As featured in Pharma Tech February 15th 2022
FDA requires performance and documentation of a line clearance in its current good manufacturing practices (CGMPs) (1). In Europe, the EudraLex Volume 4 GMP Guidelines refer to line clearance in Part 1 Chapter 5.50 (2). Other than stipulating use of a checklist, neither document provides guidance on how to perform these line clearance activities.
So, a checklist is followed, and at the end of the process, there’s a signoff. “These work instructions are typically lengthy documents (50+ pages) which explain the step-by-step process for clearing and changing over a line,” says Dave Taylor, product manager at CXV Global, an engineering solutions and resourcing organization. “Due to historic failures, this process is often then duplicated by another [operator] who will ‘buddy check’ to ensure that the first operator did not miss anything,” adds Taylor. Some companies split the line into zones for inspection; others use two operators. One operator starts at the beginning of the line, and the other starts at the end. After meeting in the middle, each operator continues, checking the work of their partner.
Unfortunately, a completed checklist and signoff do not provide evidence the line clearance has been completed satisfactorily. “It just shows the paperwork has been done,” explains Taylor. Some companies video the line clearance inspection, but this results in hours of footage to review and store. In addition, a video may not show the location or the responsible party if a line clearance omission occurs. “Video doesn’t stop errors from happening,” notes Taylor.
Ergonomics also is an issue. “Operators must bend and stretch and reach under machines,” he explains. It’s not uncommon for operators to climb ladders and perform “blind” checks of an area by feel because a visual inspection is not possible.
With batch sizes shrinking and changeovers becoming more frequent, overall equipment effectiveness (OEE) suffers. The impact of line clearance time is demonstrated in the following example. Taylor explains, “If I can run a line for two days to produce a million units, and then I have a six-hour downtime to change over, then this is okay. However, if I only need to produce 50,000 units for a specific market, then this may only take the machine three hours to run. If I then perform a six-hour changeover, the productivity and efficiency of the line are massively impacted.”
Manual line clearance takes far too long to complete, is physically arduous and not 100% repeatable, exhibits periodic deviations due to the variability of many factors, and generates a large amount of paper for each time it’s performed. “Additionally,” says Elliot Abreu, senior vice president, Xyntek, the US division of CXV Global, “the quality process . . . often remedies specific line clearance failures by adding new checks in the areas where items were previously discovered. Over time, this increases the complexity and length of the work instruction, which has a direct impact on the efficiency of the line or factory.”
Moving to automation
Like many other formerly manual processes, line clearance can now be automated. Automated line clearance offers benefits in efficiency, quality, and health and safety. With automated line clearance, CXV says that pharmaceutical manufacturers:
- Realize an 85% reduction in line clearance time
- Minimize changeover downtime and labor requirements
- Experience a double-digit improvement in machine/line efficiency
- Eliminate errors caused by overlooked rogue components on the line
- Enhance patient safety
- Remove the dependency on human decision making for line clearance
- Improve operator ergonomics by limiting the need to crawl under machines, stretch to check difficult-to-reach spaces, or scale ladders to times when an anomaly is detected
- Prevent equipment damage by stray components
- Create a repository of evidence about the state of the line at the time the clearance was performed
- Document evidence of the actions performed by the operator and the outcomes of those actions in the audit record.
The CXV Global LineClearance Assistant system, developed in partnership with life-science corporations, consists of industrial-grade cameras mounted at strategic locations inside, above, and below the machine/line along with cables, processing units, operator interface, software, and a full suite of validation documents for quick qualification.
The LineClearance Assistant system can connect to the programmable logic controller (PLC) for the line. The system alerts operators of areas to check for stray product or components and rechecks the area after the operator takes action. Before and after images, which are date- and time-stamped and audit-logged, provide concrete evidence the line was cleared properly. If desired, the system can be set up so the line cannot be restarted until the PLC receives the “ready” signal, indicating the line clearance process has been completed successfully.
The system can integrate into CXV Global’s SmartFactory line management solution, which controls and manages the batch data being sent to the line devices. It also includes an OpenApi-compatible application programming interface, so it can share information with electronic batch record, enterprise resource planning, and manufacturing execution systems. “This digital integration across the factory enables an unparalleled level of control across the line with full end-to-end traceability while increasing the [overall equipment efficiency] of the line,” says Abreu. Once validated, the system is acceptable to regulators in the United States and the European Union. It also meets regulatory requirements for electronic signature requirements such as US 21Code of Federal Regulations Part 11 (3) and EU Annex 11 (4).
Compatible with primary and secondary packaging operations for solid dose, oral health, and tubed products, the CXV Global LineClearance Assistant technology also has potential for cleanroom applications. “We would just need to put the cameras in the right kind of enclosure,” explains Taylor. Several proof-of-concept systems are in place; trials are being run; and several major pharmaceutical companies have begun the installation process.
Alongside the line clearance implementations, CXV Global hosts the Pharma Line Clearance Forum, an industry group dedicated to line clearance, which has operated in various guises for more than three years and currently includes more than 100 collaborators who meet on a quarterly basis.
EC, EudraLexVolume 4: Good manufacturing practice Guidelines, “Part 1: Basic Requirements for Medicinal Products, Chapter 5: Production,” (Brussels, 2014).
CFR 21, Part 11
EC, EudraLex Volume 4: Good manufacturing practice Guidelines, “Annex 11: Computerised Systems,” (Brussels, 2011).