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


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

International Conference on Harmonisation (ICH)

The ICH Q6B guidance "Specifications: Test Procedures and Acceptance Criteria for Bio-technological or Biological Products" states that "the quality of the materials used in the production of the drug substance (or drug product) should meet standards appropriate for their intended use."9 Further, "the quality of the excipients used in the drug product formulation (and in some cases, in the drug substance). . . should meet pharmacopoeial standards, where available and appropriate. Otherwise, suitable acceptance criteria should be established for the nonpharmacopoeial excipients."9 Standards that would appear to be appropriate for injectable drugs would be those enumerated in ICH-Q7A, which covers APIs.10

The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) brings together the regulatory authorities of Europe, Japan, and the United States and experts from the pharmaceutical industry in the three regions. They make recommendations to harmonize the interpretation and application of technical guidelines and requirements for product registration. The FDA is adopting ICH guidances, but publications note that they "represent the FDA's current thinking ... and do not operate to bind the FDA or the public."10

European Pharmacopoeia (EP)

Table 1a. Current good manufacturing practices for foods (including dietary supplements)
The EP's general monograph, "Substances for Pharmaceutical Use" (2034) governs active substances and excipients for the production of medicinal products for human or veterinary use. It states, "Unless otherwise indicated or restricted in the individual monographs, a substance for pharmaceutical use. . .is of appropriate quality for manufacture of all dosage forms in which it can be used."11 The provisions of EP general chapter 5.10, "Control of impurities in substances for pharmaceutical use," however, exclude excipients from quantitative threshold levels of organic impurities, and say only that, "the general concepts of reporting, identification (wherever possible) and qualification of impurities are equally valid."11 The EP also is adopting ICH Guidances.


Table 1b. Manufacturing requirements for excipients, according to USP <1078>6
As tables 1a, 1b and 1c clearly illustrate, the gap in cGMP requirements between food and API quality levels is vast. Even sugars that are truly processed in accordance with USP (1078) lack the degree of in-process controls for many of the criteria they have in common with APIs. More importantly, they are produced without key API GMPs, such as cleaning validation and annual quality reviews and reports. While drug makers may be able to perform raw materials tests on USP—NF sugars to check for particular impurities, they do not have the assurance of consistent impurity profiles provided by the manufacturers of these sugars, or the documented traceability that would come with these profiles.

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