The way forward
Ongoing dialogue is crucial. In June 2011, Merck Millipore hosted its second Pharma-Forum in Darmstadt, Germany, which included
discussions regarding new legal requirements for pharmaceutical excipients. Representatives from the pharmaceutical industry
discussed ways to secure the supply chain, and updated attendees on the activities of Rx–360 and the development of inspection
programs. A key message that came from the event was that the pharmaceutical industry will lose credibility if new cases of
contamination or adulteration occur. In parallel, the sentiment of participants was that regulators may be at risk of losing
control of the increasingly global and complex supply chain. It was agreed that an important solution to prevent harmful incidents
lies with improving risk-management approaches to manufacturing and supply.
The event also included discussion of the EU Directive 2001/83/EC (15) in which the EU Commission gave a mandate to the European
Directorate for the Quality of Medicines and HealthCare to establish a risk-based annual program for inspections. According
to the directive, inspections are to be performed both inside and outside of Europe and will involve manufacturing sites and
brokers/distributers holding certificates of suitability to European Pharmacopeia monographs. It is hoped that the inspections will help detect noncompliance and will result in necessary actions that may
include withdrawal of the certificate. Overall, it was agreed that finished-product manufacturers must improve their ability
to select GMP-compliant pharmaceutical ingredients suppliers and to audit/monitor them accordingly.
In the past, the risks associated with excipients were underestimated. However, the quality of excipients should match the
quality expected for APIs. Excipients are the hidden champions in pharmaceutical drug formulation; no API would work consistently
without the optimal excipient. Today, industry organizations and regulatory authorities are evolving toward more stringent
regulations. Once common standards are agreed upon, these should provide a basis for improving drug quality and patient safety.
In the absence of stringent regulatory practices and in light of the growing complexity and global length of supply chains,
selecting the right excipient is vital.
Frithjof Holtz is head of regulatory experts/customer audits and Najib Sehat is director of regulatory and technical services, both at Merck KGaA, Frankfurter Str. 250, D 64293 Darmstadt, Germany, email@example.com
1. S. Wolfgang, presentation at ExcipientFest Americas (Baltimore, MD, 2011).
2. FDA, "Advisory to Drug and Dietary Supplement Manufacturers, Compounding Pharmacies and Distributors of Excipients and
Dietary Ingredients — FDA Detects High Levels of Peroxide in Crospovidone" Drug Safety Alert (Rockville, MD, Oct. 21, 2010).
3. H.R. 1483, 112th Congress, 1st Session (Washington, DC), amended April 12 2011.
4. EC Directive 2011/62/EU, Amending Directive 2001/83/EC on the Community Code Relating to Medicinal Products for Human Use,
as Regards the Prevention of the Entry into the Legal Supply Chain of Falsified Medicinal Products (Brussels, June 2011).
5. USP 32–NF 27 <1078> "Good Manufacturing Practices for Bulk Pharmaceutical Excipients."
6. W. Bogdanich and J. Hooker, New York Times, May 6, 2007.
7. IPEC, The IPEC Good Distribution Practices Guide for Pharmaceutical Excipients (2006).
8. IPEC Position Paper, Excipient Pedigree (2008).
9. EFCG, IPEC, European Association of Chemical Distributors and the Pharmaceutical Quality Group, "Certification Standards
for Pharmaceutical Excipients: Good Manufacturing Practices, Good Distribution Practices" (March 2011).
10. Rx–360, "Rx–360 Update,"
http://www.rx-360.org/, accessed Aug. 4, 2011.
11. IPEC–PQG, Joint IPEC–PQG Good Manufacturing Practices Audit Guideline for Pharmaceutical Excipients (2008).
12. ICH, Q7 Harmonized Tripartite Guideline: Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients (2000).
13. Rx-360, Audit Guide for Basic Chemicals and Raw Materials (2010).
14. ICH, M4 Common Technical Document (1999).
15. EU Directive 2001/83/EC, Community Cod Relating to Medicinal Products for Human Use (Brussels, November 2001).