Warehouse and logistics

 

 

11.M.1 Stock management system

The European Pharmacopoeia (Pharm. Eur.) states: Medicinal products must be stored in such a way that they are protected against substance loss as well as a reduction in purity and efficacy. [...]. The objective is to avoid contamination, confusion and changes during the storage process that are beyond the anticipated levels. This is the only way to ensure that the necessary quality is achieved.

The WHO Guide to Good Storage Practice for Pharmaceuticals (Annex 9) (compiled in close collaboration with FIP - Fédération Internationale Pharmaceutique), hereafter referred to as WHO GSP, acts as a guideline. This replaces the FIP guidelines for good storage practice that are now roughly 20 years old and describes various aspects of storage (see figure 11.M-1). You will find the complete document at chapter G.1 Guide to good storage practices for pharmaceuticals.

11.M.1.1 Responsibilities

Responsibility for the storage area lies with the head of production (chapter 1 EU GMP Guideline). The guidelines for this are defined by the head of quality control and ideally, are worked out jointly.

The person responsible for the storage must regularly verify that medicinal products and starting materials are being stored correctly. At companies with a manufacturing authorisation according to chapter 1 of the EU GMP Guideline, this is the head of production. These controls may be carried out as part of the self-inspection, for example (see chapter 18.E.1 Purpose of self-inspection).

11.M.1.2 Personnel

The personnel requirements in the warehouse are such that a sufficient number of sufficiently Qualified Persons must be present to ensure that the quality assurance guidelines are complied with. Training is required to provide the necessary knowledge for carrying out tasks at the pharmaceutical warehouse (WHO GSP 3.1, 3.2). In order to avoid confusion, a careful and responsible working method is indispensable. As a rule, a large number of work steps are carried out manually, such as the application of labels that are subsequently read mechanically. Experiences gathered when assessing a delivery of starting materials are important in terms of the transportation route, e.g. to assess the extent to which it was possible to maintain the necessary refrigerating chain or to detect hidden damage.

As is the case with production personnel, those persons involved with the sampling of open products for example, must also regularly undergo medical examinations (see chapter 2.B.2 Health requirements). Persons who develop inflammatory diseases should be excluded from sampling during the infectious period. Normal clothing should be covered, or working clothing provided, to reduce impurities brought into the warehouse.

All staff should also receive training in hygiene and cleaning (see chapter 11.B Personnel hygiene) to enable them to comply with the specifications (WHO GSP 3.3).

11.M.1.3 Controlling the turnover of materials

"All materials and products should be stored under the appropriate conditions established by the manufacturer and in an orderly fashion to permit batch segregation and stock rotation. " (5.7 EU GMP Guideline).

It is convenient to set up a system that makes the selective allocation of starting material and intermediate product batches possible. A similar rule applies for the delivery of finished product batches for which an identical or like system is recommended considering the need to control their final destination. It is in the economic interests of the company to use existing quantities of starting materials as efficiently as possible within their period of use. This is also a reason why the First-expired-first-out principle (FeFo) is generally used as the basic system for stock rotation (4.12 WHO GSP). There are of course exceptions - if specific starting materials or intermediate products have to be used in particular batches, e.g. to adjust the specific contents of final products. As to how this system is to be sustained - this is largely dependent on the manner in which the production facility is managed or the form of EDP organisation used. For a system-controlled application of starting materials, the batch of a material to be used is specified by the EDP system. These aspects are always critical elements of the validation of the underlying EDP system (see chapter 9 Computer Validation).

The reconciliation of starting materials and products should be carried out regularly (5.14 WHO GSP), as well as performing a bookkeeping function, these also provide additional safeguards. At the latest, once a batch has been used up, the book inventory balance and actual balance should be compared. If deviations occur that cannot be accounted for by possible fluctuations due for example to weighing tolerances or short-shipments by suppliers, there is a risk of incorrect usage and therefore a production error. Procedures should be defined at the outset to cater for this eventuality. When a deviation of this kind occurs, a failure investigation report (see chapter 11.K.5 Failure investigation report) must be compiled (5.15 WHO GSP).

11.M.1.4 Warehouse organisation

Materials and products that have quarantine status must be separated from others to avoid them being confused with free goods. To this end, a range of different organisational forms may be applied at the warehouse irrespective of the type of warehouse management system used.

