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Safe Formula

The EXCiPACT initiative and its associated certification are making headway in assuring the safety of pharmaceutical excipients

There is a general expectation, both in the pharmaceutical industry and among government regulators, that excipients should be manufactured to appropriate Good Manufacturing Practice (GMP) principles and distributed in line with Good Distribution Practice (GDP) guidelines. The European Falsified Medicines Directive will introduce new requirements for the qualification of excipient manufacturers and suppliers by drug manufacturers, including placing responsibility upon the manufacturer of the medicinal product to assess the suitability of excipients for use in the drug product on the basis of appropriate GMP and GDP (1).

Such a development supports proposed changes to Chapter 5 of Part 1 of the EU GMP Guide, which indicates that audits are required for excipients that are considered to be high risk (2). In the US, the Drug Safety Enhancement Act includes the establishment of a register for excipient manufacturers, whereby there is an expectation that excipients be manufactured to GMP and that supply chain management is encompassed within the GMP requirements (the bill has not been enacted, but refl ects concern in the US about the safety of drug ingredients) (3). In other words, in the US, GDP is considered as part of GMP.

These legislative changes require a recognised GMP and GDP standard against which excipient suppliers and distributors may be audited. Furthermore, excipient manufacturers, distributors and users will see an increasing requirement to host or conduct site audits, which will add significant cost to their quality assurance budget.

Industry experts from the European Fine Chemicals Group (EFCG), the International Pharmaceuticals Excipients Council (IPEC) Europe, IPEC Americas, the European Association of Chemicals Distributors (FECC), and the Pharmaceutical Quality Group (PQG), worked to define suitable GMP and

GDP standards for excipients and an attendant certification scheme, EXCiPACT, which uses those standards. EXCiPACT is a voluntary, not-for-profit international organisation formed to provide an independent oversight of third-party certification of manufacturers, suppliers and distributors of pharmaceutical excipients as a means of ensuring patient safety, while minimising overall supply chain costs. The EXCiPACTTM GMP and GDP standards provide a minimum level of requirements against which excipient manufacturers and distributors may be audited. Born from the IPEC-PQG GMP and IPEC GDP Guides, requirements of the EXCiPACT standard are annexes to ISO standard 9001.

EXCiPACT certification against the GMP and GDP standards aims to reduce the audit burden and costs borne by excipient manufacturers, suppliers and users, by simplifying the audit process in a wholly transparent, robust and authenticated way. It uses only approved third-party auditors and EXCiPACT itself oversees the audit process and auditor standards. Organisations that are already ISO 9001 certified may extend that certification to the EXCiPACT GMP and/or GDP standards. Alternatively, suppliers who do not hold ISO 9001 certification

are able to obtain an equivalent certificate through the forthcoming US national standard, ANSI-NSF 363, which also uses the IPEC-PQG GMP Guide as a basis. Therefore, all manufacturers and suppliers have a choice as to which certifi cation route to follow. In either case, the requirements are the same.

EXCiPACT and EXCiPACT Certification

EXCiPACT was launched in early 2012, and was initially targeted at the European and North American markets, but there is now strong interest from countries outside of these regions who wish to use the scheme. EXCiPACT certification is recognised by the regulatory authorities in the US (FDA) and Europe (MHRA) as ‘ticking all the right boxes’ for a third-party audit scheme that can aid supplier qualification. In addition, EXCiPACT includes a requirement that non-conformities found in an audit that are deemed ‘life-threatening’, be immediately reported by the supplier to their customers. Should the supplier fail to demonstrate that this has been done, there is a provision in the agreements between all parties that EXCiPACT be notified and they, in turn, will notify the appropriate regulatory authorities.

EXCiPACT defines third-party auditor competency and training requirements, and publicises which organisations meet the EXCiPACT requirements, and hence are authorised to recommend EXCiPACT certification for GMP, GDP or both. In addition to this, certificates can only be awarded by EXCiPACTqualified auditors and organisations meeting required competencies. Certifying bodies, certified auditors and qualified organisations will be listed on the EXCiPACT website, www.excipact.org. EXCiPACT signs a legal agreement with third-party audit organisations who meet the requirements of the certification scheme rules, a key requirement of which is to hold ISO 17021 certification (or an equivalent), another being to ensure audits are conducted in accordance with the guidance described in ISO 19011 (guidelines for quality and/ or environmental management systems auditing). There are additional requirements for third-party audit organisation compliance over and above ISO 17021 and for auditing to ISO 19011.

EXCiPACT Certification Benefits and Process

EXCiPACT certification is specific to pharmaceutical excipients, internationally recognised by all stakeholders, and is applicable both to GMP and GDP. The focus is on the whole of the manufacturer’s or distributor’s quality management system at the facility named on the certificate, rather than on individual excipients. EXCiPACT certifi cation demonstrates an excipient manufacturer’s or distributor’s proactive commitment to GMP and GDP. Audit to the standard can be planned and scheduled by the manufacturer or distributor, and certifi cation and audit reports can be shared with the user at an early stage of the business relationship. Additionally, it is estimated that the manufacturer or distributor could save around 􀃀60,000 over three years in total auditing costs through time savings from not hosting audits. The excipient user could realise savings of 􀃀240,000 over the same period through the same mechanism (4). Overall, the costs of certifi cation will be borne by the excipient supplier or distributor.

