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The packaging of an item must realise various functions. It is used to wrap up the product and to protect it against physical and chemical influences on the product. The aim is to retain the specification defined for the active pharmaceutical ingredient over the period of time that was stipulated.
Furthermore, the packaging contains legally prescribed information for the final customer.
Packaging material can be divided into primary and secondary materials for functional reasons.
Primary packaging materials come into direct contact with the product and as containers, they protect the product. They include jars (sometimes dyed for UV absorption) and foil (e.g. for tablets, granulates or suppositories). These materials come into contact with the product and are therefore subject to specific requirements. The process is described as primary packaging.
Secondary packaging materials are added after the primary packaging to provide extra protection (e.g. folding cartons, paper board containers) and to comply with the legal obligation to identify the contents of the package (e.g. package inserts, folding cartons, brochures, seals). The process is described as secondary packaging.
A further distinction can be made between unprinted and printed packaging materials. Printed packaging materials contain product- and batch-related data. They include printed foils, tubes, folding cartons, labels, etc.
The EU Guideline definitions do not count packaging materials as starting materials. However, the same requirements as those for starting materials should apply when handling the packaging material. “The purchase, handling and control of primary and printed packaging materials shall be accorded attention similar to that given to starting materials.” (5.40 EU GMP Guideline). This is obvious, because it concerns materials which, as primary packaging materials, can affect the stability of the product directly and can lead to misidentification if an error is made with the labelling. From a production point of view, separate stages of handling the packaging materials should be defined, e.g. delivery, storage, allocation and processing.
The responsibilities for handling packaging materials are clearly regulated (see figure 13.A-2).
The contents of the texts on the packaging materials are defined as follows (see figure 13.A-3, figure 13.A-4 and figure 13.A-5). The following tables provide an overview of the legal requirements. Special cases are not included in this overview.
The selection of the primary packaging material begins in the early stages of the product development. The selection should take into account functional aspects, e.g. product-specific factors such as hygroscopicity and light sensitivity needed to attain adequate product stability and possible interactions (see figure 13.A-6) and incompatibilities, marketing requirements, e.g. with regard to specific foil colours or formats, and legal requirements such as childproof features. Ideally, the selection should also take into account technical aspects such as processability in order to achieve the most efficient packaging process possible. The data determined as part of the stability studies directly relate to the qualities of the primary packaging materials used. A risk evaluation within the change control process will be required if, at a later stage, primary packaging materials are replaced, e.g. due to a change in the chemical composition of the sealing lacquer or the thickness of the foil, or due to significant changes in the manufacturing process or to the replacement of plasteizer in plastic bottles.This can then lead to stability studies (chapter 14.G Stability testing) and/or variations for product authorisation.
Given that a large variety of different materials count towards the completeness of the packaging materials used (containers, stoppers, printed packaging materials, etc.), they make up a non-homogenous group. Very different testing procedures (figure 13.A-7) are therefore necessary. In addition to the control tests to check for conformity with legal requirements (pharmacopoeia, data relevant to marketing authorisation, etc.), production-specific parameters also need to be reviewed. These include, for example, the thermoforming foil shrinkage, dimensional accuracy and precision of the tactile marks positioning, torsional measurements on tamper-proof closures on bottles, testing the adhesive strength on folding cartons.
“Outdated or obsolete primary packaging material or printed packaging material should be destroyed and this disposal recorded.” (5.43 EU GMP Guideline). This means that only the up-to-date, authorised versions should be kept as stock in the warehouse. If packaging material is produced with changes that are not for legal reasons (e.g. to the colour), the use by dates can be utilised for this. In any case, a mixture of versions should be avoided (e.g. by using different tube versions in one packaging order). A regular comparison of the current specifications and/or versions with current stocks is necessary. Due to the different materials handling and stock management systems which exist in the company there are a variety of solutions to guarantee that the correct versions are used. A specific packaging material, such as a packaging insert, normally has a specific part number which is then modified for different versions. This makes it possible for a status check (in quarantine, approved, rejected) to also be conducted at this level.
13.A.4 Protection against counterfeit medicinal products
Due to the recent increase in occurrences of counterfeit medicinal products, measures to protect against such falsifications have become necessary. In addition to organisational measures aimed at preventing misappropriation during the distribution and packaging processes, there are also different technologies available in the field of packaging materials to protect the originality of the product. Some examples for solid products are listed below (see figure 13.A-8).
