In July, Merck Millipore completed an audit for EXCiPACT, a new voluntary standard for pharmaceutical excipient suppliers. We talked to Frithjof Holtz, head of MM-QS Advocacy, Merck Millipore Quality and Regulatory Management, about the process.
Contract Pharma: What was your company’s involvement in helping to set the EXCiPACT standards?
Frithjof Holtz: Merck KGaA, the mother company of Merck Millipore, was involved in EXCiPACT from the very beginning. We are involved in several associations relating to the pharmaceuticals industry, including IPEC [International Pharmaceutical Excipients Council] and EFCG [European Fine Chemicals Group]. From the very beginning, we believed the idea of EXCiPACT is a brilliant concept.
CP: What did you find so appealing?
FH: Currently, neither Europe nor the U.S. have binding regulations on GMP for excipients. Yet on a daily basis, we’re facing questions from buyers and users of excipients: “What are appropriate GMPs and are you manufacturing accordingly?”
The other challenge for industry is the increasing demand for physical audits. Regulators in North America and Europe are pushing excipient users and pharmaceutical manufacturers to do on-site audits on the supplier side.
So EXCiPACT helps address two key issues: what are the appropriate GMPs for excipients, and how do we handle the increasing demand for on-site audits? We supported EXCiPACT with our expertise to develop this scheme to answer these GMP and GDP [Good Distribution Practices] questions.
CP: Any tips for companies interested in EXCiPACT?
FH: One of the essential things to know — and this is a recommendation for anyone who’s interested in getting EXCiPACT certification — is that you can freely download the standards from excipact.org. Read it carefully, paragraph by paragraph, and if you make up your mind that you want to pursue this, then do a gap analysis. See where your quality system currently is and honestly assess it in light of the expectations of the EXCiPACT standard. This holds for both GMP and GDP audits.
This could take some weeks to analyze and figure out how to close the potential gaps. This is the time-demanding part. The EXCiPACT audit itself, at Merck KGaA headquarters in Darmstadt, Germany, took three days. During the audit, the quality system applied to excipients was validated for all the excipients manufactured and supplied from this site. An interesting aspect of EXCiPACT is that you can choose whether you want to be certified according to GMP and/or GDP. We opted for both.
CP: Why choose both GMP and GDP for the initial certification?
FH: GMP is the common standard, so there was a strong need for that. Yet I believe GDP standards will become the hot upcoming topic, a critical one in future. GMP for APIs and finished dosage forms has been a process that was implemented in the industry years ago. The process of settling the GMP for APIs took nearly 10 years; that’s how long it took to get them applied everywhere, legally binding, and an everyday practice.
Nothing’s legally binding currently for GDP for excipients, but I assume that this will become the next hot topic because of supply chain security issues. GDP will be the baseline for assuring the supply chain. It will increasingly become a focus for the authorities because of incidents that happened in the recent past. These were related both to manufacturing activities but also to issues during storage and transportation. So it just made sense to get certified for both GMP and GDP.
CP: Given the interest in supply chain issues, how closely does EXCiPACT interact with the Rx-360 consortium?
FH: I’m a member of the board of Rx-360, actually, so there’s definitely a linkage between the organizations. EXCiPACT as a standard for GMP and GDP is accepted by Rx-360. They’re complimentary in what they’re trying to achieve. Rx-360 references the EXCiPACT standard, and thus they don’t need to develop another one and duplicate efforts.
CP: What are some of the tangible results of the audit?
FH: There are quite a lot of benefits to EXCiPACT. Beyond the monetary savings, there are others that are just as important. First, you have independent certification of your quality system. That helps manage the increase in requests for audits. Audits are a challenge for the auditors and auditees, taking up time, money and resources. It can be a real bottleneck. There aren’t enough days in the year to accommodate all the customers who want to see the facilities.
Also, it’s an evolutionary standard, building on the well-established IPEC-PQG GMP guidelines and IPEC GDP guidelines for excipients. Participants — both manufacturers and users — will likely be aware of the principles that have been adapted in these standards.
The quality of the certification itself is also important. That is, the qualification process for the auditors is very demanding. The quality of the certification and how it affects the supply chain is dependent on the quality of the auditors. They’re familiar with GMP, GDP and well-trained in performing audits. Their certification is actually covered in the EXCiPACT standard. They must be certified.
