BIOEQUIVALENCE STUDY: EXEMPTIONS AND WAIVERS This presentation is based on: 1. Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System Guidance for Industry U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER).December 2017. Biopharmaceutics. 2. ICH guideline Q3D M9 on biopharmaceutics classification system based biowaivers EMA/CHMP/ICH/493213/2018 3. Guidelines For Bioavailability & Bioequivalence Studies Central Drugs Standard Control Organization, Directorate General of Health Services, Ministry of Health & Family Welfare, Government of India, New Delhi. (March 2005) Objectives of this presentation: Understand the drug regulatory requirements for:  Conducting Bioequivalence Study or  Not Conducting Bioequivalence Study for obtaining regulatory marketing authorization for pharmaceutical formulations,  Bioequivalence studies are required or mandatory for certain formulations,  Exemptions are available for Bioequivalence Studies on certain formulations,  Waivers are granted by drugs regulatory authorities in certain cases, like Biopharmaceutical Classification System (BCS) Class-I and Class-III, Pharmaceutical Drugs, and some drug products with high safety margin, Propose a clinical classification system-Biotherapeutics Classification System (BTCS) based upon:  Bioavailability of pharmaceutical drug, and  Clinical Safety Margin of pharmaceutical drug Based on this Biotherapeutics Classification System (BTCS) Waivers may be requested for some pharmaceutical drug formulations, such as those with High Bioavailability and High safety Margin.

1. BIOEQUIVALENCE STUDY:
EXEMPTIONS AND WAIVERS
Dr. Ashok Kumar Batham,
M.B.,B.S., M.D., D.C.R.,
Phone: +91 93280 18777
Email: ashokpharmacol@gmail.Com
21-12-2019 Dr.Ashok Kumar Batham, BES Exemptions & Waivers 1

2. This Presentation is based on following
publications
1. Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-
Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification
System Guidance for Industry
U.S. Department of Health and Human Services Food and Drug Administration
Center for Drug Evaluation and Research (CDER).December 2017.
Biopharmaceutics.
2. ICH guideline Q3D M9 on biopharmaceutics classification system based
biowaivers
EMA/CHMP/ICH/493213/2018
3. Guidelines For Bioavailability & Bioequivalence Studies
Central Drugs Standard Control Organization, Directorate General of Health
Services, Ministry of Health & Family Welfare, Government of India, New Delhi.
(March 2005)
21-12-2019 Dr.Ashok Kumar Batham, BES Exemptions & Waivers 2

3. Objectives of this Presentation…..contd.
Understand the drug regulatory requirements for:
 Conducting Bioequivalence Study or
 Not Conducting Bioequivalence Study
for obtaining regulatory marketing authorization for pharmaceutical
formulations.
21-12-2019 Dr.Ashok Kumar Batham, BES Exemptions & Waivers 3

4. Objectives of this Presentation…..contd.
Understand:
 Bioequivalence studies are required or mandatory for certain
formulations,
 Exemptions are available for Bioequivalence Studies on certain
formulations,
 Waivers are granted by drugs regulatory authorities in certain cases,
like Biopharmaceutical Classification System (BCS) Class-I and Class-III,
Pharmaceutical Drugs, and some drug products with high safety
margin,
21-12-2019 Dr.Ashok Kumar Batham, BES Exemptions & Waivers 4