A simple classic situation is the physical separation of released and not released materials. Separate storage areas should exist and materials should be identified with status labels (quarantined/released/rejected). The quarantine areas must be labelled and access allowed only for authorised individuals.

The random location storage system - as it is generally referred to - does not allow for the physical segregation of released and not released goods. No special storage areas are designated (e.g. inside high-bay storage). Available storing positions are either specified by the system (particularly where automated systems are used) or reported back to the system following manual storage. Status labels are not required (known as indirect labelling). The status is administered and controlled using the computer-assisted warehouse management system. It is only possible to call up the storage bay for a specific material or product via the warehouse management system.

Mixed systems that combine the use of status labels with shared storage are possible (see figure 11.M-2).

All procedures and organisation forms must be coordinated with the system to guarantee a sufficient level of safety. If, for example, physical labelling of the release status has been dispensed with, additional checks must then be performed to ensure that a given material is being used correctly - either by using the EDP system, or by having the checks carried out by personnel. In addition to the release status, it is also imperative to check the expiration date prior to use. The WHO GSP (5.18) requires that checks for overdue expiration dates are regularly carried out on stock. As soon as the period of use for a material has expired, it should be blocked automatically by an EDP system. Restricting the availability of the storage bay in the warehouse management system is an efficient means of preventing the use of a material that has not been released in a random location storage system. This method ensures that picking orders processed by warehouse personnel or processed automatically will only include released materials or products.

If no EDP-supported control exists, this function could alternatively be carried out via regularly updated lists, with their processing documented by responsible warehouse staff and reported back to the head of quality control. In order to check any interim storage of starting materials or intermediate products once they have left a warehouse, it is important to know their respective storage locations (e.g. by making entries specific to the storage location). Then, when the shelf-life expires, they can be removed on time before the production process starts. It must be ensured that out-of-date or expired material cannot be dispatched or processed.

Aspects such as release status and period of use must be graded as fully GMP-relevant and critical, and must be taken into account when validating the warehouse management system.

11.M.2 Storage areas

11.M.2.1 Size

The size of the storage premises, and all the tasks to be carried out, form an important basis for assessing the quality of a warehouse and its storage. Sufficient capacity for a range of different materials and special storage areas must be available. The risk of confusion is always increased by cramped spaces and low storage bay capacities, such insufficiencies may result in a mixture of different materials or different batches of the same material being assigned to the same pallet. To avoid confusion these practises must be avoided. The storage of small containers may be hived off from the standard high-bay storage areas and ranged in special shelving systems. For ease of handling, paternoster systems may be helpful as they allow a straightforward loading and withdrawal of goods while the materials remain sealed. Tasks such as picking can only be carried out safely if sufficient space is available. It is essential to have sufficient space, particularly in zones that are highly frequented and serve as circulation areas.

11.M.2.2 Illumination

The lighting in storage areas should be such that all tasks may be carried out correctly and safely (WHO GSP 4.16). This requirement is the only logical means of identifying storing positions or containers in non-automated warehouses. A sufficient level of illumination is indispensable in areas in which picking work is carried out and in the incoming goods and dispatch areas. As well as preventing confusion, a sensible level of illumination is also necessary to perform visual checks on the condition of the floor, aisles, pallets, containers, labels, etc.

In addition to the general requirements, specifications for the different storage areas exist. These are explained in the rules and regulations (see figure 11.M-3).

11.M.2.3 Incoming goods and dispatch

"Receiving and dispatch bays should protect materials and products from the weather. Reception areas should be designed and equipped to allow containers of incoming materials to be cleaned where necessary before storage." (3.20 EU GMP Guideline).

It is not explicitly stated whether such areas should be located inside or outside a storage building. In some cases, it may be acceptable for the incoming goods area to be located under a canopy in the open, although factors such as solar radiation and humidity must be taken into account. Goods are therefore normally received in a designated zone inside the warehouse building. Before the goods are finally stored, general cleaning is normally required using aspiration or compressed air and the relevant device must be installed beforehand.

The incoming goods and dispatch areas should ideally be separate. If space is short, additional organisational measures will be required to minimise the risk: such as temporal separation of goods receipt and goods dispatch procedures or the definition of zones within a handling area (either permanent or using mobile partitions or chain barriers).

