Macromolecular substances can be obtained by a number of methods including extraction from natural sources,modification of naturally occurring protein,mammalian cell culture in vitro,mammalian cell culture in vivo,production by microorganisms,and chemical syntheses.From a compendial perspective,macromolecular articles derived from biotechnology processes—or more specifically from recombinant-DNA(rDNA)technology,hybridoma technology,and transformed continuous cell lines—are those articles for which official names have been established.These articles have official public standards for identity,strength (potency),quality,and purity.Advances in genetics and the applications of genetic engineering have made the production of new and existing macromolecular articles technologically and economically feasible.

The technologies involved in producing a protein by biotechnological processes have been widely documented and general guidelines have been established by the federal government.The products of biotechnology may be regulated as drugs,biologics,or diagnostics,depending on their source,composition,and intended use.The novel approaches permitted by biotechnology can make it difficult to apply classic definitions of these categories and FDAhas advised manufacturers to seek clarification in the early stages of development for how a product will be regulated when classification is not obvious.1The overall regulatory scheme for biotechnology-derived products is the same as for products in the same category produced by traditional manufacturing methods,with the addition of specific requirements suited to the biotechnology-derived product.The general requirements are described primarily in the applicable parts of the Code of Federal Regulations,Title 21.NIHhas published a guideline for rDNAresearch that is mandatory for both public and private NIH-supported research.This guideline has wide acceptance and voluntary compliance is common by institutions and corporations not specifically governed by it.2Laboratory safety practices,particularly protection from potentially infectious materials,are a concern.3Producing macromolecular articles by biotechnological processes involves initially the cloning of a specific gene in the laboratory,or the construction of a synthetic gene,with subsequent insertion into a host cell and subcloning in a microorganism or cell culture;then a process development on a pilot scale to optimize yield and quality;and finally large-scale fermentation or cell culture processes.The next step,which is the most relevant to the development of compendial monographs,is the purification of the macromolecular proteins.This is followed by animal testing,clinical testing,regulatory approval,and marketing.

Development of relevant public standards for these macromolecular articles is generally closely linked to the processing technology used and the physicochemical and biological characteristics of a specific drug.Characterizations of these articles to ensure safety,purity,and activity should incorporate classical techniques as well as methods specific to the technology.There is always the possibility that these articles may cause some untoward effects in patients using them due to immunological sensitization as a result of a single (or multiple)molecular modification.Such a possibility requires precise characterization of these substances.Although it is theoretically possible to develop public standards for a macromolecular article,it is not possible to develop specific standards that incorporate all prospective methods of production.The compendial perspective is to develop public standards that can be applied to a final product without comprehensive knowledge of production details but which can ensure maintenance of safety,identity,strength,quality,and purity.

Testing for identity,purity,and activity generally requires the use of USP Reference Standards.It will be necessary to consider what USP Reference Standards might be required and how relevant they might be to the method of production as it relates to a final product's characteristics.Such decisions will be made on a product-by-product basis.Favorable consideration will be given to the use of USP Reference Standards that are representative of the specific products that have undergone clinical testing and are fully characterized.

Although early adoption in USPof general methods of analysis of macromolecular drugs could be conducive to early standardization of methods,the technology and analytical procedures are evolving very rapidly.Analytical procedures—chemical,physical,microbiological,and immunological—will be included in the specific product monographs.