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Equivalence approches for complex generics DIA 11 april 2019

This is a workshop that i gave a few days ago on bioequivalence of complex generics like peptides, polymers, liposomes, colloids, ophthamic and topical produtcts.

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Equivalence approches for complex generics DIA 11 april 2019

  1. 1. Prof. (Dr.) Bhaswat S. Chakraborty Emeritus Professor, Institute of Pharmacy, Nirma University Former Sr.VP &Chair, R&D, Cadila Pharmaceuticals Former Director, Biopharmaceutics, Biovail, Toronto Former Sr. Efficacy & Safety Reviewer, TPD (Canadian FDA), Ottawa Equivalence Approaches for Complex Generics
  2. 2. Disclaimer The views and opinions expressed in the following PowerPoint slides are those of the individual presenter and should not be attributed to DIA, its directors, officers, employees, volunteers, members, chapters, councils, Communities or affiliates, or any organization with which the presenter is employed or affiliated. These PowerPoint slides are the intellectual property of the individual presenter and are protected under the copyright laws of the United States of America and other countries. Used by permission. All rights reserved. DIA and the DIA logo are registered trademarks or trademarks of Drug Information Association Inc. All other trademarks are the property of their respective owners. 2
  3. 3. Complex Generics? GDUFA II Commitment Letter Definition Complex Mixtures • Peptides, polymeric compounds, complex mixtures of APIs, naturally sourced ingredients Complex formulations • Liposomes, colloids Complex Routes of Delivery • Locally acting such as dermatologic products and complex ophthalmologic and otic products that are formulated as suspensions, emulsions or gels Complex Dosage Forms • Transdermals, MDI, extended release injectables Complex drug-device combination products • Auto-injectors, MDI Other products where complexity or uncertainty would benefit from early scientific engagement 3
  4. 4. A Note on Pre-ANDA Program on Complex Generics Research • See FDA site https://www.fda.gov/Drugs/ResourcesForYou/Consumers/BuyingUsin gMedicineSafely/GenericDrugs/ucm578012.htm • Internal (to FDA) and external research • Successful research often translates into definitive PSGs Product specific guidances (PSGs) • If no PSG is available have a pre-ANDA meeting with FDA Pre-ANDA meeting • GDUFA II describes three types of meetings for prospective ANDA applicants seeking to develop generic versions of complex products: Product development meetings, Pre-submission meetings, and Mid-review cycle meetings. Controlled correspondence • FDA will not answer to queries regarding a new approach to BE 4
  5. 5. Product Development Meetings The product development meeting is a scientific meeting on a specific issue for a complex generic product FDA will provide advice and feedback to applicants on new or alternative approaches to demonstrating equivalence to the reference listed drug Conditions for the meeting: • The meeting must concern a complex product that does not have FDA guidance for the reference product, or • The applicant has an alternate approach to demonstrating BE (in vitro replacement of clinical endpoints) • The package must be complete, and the questions should be beyond the scope of what a controlled correspondence could answer 5
  6. 6. Product Development Meetings.. Most importantly, the meeting is designed to improve ANDA review efficiency FDA will not be answering your questions about NDA submissions After the meeting, FDA will issue official minutes within 30 days. If you’d like FDA to take your perspective into consideration, you can submit your meeting summary via the portal However, be advised that FDA minutes are the official record of the meeting. 6
  7. 7. A Complex Product A complex product is defined in the GDUFA II commitment letter and includes products with • complex active ingredients, formulations, routes of delivery or dosage forms • complex drug-device combinations • other products where complexity or uncertainty concerning the approval pathway • or other alternative approach would benefit from early scientific engagement 7
  8. 8. A Pre-Submission Meeting The pre-submission meeting with FDA is to discuss an ANDA to be submitted within the next year. At this meeting FDA can give advice that will support efficient review and improve the chance of first cycle approval • E.g., information that should be clarified before submitting the ANDA or share information from product development meetings • FDA will generally grant pre-submission meetings if an applicant had a product development meeting • If they did not have a product development meeting, FDA can still have a meeting with applicant provided review efficiency improves and FDA resources are available To request any type of meeting, you need to take several administrative steps (e.g., request a pre-assigned ANDA number to track your interactions with FDA all the way to approval) https://www.fda.gov/ForIndustry/UserFees/8