5. Objectives of this Presentation
Propose a clinical classification system-Biotherapeutics Classification System
(BTCS) based upon:
 Bioavailability of pharmaceutical drug, and
 Clinical Safety Margin of pharmaceutical drug
Based on this Biotherapeutics Classification System (BTCS) Waivers may be
requested for some pharmaceutical drug formulations, such as those with
High Bioavailability and High safety Margin.
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6. Bioequivalence Study Exemptions
Bioequivalence studies are not required
(exempted) in case of some drug formulations, and
are described in this presentation.
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7. Bioequivalence Study Waivers Based on BCS
Requirement of Bioequivalence Studies for obtaining marketing
authorization is Waived-Off by drugs regulatory authorities on the
basis of Biopharmaceutics Classification System (BCS) for drug
products falling in Class 1 and Class 3 [drugs are classified on the
basis of their (i) Solubility and (ii) Permeability].
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8. Bioequivalence Study Waivers Based on Proposed
Biotherapeutics Classification System (BTCS)
In an analogy to the Biopharmaceutics Classification System (BCS) a
Biotherapeutic Classification System (BTCS) based on the:
(i) Therapeutic Index and
(ii) Bioavailability
of the drug products is suggested.
This is included in this presentation.
In accordance to which drugs with (i) high therapeutic index and high
bioavailability, and (ii) high therapeutic index and low bioavailability may be
considered for waiver; and Bioequivalence Studies are mandated for drugs with
(i) low therapeutic index and low bioavailability, and (ii) low therapeutic index and
high bioavailability.
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9. Why Bioequivalence Studies Are Required
Bioequivalence Studies ensure:
• Translation of Chemical & Pharmaceutical Equivalence into
therapeutic equivalence
• Brand To Generic Shift & Vice-Versa
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10. Methods of Assessment of Equivalence
Between Products
1. Comparative bioavailability (bioequivalence) studies
2. Comparative pharmacodynamics studies in humans
3. Comparative clinical trials
4. in-vitro dissolution tests
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11. 1. Comparative Bioavailability (Bioequivalence)
Studies……contd.
Bioavailability: The rate and extent to which the active
ingredient or active moiety in a pharmaceutical drug
product is absorbed and becomes available at the site
of drug action when administered at the same molar
dose under similar conditions in an appropriately
designed study.
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12. 1. Comparative Bioavailability (Bioequivalence)
Studies.
Bioequivalence: The absence of a significant difference in the rate and extent
to which the active ingredient or active moiety in pharmaceutical
equivalents or pharmaceutical alternatives becomes available at the site of
drug action when administered at the same molar dose under similar
conditions in an appropriately designed study.
Bioequivalence studies with well defined pharmacokinetic (PK) end points
(Cmax, Tmax and AUC) are well accepted for ensuring therapeutic
equivalence between the Test and Reference Oral formulations.
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13. 2. Pharmacodynamic studies
• In instances where it is not possible to define
Pharmacokinetic (PK) Endpoint, a well justified
Pharmacodynamic (PD) Endpoint can be used to
demonstrate Bioavailability or Bioequivalence.
• Generally Pharmacodynamic Studies are not recommended
for oral drugs because PK endpoints are accurate, sensitive,
and reproducible.
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14. 3. Comparative Clinical Studies
Clinical trials with well defined endpoints can be done to demonstrate
bioequivalence when:
• Pharmacokinetic (PK) study in an accessible biological fluid (PK
approach) is not possible, and/or
• Pharmacodynamic (PD) approach is not possible.
• Above circumstances are very rare, therefore, use of this approach is
expected to be rare.
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15. 4. In-Vitro Dissolution Tests (Predictive of Human
In-Vivo Bioavailability)
• In vitro-in vivo correlation (IVIVC) describes the relationship
between in vitro attribute, such as the rate or extent of
drug release (dissolution profile) and plasma drug
concentration or amount of drug absorbed.
• This model relationship facilitates the rational development
and evaluation of extended-release dosage forms.
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16. Need For Bioequivalence Studies……contd.
BE Studies are required for:
• Solid oral formulations of systemically absorbed drugs.
• Evaluation of food effect
• Immediate Release (IR) dosage form is meant for serious
conditions
• Narrow therapeutic window/safety margin
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17. Need For Bioequivalence Studies……contd.
• Pharmacokinetic (PK) peculiarities - variable or incomplete absorption or
narrow absorption window, nonlinear pharmacokinetics, pre-systemic
elimination/high first-pass metabolism >70%
• Unfavourable physicochemical properties, e.g., low solubility, low permeability.
• Documented evidence for bioavailability problems
• High ratio of excipients to API.
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18. • Sustained Release (SR) or Modified Release (MR) Drug Formulations
• Non-oral and Non-injectable Formulations Designed for Systemic
Absorption - Transdermal Patches, Suppositories.
• Fixed Dose Combinations (FDCs)
• Non-solution Topical Formulations (Oral, Nasal, Ocular, Dermal, Rectal,
Vaginal, Products) – BA/BE (Pk) Studies Are Required To Assess
Unintended Systemic Exposure.
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Need For Bioequivalence Studies……contd.

