Excipient Certification: More Clarity Needed?

Published on: 

PTSM: Pharmaceutical Technology Sourcing and Management

The EU has set March, 2016 as a deadline for ensuring excipient supplier GMP compliance, but some manufacturers may still need clarification on how best to do that.

The Falsified Medicines Directive and FDA Safety and Innovation Act have required that pharmaceutical manufacturers verify that their suppliers are manufacturing excipients to cGMP standards.  Regulators in the U.S. and Europe have supported the idea of third-party auditing, and a number of different programs are now available, from ExciPact, Rx360, NSF International, and USP, to help ensure supplier compliance.

However, regulator’s expectations may still be unclear, and some companies appear to be waiting for more clarification before taking action.  IPEC consultant Irwin Silverstein recalls efforts that led to the development of NSF International’s standard for excipient cGMPs, the only national standard so far in this area.  He also outlines some of the issues and challenges facing the industry in this brief interview.

PharmTech: Please tell us about the standard?  How did it all come together, why was it needed and what was the basis for it?

Silverstein: The FDA had asked IPEA (now part of NSF International) to become ANSI-accredited for excipient GMP certification.  At the time, the only thing we had available to certify against was the IPEC Excipient GMP guide.  Ordinarily you certify against a standard. So that was our first inkling that a standard should be developed.

FDA was also interested in developing an ISO standard for excipient cGMPs, so that there would be a common set of requirements, globally. The best path to a global standard would be a national standard. That was the second impetus for developing the standard.

PharmTech: Who was involved in this work and how did it all come about?

Silverstein: IPEC Americas was first approached.  The first thing we did as a trade association, was to explore what would be involved in becoming a standards-writing body for ANSI.  After looking at the requirements and the costs, we decided that we’d prefer to partner with another organization to write the standard. We decided to work with NSF International, because they have written standards around other quality management system requirements for other materials that are sold to consumers.

NSF solicited requests for participation on a standards-writing committee. A number of us at IPEC applied, along with representatives from some excipient manufacturers and pharma company users. In addition, a group of independent experts applied, including regulators, academics and consultants. This committee started to write the standard based on the IPEC PQG guide.

PharmTech: Is there any other national standard for excipients? 

Silverstein: So far, this is the only national standard.  But, in other parts of the world there are cGMP regulations for excipients, which might be considered equivalent to Part 211 in the U.S.  For example, a GMP regulation for excipients is now in effect in China and another in Brazil

PharmTech: How are companies reacting to the idea of the standard, and to recent supply chain regulations in the U.S. and Europe?

Silverstein: We’re not seeing a rush to certification.  People are still waiting for regulatory authorities to make it clear, through observations from audits, what they expect, whether certification or a site visit. 

The EU’s Falsified Medicines Directive seemed to make clear the fact that European regulators expect a site visit.  Now, that directive is expected to be implemented in March 2016, which leaves less than one year for every supplier of excipients for the drugs that are made or used in Europe, to have a risk assessment done by their customers, all of their customers. Based on my reading of the directive, either each site must be certified to excipient GMP standards, or its customers must get reliable information, which would presuppose a site visit.  I don’t see any great rush to get on the audit list.

PharmTech:  This is sounding a lot like the situation in the U.S. with pharma serialization.  Why are certification and accreditation so important?

Silverstein:  We at IPEA decided that we would be accredited by ANSI. 

Anyone can issue a certificate. There’s nothing out there that says my own company, or I, can’t audit a facility, find good results and then put together a certificate, print it out in Microsoft Publisher and send it to the owner of that facility.  But what does it mean?  What’s behind it?

Europe’s False Medicines Directive discusses certification without setting any minimum expectations or requirements.

As to accreditation, two ISO standards get to the issue of accreditation for the purposes of certification: 17021 and 17065. When you look to using an ISO standard, you usually go to a national body, who will then accredit you to compliance with the requirements of that ISO standard. 

We were audited by ANSI every year. They did both a surveillance audit, where they accompanied us on a physical audit, and a document review, where they came to our offices and looked at our records, procedures, training and audit reports, to see that they met the requirements for what was then called Guide 65, and is now ISO 17065.

This way, an independent, recognized authority ensures that the program under which the certificate is issued meets the requirements of an international standard. To me, that’s what FDA and other regulatory agencies should expect.

