1. BCS based waiver Harmonization
Loice Kikwai, PhD
LCK Pharmaceutical Consulting
May 2nd, 2018

2. Deviating requirements defined by US-FDA and how to handle them in global product development projects

3. (Biopharmaceutics Classification System) BCS based Waiver of In-Vivo Bioequivalence Study Requirements
Biowaiver: for certain drug products, bioavailability may be measured or bioequivalence may be demonstrated by evidence obtained in vitro in lieu of in vivo data.
Therefore avoiding unnecessary human testing
IR solid oral dosage forms
PE and PA (with justification for US)
need for BE study
risk for differences
HS/HP
LS/HP
HS/LP
LS/LP

4. BCS Waiver Regulatory History
2000: US FDA Guidance for BCS Class 1
2001: EMA Guidance for BCS class 1
2010: EMA Guideline for BCS Class 1 and Class 3
2015: WHO Guideline for BCS Class 1 and Class 3
2015 final: In vitro dissolution recommendations and specifications for BCS Class 1 and Class 3
Stability and quality control
2015; final 2017: US FDA Guidance for BCS Class 1 and Class 3
EMA and US FDA: Published Individual BE or Product specific guidance's that advocate use of BCS biowaivers
FIP has published 44 monographs on BCS waivers
Japan has not implemented BCS based waiver

5. Study Requirements for BCS based Waiver of In-Vivo Bioequivalence
Solubility, Permeability and Dissolution are three factors determine the absorption of a drug from a formulation.
The drug product for which a bio-waiver is being requested should include a drug substance that is highly soluble (BCS class 1 and BCS class 3) and highly permeable (BCS class 1), and the drug product should be rapidly dissolving (BCS class 1) or very rapidly dissolving (BCS class 3).
If a drug substance has high solubility and high permeability, it is unlikely that formulation differences would affect absorption of the API, provided that:
dissolution of both formulations is rapid with respect to gastrointestinal transit time
there are no excipients that would affect gastrointestinal motility.

7. Bio-waivers –BCS Class 1 Drugs
Highly soluble
An amount of drug comparable to the highest strength/highest single therapeutic dose must be soluble in 250 mL of solution over wide pH range of 1 to 6.8 (1-7.5)
Shake-flask method or other method with justification
pH measure before and after addition of drug
Rapidly dissolving
0.1N HCl (pH 1.2); SGF w/o Enzymes, pH 4.5, and pH 6.8; SIF w/o Enzymes buffers
No surfactant and not organic solvent
Enzyme use for gelatin capsule shell
NLT 85% in 30 minutes with F2 calculation
500 ml or 900 mL or less, using basket at 100 rpm and paddle at 50 rpm or 75 rpm with justification
Sampling time points: 5, 10, 15, 20, 30, 45

8. Bio-waivers –BCS Class 1 Drugs
Highly permeable (Fa ≥ 85%)
Can be established by in vivo or in vitro methods
Extent of absorption in humans:
Based Mass-balance pharmacokinetic studies or Absolute bioavailability studies.
Stability in GIT for Mass balance studies
Intestinal permeability methods:
In vivo intestinal perfusions studies in humans.
In vitro permeation experiments with excised human or animal intestinal tissue.
Supportive data:
In vitro permeation experiments across epithelial cell monolayers.
In vivo or in situ intestinal perfusion studies in animals – limit use.
Origin of data: Sponsor or label of RLD
Literature as supportive data

9. Bio-waivers –BCS Class 3 Drugs
Highly soluble
An amount of drug comparable to the highest strength/highest single therapeutic dose must be soluble in 250 mL of solution over wide pH range of 1 to 6.8 (1-7.5)
Shake-flask method or other method with justification
pH measured before and after addition of drug
Very Rapidly dissolving
0.1N HCl (pH 1.2); SGF w/o Enzymes, pH 4.5, and pH 6.8; SIF w/o Enzymes buffers
No surfactant and not organic solvent
Enzyme use for gelatin capsule shell
NLT 85% in 15 minutes, no F2 needed
500 ml or 900 mL or less, using basket at 100 rpm and paddle at 50 rpm or 75 rpm with justification
Sampling time points: 5, 10, 15, 20, 30, 45

10. Bio-waivers –BCS Class 3 Drugs
Low permeability
It is not possible to show high permeability due to lack of data
Formulation
Qualitatively (excipients) the same and quantitatively very similar to the reference product
Due to the concern that excipients can have a greater impact on absorption of low permeability drugs

11. Bio-waivers –BCS Class 1 and 3 Drugs
Fixed Dose Combinations
Applicable for IR fixed dose combination products if all the drugs in the combination belong to BCS class 1
If all drug of the combination belong to BCS class 3 or a combination of class 1 and 3
Exceptions: No WAIVER
Modified Release Drug Products
Narrow Therapeutic Range Drugs
Dosage Forms Intended for Absorption in the Oral Cavity (e.g., sublingual or buccal tablets).

