建立評估仿制藥申請中非活性成分的全球框架-Dorsey.pdf

1、Building a Global Framework for Assessing Inactive Ingredients in Generic Drug ApplicationsPamela G.Dorsey,M.S.,Ph.D.Senior PharmacologistDivision of Bioequivalence III,Office of BioequivalenceCDER|US FDASBIA Generic Drug Forum April 9-10,2024fda.gov/cdersbiafda.gov/cdersbia2This presentation reflec

2、ts the views of the author and should not be construed to represent FDAs views or policies.Disclaimerfda.gov/cdersbiafda.gov/cdersbia3 Background Polling fellow Cluster participants Case Studies and Considerations DiscussionOverviewfda.gov/cdersbiafda.gov/cdersbia4Backgroundfda.gov/cdersbiafda.gov/c

3、dersbia5Assures the safety of inactive ingredients within drug products.Evaluation occurs during review of:Inactive Ingredient Controlled Correspondences(CCs)Abbreviated New Drug Applications(ANDAs)Evaluation in all populations the drug is indicated for(i.e.,adult and pediatric).Maximum daily exposu

4、re(MDE)for inactive ingredients calculated utilizing the maximum daily dose(MDD)from the reference listed drug(RLD)label.MDE for proposed inactive ingredient compared to amounts for the same inactive ingredient in approved NDAs or ANDAs.Applicants may submit clinical or toxicological data to use as

5、justification for a proposed inactive ingredient MDE in an ANDA submission.Inactive Ingredient Evaluationfda.gov/cdersbiafda.gov/cdersbia6 What are the practices for other regulatory jurisdictions?Are there commonalities or areas for alignment?Inactive Ingredient Evaluation Continuedfda.gov/cdersbia

6、fda.gov/cdersbia7Polling Fellow Cluster Membersfda.gov/cdersbiafda.gov/cdersbia8Comprised of membership from:US FDA Health Canada European Medicines Agency(EMA)Ministry of Health(Israel)Medicines and Healthcare products Regulatory Agency(UK)Swissmedic(Switzerland)Therapeutic Goods Administration(Aus

7、tralia)Provides a forum to foster scientific alignment between generic drug regulatory agencies.Generic Drug Clusterfda.gov/cdersbiafda.gov/cdersbia9 Sought to understand inactive ingredient evaluation practices of fellow regulatory jurisdictions within the Cluster.Seven questions sent to Cluster me

8、mbers for their responses.Polling fda.gov/cdersbiafda.gov/cdersbia10Assess the safety of inactive ingredients the same way as the reference product.Agency AEvaluates inactive ingredients especially for pediatric patients.Agency BOnly assess new inactive ingredients or inactive ingredients used in th

9、e pediatric population.Clinical data are available to inform on other risks.Assessment is based on provided data for new inactive ingredients or compliance to published thresholds for the pediatric population.Agency CReviews novel inactive ingredients.Novel including inactive ingredients used for th

10、e first time,at a greater daily exposure than what is normally administered,or new route of administration.Utilizes literature and available databases.May review supporting safety data(nonclinical/or clinical)for justification.Agency DEvaluation for inactive ingredients that are novel,given via nove

11、l route,the human dose is increased,or the administered strength(for a non-oral product)is increased.Sponsor provided information and data currently held by Agency.Agency EThe quality assessor always considers the safety of the excipients and if any uncertainties(e.g.new,or unusual excipients)the no

12、n clinic assessor is consulted.We check monographs,food legislation,reliable published data.Agency FWe assess all inactive ingredients within a generic formulation.If amounts exceed what is accepted for the Agency or the inactive ingredient is found to be novel(not in approved product or an in appro

13、ved product for the same route of administration);the applicant may submit literature,clinical data,toxicological data,etc.for review by our Office of Safety and Clinical Evaluation.US FDAQuestion 1:Does your Agency assess the safety of inactive ingredients in a generic formulation?If yes,how do you

14、 perform safety assessment?fda.gov/cdersbiafda.gov/cdersbia11Key TakeawayEach regulatory jurisdiction evaluates the safety of inactive ingredients for a test product,but approach varies.fda.gov/cdersbiafda.gov/cdersbia12Rely on databases maintained by other jurisdictions.Agency ADoes not maintain a