11.M.2.4 Sampling

"[...] If sampling is performed in the storage area, it should be conducted in such a way as to prevent contamination or cross-contamination." (3.22 EU GMP Guideline).

The risk of contamination is always present when carrying out sampling in the warehouse. Laminar-flow boxes in subdivided rooms present a possible alternative to complete discharge of the material. Depending on the degree of automation, materials are brought into this kind of cabin either via conveyor belts (integration of LF cabin into linear flow of components) or manually, in an auxiliary room. Only one batch at a time must be placed under the LF for sampling and be sampled there.

The specific order of events for the entire procedure, i.e. method for changing batches and products, handling of sampling utensils, labelling, cleaning etc., must be precisely described in SOPs. Personnel must wear protective clothing when carrying out the sampling. Once the sampling itself is complete, the LF area is to be cleaned in accordance with the specified procedures. It is recommended that a log book is kept for this area.

The organisation of the sampling is determined by the available space and timing of events at the relevant company. This means that the identification of each container can be carried out, e.g. using NIR, directly under the conditions described above. It is understood that it is also possible to carry out individual identification at a later date, providing quality control and approval has been carried out correctly. For logical reasons, this is carried out when the containers are opened (e.g. during initial weighing).

Further information is provided in chapter 14.A Sampling.

11.M.2.5 Quarantine

"Segregated areas should be provided for the storage of rejected, recalled or returned materials or products." (3.23 EU GMP Guideline).

This makes very good sense as it helps prevent unintentional use or confusion. Additional labelling (rejected) is certainly necessary in cases where 100% separation is not possible, e.g. shared use of incoming goods and dispatch areas for regular goods and rejected goods. Access to these areas must be restricted to authorised persons.

Rejected starting materials should be returned to the supplier or destroyed. Reworking is possible, although the expenditure required for validation work and the handling of questions related to registration is very high. The decision-making path must be defined at the outset and documented. Quality control must be responsibly involved in every case which means that downgrading can be carried out, i.e. a starting material whose quality does not conform with the specifications is graded as an inferior-quality product. (Example: deviations in the particle size distribution of citric acid are found during the incoming goods inspection. This is then regraded and used to make up cleaning solutions for cleaning the facility.)

When a product is rejected during the production process, it must be ensured that it is moved to quarantine. In terms of data handling, it is necessary to differentiate between storage locations. Ideally, the system settings will be such that when a material is rejected, following the compilation of a transport order, its storage location will be automatically changed to quarantine.

"Products returned from the market and which have left the control of the manufacturer should be destroyed unless without doubt their quality is satisfactory; [...]" (5.65 EU GMP Guideline). The definition of the required quality is the responsibility of the head of quality control. A written procedure that describes the analysis criteria must be defined beforehand. This assessment has to be very critical as the products will not in the meantime have been monitored by the manufacturer. Figure 11.M-4 shows critical aspects in relation to the assessment of goods that are returned from the retail sector.

Goods that are returned in the form of single packages from pharmacists must generally be regarded as critical. These should be destroyed for safety reasons. Larger quantities sent back by wholesalers who have placed incorrect orders (for example) must be evaluated individually. In these cases, the integrity of bundled packages is an important criterion. If a delivery is returned from different climate zones, this must be treated with caution as the stability of the product may have been affected. If there is any doubt about the quality of a product, it must be destroyed.

If a product is reworked, this must be approved by the head of quality control (see chapter 11.L Reworking).

11.M.2.6 Other storage areas

Highly-active substances

"Highly active materials or products should be stored in safe and secure areas." (3.24 EU GMP Guideline)

The handling of highly-toxic substances, such as zytostatics or narcotic substances as described, must ensure personnel safety and also avoid possible interference with the other storage areas and therefore materials and products stored. Special requirements exist, such as those contained in the narcotics regulation and regulations for hazardous goods.

Printed packaging material

"Printed packaging materials are considered critical to the conformity of the medicinal product and special attention should be paid to the safe and secure storage of these materials." (3.25 EU GMP Guideline).

Closed storage is recommended. A special intermediate store with air-conditioning may be required to condition the packaging material for the packaging process (see chapter 13.B.1 Allocation of packaging material).

