Will Eaden, sales & marketing manager, CI Systems, argues that computerised raw material dispensing systems make economic sense by cutting errors and improving efficiency
Accurate dispensing of raw material ingredients is a fundamental requirement for the manufacture of high quality pharmaceutical products. It is also essential that a manufacturer can demonstrate that secure systems are in place to ensure that only the correct quantity of an approved raw material of known origin and quality is used.
Good Manufacturing Practice (GMP) requires that weighing and measuring is adequately supervised and checked to ensure that the component has been released by the quality control unit after testing, the weight or measure conforms to the quantity required by the batch formula, and that each container of weighed material is labelled correctly.
For pharmaceutical products placed on the market in the EU, the relevant guidelines are contained within EU's GMP guide1 and for products destined for the US, the similar FDA rule 21 CFR parts 210 and 211 apply.2
When performed manually, the dispensing process requires hand-written records and labels that are produced by a first person and checked by a second. Separate records are maintained for weighing instrument calibration and for cleaning of weighing equipment and the weighing area.
Although errors occur infrequently in raw material dispensing, they have far-reaching implications in terms of GMP, so systems must be in place to ensure that, as far as reasonably practicable, they do not occur. The elimination of dispensing errors is, therefore, a prime reason for implementing a computerised dispensary system. Common causes of errors and the advantages of a computerised system are discussed below.
Dispensing the wrong ingredient: There is the possibility that an operator can accidentally dispense the wrong ingredient by misreading the material name on the stock label.
A computerised system uses the barcode on the stock label to identify the material to be dispensed. The barcode incorporates the material code and lot code (and sometimes also the pack number) to identify the supplier's pack of raw material. For this reason, it is not possible to identify and dispense the wrong ingredient.
Dispensing the wrong weight: It is possible for an operator to dispense an incorrect raw material quantity. The causes of this are varied, but include: an arithmetical mistake (such as might be the result of dispensing into multiple containers), misreading the balance display, an incorrect potency calculation, an incorrect unit of measure conversion or misreading a quantity from the dispensing instructions (typically by transposing figures - for example, reading 0.912 instead of 0.921).
A computerised system:
- recalculates the remaining quantity on change of dispensed container;
- forces the balance to be zeroed and the container tared before each weighing;
- enforces the use of calibrated, checked equipment only (e.g. by using daily balance validation checks);
- performs potency calculations and unit-of-measure conversions;
- requires the dispensed quantity to be within predefined tolerances before the dispensing may be completed (and the "dispensed" label printed);
- maintains an audit trail of all events.
Dispensing an expired lot: It is possible for an operator to pick and dispense an expired lot. A computerised system reads the barcode on the stock label and, if the lot has expired, warns the operator and does not allow the expired lot to be dispensed.
Operator errors: Mistakes can be the result of operators taking shortcuts in the dispensing process or not following the standard operating procedure (SOP); for instance, different operators sometimes have their own dispensing techniques.
Mistakes can also occur due to over-familiarity with the SOP. Although periodic audits can be used to ensure SOPs are being followed, there is no guarantee that procedures are being followed in the periods between audits.
A computerised system:
- enforces a consistent means of dispensing the ingredients for an order, so all operators must perform the same steps and dispense the ingredients in the same way;
- enables approval points to be configured to apply during particular stages of the dispensing cycle (e.g. when acknowledging health and safety warnings or reprinting dispensing labels) to ensure that GMP is adhered to at all times.
cleaning regimes
Contamination: Contamination of the ingredients dispensed for a product can occur when the incorrect cleaning procedure has been applied following the dispensing of a material. This is especially applicable to cleaning after the dispensing of active materials.
A computerised system enforces the cleaning regime, ensuring that the correct procedures are always applied. Specific cleaning regimes may be applied to particular materials/products. And the computerised system may be configured to require a second operator to approve either the cleaning when complete, or each stage of the cleaning process. A log of the cleaning activity is also maintained electronically.
Addition of materials: Another area where errors can occur is in the addition of pre-dispensed or bulk materials to Intermediate Bulk Containers (IBCs), process/mixing vessels or blenders. If the wrong material is added, the batch has to be destroyed.
Computerised systems use the barcode on the dispensed label (in the case of pre-dispensed material) or on the stock label (in the case of bulk material) to identify the material prior to addition. If the wrong material is identified then the system will not allow the dispenser to continue. The weight change, following addition of the material, may also be measured.
Computerised systems can also enforce the sequence in which the materials are added, thus ensuring an even distribution of the ingredients and, for those process vessels with multiple addition points, the location at which the material must be added. Furthermore, these systems will ensure that materials are added at the correct manufacturing stage.
production environments
As with any manufacturing sector, pharmaceutical production varies considerably in scale. At one end, there are plants producing comparatively large volumes of product; at the other there are small-scale operations producing 'specials' or small batches for clinical trials. In some cases, these 'specials' operations are factory-based, whereas others are incorporated within hospitals. But regardless of the size of the operation, a computerised dispensary management system can bring significant benefits.
