Issue link: https://www.e-digitaleditions.com/i/541292
Tablets & Capsules July 2015 15 Historically, regulatory agencies and pharmaceutical manufacturers have focused almost exclusively on APIs and finished drug products. But as the number of incidents of counterfeiting and contamination of APIs and excipients has grown, their attention has turned to excipients. Realizing that excipients can comprise 90 percent or more of a drug product, especially in oral dosage forms, they understand that lapses in excipient quality or safety issues can have catastrophic consequences. For example, in 1996 almost 100 children in Haiti were poisoned by a cough syrup preparation that contained glycerin contaminated with diethylene glycol (DEG). In 2006, more 100 people were confirmed dead in Panama from ingesting cough syrup that contained DEG misrepresented as 99.5 percent glycerin. While Glycerin USP is a common and safe excipi- ent, DEG is a toxic component of antifreeze. When ingested, it causes renal failure and often death, especially in children, as was the case in these two inci- dents. Both contributed to the increased global regulatory scrutiny of excipient manufac- ture and distribution. Consequences of regulations on excipients Several sections of FDASIA could have an impact on excipients. For instance, under Title III, "Fees relating to generic drugs" (also known as the Generic Drug User Fee Amendments, GDUFA), the FDA is allowed to 1) charge fees when a generic drug application is submitted, 2) inspect sites where an active pharmaceutical ingredient (API) is manufactured, and 3) impose new requirements on Type II Drug Master Files. The provision about inspecting API facilities can apply to manufacturers of excipients because some over-the- counter (OTC) drug products use an excipient to provide the therapeutic effect; that excipient is therefore labeled as the API. In these OTC products (e.g., glycerin in supposi- tories or isopropyl alcohol in rubbing alcohol), the excipi- ents have been referred to as atypical APIs. Although they have been safely used this way for decades without explicit regulatory guidelines, the passage of FDASIA changed the regulatory environment. Now, even though the process used to manufacture these ingredients and the GMP expectations have not changed, if these substances are listed as an API in an Abbreviated New Drug Application (ANDA), they would be subject to the registration and completeness assessment fees outlined in GDUFA. In fact, FDASIA's Title VII, "Drug supply chain," Section 510 (21 USC 360), was amended to include reg- istration of establishments that produce excipients and to add them to the FDA's risk-based inspection schedule. Finally, FDASIA redefined drug-product GMPs to include the safety of raw materials, thereby requiring pharmaceu- tical manufacturers to implement quality oversight of their excipient suppliers. While the FD&C Act has always required components of drugs to be manufactured under GMPs, historically, the only GMP specifically designed for use by excipient manufacturers was The Joint IPEC-PQG Good Manufacturing Practices Guide for Pharmaceutical Excipients, first published by members of the International Pharmaceutical Excipients Council (IPEC). In December 2014, the NSF/IPEC/ANSI 363 standard was adopted. The Standard was developed with participation from pharmaceutical excipient manu- facturers and distributors, drug-product manu facturers, and public health regulators. NSF/IPEC/ ANSI 363 is based on the IPEC-PQG GMP guide but has provisions not included there, such as the requirement to conduct risk assessments. It provides a sound basis for drug-prod- uct manufacturers to establish that the excipients they use were produced under appro- priate GMPs, as defined by FDASIA and the EU's FMD guidelines. Furthermore, under the National Technology Transfer and A dvancement A ct of 1995, federal agencies are permitted to adopt private-sector standards, particularly those from standards-developing organizations, wher- ever possible, in lieu of creating proprietary, non-con- sensus standards [3]. Since NSF/IPEC/ANSI 363 is a consensus standard that was developed under the aus- pices of NSF International, a standards-writing organiza- tion accredited by ANSI, and since the FDA was a mem- ber of the NSF/IPEC/ANSI 363 working group (as required by Office of Management and Budget Circular A-119), we and most others in the industry expect the FDA to use the Standard to determine the requirements of quality management systems used in the manufacture of excipients. The EU FMD Guideline requires that drug-product manufacturers complete a risk assessment of excipients used in their formulation and to define the appropriate level of GMPs to apply to each excipient based on the requirements found in EudraLex Volume 4 [4]. Further - more, the EU FMD makes it the responsibility of the "Qualified Person" at the "Manufacturing Authori sation Holder" (MAH) to assess the excipient risk in the drug product formulation. Based on the risk assigned, the MAH is to communicate the risk level to the excipient manufacturer so that appropriate measures can be taken by the excipient manufacturer to address the risk. For example, if an MAH notifies the excipient manufacturer that its excipient is used in a parenteral application and thus poses a high risk in the MAH formulation, the excipient manufacturer might be expected to use water of a quality that exceeds that of potable water to ensure the level of pyrogenic impurities in the excipient is low. Members of IPEC-Americas believe that NSF/IPEC/ ANSI 363 provides suitable GMPs for most excipients used in the majority of drug products. Most people expect the FDA to use NSF/IPEC/ANSI 363 to determine the requirements of quality management systems used in the manufacture of excipients.