Drug and device companies I work with are often resource- and time-constrained and, while we audit drug substance and drug product contract manufacturing organizations, we may give less attention to other materials such as excipients and chromatography resins, especially during early clinical development. However there are safety risks with some commodity excipients and materials, such as glycerin and gelatin capsules, to name some recent adulterated materials in the headlines and we don’t know what material may be adulterated next! It makes sense to use shared resources that are available from independent organizations to help qualify material suppliers and to monitor supply chain issues.

Most adulterated products come from supply chains unknown to the drug or device manufacturer. The European Directive 2011/62/EU (prevention of falsified medicinal products) requires drug manufacturers to verify compliance by manufacturers and distributors of active substances with GMP and GDP by means of onsite audits. The FDA has indicated that we should know the full supply chain for materials at risk and they are now reviewing supplier qualification more carefully during inspections.

Supplier qualification of any one material is multifaceted and difficult for a number of reasons:

• Qualification of a supplier is specific to a single manufacturing location and for specific materials and manufacturing operations performed at that location.
• The actual site of manufacture of a chemical or component may be different from the site where it is packaged in small quantities for the customer
• Often a number of distributors and brokers are involved with the supply of a chemical or component
• Some suppliers to the pharmaceutical industry get their materials from brokers who may change material sources at any time to reduce costs. The FDA does not require brokers of excipients to register, and very few of them have ever been inspected. How can the supply chain be verified?
• It is usually not clear on the certificate of analysis where testing was performed.

It requires considerable quality expertise and resources to establish an effective supplier qualification program, to perform supplier audits and to discover and verify the full supply chain for materials.

How can we do our best to avoid adulterated and low quality materials? Risk assessment is useful to prioritize and decide which materials suppliers require more attention. We know we need to purchase materials from suppliers that deal with high-quality manufacturers, distributors and brokers who know and monitor the entire supply chain, to avoid risk of adulteration, but that is easier said than done. How do we find out the supply chain and whether our supplier really monitors the supply chain, other than by audit after extensive confidentiality negotiations?

It makes sense to share this effort with other companies using the same materials by using whatever shared independent industry resources are available, to ensure we are using well qualified suppliers for our materials.

Audit Sharing
Audit sharing is a resource that I have used and recommend. Third party audits are accepted by the EMA and FDA as long as they are relevant. “Relevant” means the audit and report must relate to a particular supplier facility and to materials made at that facility that are used by the drug or device manufacturer and the report needs to be recent. The IPEA audit report I bought on behalf of a client two years ago covered the essential topics, was well written and told the unvarnished truth, in that it noted that the manufacturer of the relevant excipients did not audit its suppliers. (Not good news.) I expect that other organizations that offer shared audits, such as Rx-360 and others, will also offer reliable audit reports.

The International Pharmaceutical Excipients Council (IPEC) has offered a number of shared audit reports over the past few years. IPEC-Americas has more than 70 members, mostly excipient and raw materials producers and finished drug product manufacturers. IPEA (International Pharmaceutical Excipients Auditing, Inc., a subsidiary of IPEC-Americas) has launched a program to provide IPEA Certification of Conformance with Excipient GMPs and six excipient GMP Conformance Certification Audit Reports are available for $750 each. Seven other recent Audit reports are available for $1,500 each. Some of these reports cover multiple excipients made at a particular facility. The IPEA audits evaluate compliance with the NSF 363/ ANSI American National Standard for Excipient GMP.

Rx-360 is an organization focused on pharmaceutical supply chain security that currently offers shared audit reports (19 at last count), each covering a particular supplier facility and named materials: raw materials, excipients, chromatography resins, APIs. They charge non-members $5,000 for a report and members pay $2,500. They report having a backlog of 378 audit requests, which should result in a large number of useful audit reports. Rx-360 was founded in 2009 by volunteers from the pharmaceutical and biotech industry and their suppliers, with members including 25 drug product manufacturers, 31 suppliers and various associations and auditors. Their web site (www.rx-360.org) is a useful resource for current supply chain issues.

EXCiPACT plans to offer independent third party certification and supply chain assessment of manufacturers, suppliers and distributors of pharmaceutical excipients worldwide. EXCiPACT was founded in 2012 by volunteers from IPEC-Europe, IPEC-Americas, European Fine Chemicals Group (EFCG) and others to provide independent third party certification of manufacturers, suppliers and distributors of pharmaceutical excipients. Certification will be to an ISO 9001 GMP Annex, similar to IPEA excipient GMP certification. IPEC-Europe has around 76 members, mostly excipient and drug manufacturers.

