BioPharm: Priority 3 in the strategic plan also calls for developing new analytical methods, including those to determine similarity
between reference products and biosimilars as well as tools to detect physical properties of complex dosage forms. What gains
are hoped for among agency scientists in these analytical areas?
FDA: Advances in analytical methods to determine 'similarity' between reference products and biosimilars as well as tools to detect
physical properties of complex dosage forms will allow for greater confidence that there are no structural differences between
products or that any differences observed are minor. For biosimilars, this will reduce uncertainty and allow for a targeted
development program. This can also facilitate the development and approval of generics with complex dosage forms as well as
inform control strategies for quality of complex originator products.
BioPharm: Priority 3 of the August 2011 strategic plan calls for reducing microbial contamination of medical products. What specific
goals does FDA have in this area?
FDA: FDA has attempted to identify and study specific gaps in pharmaceutical manufacturing. Studies are ongoing on sterilizing
filtration, effects of terminal sterilization energies on classes of products, and methods for detection of elusive microorganisms
in drug components and manufacturing environments.
Filtration studies have included microbial penetration rates based on the cell's size and filter matrix composition as well
as penetration due to time on various filters with two sizes of growing microorganisms. The goal of these studies is to improve
filter-validation studies that previously were shown to have vulnerabilities. Future steps in the research will look into
solution conditions that encourage miniaturization of the cells, neutralize cells, or filter surface charges that enhance
cell entrapment on filter membranes.
Many products are manufactured using aseptic processing, which may be less effective than terminal sterilization. Some other
surgical products are not manufactured to be sterile at all, also posing risk. Each of these situations is the result of risk
assessments that are based on the nature of the product and its vulnerability to sterilizing energy or other conditions. FDA
and NIPTE [National Institute for Pharmaceutical Technology and Education] have initiated studies of products (the initial
focus is surgical antiseptics) to assess the effects of sterilizing energy on selected products. The goal of these studies
is to define conditions that may allow manufacturing to use processes intended to produce a sterile product, which is safer
for use in surgical procedures.
Nonsterile products often require a demonstration that microorganisms, normally expected to be in the product, will not grow
or are killed. A similar demonstration is expected of sterile products that may be used several times (e.g., multidose vials).
However, there exist microbial strains that can resist preservatives used to control contamination, and some of these strains
even grow in the presence of the antimicrobial agents. If allowed to grow, large numbers of microorganisms may reach a potentially
infectious dose upon exposure to patients. Among these species are common water bacteria that CDC [Centers for Disease Control
and Prevention] have shown to be difficult to detect using compendial methods. In collaboration with CDC and with help from
the University of Michigan, we are examining culture methods for recovering these organisms from pharmaceutical water and
products. Alternative technologies for their detection are also being considered. The goal of these studies is the development
of methods to reliably detect these potential contaminants.