  9. 9. A Pre-Submission Meeting.. A pre-submission meeting request should contain an outline of the unique, novel or complex aspects of your upcoming submission that you will present at the meeting If you have specific questions, provide appropriate background material and data related to those questions FDA will evaluate the meeting request and respond within the GDUFA II goal date. For fiscal years 2018 and 2019, FDA will grant or deny the meeting request within 30 days of receipt • For fiscal years 2020 through 2022, FDA will grant or deny the meeting request within 14 days of receipt • FDA will then conduct the pre-submission meeting within 120 calendar days from the date the meeting was granted https://www.fda.gov/ForIndustry/UserFees/9
  10. 10. A Mid-Review Cycle (MRC) Meeting A MRC meeting for a complex product is held only during the first review cycle with ANDA applicants that have participated in a prior product development or pre-submission Meeting The mid-review-cycle meeting affords an opportunity for FDA to discuss issues identified during review with the applicant The Regulatory Project Manager (RPM) assigned to the ANDA will contact the applicant to schedule the meeting (held by teleconference) ANDA applicants that participated in a product development and/or pre-submission meeting should not request a mid- review-cycle meeting contd.. 10
  11. 11. A Mid-Review Cycle Meeting.. The applicant may decline the meeting through a letter because these meetings are optional During the mid-review-cycle meeting, the RPM and certain members of the review team will participate in the teleconference FDA will provide the applicant with an update on the status of the review of its application An agenda will be provided by the RPM. The agenda will generally consist of possible deficiencies found by a discipline reviewer and/or review team. • If a letter has already been issued, the agenda will generally provide for a status update. FDA intends to send the agenda to the applicant 7 calendar days before the teleconference. https://www.fda.gov/ForIndustry/UserFees/11
  12. 12. Why such an Elaborate Approach for Complex Products? One category of complex generics has complex active ingredients such as peptides, complex mixtures, or natural source products For complex active ingredients, one approach is to apply modern analytical and quantitative analysis methods to characterize product-specific attributes & sameness thereof between API of RLD and Test For most peptide drugs, the active ingredient is clearly defined and can be well characterized However, characterizing the impurity profile of peptide-related substances and assessing the associated safety risks, including immunogenicity of generic product, is challenging https://www.fda.gov/ForIndustry/UserFees/12
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  14. 14. Why such an Elaborate Approach for Complex Products?? Because demonstration of bioequivalence of these products is really challenging One or just a few broad brushed guidelines are not adequate Often PK endpoint based crossover randomized in humans studies do now answer many relevant questions There may be requirements of demonstration of in vitro BE or some kind of modelling and/or simulation Typical 90% CI comparisons may be irrelevant The drug may be formulated alternatively only ….. 14
  15. 15. Peptide Products: Regulatory Pathways Peptides (≤ 40 amino acids) and fully synthetic peptides (<100 amino acids) are regulated as drug under FD&C Act 505(b)2 or 505(j) 15
  16. 16. Peptides: API Sameness Although compendial standards may be available for some peptides, comparative testing of the proposed generic synthetic peptide and RLD needs to be done by applying analytical methods to characterize the following properties • Primary sequence and physicochemical properties • Secondary structure • Oligomer/Aggregation states • Biological activities (by in vitro or animal studies) Irrespective of ANDA or 505(b)(2), the sameness may depend on the proposed product’s impurity profile, because differences in impurities may affect, among other things, the potential for immunogenicity. 16
  17. 17. Peptides: Impurities Peptide-related impurities • Degradation related – expected to be same between RLD and generic • Process related – synthetic process related: deletion, insertion, etc. Host-cell related impurities (rDNA origin only) Residual chemicals • As specified in FDA and ICH guidelines 17
  18. 18. ANDAs for a Synthetic Glucagon, Liraglutide, Nesiritide, Teriparatide, Or Teduglutide Requirements: • RLD – an approved peptide of rDNA origin • Active ingredient sameness and impurities Sameness of the Test API to that of the RLD with respect to: • Primary sequence and physicochemical properties, • Secondary structure, • Oligomer/aggregation states, and • Biological activity/function (by in vitro or animal studies) For each peptide-related impurity that is found in both the proposed generic synthetic peptide and the RLD, the level of such impurity in the proposed product is the same as or lower than that found in the RLD 18