19. Special BE Studies are required in New Drug Development:
• To establish link between early and late clinical trial
formulations
• If different formulations are used in clinical trials and stability
studies
• If formulations used in clinical trial are different from ‘to-
be-marketed’ formulations
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Need For Bioequivalence Studies……contd.

20. Bioequivalence Studies are Exempted (Not
Required)
A. Drugs for which data to substantiate the following is available:
When in-vitro dissolution data is considered to be sufficient
• Highest dose strength is soluble in 250 ml
• More than 80% dissolution occurs within 15 minutes
• At least 90% of administered oral dose is absorbed
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21. BE Studies are exempted (and in-vitro dissolution data is considered to be
sufficient) in case of additional (Different) strengths of the drug manufactured
by the same manufacturer, where all of the following criteria are fulfilled:
• qualitative composition of all the strengths is essentially the same;
• the ratio of APIs and Excipients in all the strengths is same, or, in the case of
small strengths, the ratio between the excipients is the same;
• method of manufacture is essentially the same;
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Bioequivalence Studies are Exempted (Not
Required)

22. 1. Drugs for parenteral administration – IV, IM,SC, IT, as aqueous
solutions containing the same API and excipients in same
concentrations.
2. Solution for oral use, containing API in same concentration,
and not containing an excipient known or suspected to affect
gastro-intestinal transit or absorption of the active substance
3. Powder for reconstitution as a solution for oral use
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Bioequivalence Studies are Exempted (Not
Required)

23. 4. Gas as a new drug
5. Otic or ophthalmic or topical product in the form of aqueous
solution containing the same API and excipients in same
concentrations.
6. Inhalation product or a nasal spray, as aqueous solution containing
the same API and excipients in same concentrations to be
administered with or without essentially the same device as the
reference product
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Bioequivalence Studies are Exempted (Not
Required)

24. Waiver of Bioequivalence Studies
• Bioequivalence studies are waived-off by drugs regulatory
authorities on the basis of Biopharmaceutics Classification
System (BCS), Class-1 and Class-3 drugs.
• Highly salutary pragmatic consideration by drugs regulatory
authorities.
• Saves time and regulatory cost of generic drugs.
• Obviates the need of unnecessary human exposure to the
risks associated with clinical research activities.
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25. Biopharmaceutics classification system (BCS)
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Class Solubility Permeability
Class-1 High Solubility High Permeability
Class-2 Low Solubility High Permeability
Class-3 High Solubility Low Permeability
Class-4 Low Solubility Low Permeability

