Analysis of nonconformities associated with storage areas detected during GMP inspection

In continuation of the analysis of violations detected during the inspection by Russian GMP inspectorate of drug manufacturers for compliance with the requirements of the Good Manufacturing Practice (GMP), several violations related to storage areas are considered.

Storage capacity

Storage areas should have sufficient capacity for the orderly storage of various categories of materials and products: raw materials and packaging materials, intermediate, bulk and finished products, as well as products in quarantine, products allowed for release, rejected, returned or withdrawn. - p. 65. (3.18) of the GMP Rules.

The GMP rules stipulate that the premises must be located, designed, built, equipped and operated in such a way that they correspond to the operations performed. All raw materials, packaging materials and products should be stored in appropriate conditions established by the manufacturer, in a certain order, ensuring the separation of the series and the established sequence of use of warehouse stocks. According to OFS.1.1.0010.15, storage rooms must be equipped with a sufficient number of cabinets, safes, racks, floor stands, pallets. It is not allowed to place drug pallets in several rows in height without using shelving. In accordance with the Order of the Ministry of Agriculture of Russia No. 145, pallets can be placed on the floor in one row or on racks in several tiers, depending on the height of the rack.

Shelf storage allows you to make the most efficient use of storage space, and the goods in packages are not damaged by the weight of each other. Rack storage system allows you to organize the orderly storage of various categories of materials and products, their loading and unloading. Pallets with materials or products should not be between racks on the floor, if during the mapping such a load of the premises was not carried out.

Examples of detectable violations:

• “The warehouse does not have sufficient capacity”, “The warehouse does not provide for the orderly storage of raw materials / materials / products”, clause 65. (3.18)., Clause 142. (5.7).

Proper storage conditions

When designing and equipping storage areas, it is necessary to provide for proper storage conditions. Storage areas should be clean and dry, they should maintain the required temperature. If special storage conditions are required (for example, temperature, humidity), then it is necessary to ensure and verify such conditions and also to monitor them. - p. 66. (3.19) GMP Rules

The GMP rules stipulate that the planning solution and the design of the premises should minimize the risk of errors and ensure the possibility of effective cleaning and maintenance. According to OFS.1.0010.15, the device, composition, dimensions of areas for storage, their operation and equipment should provide appropriate storage conditions for various groups of drugs. Shelving, cabinets and other equipment should be installed in such a way as to provide access to medicines, free passage of personnel and, if necessary, accessibility of loading and unloading operations, as well as accessibility of equipment, walls, floor of the room for cleaning. The premises for the storage of medicines must be maintained proper sanitary regime. The finishing of the premises for the storage of medicines must meet the current sanitary and hygienic requirements, the internal surfaces of the walls and ceilings must be smooth, allowing for the possibility of wet cleaning. Special instructions should be developed for cleaning spilled or scattered medicines in order to completely eliminate and prevent contamination of other medicines. In accordance with the Order of the Ministry of Agriculture of Russia No. 145, the floors in the premises for the storage of medicines must be solid, solid and even, have a dust-free coating that is resistant to the effects of mechanical and wet cleaning using disinfectants, and should not have wooden unpainted surfaces.

In warehouses, concrete floors with a durable top layer are usually made. The floor must be resistant to abrasion, without cracks, smooth and even. Dustlessness and abrasion resistance of the floor covering are very important: a gradually accumulating layer of cement dust settles on the stored materials and products. When inspecting storage areas, it has become customary that the inspector pays attention to the presence or absence of dust that can cover metal racks. However, the question of cleaning the ceilings of the high-bay warehouse still takes many by surprise. In warehouses with high ceilings and complex metal structures, it is rather difficult to clean the ceilings and fixtures. However, these surfaces must also be periodically cleaned. For these purposes, you can use the services of specialized cleaning companies that use special lifting equipment (winches, cradles, retractable ladders, etc.). But having transferred the duties of cleaning the warehouse of a cleaning company, one should not forget about monitoring the implementation of these services and training. The quality of the cleaning of the warehouse should be checked by the staff of the manufacturer; regular records should be kept of the cleaning carried out and on monitoring its implementation. Inventory for cleaning the warehouse should be properly marked, and it should be stored in its designated place.

Examples of detectable violations:

• “The internal surfaces of the warehouse are not smooth, damaged, difficult to clean,” p. 46 .;
• “Warehouse cleaning is not efficient enough,” p. 66. (3.19);
• “The cleaning activities of the warehouse, which are outsourced to another organization, are not properly controlled”, paragraph 242. (7.4);
• “The training plan did not include employees of a third-party organization that performs warehouse cleaning services”, paragraph 33. (2.8);
• “Inventory and cleaning and cleaning agents are sources of contamination”, paragraph 84. (3.37).

