Regulatory Note
Theme:Pharmacokinetics,Biopharmaceutics and Bioequivalence:History and Perspectives Guest Editors:Marilyn Martinez and Lawrence Yu
Dissolution Testing for Generic Drugs:An FDA Perspective
Om Anand,1,2Lawrence X.Yu,1Dale P.Conner,1and Barbara M.Davit 1
Received 22December 2010;accepted 21March 2011;published online 9April 2011
小米账号密码Abstract.In vitro dissolution testing is an important tool ud for development and approval of generic dosage forms.The objective of this article is to summarize how dissolution testing is ud for the approval of safe and effective generic drug products in the United States (US).Dissolution testing is routinely ud for stability and quality control purpos for both oral and non-oral dosage forms.The dissolution method should be developed using an appropriate validated method depending on the dosage form.There are veral ways in which dissolution testing plays a pivotal role in regulatory decision-making.It may be ud to waive in vivo bioequivalence (BE)study requirements,as BE documentation for Scale Up and Post Approval Changes (SUPAC),and to predict the potential for a mo
di fied-relea (MR)drug product to do-dump if co-administered with alcoholic beverages.Thus,in vitro dissolution testing plays a major role in FDA ’s efforts to reduce the regulatory burden and unnecessary human studies in generic drug development without sacri ficing the quality of the drug products.
心路
KEY WORDS:bioequivalence;biopharmaceutics;generic drugs;in vitro dissolution;quality by design.
INTRODUCTION
Dissolution testing has emerged as a very important tool in the generic pharmaceutical industry.It is very widely ud in formulation development,in monitoring the manufacturing process and as a quality control test.It can also be ud to predict the in vivo performance of certain products.Dissolution testing has been successfully ud for development and approval of generic solid oral dosage forms.Most recently,the u of dissolution testing has been extended to other solid generic dosage forms;in the cas it is generally called as in vitro relea testing or simply drug relea testing (1,2).Finally,dissolution testing plays signi ficant role in identifying the need for the bioequivalence (BE)studies related to Scale-Up and Post-Approval Changes (SUPAC)(3,4).
The purpo of this article is to summarize how dissolution testing is ud for the approval of safe an
d effective generic drug products in the USA.This article also re flects the current thinking of the US-Food and Drug Administration (US-FDA),on using dissolution and other in vitro drug relea testing in consistently producing high-quality generic drug products and reducing the regulatory burden for the pharmaceutical industry.
ROLE OF DISSOLUTION TESTING IN APPROV AL OF GENERIC DRUG PRODUCTS
In vitro dissolution testing (dissolution)plays a critical role in the life cycle of a generic drug product.In developing a dissolution test for a generic product intended to be marketed in the USA,investigators should consider the of ficial methods and standards published in the United States Pharmacopeia (USP).The USP describes ven different dissolution apparatus which can be ud to develop an appropriate dissolution method bad on the drug product characteristics (5,6).The dissolution method should be suf ficiently rugged and reproducible for daily operations,capable of being transferred between laborato-ries,and adequately discriminating to distinguish any changes that could affect the product ’s in vivo performance (7).The Division of Bioequivalence (DBE),in the Of fice of Generic Drugs,Center for Drug Evaluation and Rearch,US-FDA asks investigators to conduct compara-tive dissolution testing using at least 12dosage units each of test and reference products.Dissolution data should be generated by sampling the dissolution medium at time points ap
propriate to characterize the dissolution pro file.It is suggested that three to four or more dissolution time points (other than zero),equally spaced,be utilized for rapidly dissolving drugs (8).For dissolution of extended-relea (ER)formulations,more sampling time points are suggested,in order to adequately characterize the complete dissolution pro file.
1
U.S.Food and Drug Administration,Center for Drug Evaluation and Rearch,Of fice of Generic Drugs,7520Standish Place,Rockville,Maryland 20855,USA.2
To whom correspondence should be addresd.(e-mail:om.anand@v)
The AAPS Journal,Vol.13,No.3,September 2011(#2011)DOI:10.1208/s12248-011-9272-y
1550-7416/11/0300-0328/0#2011American Association of Pharmaceutical Scientists
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DISSOLUTION TESTING RECOMMENDATIONS
菊花插件FOR SOLID ORAL GENERIC DRUG PRODUCTS One of thefirst steps during the BE review of a potential new generic drug product is an asssment of whether the dissolution method propod for the product is the appro-priate one.As depicted in Fig.1,the DBE recommends that for generic drug products,if a USP method is available for the product,then dissolution should be conducted using that method.If there is no USP method available then the dissolution testing should be conducted using a method recommended by the FDA(FDA-recommended method). The FDA posts a list of its recommended dissolution methods (www.v/scripts/cder/dissolution/).An applicant may develop their own dissolution method if the FDA-recommended method is inadequate for their product. It is worth noting that even if the USP method is ud,the DBE asks generic applicants to submit to the Abbreviated New Drug Application(ANDA)comprehensive dissolution testing data.Thus,an applicant should characterize compa-rative dissolution testing using at least12dosage units each of test and reference products,whether it propos to u a USP method,FDA-recommended method,or its own method.In cas where the applicant develops their own method,both data using their method as well as data from the FDA-recommended method should be submitted for comparison.
