This document discusses approaches for demonstrating bioequivalence of complex generic drug products. It begins with an overview of the pre-ANDA program for complex generics, including product development meetings, pre-submission meetings, and mid-review cycle meetings. It then discusses specific challenges and considerations for complex active ingredients like peptides, as well as example complex drug products like sevelamer carbonate tablets and ophthalmic ointments and suspensions. The document emphasizes that demonstration of bioequivalence for complex generics often requires alternative approaches like in vitro studies and physiochemical characterization due to challenges with clinical endpoint studies.

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

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2

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. 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. 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. 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. 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. 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. 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. 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. 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. 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

13. 13

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. 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. 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. 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. 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. 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. 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. rDNA Expressed Synthetic Peptide Products..
Statistical standards for equivalence
• Usually not applicable unless an a clinical study is required
21

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. 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. 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. 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. 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. 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. 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. 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. 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. BE of Ophthalmic Products

32. BE of Ophthalmic Products..
32

33. BE of Ophthalmic Products...
33

34. BE of Ophthalmic Products….
34

35. BE of Ophthalmic Products…..
35

36. Complex Formulations: Bupivacaine
Liposomes Injection
36

37. Complex Formulations: Bupivacaine
Liposomes Injection
IVRT NEXT Session 2 slides
37

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. 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. 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. 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. Bodenlenz et al. Clin Pharmacokinet. 2017; 56(1): 91–98.
42

43. Dermal Open Flow Microperfusion
Bodenlenz et al. Clin Pharmacokinet. 2017; 56(1): 91–98.
43

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. Dermal Open Flow Microperfusion
Concentration profiles
Bodenlenz et al. Clin Pharmacokinet. 2017; 56(1): 91–98.
45

46. Comparative PK
46

47. Comparative PK
Bodenlenz et al. Clin Pharmacokinet. 2017; 56(1): 91–98.
47

48. BE Assessment
Bodenlenz et al. Clin Pharmacokinet. 2017; 56(1): 91–98.
48

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. 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. 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. 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. In Vitro Release Test (IVRT)
Next Session…
53

54. In Vitro Permeation Test (IVPT)
Next Session…
54

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

56. Ask