CP: What’s the training process like?
FH: The EXCiPACT standard covers the formal requirements for the auditor, including a two-day training course for them. It’s quite a process to become a certifying body, that is, to be able to conduct and certify EXCiPACT audits for the organization. That includes a physical audit of the third-party auditor’s internal processes.
CP: “Who audits the auditors?”
FH: It sounds funny, but it does make sense. If someone performs an EXCiPACT on behalf of the organization, we need to be sure that this third-party auditing firm and each and every auditor they employ is working well and qualified.
CP: How tough was the EXCiPACT audit compared to the other ones you face from regulatory bodies and clients?
FH: It was tough, because the standard is very detailed and, as I mentioned, the auditors are very experienced. They know what to ask and where to look. It was a very demanding audit, comparable to the Rx-360 experience. They were a very interesting three days. We did a lot of work to prepare ourselves for it. The audit was of our product-range called EMPROVE exp and EMPROVE bio. Both of those brands are pharmaceutical excipients.
CP: What did you learn from that process?
FH: As a company, we learned from the gap analysis to carefully evaluate all steps and really think through every requirement of the standard. The EXCiPACT standard really makes sense. The whole procedure and preparation for the project took us along a learning curve that was very helpful for the entire quality organization.
I personally learned that this kind of certification is an excellent way to approach the challenges that we’re facing as an industry. The process is something that more organizations should follow. I’m very optimistic that this program will help stakeholders throughout the pharmaceutical supply chain.
CP: How has the response been among your customer base?
FH: We received the certificate at the end of June 2013, so it’s very early. But before we got certified we were already receiving requests from customers about our status. They wanted to see the audit report. We’ll promote it going forward.
We know that an EXCiPACT certificate will never cover all audit requests, but from my perspective, it’s a means to handle the quantity of requests, but there’ll always be customers who have very specific questions. EXCiPACT certification will cover all the basic requirements, but then a customer could say, “I intend to use your pharmaceutical excipient in a very sophisticated product with very high requirements. We have some specific concerns and questions about production and quality control.” But by having EXCiPACT certification, we can make that a one-day audit instead of a three-day process.
CP: You mentioned that this is an evolutionary model. Are you looking to push the GMP and GDP standards for excipients further?
FH: I think the EXCiPACT standard is fine for the time being. There may be some clarifications necessary in future, perhaps around the process of auditing, but that’s a technical question. Concerning GDP and GMP, I really think this is state of the art, and we’re in a great place. I don’t see a need to update the standard for a while.
CP: What sorts of companies are preparing for these audits? Mainly western?
FH: Yes, but we recently received our first requests from companies from Asia. This process, too, is evolutionary. EXCiPACT launched in Europe last year, and in the U.S. in April 2013, so it will be step-wise to roll out further. The sooner suppliers of excipients become aware of this scheme and understand the reasons for EXCiPACT, the better. That’s why the standard is freely downloadable from the organization’s site, as well as publications, presentations, opinions, and other materials. We want the site to be very transparent so that newcomers can understand the standard an what went into it.
It’s a global supply chain, with suppliers and users everywhere, so it only makes sense for this standard to be applied around the world.
CP: Do you think more regulatory guidance is necessary, or do you think voluntary schemes like EXCiPACT are going to be sufficient for ensuring standards?
FH: I don’t have a crystal bowl. I think EXCiPACT is an excellent standard. The more companies that voluntarily get certified, the less need there would be for formal regulations. Over the next few years, we’ll get the feedback of the stakeholders throughout the pharma supply chain.
I really do recommend that anyone interested in this topic visit excipact.org and have a look at the materials there. It’s a very open system; you don’t need to be a member to access that and to stay informed. Have a look at the standards and the first audit results, and I think you’ll be impressed.
Frithjof Holtz is a biologist and has been working for more than 23 years with Merck KGaA, having long years of experience in quality assurance and regulatory affairs. As head of Advocacy he is responsible for the advocacy activities of the pharmaceutical raw materials business of the Merck KGaA Division, Merck Millipore. Frithjof Holtz is an active member of several international industry associations and industry initiatives as APIC and EXCiPACT, and member of the board of IPEC Europe, EFCG, and Rx-360.