13.A.5 Packaging material testing
13.A.5.1 Control tests carried out at the supplier
A variety of special methods are necessary in the field of primary packaging materials (e.g. elastomers analysis), in order to check that the quality conforms to the specifications. The time and expense devoted to the equipment and organisation required for these checks can be too much for small companies. Other systems must therefore be set up to ensure that the duty to conduct these checks is complied with. The acceptance of the primary packaging material supplier’s certificate of analysis is a simple way to reduce the extent of checks needed to the minimum of an identity test. The precise sequence for this must be specified during the supplier qualification and the contractual delimitation of responsibilities (see chapter 17 Contract Manufacturing and Analysis). The level of quality required can be sufficiently guaranteed if comprehensive control tests are conducted (during current production and also final inspections). The sampling plan should be drawn up in accordance with the Supplementary EU GMP Guideline for sampling of starting materials and packaging materials (figure 13.A-9).
The control tests carried out when the goods are received at the contract provider shall involve at least an identity test on the packaging material. The approval will be issued by the head of quality control.
To ensure that the packaging material is not damaged when taking samples upon receipt of the goods, e.g. when removing labels from a roll or when destroying the seal on bottles, qualified suppliers can send samples taken during the production process together with the packed goods. This has the advantage of removing the risk of damage and dispensing with the time-consuming sampling that would otherwise be required (repackaging, transports, etc.). If the supplier takes several samples together following an approved and established sampling plan (one for supplier analysis, one for the contract provider), the quality evaluations can be directly compared with one another (authenticity of parallel samples). The arrangements made with the supplier should include specifying the means of transport to be used, so that comparable transport conditions can be obtained for samples and for the delivered goods (e.g. to avoid the various effects on the thermolabile materials). A simple way to do this is to send the sample together with the goods. To prevent results from being incorrectly interpreted, both parties will carry out tests in accordance with specifications approved by the contract provider and with error categories.
The internal testing is normally carried out in the packaging materials laboratory. A variety of testing methods are used here. As part of the stepwise supplier qualification procedure there are also comparative control tests carried out to evaluate the supplier certificate. The packaging materials laboratories can be under the organisational control of both the head of production and the head of quality control. The release will always be issued by the head of quality control.
In addition to complying with pharmacopoeia specifications, the technical requirements must also be reviewed. Examples can be found below.
The dimensions must be checked. The folding on package inserts which have been pre-folded has to be checked. If not, this can lead to huge problems in the technical handling and also to a loss in productivity. The print quality should also undergo intensive control tests at the printers. The bar code checks are an important check. In addition to accuracy, the positioning and also the width tolerance of the bar codes are important for the production process. The luminescence tests in the packaging process must also include suitability testing. In addition, a text analysis can also be necessary. Since it might be impossible for the laboratory staff to compare texts against an up-to-date master containing a variety of languages and characters, certain important information (guiding elements) should serve as a test item (e.g. dosages that are also in foreign languages). The ideal solution to this would be proof reading, in other words, scanning the text and using the computer to compare it with the master. However, this solution is not in operation everywhere for cost-related reasons.
In addition to the control tests conducted on the package inserts an adhesiveness test for self-adhesive labels must be included. Holes found in the rolls, in other words, labels which have become detached from the backing can lead to problems in the production process.
The legibility of the code found on the folding carton both before and after the carton has been assembled is an important consideration. If the bar code is placed too close to the break edge, for example, the codes will not be legible later when they arrive at the pharmacy because the unprinted reader zone is missing. The nature of the folding cartons is a very important consideration from a processability point of view. Fibre orientation and carton composition, perforation and splice points in addition to the clip functioning and the assembly should be reviewed.
In addition to the standard control tests (chemical-analytical, physical, visual) process-specific and/or facilities-specific details should also be reviewed. Behaviour during a thermoforming process, meaning deformation and size increase and/or decreased thickness can be tested using advance simulations. When specifying tolerances it should be remembered that the combination of different packaging materials (e.g. vials, rubber stoppers, crimping caps) in the respective limit areas can cause problems in the manufacturing process. This should be considered during development.
13.A.5.3 Defect evaluation lists
When the packaging materials are being inspected upon receipt, representative random samples are taken in so far as this is possible. The sampling is carried out in accordance with defined and approved sampling plans. The exact sequence and the responsibilities for carrying the sampling out are set out in the form of organisational instructions. The random sample is evaluated with the help of statistical methods and by classification into defect categories, according to which the significance of the samples must be critically evaluated, e.g. with regard to their representativeness. There is a tendency of shifting from random sampling to a 100 % control in the course of the supplier’s packaging materials manufacturing process. However, the random sample testing has still great importance.
