Bigger than Y2K?
Deploying plant systems compliant with FDA regulations poses huge hurdle
By Alex Anderson, Contributing Editor -- Manufacturing Business Technology, 10/1/2001 12:00:00 AM
It's hard to imagine an industrial sector more challenged by regulatory red tape than the life sciences sector. Whether it's pharmaceuticals or biotechnology devices, literally every step of the manufacturing process is covered by a thick carpet of legal requirements that govern everything about a product from the instant it progresses beyond the idea stage.
"Manufacturing in life sciences is governed by current Good Manufacturing Practices [cGMP], which is pretty much self-describing," says Keith Chambers, a senior manager for process industries with Foxborough, Mass.-based Intellution, a provider of industrial automation software, including batch management and other solutions for regulatory compliance. "These are the things you do to consistently manufacture good products, and they are enshrined in regulation by the Food and Drug Administration [FDA]."
Terms such as cGMP, as well as 21 CFR Part 11—another FDA regulation impacting the life sciences sector—translate into a more pressing need for software applications that manage, control, and track the details of plant-floor processes and documentation. Vendors of industrial automation software—especially those offering applications such as batch management and supervisory control—increasingly are focused on compliance solutions for life science verticals.
Regulatory scope
Basically, cGMP boils down to two things, says Intellution's Chambers. "The first is documentation: Who did what," he says. "There must be a complete record of how a particular product was manufactured. This record includes what the specs were, and everything that went outside the specs during the process. This record can run into the hundreds of pages, and usually is kept manually. These documentation requirements impact the company's ability to ship the product. They must be reviewed before the product is shipped, and the approval process can take several weeks.
"The second involves tracking raw materials, which are typically controlled substances, like morphine derivatives," Chambers continues. "There are legal restrictions on their usage, and they have to be tracked."
Larry Leblanc, director of marketing for Wonderware, an Irvine, Calif.-based vendor of industrial automation software, concurs that regulated manufacturers face some fairly stringent requirements. "The pharmaceutical automation life cycle is unique because of the thoroughness required," says Leblanc. "A drug maker has to document, test, and verify the results of every process parameter. It must know how its process will react to a change. It must be able to prove it understands its processes and its control systems.
"Just recently, I was talking to a pharmaceutical company in which, to change one parameter in its validated system, it takes two weeks and involves about 40 people," Leblanc continues. "They must justify, understand, and document everything concerning why they want to change the parameter, and what effects it will have on the system. This is all part of the automation life cycle. As a result, production and process information is critical."
The aforementioned 21 CFR Part 11—an FDA regulation enacted in August, 1997—focuses on electronic record-keeping and electronic signatures. This new regulation is the impetus behind the need for manufacturers to improve their methods and systems for production management and record-keeping. Some experts are even comparing the information technology (IT) effort involved in 21 CFR Part 11 compliance with the IT effort for Y2K compliance.
Specifically, the regulation defines how pharmaceutical companies must capture and retain electronic signatures, "paperless" records, and reporting procedures related to the manufacture of their products. These records are vital to the day-to-day operation of every pharmaceutical manufacturer or company marketing drugs in the U.S., and are necessary for establishing an audit trail for literally every pill, capsule, and liquid produced. Such audit trails identify both the ingredients and individuals involved with the production of the drug, and are of utmost importance to the FDA.
Enforcement heats up
Though slow to enforce this regulation, the watchdog agency is now starting to turn the screws, with penalties for failing to comply with 21 CFR Part 11 ranging from citations to a full shutdown of operations. As such, many manufacturers are scrambling for compliance. Vendors are scrambling equally hard to offer systems and services that comply with the regulation.
According to Leblanc, many manufacturers are moving to electronic signatures and records, and this regulation—and the FDA enforcement—is affecting how they implement automation projects.
"Electronic Batch Records—which include batch production history, process history, and equipment history—are primary data according to the FDA," Leblanc says. "Primary data must be in a secure database and cannot ever be altered. The FDA also is concerned with configuration data, such as control strategies and recipes that are critical elements of production. If the software doesn't do it, then manual processes must be put in place to track versions and changes."
It is important to note that systems such as those for customer relationship management (CRM), which have little or no direct impact on manufacturing operations, didn't have to be compliant under cGMP. They do, however, have to meet the Part 11 standard, and vendors of these systems are way behind, though many are working on it. For example, San Mateo, Calif.-based Siebel Systems has reported that a Part 11-compliant version of its software will be available by the end of the year. Still, a recent report by Boston-based analyst firm AMR Research found that less than half of those vendors polled—across applications including CRM, enterprise resources planning systems, supply chain management, and manufacturing execution systems (MES)—claimed to offer a Part 11-compliant product.