26. Data Required To Support A Biowaiver
Request….contd.
The data should support that:
The drug substance that is:
• Highly soluble (BCS class 1 and BCS class 3) and
• Highly permeable (BCS class 1), and
The drug product is:
• Rapidly dissolving (BCS class 1) or
• Very rapidly dissolving (BCS class 3).
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27. Data Required To Support A Biowaiver Request
Sponsors/applicants requesting biowaivers based on the BCS are
required to submit:
A. Data supporting high solubility
B. Data supporting high permeability
C. Data supporting rapid, very rapid, and similar dissolution
D. Additional information
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28. Solubility
• The solubility class boundary is based on the highest
strength of an IR product that is the subject of a biowaiver
request.
• A drug substance is considered highly soluble when the
highest strength is soluble in 250 mL or less of aqueous
media within the pH range of 1 - 6.8 at 37 ± 1°C.
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29. Permeability
• Extent of absorption (fraction of dose absorbed) of a drug substance in
humans, is directly dependent on the rate of mass transfer across human
intestinal membrane.
• A drug substance is considered Highly permeable when the systemic BA or the
extent of absorption in humans is determined to be 85 percent or more of an
administered dose based on a mass balance determination (along with
evidence showing stability of the drug in the GI tract) or in comparison to an
intravenous reference dose.
• Alternatively, other systems capable of predicting the extent of drug
absorption in humans can be used (e.g., in situ animal, in vitro epithelial cell
culture methods).
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30. Dissolution
An Immediate Release drug product is considered rapidly dissolving
when a mean of 85 percent or more of the labeled amount of the
drug substance dissolves within 30 minutes, using United States
Pharmacopeia (USP) Apparatus 1 at 100 rpm or Apparatus 2 at 50 rpm
(or at 75 rpm when appropriately justified in a volume of 500 mL or
less (or 900 mL when appropriately justified) in each of the following
media:
(1) 0.1 N HCl or Simulated Gastric Fluid USP without enzymes;
(2) a pH 4.5 buffer; and
(3) a pH 6.8 buffer or Simulated Intestinal Fluid USP without enzymes.
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31. Model drugs
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Dr.Ashok Kumar Batham, M.D., Bioequivalence studies and
Biopharmaceutical Classification
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32. Examples of High Permeability (> 85%) Drugs
• Antipyrine
• Caffeine
• Ketoprofen
• Naproxen
• Theophylline
• Metoprolol
• Propranolol
• Carbamazepine
• Phenytoin
• Disopyramide
• Minoxidil
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Biopharmaceutical Classification
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33. Examples of Moderate Permeability (50-84%)
Drugs
• Chlorpheniramine
• Creatinine
• Terbutaline
• Hydrochlorothiazide
• Enalapril
• Furosemide
• Metformin
• Amiloride
• Atenolol
• Ranitidine
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Dr.Ashok Kumar Batham, M.D., Bioequivalence studies and
Biopharmaceutical Classification
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34. Examples of Low Permeability (<50%) Drugs
• Famotidine
• Nadolol
• Sulpiride
• Lisinopril
• Acyclovir
• Foscarnet
• Mannitol
• Chlorothiazide
• Polyethylene glycol 400
• Enalaprilat
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Dr.Ashok Kumar Batham, M.D., Bioequivalence studies and
Biopharmaceutical Classification
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35. Examples of Zero Permeability Drugs
• FITC-Dextran (MW ≥ 3000)
• Polyethylene glycol 4000
• Lucifer yellow
• Inulin
• Lactulose
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Biopharmaceutical Classification
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36. Examples of Drugs That Are Efflux substrates
• Digoxin
• Paclitaxel
• Quinidine
• Vinblastine
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Biopharmaceutical Classification
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37. Few Examples of Biowaivers Granted By EMEA
• Almotriptan
• Capecitabine
• Levofloxacin
• Lormetazepam
• Memantine
• Moxifloxacin
• Temozolomide
• Tramadol/Paracetamol
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Biopharmaceutical Classification
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38. Biotherapeutics Classification System (BTCS)
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39. Bioequivalence Study Waivers Based on Proposed
Biotherapeutics Classification System (BTCS)
In an analogy to the Biopharmaceutics Classification System (BCS) a
Biotherapeutic Classification System (BTCS) based on the:
(i) Therapeutic Index and
(ii) Bioavailability
of the drug products is suggested.
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40. Biotherapeutics Classification System (BTCS)
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Class Bioavailability Safety Margin
Class-I High Bioavailability High Safety Margin
Class-II Low Bioavailability High Safety Margin
Class-III High Bioavailability Low Safety Margin
Class-IV Low Bioavailability Low Safety Margin

