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Analysis of packaging non-compliances identified during Russian GMP inspection

When Russian inspectorate inspecting drug manufacturers for compliance with the requirements of the Good Manufacturing Practice (GMP), various inconsistencies are identified. Some of them are typical and are quite common. This material addresses packaging issues.


The specifications for the feedstock and packaging materials should contain (or should be referenced, where applicable) the following: a) a description of the feedstock or packaging materials, including: name and internal code (if necessary); a link to a pharmacopoeia article, regulatory documentation or regulatory document; the name of the approved suppliers and producer of raw materials or packaging materials; sample of printed materials; b) instructions for sampling and testing; c) qualitative and quantitative characteristics with limit values; d) storage conditions and precautions; e) expiration date. - Clause 112. (4.14) of the GMP Rules.

For each medicine, package size and type, packaging instructions must be approved. - Clause 118. (4.19) of the GMP Rules.

For each series or part of a series produced, records must be kept for the packaging of the series. They should be based on the relevant parts of the packaging instructions. - p. 123. (4.21) of the GMP Rules.

The batch packing records must include the following data: a) the name and batch number of the drug; b) the date (s) and time of packaging operations; c) the surname (s) and initials of the operator (s) of each main technological operation and, if necessary, the person who checked each of these operations; d) records of identity checks and compliance with packaging instructions, including results of controls during production; e) information on packaging operations carried out, including references to used equipment and packaging lines; f) samples of used printed packaging material, including samples with the serial number, expiration date and other additional marking data; g) a description of deviations from packaging instructions signed by an authorized person with a date; h) the quantity and reference to the number or name of all printed packaging materials and bulk goods issued, used, destroyed or returned to the warehouse, as well as the quantity of the finished product for preparing the material balance. Electronic control during the packaging process is the basis for not including such information; i) the signature of the person responsible for the packaging process, indicating the date - Section 124. GMP Rules.

In October 2017, at the Golden Autumn Russian agro-industrial exhibition, the head of the Production Inspection Division for compliance with the requirements of good manufacturing practice Danil Rudnyaev cited the following violation among the discrepancies identified during the inspection of veterinary drug manufacturers: “Specifications for raw materials and packaging materials, intermediate and finished products do not contain the required information. ”

Some manufacturers do not include in their specifications too detailed private information, for example, the text of the instructions for sampling and testing. But in this case, the specification should include appropriate references to other documents related to it, and these documents should be available (including during the inspection of the manufacturer). Packing instructions should include all information given in paragraph 118. (4.19) of the GMP Rules. Some manufacturers include empty packaging series templates for packaging instructions. A list of all necessary packaging materials can also be presented in the appendix to the instructions. As for the samples or copies of the corresponding printed packaging materials and samples, indicating the place of application of the batch number and expiration date of the products, they can only be referenced in the packaging instructions. These samples should be available, but they can be stored separately, especially if the size of the samples does not allow them to be attached to the instructions (for example, a large cardboard box). Samples must be labeled appropriately to prevent them from accidentally entering the packaging process.

Examples of detected violations:

• “Specifications for packaging materials do not contain the following information (or related links): name of approved suppliers / manufacturers of packaging materials; instructions for sampling and testing; expiration date ", p. 112. (4.14);
• “A sample of the marked label that matches the labels used is not included in the series packaging records”, “Samples of packaging materials are not applied to the series dossiers at the beginning of the use of a new series of material (for example, a new label roll)”, paragraph 124 e );
• “Not all deviations from packing instructions are included in the series packing records” p. 124 g).

Packaging materials

The procurement, control, and handling of primary and printed packaging materials must be given the same attention as raw materials. - Clause 175. (5.40) of the GMP Rules

Particular attention must be paid to printed materials. They should be stored in a safe environment, preventing access by unauthorized persons. Cut labels and other scattered printed materials should be stored and transported separately in a closed container, eliminating their confusion. Permission to use packaging materials should only be issued by specially designated persons in accordance with the approved procedure. - Clause 176. (5.41) of the GMP Rules

Each shipment or series of primary or printed packaging materials must be assigned an identification number or identification mark. - Clause 177. (5.42) of the GMP Rules

Upon receipt of products and packaging materials at the packaging site, their quantity, identity and compliance with packaging instructions should be checked. - p. 182. (5.47) of the GMP Rules

The materials of the primary packaging must be clean before starting the filling operation. It is necessary to ensure the prevention and elimination of any contamination, such as broken glass and metal particles. - Clause 183. (5.48) of the GMP Rules

The procurement of primary and printed packaging materials is an important process in which competent personnel should be involved. This activity should be carried out using approved specifications for packaging materials, where approved suppliers should be indicated (which should be audited regularly). It is highly desirable that all specifications be agreed upon with suppliers. Printed packaging materials should be made only on the basis of authorized graphic layouts (original layouts). Sampling and testing of packaging materials must be carried out in accordance with the instructions specified in the specifications.