APIC is a European group that offers third party API audit reports. The name refers to the Active Pharmaceutical Ingredients Committee, Sector Group within CEFIC/European Chemical Industry Council. APIC has performed three third party GMP Audits in Germany recently and is likely to do many more in the near future, considering the European Directive to prevent falsified medicines requires onsite audits of API manufacturers and distributors. A copy of an audit report is available for €1,500 (+VAT), provided that one purchases an item covered by audit from the supplier and sign a secrecy agreement with the supplier.

USP has a Verified Pharmaceutical Ingredients program and so far about 27 ingredients and excipients made by companies in the U.S., India and Turkey, have been verified.

The planned publicly accessible EU database required by the Directive showing the compliance status and certificates of GMP and GDP issued for entities inspected by Member States will also be a very useful resource to those buying APIs.

The organizations providing shared audits have various cost sharing models. For IPEC/IPEA certification, the supplier pays $22,000 initially, then $11,000 per annum thereafter. Purchase of certification audit reports reduces the annual charge to the supplier. IPEC-America’s full members are manufacturers in the U.S., Canada, and Latin America of pharmaceutical excipients or finished drug dosage forms, and pay $8,400 – 28,000 annual dues (based on their previous year’s sales). Rx-360 membership fees are $30,000 per year for large drug manufacturers, $12,000 per year for small or contract finished product manufacturers and $6,000 per year for suppliers.

I expect that supplier companies that participate in these various shared audit and certification or verification programs will gain prestige and market share as well as gain the benefit of fewer client audits, which would save them a lot of effort and expense. As one who helps companies select and qualify suppliers, I am certainly more inclined to consider qualifying a material supplier named in an audit report performed by a reputable independent organization!

It is well worth your time to find out if there are shared audits available for materials and suppliers used for your drug substance and drug product manufacturing and to review any databases that may be available on supplier compliance status and certification. These options will save you time and effort that you can spend on your other materials suppliers that are not evaluated by an independent organization.

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Helena Champion, MS, MBA, is Principal Consultant at Drug Quality Assurance, LLC. She can be reached at drugqualityassurance@gmail.com.

Notes from Pharma Forum Safety and purity for pharmaceutical raw materials is paramount Dr. Matthias Bucerius • Merck Millipore At Merck Millipore’s Pharma Forum 2012, experts from the pharma and supplier industries discussed quality assurance strategies. Rising demands on the quality of pharmaceutical raw materials and active ingredients, risk minimization, compliance, and quality were among the topics addressed at the Pharma Forum. The event provided an opportunity for the exchange of ideas on various aspects of safe raw material production. Iain Moore from the International Pharmaceutical Excipients Council (IPEC Europe) outlined the new internationally accepted certification scheme for pharmaceutical excipients, known as EXCiPACT. EXCiPACT was created in 2012 by 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). EXCiPACT is a voluntary, international certification scheme to provide for independent, third-party certification of manufacturers, suppliers and distributors of pharmaceutical excipients as a means of ensuring patient safety while minimizing overall supply chain costs. These parties are in agreement that an international pharma excipient current good manufacturing practice (cGMP) and current good distribution practice (cGDP) certification scheme is one of the tools which can help to ensure the quality and reliability of these key ingredients for medicinal products throughout the supply chain. EXCiPACT initially targeted the European and North American markets, with other interested countries following as soon as possible afterwards. Christian Wolf from Merck Millipore discussed the importance of studies on extractables and leachables. Extractables are compounds that can be extracted from packaging and process materials such as sachets, filters, and tubes when in the presence of appropriate solvents. Leachables, on the other hand, are compounds that leach from these materials into the pharma product. This includes reaction products from pharmaceuticals reacting with packaging components. In the last several years, this topic has been gaining importance for both the market registration of products as well as for product and packaging development. The EMA and the FDA have published guidelines that describe the goals of and procedures for extractables and leachables studies. Mr. Wolf demonstrated what a promising study could look like. Frithjof Holtz (also of Merck Millipore) discussed the regulatory requirements for pharmaceutical raw materials. Globalization of the pharma industry has led to increasingly complex supply chains, resulting in an increased risk associated with excipients. Additionally, the quest for more cost-effective means of supply has further increased supply chain complexity, which can reduce both the knowledge and understanding of exposure to risk. Substandard raw materials and counterfeit excipients have resulted in tragic consequences, Mr. Holtz noted. The Quality Risk Assessment (QRA) required by the 2011 EU Directive on Falsified Medicines enables the excipient user to define the appropriate GMP based on intended use. Existing guidelines like ICH Q9 do not mandate one specific QRA tool. Industry is currently working on a proposal for the guidelines framed around implementation of the falsified medicine directive.   Matthias Bucerius is head of Global Marketing Pharma Raw Materials at Merck Millipore. He can be reached at matthias.bucerius@merckgroup.com.