Lessons from Heparin

In the case of heparin, Fareed suggests that polymerase chain reaction (PCR) testing should become a standard practice. It wouldn’t hurt to find an alternative to heparin as an anticoagulant in. for instance, hemodialysis and open-heart surgery, he says. Synthetic heparin is one possibility, since it would be animal-free and could be produced start to finish within one facility.

Liu of North Carolina and research colleagues have produced milligram-level synthetic heparin, and are seeking partners for developing the compound for pilot- and commercial-scale manufacturing.

Where To From Here?

FDA’s Nasr understands that additional guidance might be needed, to spell out more clearly what the Agency expects in regards to heparin safety. For now, Nasr says, requirements are outlined in ICH Q10, which addresses the responsibility of manufacturers and their quality sys-tem to ensure quality throughout the supply chain. There are important lessons that both industry and regulators can learn from heparin, Nasr says, to minimize the chance of future crises:

• Manufacturers have the primary responsibility for product quality. They’ll need to assure the quality of all raw materials they purchase, and make sure the quality system they have is robust enough to assure quality throughout the supply chain.
• Quality by Designtype information is critical for appropriate regulatory oversight. Regulatory submissions will need to include detailed development and manufacturing information, and documentation of appropriate quality control strategy and risk assessment of the product and process.
• Modern analytical technologies must be used— not just to satisfy regulatory requirements, but as good business practice.
• Regulators must find a way to encourage and, in some cases, require the use of modern methodologies to assure product quality. That will mean periodic updating of compendia for all pharmaceutical products.

Others have their own advice. Among the primary lessons learned from the heparin affair is that supply chains have gotten increasingly complex and hard to manage. Heparin exposed the multi-layered nature of most supply chains and the sheer uncertainty that many manufacturers have in regards to their raw materials, says Jaime Velez, head of the supply chain management practice at Tunnell Consulting, Inc. (New York, N.Y.).

“Unfortunately, it’s more common than one would like to believe,” he says. “Many products are made with raw materials that are sometimes three, four or more levels deep—the end manufacturer doesn’t have any idea what’s in the materials.” Velez advises that manufacturers must create more robust raw materials oversight processes. This doesn’t just mean adding staff or creating an external supply group, he cautions.

Velez has seen many a drug manufacturer beef up supply oversight without a clear strategy and then become consumed by non-value-added work. What’s lacking is a basic methodology for tracking materials from their origins, one that includes tracking systems, increased visibility of supply operations and a modus operandi of working through multiple levels of the supply chain to get to the roots of materials. It’s a “tedious exercise,” Velez admits, but one that has to be done. Of the top 25 pharma companies, Velez estimates that two-thirds have external supply organizations, though perhaps only a half-dozen have effective, efficient practices. The rest exhibit a “fantastic level of duplication”, he says, as QA, QC, technical and supply chain representatives, planners and schedulers wrestle with who should do what.

A growing number of drug manufacturers are extending control of suppliers by sending their QA auditors to third-party manufacturers and suppliers, says Eize de Boer, PhD, global manager of Life Science Auditing at the consulting firm SGS (Princeton, NJ). This holds true not just for the oversight of active ingredients, but excipients as well. Many major multinationals have already taken these steps, he says.

Quality Contracts: The Devil’s in the Details

Contracts are also essential, and establish the specific requirements made by the manufacturer to the supplier. In the technical contract, both parties can agree upon a checklist, in which the company contracting the services lays down all the requirements for the supplier. “A checklist with an extreme level of detail is necessary, and should be an attachment to the technical contract,” de Boer says. “For example, if there is a specific concern for cross contamination, the auditor can put special emphasis on air handling units, hygienic control, environmental monitoring, etc.” A site should be visited by two auditors, so that they may confer on findings, de Boer explains.

Off-site, the auditors will study the site master file (SMF) and drug master file (DMF), and inspection documents, previous audit reports and annual product quality review. Finally, auditors and their suppliers must assess deviations and complaints. This includes a closing session where the auditors disclose deficiencies as transparently as possible, and seek management comment. This information will be contained within a final audit report.

Based upon the seriousness of the deficiencies, the plant will propose a plan for corrective action and, if approved, follow through with it. Process knowledge is also critical, Tunnell’s Velez says. Manufacturers must characterize all processes, monitor process variables (in real-time if possible), and anticipate how product and process will behave in this multivariate environment.

What are the implications of a raw material that approaches the upper side of release specifications, for example? Process analytical technologies (PAT) may be useful in this regard, and have often been too narrowly defined in industry and excluded for raw material characterization, he says.