Food and Drug Administration, HHS § 320.33

study as soon as possible but in no case changeably for the same therapeutic later than 15 calendar days after be- effect: coming aware of its occurrence. Each (1) Are not bioequivalent drug prod- report must be submitted on FDA ucts; or Form 3500A or in an electronic format (2) May not be bioequivalent drug that FDA can process, review, and ar- products based on the criteria set forth chive. FDA will periodically issue guid- in § 320.33; or ance on how to provide the electronic (3) May not be bioequivalent drug submission (e.g., method of trans- products because they are members of mission, media, file formats, prepara- a class of drug products that have close tion and organization of files). Each re- structural similarity and similar phys- port must bear prominent identifica- icochemical or pharmacokinetic prop- tion of its contents, i.e., ‘‘bio- erties to other drug products in the availability/bioequivalence safety re- same class that FDA finds are not bio- port.’’ The person conducting the equivalent drug products. study, including any contract research (b) FDA shall include in a proposed organization, must also notify FDA of rule to establish a bioequivalence re- any fatal or life-threatening adverse quirement the evidence and criteria set event from the study as soon as pos- forth in § 320.33 that are to be consid- sible but in no case later than 7 cal- ered in determining whether to issue endar days after becoming aware of its the proposal. If the rulemaking is pro- occurrence. Each notification under posed in response to a petition, FDA this paragraph must be submitted to shall include in the proposal a sum- the Director, Office of Generic Drugs in mary and analysis of the relevant in- the Center for Drug Evaluation and Re- formation that was submitted in the search at FDA. Relevant followup in- petition as well as other available in- formation to a bioavailability/bio- formation to support the establishment equivalence safety report must be sub- of a bioequivalence requirement. mitted as soon as the information is (c) FDA, on its own initiative or in available and must be identified as response to a petition by an interested such, i.e., ‘‘Followup bioavailability/ person, may propose and promulgate bioequivalence safety report.’’ Upon re- an amendment to a bioequivalence re- quest from FDA, the person conducting quirement established under this sub- the study, including any contract re- part. search organization, must submit to [57 FR 18000, Apr. 28, 1992] FDA any additional data or informa- tion that the agency deems necessary, § 320.33 Criteria and evidence to as- as soon as possible, but in no case later sess actual or potential bioequiva- than 15 calendar days after receiving lence problems. the request. The Commissioner of Food and Drugs [57 FR 18000, Apr. 28, 1992, as amended at 58 shall consider the following factors, FR 25927, Apr. 28, 1993; 67 FR 77674, Dec. 19, when supported by well-documented 2002; 75 FR 59963, Sept. 29, 2010] evidence, to identify specific pharma- ceutical equivalents and pharma- § 320.32 Procedures for establishing or ceutical alternatives that are not or amending a bioequivalence require- may not be bioequivalent drug prod- ment. ucts. (a) The Food and Drug Administra- (a) Evidence from well-controlled tion, on its own initiative or in re- clinical trials or controlled observa- sponse to a petition by an interested tions in patients that such drug prod- person, may propose and promulgate a ucts do not give comparable thera- regulation to establish a bioequiva- peutic effects. lence requirement for a product not (b) Evidence from well-controlled subject to section 505(j) of the act if it bioequivalence studies that such prod- finds there is well-documented evi- ucts are not bioequivalent drug prod- dence that specific pharmaceutical ucts. equivalents or pharmaceutical alter- (c) Evidence that the drug products natives intended to be used inter- exhibit a narrow therapeutic ratio,

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e.g., there is less than a 2-fold dif- (1) The active drug ingredient, thera- ference in median lethal dose (LD50) peutic moiety, or its precursor is ab- and median effective dose (ED50) val- sorbed in large part in a particular seg- ues, or have less than a 2-fold dif- ment of the gastrointestinal tract or is ference in the minimum toxic con- absorbed from a localized site. centrations and minimum effective (2) The degree of absorption of the ac- concentrations in the blood, and safe tive drug ingredient, therapeutic moi- and effective use of the drug products ety, or its precursor is poor, e.g., less requires careful dosage titration and than 50 percent, ordinarily in compari- patient monitoring. son to an intravenous dose, even when (d) Competent medical determination it is administered in pure form, e.g., in that a lack of bioequivalence would solution. have a serious adverse effect in the (3) There is rapid metabolism of the treatment or prevention of a serious therapeutic moiety in the intestinal disease or condition. wall or liver during the process of ab- (e) Physicochemical evidence that: sorption (first-class metabolism) so the (1) The active drug ingredient has a therapeutic effect and/or toxicity of low solubility in water, e.g., less than 5 such drug product is determined by the milligrams per 1 milliliter, or, if dis- rate as well as the degree of absorp- solution in the stomach is critical to tion. absorption, the volume of gastric fluids (4) The therapeutic moiety is rapidly required to dissolve the recommended metabolized or excreted so that rapid dose far exceeds the volume of fluids dissolution and absorption are required present in the stomach (taken to be 100 for effectiveness. milliliters for adults and prorated for (5) The active drug ingredient or infants and children). therapeutic moiety is unstable in spe- (2) The dissolution rate of one or cific portions of the gastrointestinal more such products is slow, e.g., less tract and requires special coatings or than 50 percent in 30 minutes when formulations, e.g., buffers, enteric tested using either a general method coatings, and film coatings, to assure specified in an official compendium or adequate absorption. a paddle method at 50 revolutions per (6) The drug product is subject to minute in 900 milliliters of distilled or dose dependent kinetics in or near the deionized water at 37 °C, or differs sig- therapeutic range, and the rate and ex- nificantly from that of an appropriate tent of absorption are important to reference material such as an identical bioequivalence. drug product that is the subject of an [42 FR 1635, Jan. 7, 1977. Redesignated and approved full new drug application. amended at 57 FR 18001, Apr. 28, 1992] (3) The particle size and/or surface area of the active drug ingredient is § 320.34 Requirements for batch test- critical in determining its bio- ing and certification by the Food availability. and Drug Administration. (4) Certain physical structural char- (a) If the Commissioner determines acteristics of the active drug ingre- that individual batch testing by the dient, e.g., polymorphic forms, con- Food and Drug Administration is nec- forms, solvates, complexes, and crystal essary to assure that all batches of the modifications, dissolve poorly and this same drug product meet an appropriate poor dissolution may affect absorption. in vitro test, he shall include in the (5) Such drug products have a high bioequivalence requirement a require- ratio of excipients to active ingredi- ment for manufacturers to submit sam- ents, e.g., greater than 5 to 1. ples of each batch to the Food and (6) Specific inactive ingredients, e.g., Drug Administration and to withhold hydrophilic or hydrophobic excipients distribution of the batch until notified and lubricants, either may be required by the Food and Drug Administration for absorption of the active drug ingre- that the batch may be introduced into dient or therapeutic moiety or, alter- interstate commerce. natively, if present, may interfere with (b) The Commissioner will ordinarily such absorption. terminate a requirement for a manu- (f) Pharmacokinetic evidence that: facturer to submit samples for batch

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