  19. 19. ANDAs for a Synthetic Glucagon, Liraglutide, Nesiritide, Teriparatide, or Teduglutide.. The Test product does not contain any new specified peptide-related impurity (i.e., an impurity that is not also present in the RLD) that is >0.5% & For any new specified peptide-related impurity NMT 0.5%, the impurity (e.g., the amino acid sequence and structure) has been characterized & the impurity does not affect the safety, immunogenicity and effectiveness Each peptide-related impurity that is 0.10% or greater must be identified For each new specified impurity that is NMT 5%, justifying data that any physicochemical properties, biological activity, or immunogenicity 19
  20. 20. ANDAs for a Synthetic Glucagon, Liraglutide, Nesiritide, Teriparatide, or Teduglutide… Each new impurity must not contain sequences that have an increased affinity for MHC (T-cell epitopes) & the Test product does not alter the innate immune activity FDA may recommend conducting additional comparative studies e.g., in vitro, in vivo animal, PK/PD equivalence to assess whether Test product meets relevant approval standards (methods & controls used in the manufacture, processing, and packing to assure and preserve its identity, strength, quality, and purity) If it is necessary to conduct clinical studies to establish the safety or effectiveness of a Test product, go for 505(b)(2) 20
  21. 21. rDNA Expressed Synthetic Peptide Products.. Statistical standards for equivalence • Usually not applicable unless an a clinical study is required 21
  22. 22. Complex API Products: Sevelamer CO3 Tablets Requirements (US): PSG AVAILABLE • API sameness (based on its synthetic route and comparative physico-chemical characterizations) • Two in vitro bioequivalence studies • Study 1: In vitro equilibrium binding study with and without acid pre- treatment at pH 4 and pH 7 • Study 2: In vitro kinetic binding study with and without acid pre-treatment at pH 4 and pH 7 Requirements (EU) • In-vitro equilibrium binding study and a kinetic study according to the FDA guidance • A PD study with the primary endpoint incidence of treatment emergent AEs and rate of withdrawal due to AEs. Secondary endpoint was level of phosphorus in the blood in hemodialysis patients. 22
  23. 23. Complex API Products: Sevelamer CO3 Tablets Sevelamer carbonate, is a polymer Same polymeric structure as the hydrochloride and hence same approach to BE Sameness to be demonstrated: • Degree of crosslinking • Degree of protonation • Total titratable amine: • Particle size • Elemental analysis. • Swelling index • FTIR, XRD, DSC 23
  24. 24. Sevelamer: Equilibrium Binding Study Study 1: PIVOTAL In vitro equilibrium binding study with and without acid pre-treatment at pH 4 and pH 7 • Incubate the Test and Reference products with at least eight different concentrations of phosphate, with and without acid pretreatment, at pH 4 and pH 7 • … Phosphate concentrations should be spaced along the spectrum until the maximum binding is clearly established. All incubations should be conducted at 37°C • Each binding study should be repeated at least 12 times • Length of time selected for incubation with the phosphate- containing medium should yield maximum binding Swearingen et al., J. Pharm. Biomedical Anal. 29 (2002), pp. 195-201. 24
  25. 25. Sevelamer: Kinetic Binding Study Study 2: SUPPORTING In vitro kinetic binding study with and without acid pre-treatment at pH 4 and pH 7 • Incubate the Test and Reference products with at least eight different concentrations of phosphate for at least eight different lengths of time, with two different phosphate concentrations, with and without acid pre-treatment, at pH 4 and pH 7 • Whole tablets should be used in the study • The phosphate concentrations used in each kinetic binding study should be the lowest and highest used in the corresponding equilibrium binding study Swearingen et al., J. Pharm. Biomedical Anal. 29 (2002), pp. 195-201. 25
  26. 26. Sevelamer: Analytes and Stats Standards Analytes to measure: Unbound phosphate in filtrate (to calculate phosphate bound to resin) • For the in vitro equilibrium binding study, the Langmuir binding constants k1 and k2 should be determined. The Test/Reference ratio should be calculated for k1. The 90% confidence interval should be calculated for k2 with the acceptance criterion of 80% to 120%. • For the in vitro kinetic binding study, the Test/Reference bound phosphate ratios at the various times should be compared but not subjected to the 90% confidence interval criterion. Bioequivalence based on (90% CI): The Langmuir binding constant k2 from the equilibrium binding study. Swearingen et al., J. Pharm. Biomedical Anal. 29 (2002), pp. 195-201. 26
  27. 27. Ophthalmic Ointment Products Ophthalmic Ointments are difficult to characterize and the physicochemical characteristics are difficult to correlate with in vivo performance For in-vitro BE demonstration two approaches can be important • Development of dissolution methods which can discriminate mfg. differences and can correlate the in-vivo performance of Test & RLD • Evaluate how the manufacturing differences can affect their relative physicochemical properties of Test and RLD 27