In cas where neither a USP and nor FDA-recommen-ded method is available,an appropriate new
dissolution method should be developed.The new dissolution method development report should be submitted to the ANDA,so that the DBE can evaluate the feasibility of the new method. The new dissolution method development report should include a pH solubility profile of the drug substance, dissolution profiles at different rotational speeds and dissolu-tion media.Dissolution profiles should be generated using at least three dissolution media for example,pH1.2,4.5,and6.8 buffers.Water may also be tested as an additional dissolution medium for method optimization.It may be difficult to achieve sink conditions for poorly water-soluble drugs;therefore a suitable surfactant in an appropriate concentration can be ud in the dissolution medium for the drug products(9).
For immediate-relea(IR)generic products,dissolution testing using a single method may be sufficient.For ER products,if a USP method is available then dissolution testing recommendations are bad on the product formulation and number of strengths to be marketed.As prented in Fig.2,if the USP method is adequately discriminating and the drug product is to be marketed in only one strength then dissolution data generated using only the USP method may be sufficient(9).In the ca of multiple-strength ER capsule drug products,the dissolution testing recommendations are bad on the formulation design.If multiple strengths of an ER capsule product are produced from a“common blend”then dissolution data generated using only the USP method may be sufficient,provi
ded that the USP method is adequately discriminating.For multiple strengths of an ER tablet drug product,and for multiple strengths of an ER capsule product which are not produced from a“
common Fig.1.Decision tree for ANDA sponsors to lect a dissolution method for their generic product
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blend ”,dissolution testing in addition to the USP method is recommended,in order to provide the FDA with suf ficient information to determine the optimal and most discriminating dissolution method for the product.The additional dissolu-tion testing should be conducted using at least three dissolution media,for example,pH 1.2,4.5,and 6.8buffers (8,9).Water may also be tested as a possible dissolution medium during the method optimization process (8,9).If the applicant propos to u a dissolution method other than the USP method,then it should submit dissolution data generated on 12units per strength for all strengths,for both the test (generic)and reference products using both the USP method and the applicants newly developed method.If a USP method is not available for the ER dosage form,but an FDA-recommended method is available,then it is recommended that dissolution be conducted using the FDA-recommended method.Whether additional dissolution testing is recommended depends upon the product formulation.For multiple strengths of ER tablets and ER capsules where the various strengths are not produced from a “common blend ”,additional dissolution testing is recommended on all the strengths.If the multiple str
engths of the ER capsule product line are produced from a “common blend ”,then dissolution testing in addition to the FDA-recommended method is recom-mended only on the highest strength.The additional dissolution testing should be conducted using at least three dissolution
media,
Fig.2.Decision-tree for ANDA sponsors for submitting dissolution testing data for an extended-relea solid oral generic drug product.{“Common blend ”:A batch of final blend that can be packed in different amounts providing various strengths of the capsule product.Multimedia:lower 1.2;medium 4.5;higher 6.8and water}
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for example pH1.2,4.5,and6.8buffers;water may also be ud for method optimization(9).If the applicant propos to u a dissolution method other than the FDA-recommended method, then it should submit dissolution data generated on12units per strength for all strengths,for both the test(generic)and reference products using both the FDA-recommended method and the applicants newly developed method.
For delayed-relea(DR)solid oral dosage forms,the dissolution testing should demonstrate that(a)the product is stable under the acidic conditions of the stomach(for example pH1.2);and(b)relea in the pH prent in the intestine.If a USP method is available then dissolution should be conducted using that method.If there is no USP method, then for all the strengths of a DR
product the DBE recommends that dissolution testing should be conducted under acidic conditions(pH1.2)for2h followed by neutral ,pH 6.8).In general,DR products should display acid resistance under the dissolution testing conditions (8,9).Currently,the DBE does not request additional multi-media dissolution testing for DR products demonstrating biphasic relea(10).
As stated above,for some ER and DR drug products,a USP and/or FDA-recommended method is available,but not necessarily suitable for the generic test product.In this ca, the DBE encourages the applicant to develop the most suitable and adequately discriminating dissolution to distin-guish any changes that could affect the test product’s in vivo performance.In such a ca,the DBE requests the sub-mission of a dissolution method development report.In addition,it is recommended that the submission contain results of comparative test and reference dissolution profiles generated using the USP and/or the FDA-recommended method and the applicant’s propod method.In this way, the appropriateness of the new propod method can be carefully evaluated.