In general, errors made in the dispensary are identified by the QA department when they qualify the finished product. This mitigates the risk of bad product being released and a subsequent recall. Therefore, dispensing errors tend to result in GMP issues and costly overheads to the manufacturer.
Even with a computerised system, however, there is a requirement to audit the processes and for the Qualified Person (QP) to sign off each batch. This all requires a substantial amount of paperwork to be checked, but a computerised system can significantly reduce the time required to produce and check the relevant reports.
First, the data is entered in the computerised system automatically during the weighing process, with no need for any additional inputs from the operator. This means that the necessary reports can be output virtually instantly when required, which is very different from the hours that might be needed to manually create reports for auditors.
Furthermore, if the manual report creation process requires data to be handwritten or rekeyed into a spreadsheet or other computer-based package, there is a risk that further errors will be introduced or figures will be rounded up or down.
For the auditor or QP, checking reports is far quicker if they are presented in a consistent way, with all of the data clearly legible.
There is a feeling among some pharmaceutical manufacturing companies that computerised dispensary management systems are difficult to validate because of the complexities of software-based systems. While this may have been true for early bespoke systems that were written with a monolithic structure, today's commercial off-the-shelf 'packaged' systems are straightforward to validate.
A typical factory acceptance test (FAT) for a bespoke system may require several hundred tests to be completed, each comprising multiple steps with associated acceptance criteria. However, with a package, advantage can be taken of the supplier's prior testing of core components so that only project-specific elements such as interfaces need to be subjected to full FAT for the project.
Once the FAT and installation qualification (IQ) tests are passed, the customer will perform operational qualification (OQ) tests to ensure that the system does what it is required to do. For a modular computerised system the aim of this process is to prove that the selected options are operating as required with 'real' data (usually a representative set of test data taken from the manufacturer's factory data).
performance tests
When the OQ tests are complete, the system goes 'live' and will be monitored for a short period of time, often by running the computerised system in parallel with the manual system. This performance qualification (PQ) procedure ensures that the system performs as it should in the 'real world' situation.
Depending on which computerised system is being installed, it is possible to complete the majority of implementation, integration, training and commissioning remotely, with reduced need for a representative of the system supplier to be on site. Instead, teleconferencing, web conferencing and other state-of-the-art technologies can be used to reduce the cost associated with vendor on-site support.
So far, we have mainly considered the way in which a computerised system can ensure that the correct quantity of an approved raw material of known origin and quality is used. However, there are additional peripheral benefits for computerised systems that should not be overlooked.
In most pharmaceutical manufacturing plants, the dispensing booths will operate for two shifts per day. Because the computerised system takes the place of one of the operators, it enables two people per dispensing booth to be redeployed to more productive tasks elsewhere in the plant.
Furthermore, users of computerised systems often report that the dispensing process is quicker when using a computerised system, as the checking is easier and there is no need to create handwritten records. Although this increase in productivity may take several months to build up, it is, nonetheless, a valuable benefit.
Another advantage of a computerised system is that it can be linked into the plant's Enterprise Resource Planning (ERP) or similar production management system, and usually is, to eliminate the maintenance of duplicate databases. The ERP records will, therefore, be updated automatically as dispensing occurs.
This avoids the need for data to be entered manually into the ERP system and can save operators from having to make tens of thousands of ERP data entries per year. The resulting saving in terms of human resources and data entry errors is a significant benefit.
For each raw material on the database, the computerised system will be programmed with appropriate health and safety warnings. This can help to ensure that operators always wear the appropriate personal protective equipment, and it can even be used to warn operators if a container exceeds a specified weight and the operators must therefore use a lifting device.
One of the prerequisites for a computerised system is barcoded labels on the raw materials. In some plants this may not yet be in place, so the introduction of a computerised system may require additional work up-front to implement a stock barcoding system. However, the benefits of this - including improved efficiency, better stock control and the reduced scope for errors - can make investment here an attractive proposition.
enhanced GMP
In conjunction with the barcoded stock labelling, a fully validated computerised Dispensary Management System (DMS) controls and monitors dispensing and addition operations. The system guides the operator through a predefined sequence of checks and actions and does not allow the weighing or addition to proceed if any of the checks fail. Accurate details of the weighing are recorded automatically, and the system prints barcoded labels for the containers of dispensed material, with the operator acting as the checker at every stage to confirm that the details are correct.
This process ensures consistency of operation, significantly enhances GMP and reduces the risk of rejected batches. Peripheral benefits relate to productivity, accuracy of ERP data, health and safety, and stock control.
In recognition of this trend towards the implementation of packaged systems the Good Automation Manufacturing Practices (GAMP) council has indicated its intentions to extend its guide to focus on the validation of products and packaged solutions in addition to its current emphasis on bespoke systems.