To enter the certification process, the excipient manufacturer or distributor selects one of the EXCiPACT-approved, thirdparty certification bodies to perform the assessment against the EXCiPACT GMP and/or GDP standards, as appropriate. Certification is granted if the auditor recommendation to the third-party audit organisation is accepted by a review panel that makes the final decision. Thereafter, surveillance audits occur at least once a year, covering the full quality management system in two audits, and then a triennial full re-audit to the whole standard. This level of auditing is far greater than any manufacturing authorisation holder could sustain. There is an appeals process through which a supplier may discuss an audit and report with the third-party and EXCiPACT. The process would involve experts from EXCiPACT reviewing the audit process and report, and making a decision on the status of certification.

Following the award of an EXCiPACTTM certificate, the approved manufacturer or distributor name is added to the EXCiPACT website and they are free to pass on a copy of the certificate and the audit report to their customers. By sharing audit reports in this manner, excipient users are able to make a judgement to determine that the level of GMP or GDP applied by the supplier mitigates the risks to an acceptable level in their applications. Furthermore, by issuing the report to customers, any subsequent dialogue is direct and confidential between the parties, and the excipient user can utilise the certification as part of their supplier approval process. There is the provision for confidential information in the audit report to be redacted. Because EXCiPACT GMP and GDP represent what are considered to be minimum standards, it is expected that EXCiPACT certificates are sufficient for lower risk excipients, and therefore the manufacturing authorisation holder does not then need to perform their own individual audit. However, the scheme does not prevent all audits because there will always be higher risk excipients and suppliers who demand individual attention.

Excipient users are able to verify the authenticity of the audit reports with the third-party audit organisation that performed the assessment, and also with EXCiPACT. The overall supplier status can be verified on the EXCiPACT website, where it can also be confirmed that the third-party audit organisation and auditors are approved.

As a joint initiative of the excipient manufacturer, distributor industry and excipient user, EXCiPACT Certification addresses three of the most critical challenges for the pharmaceutical industry: quality of medicines, risks in the supply chain, and the cost of assuring all of this, particularly with regard to the burden of audits. EXCiPACT fills the gap between addressing the risks in the pharmaceutical supply chain and the lack of mandatory application of GMP for pharmaceutical excipients and helps to level the playing field. Its objective is to enhance patient safety and to set clear standards that will improve the quality of medicines with an appropriate level of effort.

The EXCiPACT Standard and Scheme

In its role as overseer, EXCiPACT will perform audits of the third-party assessment companies to ensure their continued compliance to the requirements. Renewal of the authorisation of these companies to issue certificates by EXCiPACT is required. In addition to this, audits by the certification body will be independently witnessed to ensure that all aspects of the audit process are consistently applied. Furthermore, and with the agreement of the auditee, the third-party audit company may provide the full audit reports to EXCiPACT so that they can also verify the quality.

Conclusion

The risk associated with excipient production and distribution has been underestimated in the past; the European Falsified Medicines Directive introduces new requirements for drug manufacturing authorisation holders to assess the suitability of excipients for use in the drug product on the basis of appropriate GMP. EXCiPACT is a common standard for the manufacturing and handling of excipients that has been developed between excipient manufacturers, distributors and users that, if properly implemented, will ensure that drug quality and patient safety will improve.

As industry organisations and regulatory authorities evolve toward more stringent regulations, the international EXCiPACT approach to pharmaceutical excipient GMP and GDP certification will help to ensure the quality and reliability of these key ingredients for medicinal products throughout a supply chain that can stretch around the world.

Acknowledgement

The author wishes to thank Iain Moore of Croda Europe Ltd, and Allan Whiston of QA Resolution Ltd, for their help compiling this article.

References

  1. Directive 2011/62/EU of the European Parliament and of the Council, 8 June 2011
  2. Directive 2001/83/EC of the European Parliament and of the Council, on the community code relating to medicinal products for human use, 6 November 2001
  3. HR 1483: Drug Safety Enhancement Act of 2011
  4. Holtz F and Sehat N, Drug Development and Delivery 12(4): pp30-34, 2012


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Ian McKeown is Technical Marketing Manager at PQ Silicas. Ian holds a PhD and BSc in Chemistry, as well as an MBA, and is a member of the PQG Partners team, and the International Pharmaceutical Excipients Council (IPEC). Ian has more than 20 years of experience in R&D and in his role as Technical Marketing Manager aims to ensure pharmaceutical excipients are aligned with current industry and regulatory requirements.
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Ian McKeown
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