DISSOLUTION TESTING AND BCS-BASED BIOWAIVERS FOR GENERIC DRUG PRODUCTS In recent times,the regulatory perspective of dissolution has shifted due to improved knowledge and understanding of dissolution science and mechanisms.FDA’s Guidance for Industry on the Biopharm
aceutics Classification System(BCS Guidance)emphasizes how the dissolution test can be ud to grant biowaivers for highly soluble and highly permeable drugs formulated in rapidly dissolving IR solid oral dosage forms(11).
The BCS is a framework for classifying drug substances bad on their solubility and permeability,and for providing a scientific rationale to justify the granting of biowaivers for certain products(11,12).The BCS system when integrated with the dissolution of the drug product takes into account three major factors;namely,dissolution,solubility,and intestinal permeability.It is well-established that the three factors govern the rate and extent of drug absorption from IR solid oral dosage forms(11,12).
According to the BCS Guidance,biowaivers may be granted for BCS class1(high-solubility and high-permeability drug substance)products if the drug product is rapidly dissolv-ing.An IR drug product is considered rapidly dissolving when no less than85%of the labeled amount of the drug substance dissolves within30min,using USP Apparatus1at100rpm(or Apparatus2at50rpm)in a volume of900ml or less in each of the following media:(a)0.1N HCl or Simulated Gastric Fluid USP without enzymes;(b)a pH4.5buffer;and(c)a pH6.8 buffer or Simulated Intestinal Fluid USP without enzymes(11).
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小学二年级奥数战网手机安全令For a rapidly dissolving IR generic product containing highly soluble and highly permeable drug substances,appli-cants may request that the agency grant a BCS-bad biowaiver,if the following conditions are met:
&The reference listed drug(RLD)product is rapidly dissolving;and
&The test product exhibits dissolution profiles similar to the RLD product under all test conditions as defined in the guidance(11).
ANDA applicants may consult FDA’s Guidance for Industry(13):Individual Products Bioequivalence Recom-mendations Guidances for information about some potential BCS Class1drugs for which a BCS biowaiver option may be feasible.
DISSOLUTION TESTING AND OTHER BIOWAIVERS FOR GENERIC DRUG PRODUCTS—PREAPPROVAL
Comparative dissolution testing can be ud to grant biowaivers for different strengths for IR dosage forms as long as certain conditions are met(8,9).
If BE to the reference listed drug has been established for the one strength(generally the highest)of
a generic drug product line then,as per FDA’s General Guidance on Bioavailability and Bioequivalence for Orally Administered Drug Products(BA/BE Guidance)(9),an in vivo BE study requirements can be waived for one or more additional strengths bad on dissolution tests if the drug product is in the same dosage form,but in a different strength and proportionally similar in its active and inactive ingredients to the strength on which acceptable in vivo BE testing was conducted(9).
For IR generic drug products,dissolution profiles in one medium are usually sufficient to support waivers of in vivo testing if an appropriate regulatory dissolution method is established,and if the dissolution results indicate that the dissolution characteristics of the product are not dependent on the product ,various strengths have similar dissolution.If an appropriate dissolution method is not established then dissolution data in three media(pH 1.2, 4.5,and6.8)are recommended(8,9).
Dissolution can also be ud to support applicant requests for biowaivers for various strengths of a modified-relea(MR)drug product line.In this ca,the DBE may decide that it is unnecessary to conduct in vivo studies on one or more strengths bad on acceptable dissolution perform-ance,proportional similarity among strengths,and an accept-able in vivo study on one(generally the h
ighest)strength. The scope of dissolution testing differs bad on whether the MR formulation is an ER capsule,ER tablet,DR capsule,or DR tablet(9).
