee is familiar with the procedure and can perform properly.
4.10.2 A major change to the SOP requires a new training for its users. The definition of what is to be considered a major change rests with the authorized person (or the department manager).
4.10.3 Any kind of training for SOP use should be documented in the file of every person who received the training.
4.10.4 The instructor conducting the training should have a proper qualification.
4.10.5 An SOP user training protocol (appendix 4) should be kept in the respective department. The SOP training protocol confirms that the users have read and understood the procedure.
Persons responsible for the procedure should ensure the training.
5. Appendices.
Appendix 1 – the SOP distribution list.
Appendix 2 – the SOP revision form.
Appendix 3 – the first and consequent SOP pages layout.
Appendix 4 – SOP user’s training protocol. Appendix 1
To SOP # ÑÍÄ/001/01
THE SOP DISTRIBUTION (MAILING) LIST
Appendix 2
To SOP # ÑÍÄ/001/01
SOP revision form
The date and signature have to be placed in the designated area, and the form has to be returned to the documentation department of the quality assurance division as soon as possible (in no longer than 3 days). Appendix 3
To SOP # ÑÍÄ/001/01
The SOP first page layout
The consequent SOP pages layout
Appendix 4
To SOP # ÑÍÄ/001/01
SOP user’s training protocol
The report of training on SOP # _______________________________
A) I have read and understood the contents of the above mentioned SOP (instructor’s help is not required)
B) I have received sufficient training, allowing me to perform the procedure.
References
*Calibration is only acceptable when there is no state approved metrological check procedure for this measuring device.
[*] International standard samples are not covered by this document.
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