  28. 28. Ophthalmic Emulsion & Suspension Products: Disso & PC Characterization Q1/Q2 (compositionally equivalent) ophthalmic suspension formulations were manufactured using indomethacin. The manufacturing method was varied to produce particles that varied in size and viscosity A flow through dissolution device was designed so that the suspension (50 µl) is injected in the upper compartment, and the samples are withdrawn from the lower compartment under a filter membrane The upper compartment was static while sink conditions prevailed in the lower compartment with flow. In vivo experiments were carried out in albino rabbits 28
  29. 29. Ophthalmic Emulsion & Suspension Products: Disso & PC Characterization Suspensions were instilled into the eyes and drug concentrations were determined at various times until four hours from the lacrimal fluid, cornea and aqueous humour using LC/MS Computational models were built to simulate drug dissolution in the flow device and pharmacokinetic processes in the rabbit eyes. The dissolution rates increased with decreasing particle size and the dissolution lasted about two hours for indomethacin In vivo rabbit experiments revealed differences in the indomethacin suspension behaviour: smaller particle size resulted in higher ocular bioavailability and peak concentrations of indomethacin in aqueous humour, while lowering of viscosity resulted in reduced concentration in the cornea and aqueous humour 29
  30. 30. Ophthalmic Emulsion & Suspension Products: Disso & PC Characterization Prediction of intravitreal drug delivery of porous silicon particles: • The eye poses a particular challenge for delivery systems because of the sensitive foreign object response of ocular tissues • Porous silicon is an optimal material for many biological applications because of its excellent biocompatibility, degradability and versatile surface chemistry • An in vitro setup that can mimic the eye to test these delivery systems and discriminate between similar formulations (such as generics).was designed A flow cell to be used in the in vitro dissolution device has been designed to prevent leakage and maintain the pressure The quartz window provides the visualization and enable the imaging measurement. Figure 1 depicts the features of the flow cell and figure 2 is the picture of the whole in vitro dissolution study setup 30
  31. 31. BE of Ophthalmic Products
  32. 32. BE of Ophthalmic Products.. 32
  33. 33. BE of Ophthalmic Products... 33
  34. 34. BE of Ophthalmic Products…. 34
  35. 35. BE of Ophthalmic Products….. 35
  36. 36. Complex Formulations: Bupivacaine Liposomes Injection 36
  37. 37. Complex Formulations: Bupivacaine Liposomes Injection IVRT NEXT Session 2 slides 37
  38. 38. Complex Formulations: Iron Colloids (Ferumoxytol) 2 studies • Study:. Fasting, single-dose, randomized, parallel in vivo study Strength: 510 mg iron/17 mL (Dose: 510 mg) • Subjects: Healthy males and non-pregnant females, general population • Analytes to measure (in appropriate biological fluid): Ferumoxytol- associated iron in plasma or serum Transferrin-bound iron in serum • Bioequivalence based on (90% CI): Ferumoxytol-associated iron in plasma or serum • Study 2: Particle size distribution study; In vitro testing on at least three lots of both test and reference products • Parameters to measure: D10, D50, D90 • Bioequivalence based on: D50 and SPAN [i.e. (D90-D10)/D50] or polydispersity index using the population bioequivalence statistical approach. 38
  39. 39. Complex Formulations: Iron Colloids (Ferumoxytol).. The proposed parenteral drug product should be qualitatively (Q1) and quantitatively (Q2) the same to the RLD. Equivalence in the stoichiometric ratios of polyglucose sorbitol carboxymethylether, iron, and other relevant components need to be established. Sameness in physicochemical properties needs to be established. These in vitro characterizations should be conducted on at least three batches of the ANDA and RLD. Attributes that should be included in the characterization are: • Iron core characterizations including but not limited to core size determination, iron oxide crystalline structure and iron environment • Composition of carbohydrate shell. • Magnetic properties. • Particle morphology • Labile iron determination under physiologically relevant conditions. The test can be performed with ultra-filtration, in vitro hemodialysis system, the catalytic bleomycin assay of spiked human serum samples, the spectrophotometric measurement of Fe reduction, or other methods that are validated for accuracy and precision. 39