15、database for inactive ingredients and accepted levels.Inactive ingredients are considered on a case-by-case basis.Nothing is banned.Complete formulations of all drug products are recorded within a database.Agency BDoes not maintain a database.Does not maintain a database for excipients that the Agen

16、cy would consider unacceptable in your jurisdiction but may be allowed in other countries.Agency CConsultation would be sent to clinical division.Rely on its database and that of another Agency.Agency DNonclinical studies,published literature,and safety reviews from other Agencies are used.Do not ma

17、intain a database of accepted levels for inactive ingredients for prescription drug products.Agency EThe quality assessors assess the safety of the excipients based on already approved drug products containing the excipients,the amounts in relation to the route of administration,dosage regimen,durat

18、ion and exposure in relation to age of the patient.Maintains database.There is no specific list of unacceptable excipients allowed in other jurisdictions.Agency FWe maintain the publicly available Inactive Ingredient Database which contains accepted levels for inactive ingredients per unitof an appr

19、oved drug product and per maximum daily intake for that drug product.Our Code of Federal Regulations contains inactive ingredients that have general safety concerns.US FDAWhat type of data does your Agency rely on during your assessment of safety?Do you maintain a database or list of inactive ingred

20、ients which are unacceptable in your jurisdiction?fda.gov/cdersbiafda.gov/cdersbia13A few regulatory jurisdictions maintain databases for acceptable levels of inactive ingredients or have a list of inactive ingredients which are banned.Key Takeawayfda.gov/cdersbiafda.gov/cdersbia14Qualitative and qu

21、antitative composition of generic product should comply with the composition of the reference product and any deviation should be justified.Agency AThe MDD in the label for the drug product is considered or worst-case scenario(e.g.,youngest child for which the drug is indicated).For eye drops the vo

22、lume of the drop and the conjunctival sac are considered.There are challenges with topical ointments and cream,however 100%absorption of inactive ingredient is considered initially to determined if any potential problems arise.No standard weight is used.Agency BFor adults a general weight of 50 kg.R

23、efer to WHO charts for pediatric population.Agency CMaximum daily exposure is considered for inactive ingredients.If the amount is greater than what is normally delivered,the safety should be supported and reviewed.The MDD would be based on a product monograph,A standard weight of 50 kg is utilized.

24、The clinical assessor evaluates safety data studies or data in literature to determine the permitted daily exposure in humans.A weight of 50 kg is used for an adult.Agency DIf non-clinical safety assessment is considered necessary MDD is evaluated based on label and if based on weight estimation is

25、made by using information from for example WHO on age,weight and length.When dosing is by BSA(mg/m2)conversion to mg/kg to calculate MDD is done by dividing BSA dose by a mass constant(km).Special care is taken for products with a pediatric indication.Agency EIntake of an inactive ingredient is calc

26、ulated with respect to MDD in label.If no MDD is identified,maximum clinical doses are identified from clinical trials.Where local assessment is required,it is based on strength rather dose.A 50 kg weight is assumed where mg doses are specified in the label(to yield highest expected amount)and 70 kg

27、 is used where doses are mg/kg or mg/m2(for a typical adult).Agency FMDE of a drug product based on MDD of the drug product as specified in the RLD label.For drug products that do not specify an MDD or the MDD is unclear we may consult the Office of Safety and Clinical Evaluation.A weight of 60 kg i

28、s used if not specified in the drug product label.For drug products administered based on body surface area(mg/m2)a standardized average body surface area is used.Body weights for children are taken from 95thpercentile for boys CDC growth charts unless.US FDADo you evaluate the MDE of each inactive

29、ingredient based on the MDD of the drug product?If not,what is your approach?How do you assess MDDs and if not specified in the RLD label do you rely on a standard weight or BSA?fda.gov/cdersbiafda.gov/cdersbia15 For most regulatory jurisdictions MDD is determined from the RLD label.If a weight is n

30、ot specified in the RLD for dosing dependent on weight,some jurisdictions utilize 50 or 70 kg for adults.Key Takeawayfda.gov/cdersbiafda.gov/cdersbia16At times may differentiate between various grades when it is deemed relevant.Agency AGrade is not usually stated in product information.Grade is usua