GMP rules establish that the manufacturer must approve procedures for in-house labeling, quarantine and storage of packaging materials. All incoming packaging materials must be inspected to ensure that the delivery matches the order; tare places should be cleaned and marked with the required information. On acceptance of each delivery of each type of primary, secondary and printed packaging materials, procedures approved by the manufacturer and supporting records must be available. Incoming packaging materials must be immediately quarantined and kept there until permission to use is obtained. All packaging materials should be stored in appropriate conditions established by the manufacturer, in a specific order, ensuring separation of the series and the established sequence of use of stocks. At each production site carrying out packaging, control samples of each series of primary packaging materials and printed materials should be stored (printed materials may be included in the composition of control and / or archival samples of finished products).

Sometimes manufacturers ask how it is possible to check the amount of packaging materials, for example, leaflets with instructions for using the drug. If you recount them manually by the piece, it will take a lot of time, and then folding them back together with an even pile will be difficult (therefore, there may subsequently be a problem with their use on a folding device of a cartoning machine). You can check the amount of such materials, for example, using weights. It is important to understand why this is necessary at all - in order to properly compose the material balance for packaging materials.

Examples of detected violations:

• “There is no marking of packaging materials received at the warehouse”, paragraph 138. (5.3);
• “From the warehouse, packaging materials in quarantine status were transferred to production, paragraph 140. (5.5);
• “Storage of materials with different status is organized in a cell with one identification number in a computerized system”, paragraph 142. (5.7);
• “There is no accounting for packaging materials coming from the warehouse to the packaging site”, paragraph 182. (5.47);
• “No justification has been provided for the exclusion of microbiological purity control of primary packaging materials”, “Sterility control for primary packaging materials is carried out by outsourcing (they are sterilized by the Contractor and returned to the Customer along with supporting documentation), but periodic verification of this process is not provided - the sterility test is not carried out ”, paragraph 175. (5.40), paragraph 183. (5.48);
• “Control samples of primary packaging materials are not stored at the site”, “Control samples of each series of primary packaging materials and printed materials are not organized”, paragraph 6. (2.2) of Appendix No. 18 (19).

Packaging operations

When planning packaging operations, particular attention should be paid to minimizing the risk of cross-contamination, confusion or substitution. It is not allowed to pack products of various types in close proximity to each other, with the exception of cases involving physical separation. - Clause 179. (5.44) of the GMP Rules

Before starting packaging operations, measures must be taken to ensure that the work area, packaging lines, printing machines and other equipment are clean and do not contain any previously used medicines, packaging materials or documents if they are not required for the planned operation. The line must be cleaned in accordance with the approved procedure. - Clause 180. (5.45) of the GMP Rules

The name and batch number of the packaged product must be indicated on each packaging unit or line. - p. 181. (5.46) of the GMP Rules

GMP rules establish that planning decisions of production areas and in-plant storage areas should ensure consistent and logical placement of equipment and materials, minimizing the risk of confusion of various drugs or their components, ensuring no cross-contamination and minimizing the risk of skipping or improper implementation of any stage in production or control. Simultaneous or sequential operations with different products in the same room are not allowed, unless there is no risk of confusion or cross-contamination.

Sometimes manufacturers wonder what height should be the partitions in the secondary packaging room, which share the equipment of the various packaging lines. There is no requirement that these partitions be as high as the ceiling. But they must be so high and long that they prevent the risk of accidentally mixing up various drugs or packaging components.

GMP rules establish that in order to prevent cross-contamination, appropriate technical and / or organizational measures should be provided, including control of residues and the use of labels indicating the status of equipment cleaning. Throughout the entire production process, all used raw materials, packaging materials, containers for bulk products, basic units of equipment and, if necessary, premises must be labeled or otherwise indicated with the products or processed raw materials and packaging materials, as well as the dosage and serial numbers of manufactured products.