11.M.3 Storage conditions

11.M.3.1 Temperature and humidity

"Storage areas should be designed or adapted to ensure good storage conditions. In particular, they should be clean and dry and maintained within acceptable temperature limits. [...]" (3.19 EU GMP Guideline).

Starting materials, intermediate product and medicinal products must be stored at suitable temperatures and humidities. Consequently, special storage areas that guarantee the necessary conditions may have to be available, e.g. cold store or storage areas with tightly-controlled humidity limits. Stability data or periods of use based on established temperature and humidity ranges normally exist for such stored goods. It is imperative to use these specifications as the nominal values for storage conditions in order to be able to adopt expiration data from suppliers, for example (see figure 11.M-5 and figure 11.M-6). The upper limit of 30 °C specified by Good Storage Practice for exceptional cases must be critically examined in the light of standard specifications for warehouses. The decision as to which specification should be used to store a material therefore can and must be made with reference to the storage instructions that are based on the stability data (WHO GSP 4.17, see chapter G.1).

The suitability of a given storage area must be verified. "[...] storage conditions [...] should be [...] provided, checked and monitored." (3.19 EU GMP Guideline). Temperatures and humidities can be monitored permanently using measuring systems with recording functions, e.g. thermohygrometers with chart recorder functions, or an EDP system. In figure 11.M-7, the aspects to be considered when using measuring instruments are listed. Ideally, these should be coupled with an alarm system that indicates when values are outside the specifications or when alert limits have been reached and/or initiates control steps. For all measuring systems, it is important to define the data acquisition rate. The requirement for the recording interval (in minutes) depends on the type of product, the storage location and the anticipated speed at which an objective criterion may change. For example, temperatures are likely to change more slowly in high-bay storage areas than in refrigerators. If measuring instruments with integrated electronic data storage (data loggers) are used, the evaluation frequency must be defined according to the amount of memory available. The service life of the batteries is drastically reduced when data loggers with integrated sensors are used at temperatures below 15 °C. This must always be taken into account when determining the period during which readings are taken. A simple method of compensating for the resistance to heating of storage goods in refrigerators is to place the sensor in a liquid. It is understood that this must not interfere with the storage goods.

Measuring instruments must be regularly calibrated (WHO GMP 4.17). The data must be stored as secondary documentation.

The number and positioning of the measuring points must be defined within the scope of the room qualification. To do this, it is necessary to compile a room profile showing the distribution of temperature and humidity within the room and the suitability of the subsequent measuring points in terms of their representativeness. A simple way to achieve this is to divide the warehouse up according to a coordinate system. The vertical areas under the roof, in the middle, and directly above the floor, as well as corridors or exit areas with additional air movements should be checked at various horizontal positions. Seasonal fluctuations must be taken into account, e.g. to record critical temperature increases in the uppermost shelving compartments. According to WHO GSP (4.18), temperature sensors should be positioned at the points where fluctuations are the greatest. During these investigations, it must be assumed that the warehouse is full in order to exclude the influence of the room charge due to e.g. altered air flow. As a result of the profile creation and/or monitoring, the installation of air-conditioning units or the segregation of storage areas with special air-conditioning may be necessary.

It must be established whether the daily average of temperatures should be used as the actual value and compared with the nominal value or whether individual peak values should be used. If individual values only deviate by a few Kelvin degrees from the average across a 24-hour period, the daily average can be used for assessment. The same applies for humidity values. One of the tasks of the room qualification is to show this (see chapter 3.G Room qualification).

A procedure must have been established to deal with deviations from the specifications in which information and decision-making paths are defined. For example, a similar system for the handling of deviations as used in the production area, may be used for obtaining information. This has the advantages of a higher-level system that automatically involves the decision makers in manufacturing, quality control and quality assurance. In straightforward cases, infringement of the guidelines for the storage conditions leads to rejection of the material by quality control followed by destruction. This is a decision that is made in each individual case, taking the temperature and moisture sensitivity of the material into account (e.g. insulin suspensions, suppositories or hard gelatine capsules). Retesting of the material is one way to preserve the usability of high-priced products or materials and must be specified in individual cases by the head of quality control (see chapter 14.H Out-of-specification results).

