In the past few years, concerns have been growing about the security of the pharmaceutical supply chain. Despite the checks and balances that are already in place, in today’s increasingly globalized market it is all too easy for an unscrupulous trader or supplier to introduce counterfeit raw materials into the supply chain. Equally, companies that do not meet strict quality standards may sell non-compliant intermediates or ingredients, and these may not be discovered until it is too late.

The real danger is that these substandard materials can end up being used in the manufacture of final dosage forms, putting patients at risk. High profile instances of contamination have highlighted the risks of an insecure supply chain; the heparin incident and the melamine in baby milk issue made headlines, and led to lives being lost. Both of these cases involved criminal behavior, with profit being put ahead of patients. We do not want this to happen again, because patient safety is far too important.

Substandard Products

It might seem unlikely that substandard medicines could reach patients, yet the World Health Organization estimates that 10% of all medicines sold around the world are counterfeit. This figure rises to 30% in developing countries and may, in reality, even be higher.

According to the U.S. Government Accountability Office, in 2007 only 11% of manufacturing sites outside the U.S. were inspected by the FDA — and just 19 of 700 facilities in China. With FDA funding tight, there is no way regulators could carry out a comprehensive inspection program of every facility around the world that supplies the pharma industry.  

This is why in 2009 a group of industry players got together to establish Rx-360 (www.rx-360.com), a not-for-profit international pharmaceutical supply chain consortium. It currently has 64 members, including both pharmaceutical and biopharmaceutical manufacturers and suppliers of intermediates and APIs, plus trade associations and independent auditors as observers.
The consortium was formed after discussions between several speakers and delegates at a conference hosted by FDA and the Parenteral Drug Association (PDA) on ensuring the integrity of the pharmaceutical ingredient supply chain. Their idea was that if companies came together to pool their resources, information and audit data, it would be a big step towards increasing the coverage of inspections, and more suppliers would be able to be properly audited.

Rx-360’s aim is to ensure that supply chains are completely secure and reliable, and able to deliver the right materials with the right quality to manufacturers. This would leave healthcare practitioners and patients secure in the knowledge that the materials used to make medicines were exactly what they should be. While regulators and legislators around the world are, quite rightly, putting measures in place at a local level, the international nature of the pharmaceutical business means this cannot provide sufficient protection. The global Rx-360 consortium complements these efforts, to give an overall level of consistency in quality requirements and implementation, and stamp out the market for unscrupulous operators.

Establishing Guidelines

One of the most important functions of the Rx-360 consortium and its Audit Standards Working Group is to establish guidelines for raw materials, and ensure they are adhered to by suppliers. It is also working with research institutions to develop technologies that will improve the security of the supply chain, and is acting as a ‘clearing house’ to collate reports of any suspicious activity. This activity might consist of contamination, suspected tampering, adulteration of materials or even disruption in the supply chain that might encourage unethical individuals to take advantage of a raw material shortage by offering counterfeit or substandard materials.

The shared audits are also key because carrying out a supplier audit is an essential, but expensive, business. A wealth of audit information has already been accumulated by pharma and biopharma companies, with many suppliers having undergone multiple audit processes. Although different companies are looking for different things from their audits, a lot of commonality remains among them. If this information could be shared in a way that does not impact business confidentiality, then it would free up resources to enable a greater number of different suppliers around the world to be audited. It would save time for the suppliers, too, as the amount of time it takes to host auditors can be significant.

Three standards were used when setting up the pilot program, one each for APIs, excipients and basic chemicals, since the precise requirements for each are different. These are used alongside a supply chain security checklist, which includes security controls such as access restrictions to facilities and products.

A sub-team from Rx-360 (of which SAFC was part), focused on the raw materials standard checklist; this was the most difficult to create as we were unable to leverage findings and standards from other industry sectors. While there is clarity on the requirements for excipients and APIs, as these are under regulatory control, there have been no truly global or consistent expectations of what constitutes a key raw material, nor what standards should be expected. This has always been a challenge when raw material suppliers are audited.

