Contains Nonbinding Recommendations
identifiers. We recommend that you periodically evaluate the implemented procedural controls
for their effectiveness. You should take appropriate corrective action when indicated by the
evaluation or when other events warrant.
B. Biological and Biotechnological Products
1. General Considerations
The manufacturing process is critical to ensure the correct composition, quality, and safety of
biological and biotechnology products. For these products, it can be difficult to distinguish
changes in quality attributes, or predict the impact of observed changes in quality attributes on
safety. This is especially true for phase 1 clinical trials where knowledge and understanding of a
phase 1 investigational drug is limited and where comprehensive product characterization is
often unavailable, especially for products that are difficult to characterize. Therefore, it is
critical to carefully control and record the manufacturing process in conjunction with appropriate
testing to reproduce a comparable phase 1 investigational drug as may be necessary. Properly
stored retained samples (e.g., API or drug substance, in-process material, phase 1 investigational
drug) that can be subsequently analyzed for comparison, can provide important links in
reproducing comparable biological and biotechnological products.
You should have in place appropriate equipment and controls in manufacturing to ensure that
unit operations with safety-related functions (e.g., viral clearance, virus/toxin attenuation,
pasteurization) perform their function with a high degree of assurance. Specific testing may also
serve to complement these functions. In manufacturing, you should use testing for safety-related
purposes such as viral loads, bioburden, detoxification of bacterial toxins, virus clearance (i.e.,
removal or inactivation), and removal of residual substances (e.g., antibiotics, chemicals) as
appropriate (see section VI.B.2).
2. Adventitious Agent Control
When evaluating the manufacturing environment for biological and biotechnology phase 1
investigational drugs, it is of particular importance to evaluate for susceptibility to contaminate
the environment with biological substances, including microbial adventitious agents (e.g.,
bacterial, viral, mycoplasm), that may remain from previous research or manufacturing activities.
Some biological and biotechnology phase 1 investigational drugs, including those made from
pathogenic microorganisms, spore-forming microorganisms, transgenic animals and plants, live
viral vaccines, and gene therapy vectors, warrant additional containment considerations. We
encourage you to discuss such containment issues with the applicable Center within FDA (i.e.,
product and facility group with responsibil
ity for the product) prior to engaging in manufacturing.
In addition to the recommendation in section VI.A, multi-product facilities should have in place
cleaning and testing procedures that ensure prevention and/or detection of contamination by
adventitious agents. To the extent possible, we recommend the use of dedicated equipment
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