Attachment II - Page 26 
30080 Federal Register / Vol. 49, No. 252 f Monday, December 31, 1984 / Notices 
strategies are product-specific rather 
than technology-specific. For example, 
review of the production of human viral 
vaccines routinely involves a number of 
considerations including the purity of 
the media and the serum used to grow 
the cell substrate, the nature of the cell 
substrate, and the characterization of 
the virus. In the case of a live viral 
vaccine, the final product is biologically 
active and is intended to replicate in the 
recipient. Therefore, the composition, 
concentration, subtype, immunogenicity, 
reactivity, and nonpathogenicity of the 
vaccine preparation are all 
considerations in the final review, 
whatever the techniques employed in 
“engineering" the virus. 
Scientific considerations may dictate 
areas of generic concerns or the use of 
certain tests for specific situations. For 
example, a hepatitis B vaccine produced 
in yeast (via recombinant DNA 
techniques) would be monitored for 
yeast cell contaminants, while distinctly 
different contaminants would be of 
concern in a similar vaccine produced 
from the plasma of infected patients. 
In order to provide guidance to 
current or prospective manufacturers of 
drugs and biological products, the FDA 
has developed a series of documents 
describing points that manufacturers 
might wish to consider in the production 
of interferon,, monoclonal antibodies, 
and products of recombinant DNA 
technology, as well as in the use of new 
cell substrates. These documents, called 
"Points to Consider . . .", are available 
from the Agency upon request. 
Administrative jurisdiction within 
FDA’s various organizational units are 
the same for a given product, whatever 
the processes employed in its 
production. 
Nucleic acids used for human gene 
therapy trials will be subject to the same 
requirements as other biological drugs. 
It is possible that there will be some 
redundancy between the scientific 
reviews of these products performed by 
the National Institutes of Health and 
FDA. 
Obligations Under the National 
En vironmental Policy Act 
All premarket approvals of FDA- 
regulated products are subject to the 
requirements of the National 
Environmental Policy Act (NEPA) as 
defined by the Council on 
Environmental Quality's regulations (40 
CFR Parts 1500-1508) and as further 
described by FDA’s NEPA-implementing 
procedures (21 CFR Part 25, revision 
proposed December 11, 1979; 44 FR 
71742-71752). For new products or major 
new uses for existing products, these 
procedures ordinarily require the 
preparation of an environmental 
assessment. An environmental impact 
statement is required if manufacture, 
use, or disposal of the product is 
anticipated to cause significant 
environmental impacts. 
Scientific Issues Surrounding Specific 
Products 
There are some scientific issues raised 
by specific products manufactured with 
recombinant DNA technology. First the 
molecular structure of some products is 
different from that of the active 
molecule in nature. For example, the 
“human growth hormone” from 
recombinant microorganisms has an 
extra amino acid, an amino-terminal 
methionine hence, it is an analogue of 
the native hormone. Such differences 
may affect the drug’s activity or 
immunogenicity and these 
considerations, among others, may 
affect the amount of clinical testing 
required. However, FDA possesses 
exensive experience with evaluation of 
analogues ofnative human 
polypeptides, a number of which have 
been approved for marketing. 
Second, appoval of the product 
application for pharmaceuticals is also 
approval of the sponsor’s processing 
techniques, and FDA must determine 
whether the quality assurance within 
the manufacturing process is adequate 
to detect deviations that might occur, 
such as the occurrence of mutations in 
the coding sequence of the cloned gene 
during fermentation. Such mutations 
could, in theory, give rise to a 
subpopulation of molecules with an 
anomalous primary structure and 
altered activity. This is a potential 
problem inherent in the production of 
polypeptides in any fermentation 
process. One way FDA has dealt with 
these situations in existing IND's is to 
require batch-by-batch testing with 
appropriate techniques to ensure that 
the active drug substance is 
homogenous and has the correct 
identity. 
Summary 
FDA's administrative review of 
products, including those that employ 
specialized biotechnological techniques 
such as recombinant DNA in their 
manufacture, is based on the intended 
use of product on a case-by-case basis. 
Although scientific considerations may 
dictate areas of generic concerns for 
certain techniques, e.g., the possibility of 
contamination with adventitious agents 
or oncogenes when cultured mammalian 
cells are the source of a drug, the use of 
a given biotechnological technique does 
not require a different administrative 
process. Regulation by FDA must be 
based on the rational and scientific 
evaluation of products, and not on a 
priori assumptions about certain 
processes. 
FDA Approved Drugs and Biologies of 
New Biotechnology (Recombinant DNA 
and Hybridoma Techniques) 
Hormones 
Human insulin (*) 
In Vitro Diagnostic Products 
Anti-Human serum (“) 
Anti-Human serum anti-C3d (**) 
[I ,M ]Antibody to Hepatitis B Surface 
Antigen (**) 
ENVIRONMENTAL PROTECTION 
AGENCY 
Proposed Policy Regarding Certain 
Microbial Products 
summary: This notice describes how 
EPA plans to address certain microbial 
products of biotechnology under the 
Federal Insecticide, Fungicide, and 
Rodenticide Act (FIFRA) and the Toxic 
Substances Control Act (TSCA). The 
notice outlines EPA’s plan for review of 
nonindigenous and genetically 
engineered microbial pesticides under 
FIFRA, and EPA’s interpretation of the 
new chemical premanufacture 
notification (PMN) provisons of TSCA 
section 5 for new genetically engineered 
microorganisms used for commercial 
purposes. Public comment is requested 
on scientific and policy issues raised by 
this notice. 
ADDRESS: Because some comments may 
contain confidential business 
information, all comments on the EPA 
portion of this notice should be 
identified by Docket Number OPTS- 
00049 and addressed to: Document 
Control Officer (TS-793), Office of Toxic 
Substances, Environmental Protection 
Agency, Rm. E-409, 401 M St., SW., 
Washington. D.C. 20460. 
Information submitted as comments 
on the EPA portion of this notice may be 
claimed confidential by marking any 
part or all of that information as 
“Confidential Business Information.” 
Information so marked will not be 
disclosed except in accordance with 
procedures set forth in 40 CFR Part 2. A 
sanitized copy of any material 
containing Confidential Business 
Information must be provided by the 
submitter for inclusion in the public 
record. Information not marked 
confidential may be disclosed publicly 
by EPA without prior notice. 
‘Produced by recombmant DNA technique. 
“Produced by hybridoma technique. 
[ 380 ] 