31、lly recorded in regulatory information.Agency BNo unless there is a reason to do so(e.g.,particle size).Agency CWhen considering if an inactive ingredient is novel,different grades are not generally considered unless there is literature that states otherwise.Agency DConsidered only in safety assessm

32、ent where impurities are recognized to contribute to toxicity of an inactive ingredient.Agency EThis may be done on a case-by-case basis.Agency FConsiders different grades of inactive ingredients.Justifications can be made by leveraging data for various grades present in the same inactive ingredient

33、 group.US FDADo you differentiate between different grades for an inactive ingredient for a solid oral dosage form or do you leverage data from various grades of the same inactive ingredient?fda.gov/cdersbiafda.gov/cdersbia17Most regulatory jurisdictions evaluate difference in grades for inactive in

34、gredients on a case-by-case basis.Key Takeawayfda.gov/cdersbiafda.gov/cdersbia18Considered in specific cases(e.g.,use of alcohol in formulation indicated for pediatric population).Agency ACase-by-case basis considering risk versus benefit.Agency BOnly assess new inactive ingredients or inactive ingr

35、edients used in the pediatric population.Clinical data are available to inform on other risks.Assessment is based on provided data for new inactive ingredients or compliance to published thresholds for the pediatric population.Agency C Will consider if the data submitted is sufficient to characteriz

36、e safe use in the intended population,and according to the duration of use and route of administration of the drug(and inactive excipients).Particularly for pediatric formulations,the clinical division will additionally assess excipients as per what is presented in ICH guideline E11(Clinical Investi

37、gations of medicinal products in the pediatric population).Duration of use:Yes,it is considered.Agency DConsidered as needed.Acceptable levels can vary or be justified from duration,indication,etc.For excipients exhibiting low toxicity,acceptable levels will generally show widespread applicability a

38、nd continue to be acceptable in more sensitive groupsAgency EThe context of use is considered with respect to patient population and route of exposure and in some cases also rate of administration.Pediatric population is always considered.Duration of treatment can also be considered in some cases.Ag

39、ency FWe consider context of use when evaluating inactive ingredients.We evaluate all inactive ingredients in pediatric or renally impaired population.Duration of use is also considered in drug products indicated for the pediatric population.We also justify inactive ingredient amounts based on the s

40、ame route of administration as exposure may vary greatly.US FDADo you consider the context of use for the drug product in which the inactive ingredient is present(i.e.,population,duration of use,or route of administration)?fda.gov/cdersbiafda.gov/cdersbia19Most regulatory jurisdictions considered co

41、ntext of use on a case-by-case basis.Special attention given to pediatric population.Key Takeawayfda.gov/cdersbiafda.gov/cdersbia20Flavoring agents and colorants should comply with internationally accepted purity criteria in food use.Agency AFlavorings must comply with food legislation.There is no r

42、egulatory requirement to label natural ingredients in medicines).Colors the same colors as used in foods can be used in medicines.Agency BConsider the national food regulations for flavoring agents and colorants and take published thresholds into consideration.Agency CColoring agents must be in acco

43、rdance with Food and Drug Regulations,The full list of components should be provided including the qualitative&quantitative formulation.Interactions between the excipients and/or the API would be assessed(e.g.,degradation products).Compatibility studies would be considered.Otherwise,no other special

44、 considerations.Agency DIf it is a new flavor or coloring agent,assessment will be through submitted nonclinical data,or acceptability by reference to approval for use in food.Special consideration will be given to sub-excipients depending on dose(rather than mere presence).Agency EFlavoring agents

45、should comply with food legislation and where applicable the exposure of any excipient with known safety concerns are evaluated.There are special considerations for components with known safety concerns,specific considerations for youngest age groups.Agency FThe established use for color additives c

46、an be found in Title 21 Code of Federal Regulations Sections 70 through 82.In general,we evaluate flavors as a whole by utilizing amounts present in other approved products for the same context of use.However,if the flavor is determined to be novel,then the individual components of the flavor are ta

47、ken into consideration.All inactive ingredients such as benzyl alcohol or propylene glycol may need further justification for use in the flavor if it is contained in a drug product indicated for the pediatric population.US FDAHow do you assess safety of flavoring agents and colorants?fda.gov/cdersbi

