Excipients have never been more important in pharma production, especially having grown rapidly in prominence with the increasing complexity of drugs entering the pipeline and biologicals and new modalities such as mRNA.
In this interview, Dr Moore discusses the vital role EXCiPACT plays in promoting and certificating both GMP and GDP practices, as well as what more can be done to try and encourage the development of novel excipients.
CPhI Discover: Can you explain the history and purpose of EXCiPACT?
IM: EXCiPACT is a not-for-profit organisation set up in Brussels in 2012 and formed from members of the International Pharmaceutical Excipients Council in America, China and Europe, along with European Association of Chemical Distributors (FECC), the Pharmaceutical Quality Group in the UK) and, more recently, by the Jiangsu Pharmaceutical Packaging and Pharmaceutical Excipients Association (SPPEA).
As EXCiPACT is an association of associations, impartiality is assured. Its purpose is to help reduce the regulatory burden on pharmaceutical excipient manufacturers and distributors worldwide by introducing a third-party GMP/GDP auditing and certification system. Since 2012, EXCiPACT has issued more than 130 certificates to organisations around the world supplying excipients registered with EXCiPACT.
CPhI Discover: What does this audit process involve and how is it done?
IM: The process begins with an excipient supplier contracting with a registered EXCiPACT Certification Body (CB), who provides an auditor qualified and trained through the EXCiPACT certification scheme to do the EXCiPACT GMP or the GDP audit.
The conclusion of that audit, if successful, is a certificate; but, more importantly, an audit report providing the supplier with any corrective action plans. Full audit reports are made available by the excipient supplier directly to their customers to allows those customers producing pharmaceutical drug products to qualify the excipient suppliers more efficiently.
During COVID-19, this burden has increased dramatically because drug producers are unable to perform physical audits owing to travel restrictions, especially internationally. So how do they qualify their excipient suppliers? EXCiPACT certification is a very viable and beneficial alternative to audits performed by the drug product manufacturer.
CPhI Discover: How do you feel about remote monitoring, not just for excipients but pharma in general?
IM: Remote auditing certainly has a role to play now and in the future. The pandemic has accelerated this change … even though the direction was becoming clear. We asked ourselves, even though they’re not perfect and not as good as being on-site, “can we use remote audits?”
We can, but only after the CB has made a positive risk assessment of the supplier to determine if they have a good history, understand their operations and have previously audited them.
In EXCiPACT, the audit cycle follows the traditional ISO 3-year cycle, with an initial certification audit, followed by two annual surveillance audits and a recertification audit at the end of the third year. There must be a physical audit as part of the initial certification and the recertification. The surveillance audits in between for the time being can be done solely remotely.
CPhI Discover: What about a post-COVID world, a couple of years down the line? For example, the FDA is under pressure to audit everyone all over the world and they probably do not have enough staff to do that with facilities globally.
IM: The genesis of EXCiPACT was to lower the audit burden. Successful excipient suppliers might have 200, 300 or even 400 customers, so they all must visit the site and audit. Experience shows that manufacturing locations can only really accommodate one or two visits a month. More than that requires employing people just to host the audit.
EXCiPACT saw this issue prelaunch some 10 years ago and the situation during this pandemic has accelerated the value of third-party certification. The other factor that has been a great improvement is ascertaining GMP for excipient guidelines from the European Union.
These require a risk assessment for both the excipient and its use in the drug product formulation and an assessment of the excipient’s supplier capability as a means of determining the GMP required in the manufacture and supply of the excipient. The guidelines expressly allow the use of certificates held by the supplier to be part of the assessments.
CPhI Discover: It is an interesting time for excipients, with more complex formulations, vaccines and biologics. What is your perspective?
IM: The science going forward is moving away from simple small molecules for APIs to more complex biologics … and the interaction of those molecules with the excipients is much more demanding.
Therefore, to maintain safe and effective delivery of the drug product requires exceptional excipient quality and a deeper understanding of the manufacturing process.
In the future, we believe that the available excipients listed in the FDA inactive ingredients database (IID) will have to be refined and will demand superior or revised quality requirement for those excipients. This is happening already for those materials when used in specific situations.
CPhI Discover: There are business model challenges in terms of developing novel excipients; where do you stand on that? Can we change that? Will it change?
IM: This remains a very frustrating area that must change. There has been a complete logjam, particularly in Europe; so, if a manufacturer makes a novel excipient, they recognise the risks involved in investing the time and effort needed to design the material and its properties, and to recover that investment from the market.
But, from the drug product manufacturer perspective, there is an even bigger risk because it is a novel excipient. The regulator will treat a novel excipient in the same way as any API, so it gets the same level of scrutiny and they want the same level of detail in the submission. In the US, they have a drug master file system: one for excipients and one for APIs.
The good news of a drug master file from the excipient manufacturer’s perspective is that the intellectual property is only shared with the agency and not with the customer.
This then permits the excipient manufacturer to have more than one customer. However, in Europe, as things stand, the manufacturer would be giving away the entire dossier to the customer because there is no other way for the novel excipient to be assessed, other than as part of the full drug product application.
CPhI Discover: What would the solution to that be then? Will several major excipient manufacturers work together with big pharma with a 10-year view on this? Is it a regulatory issue where you go to the regulator and request a more expedited approval on some excipients or lower cost approval?
IM: This is where IPEC comes into play, as a trade association petitioning the industry. What’s really needed is a good dialogue with the legislators and the regulators to identify if there are ways in which the excipients industry can address some of the barriers that are preventing the development of novel excipients.
This will have to evolve to a situation in which there is a drug master file system, the basic manufacturing controls, GMP and the basic toxicological effects of the excipients can be evaluated by the regulators quickly … thereby protecting intellectual property without compromising the quality of the assessment.
CPhI Discover: Do you have reasonable hopes for a few new excipients or is it more of a case of a 10-year timeline?
IM: We hope not, but things have not tended to move fast in this industry. It is not really a problem if we put our minds to it.
It's a question of wanting to do it, getting to work together: industry, regulators and, in some cases, even the legislation may have to be adapted. But if we get together, we can do it. Look at what we have achieved with developing vaccines in the last 10 months, and ask why don’t we do it all the time?