The GMP rules stipulate that all raw materials, packaging materials and products should be stored in appropriate conditions established by the manufacturer. It is recommended that the specifications established by the drug manufacturer for the raw materials be agreed with the suppliers. According to OFC.1.1.0010.15, in each storage room it is necessary to maintain the climate regime, observing the temperature and humidity of the air, established by a pharmacopoeial article or regulatory documentation for medicines. The proper quality of immunobiological drugs, the safety and effectiveness of their use is ensured by the “cold chain” system.

Temperature and humidity are the main parameters controlled in stock. Unfortunately, violations related to the monitoring of these parameters, validation, and temperature and humidity mapping of storage areas are still often encountered when inspecting drug manufacturers.

Examples of detectable violations:

• “Raw materials / materials / products are not stored under the conditions established by the manufacturer”, paragraph 142. (5.7);
• “No qualification / re-qualification of the raw materials / products warehouse, protocols and reports not submitted”, p. 22., p. 45. Appendix No. 15;
• “The locations of the temperature / humidity sensors in the warehouse were not selected in accordance with the analysis of the results of the initial mapping of the premises”, p. 49. (3.3);
• “The time / temperature of the location of thermolabile drugs outside the established storage conditions has not been determined”, paragraph 76. (61) of Appendix No. 2, item 1., item 19. of Appendix No. 15.

According to OFS.1.0010.15, the labeling of moisture-sensitive medicinal products, as a rule, contains the instruction: “Store in a dry place”. When storing such medicines, it is necessary to create conditions so that the relative humidity of the air does not exceed 50% at room temperature (under normal storage conditions) or equivalent vapor pressure at another temperature. Fulfillment of the requirement also provides for the storage of a moisture-sensitive drug in an airtight (moisture-proof) consumer package that provides the specified protection and storage conditions when handling the drug.

Among the answers to some frequently asked questions published on the Rosselkhoznadzor website in April 2018, the following comment is made on the question of the criticality of comments when the storage conditions of finished medicinal products are not followed, in particular the relative humidity of the premises (“dry place”): “Storage conditions of finished medicinal products must comply with the requirements of the registration dossier. If the registration dossier provides for storage of the medicinal product in a “dry place”, then such storage conditions should be provided by the manufacturer of the medicinal product. In the event that the drugs are inspected in a sealed package, which excludes the effect of moisture on the drug (hermetically sealed vials, ampoules, bottles, etc.), the manufacturer submitted documents for changes regarding storage conditions, submitted to the registration dossier and inspectors commission copies of documents confirming that these documents were taken into work by the Rosselkhoznadzor, the commission of inspectors will not consider non-compliance with the storage conditions a “dry place” for such drugs. In this case, the newly declared storage conditions in terms of relative humidity should be respected. "

Examples of detectable violations:

• “The storage conditions for finished products stipulated by the registration dossier for medicinal products (in particular, the requirement“ Store in a dry place ”)” clause 5., clause 66. (3.19) are not observed.

Acceptance and shipment zones

At the points of acceptance and shipment, the raw materials, packaging materials and products should be protected from the effects of weather conditions. Receiving areas should be designed and equipped so that containers with incoming raw materials and packaging materials can be cleaned before storage. - § 67. (3.20) of the GMP Rules of the Russian Federation.

To protect warehouses from the effects of weather conditions at the zones of acceptance and shipment, awnings and lock systems are used. The gates of the warehouse must be permanently closed, excluding the time of unloading and loading. If the warehouse is operating in a fairly intensive mode, then the gate may remain open for a longer time, therefore, in modern warehouses, for such cases, aperture seals are used. The dockshelter operates according to the gateway principle and is able to reliably close the gaps that form between the vehicle body and the actual place of acceptance or shipment.

The need to clean containers with incoming raw materials and packaging materials may arise both in the case of adverse weather conditions and contamination during previous storage and transportation. Therefore, the place of acceptance in the warehouse should be equipped with inventory and materials for cleaning the packaging. It can be a vacuum cleaner, napkins, brushes, containers for removed external protective film or packaging, etc. (marked inventory stored in its designated place).