  40. 40. Topical Dermatological Drug Products Comparative bioavailability from topical dermatological drug products can be computed through dermal PK sampling, using in vivo techniques known as microdialysis or open flow microperfusion These are conducted by inserting a fine, semi- permeable tube, called a probe, into the dermis layer of the skin As a physiological buffer solution flows through the probe, the concentration of drug in the dermis equilibrates with the solution inside the probe, and that concentration can thereby be monitored/measured over time as the solution is collected 40
  41. 41. Products and Study Design T = Acyclovir cream 5 % (Acyclovir 1A Pharma—Creme; 1A Pharma GmbH, Vienna, Austria) R = Acyclovir cream 5 % (Zovirax®; Valeant, Bridgewater, NJ, USA) • R1 = Central site; R2 = Non-central site Study design: Replicate; T and R acyclovir cream 5 % products; n = 40 (20 subjects in the independent replicate leg design used for this study) After enrolment and qualification of study subjects based upon the protocol inclusion and exclusion criteria, a set of three treatment sites (referred to as the ‘test triad’) was demarcated on each thigh Twelve dOFM probes were inserted intradermally (two replicate probes per treatment site) and dermal interstitial fluid was continuously sampled at 1 µL/min using sterile perfusate 41
  42. 42. Bodenlenz et al. Clin Pharmacokinet. 2017; 56(1): 91–98. 42
  43. 43. Dermal Open Flow Microperfusion Bodenlenz et al. Clin Pharmacokinet. 2017; 56(1): 91–98. 43
  44. 44. Topical Dermatological Drug Products This approach would facilitate the in situ measurement of drug concentrations in the dermis at different sampling time points, which can be compared between generic drug products and their corresponding RLDs This approach can be utilized to compare the rate and extent to which a drug becomes available at or near the site of action in the skin when applied topically in semisolid dosage forms like creams, ointments and gels, or even in topical patches This does not rule out in vivo BE rather quality and performance from multiple, rationally selected, in vitro and/or in vivo approaches can be integrated 44
  45. 45. Dermal Open Flow Microperfusion Concentration profiles Bodenlenz et al. Clin Pharmacokinet. 2017; 56(1): 91–98. 45
  46. 46. Comparative PK 46
  47. 47. Comparative PK Bodenlenz et al. Clin Pharmacokinet. 2017; 56(1): 91–98. 47
  48. 48. BE Assessment Bodenlenz et al. Clin Pharmacokinet. 2017; 56(1): 91–98. 48
  49. 49. Conclusions Probe depth: • Consistent probe depths were confirmed for the R treatment sites (R 1: 0.83 ± 0.20 mm, R 2: 0.81 ± 0.22 mm, p = 0.5329). The mean probe depth (T: 0.73 ± 0.18 mm, p = 0.0007) was lower in the T treatment sites than it was in either R site, but a regression analysis indicated that there was no significant impact of probe depth on the AUC for acyclovir (p = 0.1001). Bioequivalence R2 vs R1: • BE was confirmed for the positive control products (R2 vs. R1) for AUC0–36h (0.86–1.18) and C max (0.86–1.21). 49
  50. 50. Conclusions Sample size recalculation: • An exploratory statistical re-sampling procedure showed that n = 36 (18 subjects in this study design) would have been sufficient to demonstrate BE for R2 vs. R1 based on AUC0–36h and n = 38 (19 subjects in this study design) would have been sufficient based on C max Bioequivalence R2 vs R1: • The negative control products (T vs. R 1) failed to demonstrate BE for both parameters, AUC0–36h (0.69– 1.05) and C max (0.61–1.02). Bodenlenz et al. Clin Pharmacokinet. 2017; 56(1): 91–98. 50
  51. 51. Challenges in BE Determination of Topical Products BE assessment of locally acting topical dosage forms using traditional PK endpoints is challenging. Historically, there were limited options for alternate approaches to PK or clinical endpoint BE studies FDA recognized the need to find more sensitive and efficient surrogate approaches to demonstrate BE for topical dermatological products. Development of new alternate BE approaches using a collective weight of evidence from in-vitro studies (e.g. IVRT, IVPT) 51
  52. 52. In Vitro BE Option: Acyclovir Cream Formulation Q1/Q2 Sameness: The test and RLD products are qualitatively and quantitatively same. Q3 Similarity: The physicochemical properties of test and RLD products are similar. In Vitro Release Test (IVRT) Studies: The test and RLD products have an equivalent rate of acyclovir release. In Vitro Permeation Test (IVPT) Studies: The rate and extent of acyclovir permeation through excised human skin from the test and reference products are comparable. There are other options e.g., In Vivo Clinical study 52
  53. 53. In Vitro Release Test (IVRT) Next Session… 53
  54. 54. In Vitro Permeation Test (IVPT) Next Session… 54
  55. 55. References Pre-ANDA Program https://www.fda.gov/Drugs/ResourcesForYou/Consumers/BuyingUsingMed icineSafely/GenericDrugs/ucm578012.htm Complex mixtures and Peptides https://www.fda.gov/ForIndustry/UserFees/GenericDrugUserFees/ucm549 165.htm Ophthalmic products https://www.fda.gov/ForIndustry/UserFees/GenericDrugUserFees/ucm549 164.htm Bupivacaine Liposomes Injection: Draft PSG available Ferumoxytol Iron Colloid Injection: Draft PSG available 55
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