Since when packaging products in primary packaging materials, they come into contact with the environment, this process must be carried out in clean rooms. Materials that may become a source of contamination should not enter these rooms. Controlling the presence of residues on the packaging line is an important process that has already undergone significant evolution in some enterprises. The first method for monitoring line clearance was to simply use the worksheet with one operator. A new method was the use of two operators, one of which carried out an additional check. In the following method, the operator checked the line, following the serial numbers that showed him the way (special stickers on the equipment). The next method already included the operator following the line drawn on the floor with stickers indicating the number of specific points for inspection. It is possible that this verification method can be further improved. It is only important to understand that stickers that can be used to mark equipment should not peel off over time and become sources of contamination.

Examples of detected violations:

• “There is a simultaneous / sequential transaction with different products in the same packaging room when there is a risk of confusion or cross-contamination”, paragraph 55. (3.8), paragraph 144 (5.9);
• “There is no labeling of premises and equipment in the packaging premises, including the indication of the cleaning status”, 154. (5.19) g);
• “On the packaging line there were simultaneously two series of bulk products (one of them in waste), although there is a note in the journal about cleaning the line before starting the packaging process for a new series”, paragraph 180. (5.45);
• “There are no identification labels on the packaging line”, paragraph 147 (5.12.), Paragraph 181. (5.46).


It is recommended to mark as quickly as possible after packing and capping. The necessary measures must be taken to ensure that no confusion or mislabelling occurs. - p. 184. (5.49) of the GMP Rules

The correctness of any printing operations (for example, applying series numbers, expiration dates), carried out either as a separate technological operation or during the packaging process, must be carefully monitored and documented. Particular attention should be paid to manual markings, which must be checked regularly. - Clause 185. (5.50) of the GMP Rules

Special precautions must be observed when using cut labels and labeling outside the packaging line. To prevent confusion of printed material, it is recommended to use labels on a roll instead of cut labels. - p. 186. (5.51) of the GMP Rules

Marking of packaging materials by printing or embossing should be distinct and resistant to fading or abrasion. - p. 188. (5.53) of the GMP Rules

Labels or cardboard packs marked on them must be stored and transported separately in a closed container, eliminating their confusion. The containers used for them should, in turn, be clearly marked. The movement of these materials to the packaging line must be monitored and recorded.

Cut labels are labels for drugs that are “cut” from a sheet or label roll. According to paragraph (g) of § 211.122 “Materials examination and usage criteria” of Section 21 CFR, Part 211, Part G, when using cut labels, packaging and labeling operations must include one of the following special control procedures :

1. The allocation of lines for labeling and packaging of each individual dosage of each individual product;
2. The use of appropriate electronic or electromechanical equipment to conduct a 100% verification of the marking during operations or after completion; or
3. The use of visual inspection to conduct 100% verification of correct labeling during manual marking operations or after completion. Such verification should be carried out by one person and independently verified by a second person.
4. The use of any automated method, including the distinction between the size and shape of the label, which physically prevents incorrect labeling using equipment for marking and packaging.

It is important to remember that in accordance with Article 46 “Labeling of Medicines” of Federal Law dated April 12, 2010 No. 61-ФЗ “On the Circulation of Medicines”, the serial number, release date (for immunobiological medicines) and the expiration date on the primary and secondary (consumer) drug packaging should be indicated in a legible font.

Examples of violations identified: “Simultaneous labeling of different series of products is carried out in one room, while there is no physical separation, which can lead to confusion,” paragraph 184. (5.49).

Packaging control

The manufacturer must carry out checks to ensure that all electronic code readers, label counters, and similar devices work correctly. - p. 187. (5.52) of the GMP Rules.

When monitoring the process of packaging products on the line, in particular, the following should be checked: a) (a) the general appearance of the packages; b) (b) the completeness of the packages; c) (c) the use of appropriate products and packaging materials; d) (d) the correct application of any marking; e) (e) the correct operation of control devices on the line. - p. 189. (5.54) of the GMP Rules.

Samples taken from the packaging line should not be returned back to the line. - p. 190. GMP rules.

GMP rules establish that records should be kept during each action and in such a way that all significant activities related to the production of medicines can be traced.

Particular attention must be paid to the proper maintenance of records confirming the performance of the packaging process control (IPC). Modern high-speed packaging lines include equipment equipped with a large number of electronic control devices: video cameras that monitor the availability of the product in the primary packaging; sensors monitoring the completeness of the secondary packaging and shipping containers; sensors for reading the pharmaceutical code from packaging components, etc. Verification of the correct operation of these devices and other types of line checks should be performed at the beginning of the packaging process, and then at certain intervals. Typically, these checks are carried out by the personnel of the packaging site, and additional control is performed by the personnel of the quality control unit.