For ER-beaded capsule formulations,in vivo BE studies are recommended for one strength,usually the highest.Other strengths can be deemed bioequivalent to the corresponding strengths of the RLD if BE is established in vivo for one strength,the various strengths differs only in the number of
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Dissolution Testing for Generic Drugs
beads containing the active moiety,and dissolution profiles are similar for each strength using the recommended dis-solution method(9).For ER tablet formulations,the in vivo BE studies are recommended for one strength,usually the highest.The other strengths of the product line may be deemed bioequivalent to the corresponding strengths of the RLD.The criteria for this determination are that(1)the lower strengths are in same dosage form;(2)active and inactive ingredients are proportionally similar;(3)the drug relea mechanism from all strengths of the formulations is the same;and(4)the dissolution profiles of the strength that underwent acceptable in vivo BE testing and the other strength(s)is(are)similar in at least three dissolution media (e.g.,pH1.2,4.5and6.8)(9).To su
pport biowaiver requests for various strengths of a DR product line demonstrating biphasic relea,the DBE considers dissolution data in a manner similar to the process for IR products in that dissolution testing using standard dissolution method for the product is recommended and multimedia dissolution testing is generally not requested.For MR products containing both DR and ER components,the DBE may request additional dissolution testing of strengths other than the one ud for in vivo testing;the scope of the request will depend on whether the product is a capsule or tablet,as described above. ROLE OF DISSOLUTION TESTING IN POST-PPROV AL CHANGES OF GENERIC DRUG PRODUCTS
FDA’s SUPAC Guidance for Industry provides a more simplified path to the industry to test and report the manufacturing changes of various types of pharmaceutical products formulations.Comparative dissolution testing between the pre-manufacturing change(Bio-batch)and post-manufacturing change plays very significant role in approval of SUPAC changes.The SUPAC Guidances define the various categories of the post-approval changes in form of“Levels”(3,4).
In addition to chemistry and manufacturing documenta-tion,comparative dissolution data are required to support the approval of intended change.According to the SUPAC Guidance,if a product is an IR solid oral dosage form,for any level1or level2change,dissolution testing may be adequate(no
BE study)to support agency approval of the post-approval change.For“site change”level3changes, dissolution testing may be adequate(no BE study)to support approval of the post-approval change.For all other level3 changes,both dissolution testing and an in vivo BE study are necessary to support the approval of the post-approval change.However,if an acceptable and validated in vivo/in vitro correlation(IVIVC)is available then the requirement for BE study may be waived(3).
For all level1changes to approved MR generic formulations,it is necessary to conduct comparative dissolu-tion testing on the pre-change and post-change products using a standard dissolution method(4).To support most level2 changes,it is necessary to compare pre-change and post-change products in the compendial dissolution medium plus generate comparative multi-point dissolution profiles in at least three other ,water,0.1N HCl,and USP buffered media at pH values of4.5and6.8).It is recom-mended that pre-change and post-change product dissolution profiles be compared statistically,generally by using the f2 similarity factor test to confirm mathematically that the pre-change and post-change product dissolution profiles are not significantly different(8).Note that if the agency determines that the above comparative dissolution testing is acceptable, then it is not necessary to conduct an in vivo BE study of the post-approval formulation.
For all level3changes to MR products,and for some level2changes,it is necessary to conduct an in vi
vo study (new product vers reference listed drug)to demonstrate that the post-approval product is bioequivalent to the corresponding RLD.However,an established IVIVC for the product can significantly reduce the regulatory and economical burden for obtaining agency approval of level2 and level3changes to MR products.If an established IVIVC is available,then comparative pre-change and post-change product dissolution profiles using only the standard regula-tory dissolution method may be adequate to support approval of the change(s)(3,4).Therefore establishing an IVIVC at the development stage of the product can greatly reduce the number of BE studies required for any SUPAC type of changes and save resources and reduce the regulatory burden for applicants.
DISSOLUTION TESTING AND ALCOHOL-INDUCED DOSE-DUMPING OF GENERIC MR ORAL DRUG PRODUCTS
MR drug products are intended to relea the drug slowly into the systemic circulation and offer the advantage to patients thatfluctuations in plasma concentrations are mini-mized.The in vivo relea mechanism can be altered if an MR formulation is administered with alcohol,leading to do dumping.The conquences of do dumping of certain drugs could lead to rious or even fatal adver events in some patients(14).
古代马车简笔画FDA recognizes that alcohol-induced do dumping can po a rious safety concern for some MR drug products.In respon to the agency’s concerns about this safety issue,the DBE adopted a policy of requesting information on in vitro do dumping in the prence of alcohol in its review of ANDAs for certain class of MR drug products,for example all MR opioid products(14).The DBE’s current policy is to request that ANDA applicants perform an in vitro do dumping in alcohol test on a particular generic product if the approval package for the corresponding RLD shows that in vitro do dumping in alcohol test results were requested by the agency for the New Drug Application(NDA)for the product.The MR drug products for which the DBE requests the in vitro do dumping in alcohol test can be located in FDA’s Guidance for Industry,Individual Products Bioequi-valence Recommendations Guidances(13).
内地票房排行榜实时The in vitro do dumping in alcohol test is a dissolution test designed to assure that any potential for in vivo do dumping in the prence of alcohol for a generic MR drug product is either not prent or,if prent,not significantly different from that of its corresponding RLD.Since patients may be switched from the RLD to the corresponding approved generic version,it is important to provide assurance that ethanol will have the same effects on drug relea from a generic MR formulation and the RLD.
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