The pharmaceutical industry can barely breathe without mentioning any number of acronyms that govern—and in some cases, ease—the packaging process: 21 CFR Part 11, GAMP, JETT, FAT, PAT and URS are just a few of them, all part of the complicated process called validation.
Simply stated, validation means that the pharmaceutical companies must document each step of the manufacturing process, including packaging, and verify irrefutably that each step, each process, each machine does exactly what it’s supposed to do—each time. This ensures the safety and quality of the medicines that so many people depend on every day.
“Validation ensures that the right product is in right package, that the product has been properly prepared, and that it has the right label. Everything can be traced back for each of the lot numbers,” says Craig Nelson, president, Mission Controls, a machine manufacturer and systems integrator. “We also need to know the containers themselves can be traced back. We have tamper-proof lids to keep someone from putting something into an aspirin bottle on the shelf, but what if someone puts a coating in a bottle?”
“The challenge with validation is that it’s the responsibility of each pharmaceutical company to develop its own program to respond to FDA guidelines,” says Dave Schuh, vice president of sales and marketing at MGS Machine Corp. “But no matter how pharmaceutical companies choose to respond, at the end of the day they’re the ones responsible for compliance.”
“The FDA is looking for proof that the process is in control,” says Jeff Jackson, product manager at the Pharmaceutical Div. of Bosch Packaging. “Every customer has its own way of doing that. We have to meet each customer requirement.”
What makes the process more complicated is the fact that there are no clear guidelines that specify exactly how validation is to be done. So each manufacturer, ultimately responsible for every bit of validation in its processes, interprets the process differently and passes different requirements on to the packaging machinery suppliers. And that’s exactly where pharmaceutical manufacturers need help from packaging solution providers.
The fundamental process for validation has been in place for 10 years: the pharmaceutical company develops qualifications for a packaging machine and passes them off to the supplier, who then designs and manufactures the equipment. The pharmaceutical company then tests it, approves it, and begins operations.
But the FDA made this simultaneously easier and more difficult in September 2004 with the report “Pharmaceutical cGMP’s for the 21st Century—A Risk-Based Approach.” Current good manufacturing practices (cGMPs), sometimes known as good automated manufacturing practices (GAMP), have long been a standard practice in the pharmaceutical industry, but new technologies and approaches to quality assurance required more flexibility—and thus more variability—in the validation process.
The cGMP report discusses the integration of more science into the development and deployment of a new product, and it places the onus on the pharmaceutical companies to demonstrate that they understand what can and cannot affect the quality, stability, and efficacy of the product.
“With the FDA’s risk-based initiative to cGMPs, the FDA is trying to offer an olive branch to the industry,” says. Bikash Chatterjee, COO, of Pharmatech Associates, a consultancy serving the regulated life sciences industry. “Essentially the FDA said, ‘We’re looking for sound science—if you can justify to us that the decisions you have made regarding your critical systems, processes and equipment are scientifically sound, that’s good.’”
The cGMP guidelines, however, make assumptions that make the validation process more difficult. For example, the guidelines assume that each system is custom-designed, which leads to some manufacturers of standard machinery to conclude that the guidelines don’t apply to them. As pharmaceutical manufacturers push the issue, more packaging machine manufacturers find themselves being required to provide validation documentation to their customers.
“The industry kept hammering, so some companies created the documents that would normally be done in the process of designing, even though the product has already been designed,” says Howard Leary, vice president of engineering at Luciano Packaging Technology.
The initial design of the packaging machinery is documented in the Design Qualification, which creates an audit trail from the initial design specifications through the implementation of the new machinery. Savvy manufacturers understand that this upfront documentation can save a lot of trouble further down the road.
“One of the main things the FDA looks for is the upfront documentation, like the design qualification,” says Leary. “To do the spec up front is a more organized way to go.”
Even before the design qualifications, though, are the user requirement specifications, or URSs, which come from the pharmaceutical companies. A well-written URS drives the functional spec, again easing the process on the back end with some effort on the front.
In a perfect world, the pharmaceutical company can simply write the URS, hand it to the machine builder, and then accept delivery of the machine, complete with documentation. The challenge is that many times the pharmaceutical company is investing in a new machine or packaging line but can’t know exactly how the line is going to work, or what they need to do to write a URS.
