by Salvatore Salamone
April 15, 2005 | In March, the FDA used federal marshals to seize millions of tablets of Paxil CR and Avandamet from GlaxoSmithKline manufacturing plants in Tennessee and Puerto Rico.
The tablets were seized because the FDA had detected a problem with the pills as far back as February 2002. The pills tended to split. The problem persisted despite an FDA warning letter and more plant inspections in the past few years.
The story about the seizures, reported in The New York Times, noted that “despite the absence of evidence that the pills had harmed anyone, the [FDA] said, a drug maker must be able to assure the public that its products are properly made.”
This example illustrates how seriously the FDA takes the pharmaceutical manufacturing process and how severe the consequences can be when companies are unable to comply with mandated current good manufacturing practices (cGMP).
Companies are required to maintain standard operating procedures (SOPs) that detail every step of a drug’s manufacturing process, including information about who is responsible for carrying out various manufacturing and quality assurance and control tasks, how the people involved are trained, and what steps must be taken when something goes wrong.
Generally speaking, 21 CFR Part 210 governs cGMP for the manufacturing, processing, packaging, or holding of drugs, and 21 CFR Part 211 is for cGMP for finished pharmaceuticals. For example, a liquid medication leaching through a plastic container would be covered by Part 210, but a pill breaking apart after it ships would likely be covered by Part 211.
While there are no hard numbers, industry experts estimate up to 90 percent of companies today use paper SOP documents to meet cGMP. Not surprisingly, pressure is building on pharma to convert SOPs to digital form to improve access and trackability. But making this leap isn’t easy. Systems used to create, modify, store, and share the documents in electronic format must be Part 11-compliant.
Evolving Toward Digital
Many companies have kept their manufacturing SOPs in paper format because it is easier than undertaking a conversion. Quite often, SOPs apply to only one manufacturing plant, so documents can easily be shared within the facility. Management of master documents becomes more challenging when they go beyond a single facility.
A few companies have resorted to a hybrid approach. They use paper master documents with bar codes, and use a database to track the status and location of each document.
Increasingly however, companies are creating electronic versions of their SOPs for cGMP.
“The [paper-based] process is very labor intensive,” says Ashley Peacock, validation manager at Albany Molecular Research, a chemistry-based drug discovery and development company. A full-time person was required to manage Albany Molecular’s SOP documents in what was a 100-percent paper system. “We just knew we had to move to something electronic,” Peacock says.
Similarly, Merck’s U.K.-based subsidiary Merck Sharp & Dohme’s (MSD) primary manufacturing site used signed paper masters of its SOP documents.
“We were managing lots of hardcopies. It was very time-consuming,” says Joanna Hills, site documentation specialist at MSD. “We relied on a lot of people, doing a lot of things at the right time,” she says.
Both companies decided to convert to electronic systems, but took very different approaches.
MSD decided to simplify SOP management by moving to an electronic system that would support features such as workflow management, digital signatures, audit trails, and version control to ensure compliance. Also, a different content management system was already being used for other documents, and any new solution would have to work with this existing system.
Hills evaluated content/document management systems that would provide the needed level of document control and security for compliance. Unfortunately, the existing document management system did not support features required to create regulated cGMP documents.
MSD also looked at a Web-based cGMP solution called Alibaba, from Solabs. Alibaba integrated with the existing system, essentially functioning as a compliance portal that allows approved documents to be deposited into the existing system. Users check SOP documents in and out of the system, and the Alibaba software supports features such as workflow management, digital signatures, and version control, and tracks document status.
In contrast, Albany Molecular started from scratch, giving Peacock considerable flexibility when choosing a system. Peacock chose a compliance management system from MetricStream, basing his decision not only on technical merit but also “because [the company] had a good balance of life science experience and general industry experience.”
MetricStream’s software automates the collection and management of all quality and compliance data within an organization. Specifically, the software helps automate audits, change control, and corrective actions.
MSD and Albany Molecular agree that their respective vendors’ (Solabs and MetricStream) plentiful life science experience paid dividends during implementation. Both were well acquainted with the regulatory issues involved in securing the documents and able to provide more then perfunctory advice.
Indeed, most major content management vendors have beefed up their compliance support, especially strengthening 21 CFR Part 11 features. Some vendors such as EMC/Documentum and Open Text have combined workflow management with their security and content management systems. These latter systems meet the FDA’s requirements for safeguarding documents, and also help automate business processes within a company.
It’s important to note that Part 11 compliance still requires the appropriate staff to initiate, review, amend, and approve SOP documents. Integrating workflow management lets companies automate needed staff reminders. For example, a workflow can be set up to issue relevant alerts every time a new document is created that requires a manager sign-off.
Sometimes cGMP compliance systems can also be extended to other like tasks. At Albany Molecular, for example, soon after starting the project corrective action/preventative action (CAPA) became very important. So a second implementation phase incorporated other documents.
The bottom line is that for a long time, pharmaceutical manufacturing facilities have maintained paper copies of their SOPs. In many cases, the documents really applied to the operations at only one facility, so management of the hardcopies, while time consuming, was deemed acceptable.
Today, companies are finding that, due to new drug safety requirements (especially new programs that look at the safety after approval), there is a greater need to have the information within manufacturing cGMP SOPs available to other groups with the organization. This is pushing companies to convert from paper-based to electronic systems for managing their cGMP SOPs. l
art credit: Terry Miura