Additionally, the report—which polled 18 life sciences manufacturers and a large number of software vendors—uncovered a number of challenges facing the industry as it struggles toward electronic-record (e-record) compliance:
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All product and consumer safety e-records must become compliant.
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The majority of companies are treating the issue as an IT problem rather than a business problem.
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Regulatory executives lack the supply chain and business process expertise to lead cross-functional business process change.
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Systems that were validated as compliant to cGMP standards are not necessarily Part 11-compliant.
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There still is confusion in the industry about what exactly constitutes an e-record.
"Part 11 rectification is being compared to Y2K because it's an IT responsibility to fix," states Roddy Martin, an AMR analyst, in the report. "For Y2K, however, it was easier to create a sense of urgency with program management and resource allocation throughout the organization, including executive levels."
According to Martin, early estimates of the cost of Part 11 compliance run from $100 million to $250 million per company, though some believe this could be reduced from $1 million to $2 million per $1 billion in revenue if rectification efforts are coordinated, and common solutions are implemented across the business.
The low end of this estimate accounts for companies that have maintained control of compliance using a standardized set of industrial automation and production management applications, while the higher side is reflective of organizations that have a large number of legacy and homegrown plant-management systems.
Based on interviews Martin conducted with manufacturers and consultants, he estimates that between 80 to 90 percent of the processes currently in use in validated operations are paper-based. "The move to e-records has been slow, except in the implementation of such applications as MES," he reports.
Meeting 21 CFR Part 11 requirements has been less of a headache for Hans Koenig Bastiaan than it might be for some of his peers. Bastiaan saw the writing on the wall more than six years ago and made sure to think about e-signatures when he was looking for a manufacturing operations control system for Genentec. The San Francisco-based company uses human genetic information to develop and manufacture drugs that fight cancer, break up blood clots, and help patients recover from heart attacks.
"Before it became law it was well known that instructions had to be signed off. I just started following the logic. If you used an automatic control system, it was logical that you had to have a facility for electronic signatures," says Bastiaan, Genentec's associate director of process automation.
To that end, Genentec selected a batch management solution, now known as InBatch, from Wonderware. "It could run recipes and instruct equipment and operators, and it had a facility for electronic signatures," says Bastiaan. "That was why we wanted it.
"In the manufacturing process, there are many different processes that identify or correlate to a particular batch," Bastiaan continues, adding that one of his goals was to tie that data directly to the making of a particular batch or lot, thus providing a defensible audit trail.
Therein lies one of the arguments for automating the process, says Bastiaan. "Having all that data in one system is far more efficient than when it was spread out over different databases, or on paper," he says.
Time for action
"There are two issues facing the industry," says Intellution's Chambers. "There is tremendous benefit to be had by applying electronic methods to documentation and automating something that used to be done manually. This is the good news. On the other hand, many organizations have been taking advantage of the allowance without following the rules. They now find themselves in the position of having invested a lot of money and time in non-compliant systems."
Intellution applications—such as iBatch for batch management, and iWorkinstruction, which addresses electronic record-keeping—are 21 CFR 11-compliant. In addition, Intellution recently launched a services group focused entirely on helping pharmaceutical companies meet 21 CFR Part 11 standards. This services group, which is vendor-neutral, will initially focus on pharmaceutical companies, but Chambers says it will expand to encompass medical device manufacturers and other affected companies.
The new group provides customer training, detection of what is needed to develop a compliant solution, and a detailed assessment of a client company's current state of readiness. It also will provide an action plan for moving toward compliance, and ongoing maintenance to help customers maintain the standards necessary for compliance.
Software vendors face their own challenges in response to 21 CFR 11. "The biggest concern for vendors is version management," says Wonderware's Leblanc. "Customers are asking us to provide version management and audit trails for everything. They must have a record of every version of software they had so they can go back and show the FDA anything they want. That's probably the biggest headache for everyone right now—tracking this automation configuration data."
Additionally, AMR found that 40 out of 45 process control systems could not be made Part 11-complaint because that version of the software was no longer supported. In other cases, vendors stated they had no intentions of becoming compliant because their life sciences market share did not justify the cost.
The good news is that FDA inspectors are not expecting manufacturers to be Part 11-compliant when they knock on the door, says Leblanc. "What they do expect to see is a plan to become compliant," he says.
This gives companies time to follow Martin's primary recommendation: develop a three-year business-driven plan to assess compliance needs and rectify or replace systems. At the same time, however, Martin recommends taking a business improvement approach, rather than just fixing the IT part of the problem. That's an approach that's bound to resonate with managers involved with manufacturing execution.
| For more info: | ||
| Intellution www.intellution.com |
Siebel Systems www.siebel.com |
Wonderware www.wonderware.com |
