Although there is awareness among the biopharmceutical industry of the challenges and trade-offs associated with monitoring
the safety of drug products, there does not seem to be a clear and consistent understanding of characteristics correlated
with the presence of critical-to-quality deviations of a product at the commercial scale (1). The intent of this paper is
to initiate an understanding of product and site characteristics that statistically correlate with quality performance of
biopharmaceutical commercial products. Towards this objective, a comprehensive survey on related topics is underway at the
Massachusetts Institute of Technology (MIT) Center for Biomedical Innovation (CBI). The interim results described in this
research represent survey results from 34 commercial-scale biopharmaceutical products at 11 international sites. This research
builds on analysis done by the MIT CBI team earlier this year (2).
Some regulatory agencies, including FDA, have actively pursued a risk-based approach to manufacturing site inspection because
their inspections are site-specific and not restricted to an individual product (1). Explicit inputs that FDA uses for its
risk-based selection of sites to inspect include the types of products manufactured (e.g., prescription versus over-the-counter,
approved versus unapproved, therapeutic classes); the control and/or contamination potential of the manufacturing environment
(e.g., facility size, facility type, number of drug products, sterility requirements); and cost of inspection (e.g., domestic
versus international locations). These inputs are logical for consideration of total risk to quality at the level of a site,
but, in this research, the focus regarding quality is on the product.
A comprehensive survey on topics related to site characteristics, quality approaches, quality activities, perception of relative
consistency of regulators, product-level process details, and product-level compliance performance has been developed by MIT's
CBI. The survey includes questions that result in a total of 57 variables across these topic areas. The developed survey was
tested with industry representatives and then deployed over the past 18 months as a secure web-based questionnaire directly
to biopharmaceutical manufacturing sites through several different channels. The individuals targeted for inclusion as survey
respondents have been manufacturing plant managers or their representatives.
In total, 20 sites representing 52 manufactured products have completed the survey. These responses have been filtered to
focus on commercial-scale manufacturing and products for which all relevant information was provided. This reduced the number
of products included thus far to 34 across 11 sites.
The research is supported by the Alfred P. Sloan Foundation of New York City.
RESULTS AND DISCUSSION
Characteristics of the products and sites
The demographics of the 34 products included in the analysis are organized into the following groups:
Twenty-nine of the products surveyed are marketed in the US; 24 in Canada; 33 in Europe; 26 in Japan; 17 in South America;
and 20 in Asia (outside of Japan).
Product and process:
Product type: 27 of the products surveyed are therapeutic proteins; 12 are antibodies
- Processing: 25 of the products surveyed are produced by mammalian cell culture; 9 by microbial fermentation
- Complexity: 15 of the products are perceived as above average in process complexity
- Role of quality by design (QbD): 10 of the products are significantly impacted by use of a QbD approach.
Characteristics of the manufacturing site:
- Geographic location of commer-cial manufacture: 6 are based in in Asia; 12 in Europe; and 16 in the US
- Contract manufacturing: 14 of the products are manufactured in a site that does greater than 40% of their work as contract
- Other biologic products at the site: 15 of the products are manufac-tured in a site that also manufac-tures more than five
- Use of third-party quality inspections: 24 products surveyed are manufactured in a site that has had multiple third-party
quality inspections (for practice) in the past five years.
Based on these overal demographics, the products in the MIT CBI survey represent a reasonably diverse set of biopharmaceutical
products, processes, and manufacturing sites.