Excipact is playing the role of an international standard-setting body. They are accrediting the certifying bodies that go out to do audits against the Excipact scheme. They train auditors, and only trained auditors can do the audits.  They are playing the role of ANSI, even though they are not a national organization.  However, they do have deep understanding and knowledge of what is needed with excipients.

PharmTech:  How important is ISO 9001 certification?

Silverstein: Our colleagues in Europe are very ISO 9001-centric, and put a lot of validity into being certified to ISO 9001.


Excipact certifies companies that are already compliant with 9001 or gets them to certify to both Excipact and 9001.  The latter requires a registered lead auditor for ISO 9001. In the US, so far, the pharma industry hasn’t put as much credence on compliance with ISO 9001. 

9001 is a good foundation, because documentation and records requirements are very much the same as they are for excipient GMPs. 

PharmTech: Based on what you’re seeing, does the industry need regulatory mandates for certification? 

Silverstein: There are companies that do audits, but they are in the minority. Because there just isn’t enough to host everyone as a customer. The only way to properly assess the supplier of excipients, if you can’t do an audit, is to rely on the certification and the audit report that is the basis for certification.

The EU has said that only approved countries will be allowed to import APIs into Europe.  That would require an audit and certification of each supplier. Nobody really took that seriously until the EU shut the door, and said, ‘If you’re not on the list…you can’t bring excipients into Europe.’ 

Everyone scrambled to get on the list. But now, what will happen in March, when European regulators see that many drugs are being sold in Europe, when the supplier companies have not been assessed by the manufacturing company.  There will be a rush to certification. It’s not going to happen overnight.

PharmTech:  Is FDA doing anything specifically in excipients?

Silverstein: We watch closely what FDA is doing.  They’re currently putting together requirements for food audit and certification.  We’re expecting that the drug side of the Agency will be looking at what the food side is developing, and may implement a similar type of audit for excipients in the future.  At this point, though, it is not that high on the priority list.

PharmTech: Pharma is still a relatively small portion of most excipient suppliers’ businesses.  What incentive do they have to seek certification. Is more education needed in the types of quality testing that pharma requires?

Silverstein: IPEC has been trying to provide that education, and we’ve ramped up webinars and training on various aspects of the issue, but the companies supplying excipients range widely.  Some have very incidental pharma businesses, while others have significant interests in the pharma market. 

In the end, it is a balancing act. If you push too hard on the regulations, you’ll reduce competition and eliminate the availability of certain excipients for pharma.

That’s why I think it would be inappropriate to establish a deadline by which everyone should meet standards.  We don’t want to drive anyone out of business if they’re actually making good materials that are safe for patients’ use.

PharmTech: Where do you see the greatest vulnerability in terms of excipient quality? How would a standard and certification program help address this weakness?

Silverstein : Risk to patients comes, mainly, from cross-contamination and contamination of product. We have to be vigilant about extraneous materials getting into the excipient, and also, any cross-contamination from nearby operations. Some excipients are made at chemical plants, where industrial chemicals such as pesticides may also be made. Nobody wants to see contamination from anything with potential pharmacological effects.

The rest is a documentation issue, and proving that products have been manufactured the way they are supposed to be, with all procedural and process controls in place to avoid the risk of contamination and cross contamination.

PharmTech: Europe has passed regulations on traceability of excipients. Do you see anything analogous to that being proposed here in the US?

Silverstein: The problem with excipients is that they are sold in less than truckload volumes.  Common carriers are provided with a bill of lading and told where to deliver each shipment.  Unless they’re delivering a full truckload, which can be sealed, there is limited control.

A manufacturer may put several pallets on a truck, but then that material is often sent to a warehouse where it is cross stocked, and then put on a different truck.  It is hard to ensure a standard level of cleanliness.

It is difficult to see how the industry can move past this.  APIs can be put on smaller trucks, where products can be sealed and temperature controlled.  If we require that for excipients, costs will be driven up significantly.

Given the realities, we have to rely on the integrity of packaging.  Tamper- evident seals should be used for excipient transport.  Today, more companies are moving toward unique tamper-evident seals with their company name and logo.  

Regulating the supply chain for excipients will be much more difficult than for it is for finished pharmaceuticals, because you can afford to do so much more to protect drugs. On the flip side, however, it’s much more attractive to counterfeit pharmaceuticals than it is excipients.