“Often the back office is writing the specs, and the engineering guys are doing the validation checks and testing it, then they have to go back and rewrite the documents to reflect what they found in the process,” says Dave Whittenton, business development manager at Rockwell Automation. “That’s what’s introducing the inefficiencies.”
“We respect the fact that some end users really struggle with the URS,” says Schuh. “To help them we’ve developed templates that are populated with information to describe the functional specification for the base equipment.”
Also developing templates is the JETT (Joint Equipment Transition Team) Consortium, a special interest group of the International Society for Pharmaceutical Engineering created to help ease the cGMP process. JETT aims to improve communication between users and suppliers of automated production and process equipment to meet validation requirements more effectively. The group offers a number of documents and templates for various validation processes (www.jettconsortium.com).
“JETT is looking at some of the documentation, like design requirements, and developing templates based on cGMP that have a validation checklist, or something very similar,” says Whittenton. “You can just pull down the template for a bottle capper, for example.”
“As a supplier, we invest in keeping abreast of user groups working on validation standards, and working on processes for users and suppliers to interact, like the JETT Group,” says Schuh. “End users and suppliers can together hash through specifics of how to interact and develop a process flow that improves efficiency in improving equipment.”
“We see a lot of user requirement specifications, and the trend now is to re-evaluate how to write a URS and how we can improve the URS documentation,” says Whittenton. “The entire industry needs to get better at writing those.”
But not every supplier is enthusiastic about documentation.
“If someone doesn’t have or is unwilling to provide it, we as an integrator may not select them for a line,” says Leary. “Some companies have a standard machine and that’s what they sell, and other activities are a burden for them.”
In other cases, the customer is willing to pay extra to have those documents created. But the machinery manufacturer might not have qualified people to create the documentation. Only in the past decade or so have packaging companies begun to understand this requirement, according to Leary.
“When manufacturers do their homework, they lay that all out, and the detail of the specification documents becomes the supplier’s responsibility,” says Leary.
The industry responded to the cGMP report with Process Analytical Technology, or PAT, a system to design, analyze, and control manufacturing and packaging processes through timely measurements of critical quality and performance attributes. The goal of PAT is to understand and control the processes with the assumption that quality can’t be tested into products, but rather should be built in by design.
The PAT framework aims to apply the “quality by design” tenet to ensure a predefined quality at the end of the manufacturing process, improving efficiencies while simultaneously reducing risks to quality. In-line measurements and controls will reduce cycle times, prevent rejects and scrap, and improve operator safety and overall efficiency. The FDA has since created several subcommittees to provide recommendations on how PAT could be adopted throughout the industry.
“PAT fundamentally allows you to release your product without any additional release testing,” explains Chatterjee. “Currently you sample it, it goes to lab, you test it, and then you can ship it. PAT says that if you can demonstrate that you’re controlling and monitoring the critical attributes associated with the process—the number of pouches, verification of that number, the proper label, the right country, legible printing, etc.—the packaging machine can guarantee that the product will meet your quality standards. It’s the ultimate quality assurance.”
PAT is taking off slowly—it requires a high level of collaboration between the customer and the supplier during the equipment design and development process. It also requires “smart” machines and sensors that can communicate not only the state of the process, but the state of the sensor as well. This has led to a new generation of integrated controls.
In the past, equipment simply controlled its own functions; three or four other systems tracked what was being fed to it, or measured downtime, or tracked performance. But now the machine “knows” when it’s a good machine and when it’s not.
This requires a lot more validation, but in the end it makes the process easier and more efficient, especially when it comes to changeovers, which are another huge challenge to validation.
Some estimate that up to 70% of unexpected downtime is due to errors in changeover, which traditionally relies on paper-based standard operating procedures. But a new approach builds those procedures directly into the batch engine on the packaging machine, automating the changeover and retaining all the documentation in electronic form.
“It essentially uses the control platform on the machine to verify that the operator performed the SOP tasks automatically, and keeps an electronic record,” explains Whittenton. “It could also be integrated into a plant-wide recipe through the MES system, or you could do it manually by scanning the bar code on a carton blank, which kicks off the SOP—giving instructions for changing the inserts, calibrating, changing out, retesting. The operator has to go back and validate each task on the controller, and the platform is monitoring the change of the machine.”