In warehouses it is necessary to have a separate area for the accumulation and storage of wooden pallets in controlled conditions. It is necessary to obtain wooden pallets from reliable sources that guarantee the absence of volatile chemical contaminants (such as TBA - 2,4,6 tribromoanisole) in the wood used for their manufacture. Pallet changers (pallet changer or pallet inverter) can be used not only to replace one wooden pallet with another, but also to replace a wooden pallet with a plastic one.

Examples of detectable violations:

• “At the place of acceptance / shipment of raw materials / materials / products, adequate protection from weather conditions is not provided”, paragraph 67. (3.20).

Quarantine mode and access to storage areas

If the quarantine mode is ensured by storing products in separate zones, then these zones should be clearly marked, and access to them is allowed only to personnel who have the appropriate authority. Any other system replacing physical quarantine should provide equivalent security. - § 68. (3.21) of the GMP Rules of Russia.

The GMP rules stipulate that incoming raw materials, packaging materials and finished goods produced should be immediately quarantined using the principle of separate storage or through organizational measures, and kept there until a permit to use raw materials or a permission to release finished products is received.

The quarantine mode in the warehouse can be provided in various ways, for example: use of various premises - for storage of products and materials that are in different status; the use of color marking (for example, according to the “traffic light rule”) or color marking with administrative division - for separate storage areas in one room. If the change in the status of products and materials is supported by a computerized system, then it should be validated.

Access to storage areas should be restricted. Integrated video surveillance and security systems can be installed in warehouses - for round-the-clock monitoring of the territory. To restrict access to individual zones, complex systems can also include automated devices to deny or restrict access (ACS - access control systems). If access control is supported by a computerized system, then it should be validated. Doors can be simply locked with a key, but it is necessary to determine where and how keys are stored, who has the right to use them. There should be a list of employees who are entitled to be in storage areas.

Examples of detected violations:

• “The incoming raw materials / materials are not placed in quarantine, which operates on the principle of separate storage / due to organizational measures, and are not contained in it before obtaining permission to use raw materials / materials”, “The method of storage of products does not guarantee the release from the warehouse only allowed to to the output of products ”, p. 68. (3.21), p. 140. (5.5), p. 194. (5.58).

Sampling in stock

Sampling of raw materials and primary packaging materials, as a rule, should be performed in a separate area. Sampling carried out in the storage area should be carried out in such a way as to prevent contamination or cross contamination. - p. 69. (3.22) of the GMP Rules of Russia

GMP rules stipulate that the manufacturer must approve procedures for sampling, containing information about the methods and equipment used, the quantities to be taken, and any precautions to be taken to avoid contamination of the material or any deterioration in its quality. According to OFS.1.0004.15, all operations related to sampling should be carried out properly in a separate room or in a designated area using appropriate equipment and sampling tools. The method of selection should include the prevention of contamination of drugs and materials from which samples are taken, the samples themselves, as well as other drugs, materials and the environment. For sampling, samplers are used that correspond to the physical condition, type of product packaging, made of a material that does not contaminate products and does not react with it.

Sampling training should be organized directly in the sampling area. If their preparation is carried out in the laboratory of the quality control department, then it is necessary to clearly regulate and monitor the transfer of instruments to the sampling zone. The sampling zone for raw materials and primary packaging materials should be designed as a classified area, have airlocks for personnel and for transfer of materials. The cleanliness class of the sampling area should correspond to the class required for the rooms or areas where these raw materials and materials will be used later. The sampling room should be equipped with a unidirectional airflow installation. Sampling of sterile raw materials and materials, which are carried out under aseptic conditions in the absence of subsequent sterilization, should be carried out in the zone of cleanliness class A with the environment of cleanliness class B. Inventory and materials for cleaning in the sample room and for cleaning equipment and tools Sampling should be appropriately marked and stored separately.

Examples of detected violations:

• “The sampling area in the warehouse is improperly equipped, which may lead to contamination of raw materials / materials from which samples are taken”, “Microbiological air monitoring is not carried out in the laminar for sampling of raw materials / materials”, paragraph 16.a (i) ;
• “The room for sampling of sterile raw materials and materials that are handled under aseptic conditions, according to the results of annual qualification, certified as class D premises”, paragraph 4. (2), paragraph 5. (3).

The GMP rules found that the selected control samples should be a representative sample of a series of raw materials, packaging materials or finished products. The manufacturer must approve procedures or measures to ensure the authenticity of the contents of each container of the feedstock. Containers from which samples were taken should be labeled. The label of the container with the selected samples should contain its contents, the batch number, the date of sampling, and the designation of the package from which these samples were taken. According to OFS.1.0004.15, the sampling of point samples is carried out with a suitable sampler from different levels: the upper, middle and lower layers of each selected packaging unit. Selected samples should be representative, that is, obtained using a sampling procedure that ensures that different parts of a series or different properties of heterogeneous products are represented proportionally. The representativeness of the samples taken is the basis for subsequent representative results of the analytical tests.