41. Bioequivalence Study Waivers Based on Proposed
Biotherapeutics Classification System (BTCS)
In accordance to this classification:
Bioequivalence Studies should be mandatory for BTCS Class-
IV drugs,
Biowaivers should be granted for BTCS Class-I Drugs, and
Biowaivers may be considered on a case-to-case basis for
BTCS Class-II and Class-III Drugs.
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42. DBCS Class-I (High Bioavailability & High Safety
Margin)…….contd.
• Paracetamol (88%)
• Tramadol (75%)
• Tramadol-Paracetamol
(75% and 88%)
• Ibuprofen (>80%)
• Naproxen (100%)
• Baclofen (70%)
• Glimepiride (~100%)
• Glipizide (95%)
• Glyburide (90-100%)
• Sitagliptin (87%)
• Fluoxetine (80%)
• Escitalopram (80%)
• Trazodone (81%)
• Diazepam (100%)
• Lorazepam (93%)
• Alprazolam (88%)
• Clorazepate (91%)
• Aripiprazole (87%)
• Clonazepam (98%)
• Levetiracetam (~100%)
• Pregabalin (>90%)
• Lamotrigine (98%)
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43. DBCS Class-I (High Bioavailability & High Safety
Margin)………contd.
• Memantine (~100%)
• Galantamine (100%)
• Pramipexole (>90%)
• Fluconazole (90%)
• Isosorbide-5-mononitrate
(93%)
• Gemfibrozil (100%)
• Prednisone, Prednisolone,
Methylprednisolone (80%)
• Amoxycillin (93%)
• Cephalexin (90%)
• Cefazolin (>90%)
• Levofloxacin (99%)
• Moxifloxacin (86%)
• Clindamycin (87%)
• Linezolid (100%)
• Doxycycline and
Minocycline (95%)
• Metronidazole (99%)
• Isoniazid (100%)
• Dapsone (93%)
• Trimethoprim (>63% and
Sulfamethoxazole ~100%)
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44. DBCS Class-I (High Bioavailability & High Safety
Margin)
• Tamsulosin (100%)
• Solifenacin (90%)
• Letrozole (~100%)
• Leflunomide (95%)
• Lenalidomide
(>80%)
• Cidofovir (98%)
• Esomeprazole (90%)
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45. DBCS Class-II (Low Bioavailability & High Safety
Margin)
• Alendronate (0.7%)
• Ibandronate (0.63%)
• Aliskiren (2.6%)
• Lovastatin and Simvastatin (<5%)
• Atorvastatin (12%)
• Azithromycin and Erythromycin
(~35%)
• Buspirone (3.4%)
• Cinacalcet (~12%)
• Propranolol (26%)
• Lisinopril (25%)
• Ramipril (28%)
• Vardenafil (15%)
• Valsartan (23%)
• Olmesartan (26%)
• Losartan (35%)
• Dronabinol (10-20%)
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46. DBCS Class-III (High Bioavailability & Low
Safety Margin)
• Digoxin (74%)
• Quinidine (80%)
• Procainamide (83%)
• Phenytoin (90%)
• Phenobarbitone (100%)
• Leflunomide (93%)
• Lenalidomide (95%)
• Imatinib (>80%)
• Erlotinib (98%)
• Busulfan (60% mercaptopurine)
• Cyclophosphamide (70%)
• Emtricitabine (74%)
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47. DBCS Class-IV (Low Bioavailability & Low
Safety Margin)
• Cyclosporine (28%)
• Sirolimus (15%)
• Tacrolimus (25%)
• Cytarabine (<20%)
• Vinorelbine (27%)
• Paclitaxel (6.%)
• Mercaptopurine (12%)
• 5-Fluorouracil (28%)
• Idarubicin (28%)
• Isotretinoin (40%)
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48. Comments & Suggestions on Proposed BTCS
• Acceptance and use of the proposed Biotherapeutics Classification
System (BTCS) will:
• obviate the need of unnecessary Bioequivalence Studies,
• save time and regulatory cost of generic drugs, and
• obviate the need of unnecessary human exposure to the risks
associated with clinical research activities.
• Comments & Suggestions of the readers on Proposed BTCS are
solicited
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49. 21-12-2019 ANTI-DEPRESSANT DRUGS. Dr. Ashok Kumar Batham,M.D., 49