The consistency of standards
Another challenge to validation is the consistency of the validation procedures themselves. The equipment manufacturer might believe that because they understand the machine better than anyone else, they should conduct the validation. But the end user—who is ultimately responsible—might not want to have several different manufacturers applying several different validation procedures, each with different courses of action, vocabularies, and document structures.
“The consistency of validation has become increasingly important,” says Whittenton. “OEMs are improving the situation by offering not just a single machine, but rather a whole packaging line.”
Consistency also plays a role in the integration of the machines. For example, a pharmaceutical manufacturer might want all the machines in a line, or in a plant, to conform to common standards in software and operating system.
“One customer decided to pick a standard for the controllers and all equipment across the board, and he told the manufacturers that they needed to have Ethernet on their machines in order for them to be considered,” recalls Nelson.
“The pharmaceutical companies are looking more to the OEM community to provide process sales of packaging lines,” says Whittenton. “They don’t want to buy islands, or a single machine for each process. They believe that will ease the validation process, and companies are stepping up to the plate and integrating.”
“We’re seeing this in 80 percent of packaging across the board, to have the systems unified ahead of time with the same operating system and communication,” says Nelson. “It’s such a simple thing to do. That alone removes so many hurdles to get them up, running, and validated.”
As smart machines become more prevalent, the process of validating the software becomes more complex. But by making the software modular, manufacturers are further easing the validation process.
For instance, a packaging machine might have 20 servo axes, which are all basically the same subroutine. Instead of validating each axis performance individually, could you validate the subroutine once and be done?
“If I can create a modular code or subroutine and validate that block and then manage that block and reuse it within a certain element or platform, would I have to validate it again?” suggests Whittenton. “There’s a lot of philosophy about how to implement this. If you had a positioning cam subroutine, the OEM could provide the software code with a validation packet explaining how to validate that code. But is this a huge benefit, or just huge marketing? It’s not really saving that much in the cost.”
Factory acceptance tests
The final phase of the new machine is the factory acceptance testing, or FAT, where the machine is run through its paces at the factory where it was built to ensure that everything works properly, and to complete the final validation stages.
“It used to take only a couple of hours to make sure things are running the right way during a factory acceptance test, but today it can take eight to ten weeks to put the equipment and software through the necessary challenges to demonstrate that it will meet today’s quality compliance standards,” says Chatterjee.
“We’ve developed user-editable documentation templates so that we can transfer that information to the end user early on in a project, or we can do more of the spec work for them up front,” says Schuh. “Some customers are looking into executing some portions of the commissioning work during the FAT in the supplier’s factory, with the goal of trying to improve the overall efficiency of a given project. It’s getting mixed results, but it’s a great example of people working together to optimize program results.”
This collaboration might well be the key to success in easing the overall validation burden. Packaging suppliers need to better understand quality systems, which in itself is a huge challenge for smaller companies. But pharmaceutical companies can help by working with smaller, specialized suppliers to help them understand what they need to get out of the process.
“Suppliers need to participate at a more intimate level regarding how these subsystems could affect the quality of the product,” says Chatterjee. “The whole process is forcing packaging suppliers to be more involved in infrastructure development and deployment of the equipment.”
“We learned from working with our customers what they’re really looking for,” says Leary. “Once you produce some of these documents, you have a good understanding. Each company has different approaches and different regulatory departments, but with most companies, if they come up with a good design document, it’s accepted.”
“I strongly encourage companies to create a business team, with the heads of each division on both the client and supplier side, along with people with budget, technical, quality, and deployment responsibilities,” says Chatterjee. “They need to set goals and milestones and to track those on a regular basis to see what’s going on and what needs to happen.”
Chatterjee predicts that as machines and processes become more complex, joint teams will become more prevalent. And with that collaboration will come better understanding, and greater success.
“The machinery industry needs to understand validation requirements and how to support them, not just the schematics and parts lists, but the entire document package that comes with the machine and verifies that it’s complete and accurate,” says Leary. “The packaging industry has learned that this is important. Compared to ten years ago, there’s a tremendous difference with suppliers.”