We used APIs as a starting point, along with other industry standards, to establish the guidelines to which we should be working. We then developed a list of audit questions for the pilot program. Other SAFC team members joined to work on the API guidelines. Some questions will likely be the same for all customers, for example, about water purity or training procedures. Others might be more product- or process-specific, but there will still be a large amount of commonality across the board regarding requirements.

Audit Pilot Program

As a key supplier for many pharmaceutical and biopharmaceutical companies, we believed it was important for us to be involved in the pilot program. Our Cherokee site in St Louis, MO was audited over two days at the beginning of May, and our facility in Buchs, Switzerland at the beginning of August. The audit process itself was both cordial and professional. It became clear that some improvements to the process will be necessary, as one might expect for a pilot program. For example, some audit observations within the written report were neither reviewed nor discussed during the audit. To a degree, the auditors used their own checklists as a basis for the process, and matched them up with the Rx-360 checklist, rather than using the Rx-360 list itself, which will also need to be addressed.

This type of feedback will be shared at an Rx-360 board meeting (which will have taken place by the time this article is published). In my opinion, the pilot program has been a very good start. My initial feedback is that it is going to take some time for everyone to get used to the process. For example, one member company recently requested an audit of our Cherokee site, for the exact same product that was audited by the Rx-360 process in May. This is because companies have yet to change their internal procedures to allow for third-party auditors.

A couple of other companies, meanwhile, have told us they are happy to use the Rx-360 audit; another one will accept it but still wants to visit the site to confirm a few points, as the product we supply is a critical raw material to them. Even if a company does want to carry out some extra auditing of its own, this should only take a day, rather than the two or three required for a full audit. The Rx-360 audit will also help in pre-qualifying potential new suppliers, so a company can be reasonably confident they will meet its needs. The audit teams should be more informed when they arrive, and not need to go over the whole audit list again. If anything does need to be clarified, perhaps an issue specific to their own product, volume-related concerns or particular packaging requirements, they can then focus on these points.

So far, 17 audits have been completed, with 14 reports lodged in the Rx-360 database for members to consult. The working party has already begun to look at requests for the next round of auditing, and it is now starting to look like a process, not simply a pilot project. Of those 17 initial audits, the majority were conducted in the U.S. and western Europe, but companies in China and Japan were also audited. It is important that the whole process starts to gain international acceptance — Rx-360 is a global organization, and we need to ensure that suppliers all over the world are included.

Looking to the Future

Once all 25 audits in the pilot program have been completed, the consortium will be in a good position to say how well it is working, and what needs to be done to improve the audit process and the way the information is reported. We have now reached a critical mass regarding the number of companies that are participating in the shared audits, and these members are already starting to benefit from the increased information they gain by sharing. While some companies remain to be convinced that it is right for them, we aim to persuade most that this is the right way forward, and that access to richer, broader datasets and increased efficiency of the process will be in their best interests.

It is clear that some pharma and biopharma companies still need to get their internal procedures lined up, but the initial results of the pilot are extremely promising, and people within the quality control functions of both suppliers and pharma/biopharma companies understand its importance. The next task is to ensure that procurement staff, even up to the chief executive officer, see that this as a critical issue for their business. It is not just a quality initiative; it is a business initiative.

Collaborative programs like this are essential if we are going to be able to ensure the security of the pharmaceutical supply chain going forward. It makes no sense if we are in a situation where 100 different customers audit a single facility, while another 99 go unaudited. Safety is not a competitive advantage. It is a core part of the pharmaceutical industry’s license to operate. By working together in this way, we will be able to pool our resources to increase the security of the pharma supply chain, to the ultimate benefit of patients and their safety.

The audit program has already proved the value of the consortium, and the level of interest in it is continuing to grow, along with its acceptance. It will take time for the mindset to shift from company ownership to industry ownership, but I believe this is the way we need to align in a global industry. It is also important that the program has gained acceptance by government agencies to augment their own efforts. This is a collaborative effort across industry and the regulatory bodies for the common good and it is something that none of us can do on our own.

Tom Beil is vice president of Quality & Regulatory Affairs at SAFC. He is also a board member of the Rx-360, the international pharmaceutical supply chain consortium. He can be reached at [email protected]. For more information about Rx-360, please visit www.rx-360.com.