The control tests conducted upon receipt of the goods are carried out with authentic samples (supplier’s random sample and/or internal sampling by the company). Defect definitions and the way that these are classified into categories should be drawn up before evaluation takes place. Acceptable Quality Limit values (or acceptable quality level) must be specified. These values represent the maximum number of defects that are acceptable (depending on the size of the random sample). The following table shows that with low AQL values, meaning very strict quality requirements, but with the same base quantity (e.g. batch size) considerably fewer defects are accepted and/or the number of random samples increases. If the maximum acceptable number of defects is exceeded, this constitutes an OOS result
The classes of defect with their subdivisions and/or classifications must each be defined individually. This includes summarising categories of over-critical and critical defect or other subdivisions. Existing defect evaluation lists are frequently adopted for this purpose, e.g. ECV volume: Quality Assurance of Cosmetic and Pharmaceutical Packaging Material.
A) Over-critical defects
These include defects which endanger human life (such as confusing text errors, lack of sterility) or defects which are against legal requirements (by not conforming with pharmacopoeia specifications).
B) Critical defects
These include defects where there is a possibility that a patient or consumer could be harmed. They can also result in damage to the production equipment. These include deformed glass vessels, for example (wedges in the inlet or a leaky closure) or faulty threads on bottles (leaks).
C) Major defects
Major defects are described as such if neither humans nor the product itself is endangered, but the error leads to reduced efficiency during production. A complaint from market sources is also considered possible. Examples include: Crimping caps with deformations (they cannot be screwed on), folding cartons which have been pressed down too hard (and cannot be assembled), illegible code marks.
D) Minor defects
These mostly include presentation errors which do not directly affect the quality of the product (e.g. scratches on the surface, slight displacements in graphic layouts)It is also possible to summarise numbers of single errors within classes of total number of errors. This is a further possibility for a global evaluation. This can also lead to problems. Changes to the items checked (e.g. by conducting an additional check) increase the likelihood of the material being rejected. The considered and continuous use of test item-specific AQL values appears to be the more rational method and is equal to a monitoring system.
The AQL values specified must be re-collected with a view to their use on markets with different quality requirements (e.g. weighing up of minor presentation defects without damaging the product quality on the Japanese market). Existing error lists and/or categorisation systems are therefore not transferable without further review and must be critically examined in the individual case.
In principal, a distinction can be made between qualitative control tests whilst retaining the test item and time-consuming, destructive and quantitative control tests on the other hand. The AQL values for the second group are adapted because the random sample sizes are reduced, or revised downwards.
Packaging materials must be stored under suitable conditions. This means that the quality of the storage rooms must be defined and monitored. The temperature and humidity should be monitored in order to monitor the retention of these required values. The paper-based packaging materials (package inserts, folding cartons) are moisture-sensitive.
“Particular attention should be paid to printed materials. They should be stored in adequately secure conditions such as to exclude unauthorised access.” (5.41 GMP Guideline). This can be achieved in terms of both the rooms and the organisation. The storage can be in segregated storage areas, which can be achieved by using lockable pallet bays (e.g. inside a grating) or special rooms. In high-bay storage a product can be stored at a great height and cannot be reached easily (e.g. using a standard ladder). This makes it especially necessary for the warehouse staff using the lifting device to have authorised access to all the printed packaging materials. This is a possibility for small companies in particular. From the point of view of security, the use of lockable rooms to which only selected warehouse staff have access is preferable. The aim is to restrict easy access, to only admit defined people and to control of receipt and delivery packaging materials.
When redeliveries are received from the packaging area, it should be ensured that the packaging material has been sufficiently wrapped (e.g. has each roll of foil been wrapped, are there any breakages). The redelivery process for partial quantities is only possible for unused quantities of material. Quantities which contain variable data should be destroyed if possible. If labels, for example, need to be pre-printed, sufficient measures must be taken to ensure that no cross-mixing or misidentification can take place. This means that in addition to unambiguous labelling, the quantity has also been sufficiently sealed inside a plastic container, for example. The same requirements as those for the allocation of packaging shall apply to the redelivery process (see chapter 13.B Packaging process). The requirement that packaging materials be stacked on pallets must be complied with so that no damage is caused to the materials.
“Each delivery or batch of printed or primary packaging material should be given a specific reference number or identification mark.” (5.42 EU GMP Guideline). This clear obligation to label complies with the requirements for starting materials. Similarly to those requirements, the status checks (quarantined, released, rejected) can only be conducted physically, e.g. by affixing labels (using different colours as a signal system) or organisationally, e.g. using a warehouse management system (e.g. by inputting a pallet place number for the requirement) only if the product has the status released. Each separate container, that is, also each roll of foil must be clearly identifiable (see chapter 13.B Packaging process).