Regulatory Gaps Regarding Sugars Used in Injectable Biopharmaceuticals - Are sugars used to stabilize lyophilized proteins appropriate for the end use? - BioPharm International

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Regulatory Gaps Regarding Sugars Used in Injectable Biopharmaceuticals
Are sugars used to stabilize lyophilized proteins appropriate for the end use?


BioPharm International
Volume 19, Issue 5

While the BPC guidance document states that there are situations in which these materials should be produced under the same GMP conditions as finished drugs, it also stresses that such controls are not necessary in most cases. Sugars seem to be regarded in the latter category due to their long-term safe usage in oral applications. Notably, this guidance was last published in May 1994, but that was due to "editorial changes;"5 the last content revision was in September 1991—more than 14 years ago.

Food and Drug Administration (FDA)

The FDA guide to inspection of BPCs is applicable to all BPCs produced in the United States or in foreign countries intended to be exported to the US or to be delivered to a US overseas base. A key part reads:

"Although the GMP regulations under 21 CFR, Parts 210 and 211, apply only to finished dosage for drugs, Section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act requires that all drugs be manufactured, processed, packed, and held in accordance with current good manufacturing practice (cGMP). No distinction is made between BPCs and finished pharmaceuticals, and failure of either to comply with cGMP constitutes a failure to comply with the requirements of the Act. There are many cases where GMPs for dosage for drugs and BPCs are parallel. For this reason, the requirements under Part 211 will be used as guidelines for inspection of BPC manufacturers, as interpreted in this document. Although strict observance of GMPs, approaching or equaling those expected for finished drug products, may be expected in some types of bulk processes, in most others it is neither feasible nor required to apply rigid controls during the early processing steps."5

United States Pharmacopoeia and National Formulary (USP—NF)

USP <1078> "Good Manufacturing Practices for Bulk Excipients — General Guidance" combines existing governmental regulatory GMP principles and international quality management system requirements as developed by the International Organization for Standardization (ISO), using as its framework ISO 9002, which is appropriate for manufacturing. The sections of USP <1078> provide an overview; as the chapter says, "no attempt has been made to include details specific to particular excipients."6 The chapter notes that many excipients have other applications than for pharmaceutical uses, thus their manufacture often reflects chemical industry standards rather than those of the pharmaceutical industry.6 It also states that the end use of the excipient should be identified and considered during facility inspections.

However, as the first guidance that specifically addressed the manufacture of bulk pharmaceutical excipients, the provisions of USP <1078> are more appropriate for oral product specifications. NF monographs typically include the name of the excipient, description, packaging and storage conditions, labeling, identification, microbial limits, acidity or alkalinity, loss on drying, specific surface area, limit tests, organic volatile impurities, and assay. The NF monograph for sucrose, which is commonly used to stabilize proteins, currently has no compendial testing requirement for microbial limits.7

USP standards are enforceable by the FDA for drugs manufactured or sold in the US. The US Pharmacopeial Convention, Inc., is an independent standards organization; the USP—NF that it publishes contains legally recognized standards for more than 3,500 drugs and 250 excipients, vitamins, minerals and botanicals, and is the only official pharmaceutical compendium in the world that is not published by a government agency. It is sold in 131 countries and "acts as a reference point to many regulators in countries that lack an official Pharmacopoeia, which it will continue to do as pharmaceutical manufacturing becomes increasingly globalised."8


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