Special attention should be paid to the procedures for closing containers after opening them during sampling. With the general principles of inventory turnover (FIFO / FEFO), containers from the warehouse, the integrity of which was violated during sampling, should be transferred first to production.

Examples of detected violations:

• “The selected control samples do not represent a representative sample of a series of packaging materials”, paragraph 215. (6.12);
• “Representativeness of samples is not ensured when sampling raw materials”, “The presented samplers do not allow for representative sampling of raw materials”, paragraph 7. (4) of Appendix No. 8.

Storage of rejected, withdrawn and returned raw materials

For storage of rejected, withdrawn or returned raw materials, packaging materials or products, isolated areas should be provided. - p. 70. (3.23) of the GMP Rules of the Russian Federation.

The GMP rules state that declined materials and products must be clearly labeled and stored separately in restricted access areas. Recalled products must be marked and stored separately in a safe area until a decision is made on its further use or destruction.

Separate closed shelves that are physically isolated (for example, a Rabitz grid) can be allocated in the warehouse, which precludes access to the defective, withdrawn or returned raw materials, packaging materials or products stored there. The size of the isolated area should be sufficient to store the entire series. When inspecting drug manufacturers, inspectors point out that the requirement for insulated areas in warehouses applies to fully computerized storage systems (which, initially, must be validated).

Examples of detectable violations:

•  “There are no isolated storage areas for storing rejected / recalled / returned raw materials / materials / products”, p. 70. (3.23).

Storage of highly active substances

Highly active substances and medicinal products for which special storage conditions are established by the regulatory legal acts of the Russian Federation must be stored in safe and protected areas. - p. 71. (3.24) of the GMP Rules of Russia.

According to OFS.1.1.0010.15, when arranging premises and organizing storage of hazardous medicinal products, it is necessary to be guided by the requirements of federal laws and regulatory legal acts of the Russian Federation. Storage of narcotic and psychotropic medicinal products must be carried out in accordance with federal laws and regulatory legal acts of the Russian Federation. In accordance with the Order of the Ministry of Agriculture of Russia No. 145, separately from other groups of drugs are stored: narcotic and psychotropic drugs, precursors; potent and poisonous drugs that are controlled in accordance with international law.

Storage of printed packaging materials

Safe and reliable storage of printed packaging materials should be ensured, as they are considered critical to ensure that the medicinal product meets the established requirements. - p. 72. (3.25)

The rules of the GMP found that special attention should be paid to printed materials. They must be kept in safe conditions, excluding access by unauthorized persons. Cut labels and other separate printed materials should be stored and transported separately in a closed container, preventing their entanglement. Return to the warehouse unmarked packaging materials produced in accordance with the approved procedure.

Safe storage conditions for printed materials can be provided in various ways, for example: using a separate room to store them; allocation of a lockable zone or use of lockable lockers for storage in the common area. Labels for different products cannot be stored on the same pallet. When returning to the warehouse, it is necessary to calculate the returning packaging materials.

Warehouse areas play a significant role in the quality assurance system of a pharmaceutical enterprise. When inspecting drug manufacturers for compliance with the requirements of the GMP Rules, many aspects of the functioning of the warehouse are controlled as strictly as in inspections of production areas and quality control zones. In addition to the aspects described in this article, when preparing storage areas for inspection, attention should also be paid to other important issues, such as: lighting and ventilation in premises; ensuring the protection of premises from the penetration of insects or animals; calibration and verification of scales and other measuring instruments, recording and control devices; checking the integrity of the packaging and seals, compliance with the supplier’s labels on each delivery note; weighing raw materials in stock and its issuance in production; marking; documentation; staff training, etc

In the preparation of the material used:

• GMP Rules, approved by Order of the Ministry of Industry and Trade of Russia of June 14, 2013 No. 916;
• General Pharmacopoeial Article OFS.1.1.0004.15 "Sampling";
• General pharmacopoeial article OFS.1.1.0010.15 “Storage of medicines”;
• Order of the Ministry of Agriculture of Russia dated April 15, 2015 No. 145 “On approval of the Rules for storage of medicines for veterinary use”;
• materials of seminars and articles published in Russia.