Sometimes manufacturers ask themselves what exactly is meant by “samples taken from the line that cannot be returned to it”. Perhaps it should also be clarified that, first of all, we are talking about samples taken outside the line. Individual packaging components can be returned to the line - after their additional verification, and only at certain places (in particular, in front of the control devices), taking into account the returned quantity (this is important when calculating the output and drawing up the material balance). To prevent the risk of accidental confusion, such actions should be carried out under control, and the sequence of their implementation should be clearly described in the appropriate procedure.

Examples of detected violations:

• “The time of inspections carried out on the line at the beginning of the packaging process is not indicated”, paragraph 106 (4.8);
• “Samples taken from the line are repeatedly returned to the line”, paragraph 190.

Completion of the packaging process

If unforeseen circumstances arose during the packaging of a product, it may be returned to production only after a special inspection, investigation and with the permission of a person with the appropriate authority. These actions must be in the form of a protocol that must be stored in the prescribed manner. - p. 191. (5.55) of the GMP Rules.

If there is a significant or unusual discrepancy established during the preparation of the material balance between the number of bulk products, printed packaging material and the number of finished product units produced, it is necessary to investigate and establish the reason for this discrepancy before issuing a permit for release. - p. 192. (5.56) of the GMP Rules.

After completion of the packaging operations, any remaining packaging materials with the serial number printed on them must be destroyed with subsequent documentation. Return to the warehouse of unlabelled packaging materials is carried out in accordance with the approved procedure. - Clause 193. (5.57) of the GMP Rules.

GMP rules establish that the manufacturer must carry out checks of outputs and material balance to ensure that there are no deviations exceeding the permissible limit values. Processing rejected products is allowed in exceptional cases, provided there is no deterioration in the quality of the finished product and all requirements of the specifications are met. Processing should be carried out in accordance with the approved industrial regulations after assessing the possible risk, followed by documentation. Expired or unusable printed or primary packaging materials must be destroyed with paperwork. Rejected materials and products must be clearly labeled and stored separately in restricted areas.

Many manufacturers outsource waste disposal activities. In this case, it is necessary to consider what types of waste and in what form are transferred for destruction. A particular risk may be the waste of printed packaging materials that have not previously been rendered unusable (the possibility of subsequent falsification of products).

Examples of detected violations:

• “There is no material balance on packaging materials in the series dossier”, “The manufacturer does not check the yields and material balance to make sure there are no deviations”, “The permissible limits for the output of finished products at the packaging stage are not established in the documentation”, paragraph 143 . (5.8);
• “When packaging products, the rejected printed packaging materials are not counted; when compiling the material balance, the difference between the number of materials received and the number of used and actually rejected materials is not taken into account”, paragraph 192. (5.56);
• “It is not envisaged to conduct a preliminary documented risk assessment in the event of a decision to repackage products,” “The process of extracting syringes with vaccine from blisters and re-returning these syringes to a blister machine is not validated with a subsequent study of the stability of the returned product”, paragraph 198. ( 5.62);
• “Expired printed / primary packaging materials are not destroyed with documentation”, paragraph 178. (5.43);
• “There is no documenting the transfer to destruction and actual destruction of the remaining packaging materials with variable data about the series”, “There is no document describing the procedure for dealing with the remains of packaging materials after completion of packaging operations”, “The procedure does not provide for the calculation of the actual quantity packaging materials returned to the warehouse ”, paragraph 193. (5.57);
• “Discarded and unusable packaging materials are stored in a shared area,” 197. (5.61).

Packaging and labeling are important elements of a drug. According to available data, a significant number of claims and subsequent product recalls from the market are associated with errors and inconsistencies in the packaging process. In addition to the aspects described in this article, in preparation for the inspection, attention must also be paid to other important issues, including qualification of packaging equipment, validation of the equipment cleaning process and packaging process, compliance with the “cold chain” conditions for packaging heat-sensitive products, etc.

To prepare this material used:

• GMP rules approved by Order of the Ministry of Industry and Trade of Russia dated June 14, 2013 No. 916;
• Section 21 of the United States Code of Federal Regulations (CFR), part 211, subpart G, “Packaging and Labeling Control”;
• materials of seminars and articles published in Russia.

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