FDA issued a white paper in April 2007 describing the agency's experience in evaluating and approving second-generation products
and manufacturing changes for biologics. The white paper provided evidence of FDA's technical and legal ability to assess
such products. The differences between producing protein products and small-molecule drugs, the paper explained, has produced
a range of testing and regulatory approaches. FDA says the crucial issue in determining the extent of safety and efficacy
studies the agency requests to support approval of follow-on protein products is how much structural similarity exists between
the new drug and the original product. The agency weighs the robustness of the manufacturing process; the degree to which
structural similarity can be assessed; the extent to which the mechanism of action is understood; the existence of valid,
mechanistically related pharmacodynamic (PD) assays; comparative pharmacokinetics (PK); comparative immunogenicity; the amount
of clinical data available; and the range of experience with the original product.
Conventional drugs can be verified analytically, making it fairly easy for generic makers to produce duplicate drugs with
the same active ingredient, strength, dosage form, and route of administration as the innovator drug, the agency explains.
Under the Hatch–Waxman Act, generic drugs can be approved generally if they contain the same active ingredient, document bioequivalence,
and demonstrate adherence to good manufacturing practices. Even though small-molecule drugs can be produced by multiple pathways,
they usually can be characterized sufficiently to demonstrate homogeneity and purity.
Because protein products are typically much larger, more complex, and often heterogeneous mixtures, many cannot be fully characterized
using available analytical techniques, FDA states, and even well-characterized and highly purified proteins exhibit slight
differences in structure. Recombinant products can vary slightly from lot to lot even from the same manufacturer, and product
quality can vary depending on source material and the processes used to extract and purify the product.
At the Senate hearing in March, former FDA official Jay Siegel, now at Johnson & Johnson, described how a seemingly minor
formulation change involving the stabilizer for "Eprex" (epoetin alfa) increased immunogenicity and led to serious red-cell
aplasia in patients. Apparently, the new stabilizer, polysorbate 80, leached organic chemical compounds from uncoated rubber
stoppers used in certain prefilled syringes, thereby causing the change in immunogenicity.
A white paper the Biotechnology Industry Organization (BIO) released in April 2007 similarly described the structural and
physical characteristics of large molecules, claiming that they make it difficult to show the comparability or similarity
of follow-ons. Proteins are based on four different structural characteristics and may also be glycosylated, factors that
are critical to product safety and effectiveness. Even a small variation such as the substitution of a single amino acid or
the alteration of a pattern of sugar residues, said BIO, "can dramatically alter the biological activity of the protein."
Manufacturing changes also may affect the safety or efficacy profile in ways not easily detected by standard chemical and
molecular-biology characterization techniques.
Unlike small molecules, biologics are "particularly sensitive to manufacturing-process issues," the paper pointed out. Chemistry,
manufacturing, and controls information, including product specifications, analytical-testing procedures, equipment, purification,
and fermentation processes, is "extremely important" for ensuring that a biological product is safe, pure, and effective.
The development of reliable, consistent manufacturing processes that use cell cultures or other living organisms is "substantially
more demanding" than developing the chemical synthesis and purification steps for a conventional drug. Today's biotechnology
production processes are "incapable of yielding compositions that are homogeneous and objectively characterized," BIO stated.
The information provided by analytical testing is important in determining whether additional clinical trails are necessary
to bring a follow-on to market. Biotechnology manufacturers maintain that only extensive comparison studies can rule out clinically
significant differences. FDA officials observe, however, that the extent of additional studies should be based on the complexity
of the product, its clinical use, and experience as a treatment. "Some degree of clinical assessment of a new product's immunogenic
potential will ordinarily be needed," said Woodcock. But this could range from small PK studies to larger randomized trials.