48、afda.gov/cdersbia21 Some regulatory jurisdictions state that flavorings and coloring agents must comply with criteria in their jurisdiction for food.Others have separate regulations for coloring agents.Subcomponents may be given special consideration if there are known safety concerns.Key Takeawayfd

49、a.gov/cdersbiafda.gov/cdersbia22Does not maintain such a list.Agency AFollows national guidance.Agency BYes.“Pharmaceutical excipients of particular interest”.Agency CThere is no list.However,as part of the label review,we consider the following non-medicinal ingredients for safety reasons and inter

50、nal consultation are done to determine if a warning statement is recommended for the label:Aspartame,benzyl alcohol,lactose,sucrose,latex,peanut oil,sepitrap 80(polysorbate 80 and magnesium aluminometasilicate)Agency DYes,if certain ingredients are present they are required to be declared on a medic

51、ines label.This includes sulfates and benzoates.This list also contains certain restrictions and labelling requirements(e.g.,tartrazine).Agency EYes,there is a list.In addition,there are databases or specially compiled lists that include excipients that may need a warning statement in the label.Agen

52、cy FA list of inactive ingredients needing warning statements in the label are contained in Title 21 Code of Federal Regulations Section 201(e.g.,metabisulfite and tartrazine).US FDADo you maintain a list of inactive ingredients that may need a warning statement in the label(e.g.,tartrazine)?fda.gov

53、/cdersbiafda.gov/cdersbia23Some jurisdictions do not maintain a list of inactive ingredients that may need a warning statement.Others consult internal guidelines or regulations.Key Takeawayfda.gov/cdersbiafda.gov/cdersbia24Case Studies and Considerationsfda.gov/cdersbiafda.gov/cdersbia25ANDA submitt

54、ed for“Drug A”Delayed-release Capsules Consult sent to Office of Safety and Clinical Evaluation for evaluation of proposed level for talc.Proposed level was higher than maximum approved level.Talc is generally recognized as safe(GRAS)as a food additive.Conversely talc is not absorbed in the GI tract

55、 which may worsen GI adverse events associated with therapy for this drug product.Adequate information could not be identified to justify lifelong use at the proposed levels in adults and children.Amount of talc was determined to be unacceptable.Case Study I:Evaluation all Inactive Ingredients in Dr

56、ug Productsfda.gov/cdersbiafda.gov/cdersbia26ANDA submitted for Nystatin and Triamcinolone Acetonide Cream,100,000 units/g;0.1%Treatment of cutaneous candidiasis.Consult sent to Office of Safety and Clinical Evaluation for evaluation of a proposed level for inactive ingredient“X”.Proposed level was

57、higher than maximum approved level.Proposed amount of“X”significantly exceeded currently approved amounts for topical products.“X”is a penetration enhancer for topical products,whereas lower weight“Xs”are minimally absorbed through the skin.Concern for increase absorption of APIs,namely triamcinolon

58、e in children.The amount of“X”was found unacceptable and could not be justified.Case Study II:Evaluating Different Grades of Inactive Ingredientsfda.gov/cdersbiafda.gov/cdersbia27 Evaluation of all inactive ingredients in a drug product could prove useful,especially for vulnerable subpopulations.Eva

59、luation based on grades may adequately define the safety profile of inactive ingredients.Considerationsfda.gov/cdersbiafda.gov/cdersbia28Summary Commonalities exist between regulatory agencies in the Cluster regarding evaluation of inactive ingredients for drug products.Further exploration of these

60、areas is needed to determine if we can alleviate burden on industry for justifying proposed inactive ingredient amounts while ensuring safety.fda.gov/cdersbiafda.gov/cdersbia29Office of Generic DrugsPartha Roy,Ph.D.(OB/IO)Nilufer Tampal,Ph.D.(OB/IO)April Braddy,Ph.D.(OB/DBIII)Ke Ren Ph.D.(OB/DBIII)Yi Zhang,Ph.D.(OB/DBIII)Rong Wang,Ph.D.(OB/DBI)Robert Dorsam,Ph.D.(OSCE)Melanie Mueller,Ph.D.(OSCE)Sarah Ibrahim,Ph.D.(OGD/IO)Debbie Cordaro,(OGD/QMS/IO)Acknowledgements