11.M.3.2 Sanitation

Storage areas must be clean and dry. Should these criteria be neglected, the diversity of materials then provides conditions that are ideal for the nourishment of microorganisms, vermin, animals and insects. Storage areas are usually assigned to the hygienic areas F or G as part of the self-classification (also taking the other ratings into account). As with the production areas, written sanitation programmes that describe the cleaning procedures and intervals must exist (see chapter 11.D Sanitation programme). Sources of contamination should be avoided whenever possible. Contaminated and defective wooden pallets must be replaced by new or clean wooden, plastic or metal pallets prior to storage, for example. The use of clean wooden pallets in the warehouse is permissible. However, before being brought into initial weighing or production, the containers must be re-palletted on plastic or metal pallets. Open containers must be avoided without fail in order to protect the material or product and also to prevent contamination of the environment. Containers opened for sampling must be properly sealed afterwards. Where doubt exists, return deliveries from the production area are to be cleaned, e.g. by means of aspiration.

Pest control

In addition to the usual cleaning, these areas must be subjected to pest control measures. This is necessary as there is a direct connection from these areas to the outside world and deliveries of raw materials may also carry vermin. One preventative measure is to re-pallet the materials prior to storage, e.g. in tandem with the identity test of individual containers using NIR. During pest control, the type and quantity of the various species are defined using species-specific traps (e.g. pheromone traps) and active prevention can also be achieved (e.g. using UV fly killer lamps) at critical locations such as exit doors leading into the open air.

The type, the number and positioning of the traps for monitoring purposes should be determined by specialists (biologists/zoologists) as knowledge of individual species is required. This may be achieved through outsourcing to specialists who will provide a map showing the precise locations of the various traps. This makes the assessment of pest numbers, species and locations possible. These numerical estimations, carried out at regular intervals (e.g. monthly or quarterly), are subject to evaluation. It is important to specify that the contract giver always has responsibility for this and that delegation is not possible. The action to be taken in the event that defined limits are exceeded and trends emerge must therefore be determined at the outset within the scope of the SOPs (4.26 EU GMP Guideline). This could for example be the shortening/extending of intervals, changes in the number of traps as well as structural changes as preventative measures. The highest priority is to prevent the entry of pests.

Monitoring and evaluation may be carried out by authorised functions, e.g. quality assurance. Responsibility for the area of pest control ultimately lies with the head of production.

11.M.4 Receipt

The operational sequence at the warehouse should be defined in writing. The type and procedure for storage as well as the flow of goods and information should be described (WHO GSP 5.1).

It is recommended that procedures are provided in the form of checklists and are documented. In this way, the working method is standardised as far as possible. This is explained using the receipt of goods as an example.

Receipt has an important control function. "For each delivery, the containers should be checked for integrity of package and seal and for correspondence between the delivery note and the supplier's labels." (5.27 EU GMP Guideline). Only products and materials that meet the quality requirements may be used. An operating procedure should exist that describes how receipts should be checked for tampering and damage. In every case of damage, checks should be carried out to determine the extent to which the contents have been affected. The loss of a seal (originality closure) as a result of mechanical loading is certainly likely to increase the scope of subsequent tests but this does not automatically mean that it will be necessary to destroy the material. Containers that have been extensively damaged should not be accepted and a damage report should be compiled. The decision as to whether damage should be evaluated must be made by quality control. Procedures must be defined at the outset. In each case, all distinctive features should be documented - this makes retrospective consideration as well as the evaluation of suppliers and forwarding agencies possible.

The check of the uniformity of the delivery as well as its conformity with the order and delivery documents is specified in the WHO GSP (5.7-5.9). In addition to the commercial aspect of this check, a safety function is also carried out. If different batches of a material or product are delivered at the same time, it is recommended that these are separated, e.g. by re-palletting individual containers, to avoid confusion from the outset.

Usually, the containers are labelled manually upon receipt of materials or products. These labels must be compiled carefully (see chapter 11.H Identification). Ideally, the number of labels is controlled by the warehouse management system. A freely-selectable, uncontrolled number of labels is not acceptable. However, if it is only possible to adjust the number of labels manually, it must be ensured that superfluous labels are not destroyed without documented comment. If the number of containers has been calculated incorrectly, this error will become apparent when the labels are applied. If there are 7 containers and 8 printed labels, the label with the information "8 of 8" will remain unused; this must be corrected either by changing the container labels directly or by printing them again. Sometimes the printout cannot be repeated directly as some systems are equipped with safeguards to prevent misuse. Whatever the case, the reason for any action taken must be provided in writing. Manual initiation of routine reprinting must be avoided whenever possible.

