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.
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.
Figure 1. Degree of regulatory control by product category, ranked in descending order.
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