Regulatory Gaps Regarding Sugars Used in Injectable Biopharmaceuticals

Are sugars used to stabilize lyophilized proteins appropriate for the end use?
May 01, 2006
Volume 19, Issue 5

In the rapidly evolving biopharmaceuticals industry, technical developments frequently outpace regulatory developments. One such area is in current good manufacturing practice (cGMP) guidelines for the manufacture of excipient sugars used to stabilize lyophilized proteins for injectable biopharmaceutical drugs. The industry needs clarification of the cGMP expectations for selecting and qualifying these injectable drug ingredients

In a 2004 letter to the FDA, the Biotechnology Industry Organization (BIO) stated that:

"the manufacture of all protein products generally involves numerous highly variable and specialized steps, which must be tightly controlled to ensure the consistent production of pure, potent, and high-quality products. The manufacturing process is particularly critical to the overall safety and effectiveness of protein products. Seemingly trivial changes to the purification process have the potential to alter the purity profile of the product and cause changes to its safety and effectiveness. The ability to identify impurities during the manufacturing process enables manufacturers to design a purification process that will isolate and remove the contaminants."1

Regarding formulation and filling of the purified product, BIO notes that, "a change in any of the equipment, the product contact materials, or methods used in these final steps (including freeze-drying) may affect product integrity."1 .

From the initial cell lines to fill and finish, high-value, sensitive proteins have been handled in cleanroom conditions with validated and documented processes that meet cGMP criteria for active pharmaceutical ingredients (APIs) or injectable ingredients. The sugars used to stabilize these proteins for lyophilization, however, often have not been subjected to similar standards of scrutiny, purity, and documentation.

Since the initial research findings that adding excipients to solutions helped protect protein structures during the folding and unfolding involved in freeze-drying and reconstitution, sugars that are qualified as excipients for oral drugs typically have been utilized. In the early days of the biopharm industry, these sugars were widely available as pharmaceutical ingredients. They are often produced under food-processing GMP conditions, with limited testing of samples for the presence of impurities, and labeled as meeting compendial specifications for orally administered drugs.

Figure 1. Degree of regulatory control by product category, ranked in descending order.
Most therapeutic protein drugs must be administered by injection, which requires a much higher purity level than is required for drugs taken orally (Figure 1). Food-grade sugars used as taste-improving pill coatings are a minor ingredient, and their impurities are filtered by digestion. When stabilizing lyophilized proteins, however, sugars are regularly used in ratios of up to 100:1 by weight, and are injected—sometimes directly into the bloodstream. Adverse patient reactions have been associated with sugar polymers in injectable drugs,2,3 and protein stability and efficacy can also be compromised by microbial contaminants and trace metal ions.


According to Rafidison and Ulman:

"Currently, control of excipient manufacturing and distribution is not a key priority for regulatory authorities or pharmaceutical manufacturers, perhaps due to the fact that most of these excipients originated in the food industry and have generally recognized as safe (GRAS) status. However, with the emergence of novel excipients and delivery systems, better control of these materials becomes increasingly important."4

Typically, regulatory agencies are not directly involved in monitoring excipient manufacturers. Or, as indicated in the FDA guidance to investigators of Bulk Pharmaceutical Chemicals (BPC), "inspections of manufacturers of inactive ingredients will only be conducted by special assignment or for cause."5

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