Records of receipts with information on suppliers, the supplier's batch designation and goods receipt data must all be retained as secondary documentation. It is possible to keep a receipt log book or to generate a similar list with time references using the warehouse management system. Figure 11.M-8 shows a checklist for processing a receipt.

Analogous to the receipt procedure, all other goods movements must also be described using operating procedures. The flow of components to and from production may only be carried out according to written procedures or EDP-controlled processes.

11.M.5 Identification using material and batch number

An identification procedure is necessary in order to selectively assign a material or product throughout its life cycle in the warehouse, production, and dispatch areas. One of the objectives of this is to ensure the traceability of starting materials and finished products. Unambiguous identification is normally achieved using a combination of different code systems. Material numbers are often used. In doing so, it is recommended that certain material or product groups (raw materials, packaging materials, in-process materials, finished products etc.) are assigned specific number ranges that can be easily identified. Furthermore, batch numbers and receipt numbers are also used; the latter are of significance if several different receipts of starting materials from the same supplier batch exist, and if the batch notation system does not provide any means of identifying their chronological sequence. In a warehouse management system, a receipt number is not required if the two receipts referred to above contain different batch numbers. The relationship to the supplier batch is established via the system in order to possibly reduce the scope of the incoming goods examination or testing.

Generation of batch numbers

This code number may take different forms and is generally alphanumeric in character. It may contain different information (see figure 11.M-9). It must be ensured that these codes are unique and that repetition is not possible, whether coincidental or intentional. These codes may be generated automatically by an EDP system or manually via a batch book. There must be a set procedure to follow in every case as defined by an operating procedure. For the EDP-supported version, a reliability check must be carried out as part of the validation.

11.M.6 Dispatch and transport

Products should only be dispatched if a written order exists (WHO GSP 7.4). As is the case with the receipt of goods, dispatch is a critical step during which misidentification must be avoided. The use of checklists is also recommended here. Ideally, the product will be checked at the picking stage using a bar code scanner. A second person should check and sign the compilation of a dispatch order.

The type of dispatch container to be used should be precisely defined in the instructions. If the correct container has been chosen, this guarantees that the product will also be protected if it is dispatched to another climatic zone. The label on this dispatch container should at least include the dispatch date, the name and the address of the recipient as well as the product description (name, dosage form, strength, batch number), the quantity dispatched and the transport and storage conditions (WHO GSP 7.7).

"The distribution records should be readily [...]" (8.12 EU GMP Guideline). The dispatch documentation must be stored as secondary documentation and must be available at short notice.

Particular care should be taken when using dry ice in refrigerating chains. In addition to occupational safety measures, it must be ensured that the product does not come into contact with dry ice (WHO GSP 7.2) to prevent negative consequences, e.g. localised freezing.

The basic requirement that the quality of the starting materials and the finished product must not be adversely affected also of course applies for the area outside of production and the warehouse: this means that the same specifications for storage temperature and humidity must also be applied for the delivery of starting materials. The extent to which variables affect the properties and stability of materials is difficult to calculate (such as temperature peaks on the loading surface of a heavy goods vehicle). It may therefore be advisable in the case of sensitive and highly-priced materials to request the inclusion of measuring instruments (data loggers) (see chapter 11.M.3 Storage conditions) that record the conditions in transit: these may then be evaluated during the incoming goods inspection. The same applies for finished products and for these it should also be ensured in this case that the necessary temperature and humidity conditions are complied with during transportation to, for example, central distribution warehouses. For overseas dispatches, e.g. involving sea crossings that last for several weeks, the use of measuring instruments is particularly advisable as the product may also pass through different climatic zones during the journey and the resulting fluctuations may be considerable. As a rule, as with the selection of suppliers, qualified forwarding agents or courier services should be used.

For company-internal transportation, e.g. within production or for exchanges between warehouse and production, it should also be observed that these should take place as intended. To ensure this, written procedures should exist and be documented accordingly irrespective of the existing degree of automation.