This article focuses on upgrading and improving a packing process to comply with current good manufacturing practices. The authors sought to maintain proper quality assurance for finished products.
For this reason, the packaging process should be analyzed, and manufacturers should take into account the occurrence of deviations such as equipment and component failures, human error, operational errors, and other deviations that negatively affect the final process result (2–4). Risk analysis (RA) methods are valuable tools for mitigating fault events by focusing on the cause–effect interrelations that create them. RA methods thus facilitate fault elimination or, when faults cannot be eliminated, fault reduction.
In today's pharmaceutical industry, most processes are conceived and designed with a high level of automation to minimize operator intervention. Nevertheless, economic considerations lead companies to retain manual operations in certain situations. The packing process that is the subject of this study is one example. In such a process, a fault-tree analysis (FTA) approach can greatly help determine critical process points. The approach also helps manufacturers introduce barriers against equipment and operator failure and minimize their probability of occurring (5, 6). Following these considerations, the packing line was arranged, bearing in mind the potential failures to which the final result could be exposed. The arrangement was validated by challenging the process to demonstrate its effectiveness.
Packing process description and considerations
- Failure in product temperature requirements during the packing process (which exclusively applies to products that require refrigeration)
- Failure of packing material to display the corresponding primary product information (e.g., batch manufacturing date, batch number or identification code, and batch expiration date)
- Lack of correspondence between product specifications, printed packing material (e.g., vial labels, cartons, leaflets, MUBs, and shipping labels), and documentation (e.g., QA release authorizations, packing order, and records created during packaging)
- Failure to comply with cleaning and line-clearance requirements for areas involved in the packing process, including labeling machine and all workstations, to avoid product-batch cross contamination.
- Ensure cold-chamber qualification on at least a yearly basis to demonstrate consistency in keeping product temperature between 2 and 8 °C. Perform a similar study in the acclimatization room.
- Establish a metrological assurance plan, created by the QA department, to guarantee verification and adjustment of cold-chamber temperature controllers on at least a yearly basis.
- Monitor cold chambers daily. Monitor acclimatization- and packing-room temperatures linked to standby and transfer follow-up of each product batch. Standard operational procedures (SOPs) and supervision must be implemented accordingly.
- Implement an SOP to mitigate possible interruptions during the packaging of refrigerated products, and ensure that the quality of these products is preserved.
- A first level to detect and eliminate possible faults in product-vial labeling and primary-information imprinting in which the labeling-machine automatically senses and rejects unlabeled vials or nonimprinted vial labels.
- A second level to detect and eliminate possible faults in product-vial labeling and primary-information imprinting in which a buffer operator visually inspects and rejects unlabeled vials, nonimprinted vials, badly pasted or wrinkled labels, and illegible, misplaced, and erroneous imprints.
- A third level to detect and eliminate possible faults in product-vial labeling and primary-information imprinting (also for previously prepared printed packing material) in which packing operators visually inspect and reject unlabeled vials, nonimprinted vials, badly pasted or wrinkled labels, and labeled vials or cartons with illegible, misplaced, or erroneous imprints.
- A fourth level to check for MUB completion in which the first end-of-line operator looks for missing packed units, leaflets, and vials by weighing. The second end-of-line operator performs visual inspection to verify proper MUB manual sealing and correct primary-information printing on the corresponding label.
- A fifth level to check for shipping-box completion in which a handler operator looks for missing multiple boxes by weighing and performs visual inspection to verify proper shipping-box sealing and correct primary information printing on the corresponding label.
- A documented, in-process control implemented at intervals by a supervisor who visually inspects printed packing materials and their primary information. The supervisor also checks the appearance and completion of packed units by taking MUB samples from the end of the line. A similar in-process control is also implemented for previously printed packing material during the imprinting of cartons, MUBs, and shipping-box labels.
- Documented control performed by the supervisor to ensure the cleaning and line clearance for all involved areas at the beginning and end of each process.
Validation of proposed packing-line configuration and organization
To establish an acceptance criterion in each run, a single sampling plan for normal inspection was employed based on a general inspection level II and 0.10 acceptance-quality limit index (10). It was established that if any of the deliberately defective vials were not detected during a run, the packing-line performance would be considered unsatisfactory. The test also required the detection of all other faulty vials that resulted from errors in labeling-machine operation.
The packing operators' ability to ensure MUB completion was simultaneously verified by weighing MUBs at the end-of-line workstation. Based on the above qualification, an operational procedure determined weight limits at the beginning of each packing operation by averaging the weight of the first three complete MUBs leaving the line. A tolerance of ±1.8 g (i.e., the weight of the lightest leaflet) was established.
Results and analysis
The experiment demonstrated that a risk-analysis approach based on a fault-tree analysis model of the packing process achieved upgrades and improvements. Packaging operations were arranged according to the analysis. The new arrangement resulted in a product that was consistently packed and identified according to established requirements and current regulations.
Validation demonstrated the effectiveness of barriers against failures, which were implemented throughout the packing line, in detecting and rejecting faulty vials. The barriers detected faulty vials deliberately included in the tests and also the nonprogrammed faulty vials resulting from labeling-machine operation failures. The barriers did not compromise the correct completion of multiple boxes, which reached 100%. The system therefore ensures an exceptionally low probability of product failure and unacceptable defects at the process outlet.
This level of assurance can, in principle, significantly reduce customer complaints. It can also reduce the need for product recalls in the worst case, which normally cause great losses for each batch withdrawn from the market.
A colleague of the authors suggested a test of the end-of-line weighing station during packing-process validation by moving several MUBs along the line with one leaflet missing from each. The authors stand by the original concept followed in this study. Key process components must be qualified before the packing line is validated as a whole. The process is validated by integrating all qualified components and simulating normal process function as closely as possible without compromising the regular course of the process by adding an extra challenge. The authors believe that the technical balance's sensitivity for detecting missing components should be determined in advance. Then, one can focus on the objective of process validation, which is to evaluate the packing operator's ability to deliver completed MUBs throughout the simulation runs. Nevertheless, the above suggestion could be analyzed in a further revalidation of justified in-process changes.
Arturo Toledo Rivero* is the head of the research and development department, Nelson Sierra Prado is the head of the validation group, and Yohann Pérez Molina is a quality engineering specialist at LIORAD Laboratories, Ave. 27A No. 26402, La Lisa, Havana, Cuba, tel. 1537 2717935, fax 1537 2717899, firstname.lastname@example.org [email@example.com]
Ian Toledo de Zayas is a logistics specialist at DUJO Business Group.
*To whom all correspondence should be addressed.
Submitted: Aug. 8, 2007. Accepted: Nov. 1, 2007.
1. European Commission, "Production", in Volume 4—Medicinal Products for Human and Veterinary Use: Good Manufacturing Practice, (European Commission, Brussels, Belgium, 2005), pp. 47–49.
2. ISPE, "ISPE Baseline Guide—Packaging, Labeling, and Warehousing," (ISPE, Tampa, FL, vol. 7, rev. B, 2005).