12. Conclusion - Publication
The BCS is well established as a valid approach for waiving the requirements for in vivo BA and BE studies of Class I and Class III IR solid oral dosage forms in both new and generic drug development.
The US-FDA, EMA, and WHO presently show good convergence with respect to the types of studies and documentation needed to establish that a drug is Class I or Class III.
Nonetheless, these differences are such that, by applying the most conservative of the approaches, it should be possible for a sponsor to design the same set of BCS biowaiver studies in preparing a submission for worldwide filing to satisfy US, European, and emerging market regulators.
It is hoped that the availability of BCS Class I and Class III biowaivers in multiple jurisdictions will encourage more sponsors to request waivers of in vivo bioavailability/bioequivalence testing using the BCS approach.

14. Data Submission Requirements – BCS 1 and 3
Data Supporting High Solubility
Description of test methods (analytical method, buffer composition).
Information on chemical structure, molecular weight, nature of drug substance, dissociation constants.
Test results summarized in a table with solution pH, drug solubility, volume to dissolve highest dose strength.
Graphical representation of mean pH-solubility profile.
The drug substance should also be chemically stable for 24 hours over this same pH range.

15. Data Submission Requirements – BCS I and 3
Data Supporting Rapid, Very Rapid and Similar Dissolution
A description of test methods, including information on analytical method(s) and composition of the buffer solutions
A brief description of the IR products used for dissolution testing
lot number, expiry date, dimensions, strength, and weight
Dissolution data obtained with 12 individual units of the test and reference products at each specified testing interval for each individual dosage unit.
A graphic representation of the mean dissolution profiles for the test and reference products in the three media.
Not less than 85 % of labeled amount are dissolved within 15 min in each of three buffers (pH 1.2, pH 4.5 acetate buffer, pH 6.8 phosphate buffer) – no further profile comparison of T and R is required
Not less than 85 % of labeled amount are dissolved within 30 min in each of three buffers (pH 1.2, pH 4.5 acetate buffer, pH 6.8 phosphate buffer)
Data supporting similarity in dissolution profiles between the test and reference products in each of the three media, using the f2 metric.

16. Data Submission Requirements – BCS 1 and 3
Data supporting High Permeability:
Class III: It is not possible to show high permeability due to lack of data
EMEA: Reliable investigations in human:
Data from absolute bioavailability and mass-balance studies could be used to support this claim.
BE between aqueous and solid formulations of a particular compound administered via the oral route may be supportive as it indicates that absorption limitations due to (immediate release) formulation characteristics may be considered negligible.
USFDA: For human pharmacokinetic studies, information on study design and methods used along with the pharmacokinetic data
For direct permeability methods, information supporting method suitability with a description of the study method, criteria for selection of human subjects, animals, or epithelial cell line, drug concentrations, description of the analytical method, method to calculate extent of absorption or permeability, and information on efflux potential (if appropriate).
A list of selected model drugs along with data on the extent of absorption in humans used to establish method suitability, permeability values and class for each model drug, and a plot of the extent of absorption as a function of permeability with identification of the low/high permeability class boundary and selected internal standard.
Permeability data on the test drug substance, the internal standards, stability information, data supporting passive transport mechanism where appropriate, and methods used to establish high permeability of the test drug substance.
See Summary tables for BCS - pproved/approvalapplications/abbreviatednewdrugapplicationandagenerics/ucm pdf

17. Additional Data Submission Requirements – BCS 1 and 3
The manufacturing process used to make the test product should be described briefly to provide information on the method of manufacture
A list of excipients used, the amount used, and their intended functions should be provided.
Excipients used in the test product should have been used previously in FDA-approved IR solid oral dosage forms.
See IIG website:
In addition, it is important to provide quantitative comparison of excipients between the test and reference product, for BCS class 3 drug products.

18. Exceptions: Data Submission Requirements
Permeability data (experimental or published) are always necessary unless the RLD label clearly states that the absolute bioavailability of the product is greater than 90% provided that:
The firm references said label AND
The Agency’s “BCS Committee” has deemed the drug substance to be BCS Class I based on the information in the label.
It is noted that Dissolution and Solubility data are always* required from the applicant.
*Exception: The RLD label calls the drug substance ‘BCS Class I’ and the BCS Committee has deemed the substance to be ‘BCS Class I’. In this case, only dissolution data would be required.

20. Introduction and Background
The guidance is intended to describe when a standard release test and criteria may be used in lieu of extensive method development and specification-setting exercises.
(Stability and quality control)
When final, this guidance will supersede the guidance for industry on Dissolution Testing of Immediate Release Solid Oral Dosage Forms (August 1997) for biopharmaceutics classification system (BCS) class 1 and 3 drug substances in immediate-release drug products that meet the criteria in this guidance.
Class 1: High Solubility - High Permeability Drugs
Class 3: High Solubility - Low Permeability Drugs

21. Eligible Products Dosage Form Solubility (BCS Class I and III)
Solid orally-administered immediate release dosage forms, (tablets and capsules) that are meant to be swallowed.
It does not include chewable tablets, and does not apply to orally disintegrating tablets.
Solubility (BCS Class I and III)
Drug substance highly soluble with the highest dose strength soluble in 250 mL or less of aqueous media over the pH range of
The drug substance should also be chemically stable for 24 hours over this same pH range.
Therapeutic Class
Does not apply to narrow therapeutic index (NTI) drugs
Time to Maximum Plasma Concentration
If the time to maximum plasma concentration is critical to the intended use, this guidance does not apply.
Early or rapid onset of action (e.g., rapid analgesia, rescue medications, etc.)
Manufacturing and Testing History
Manufacturing and testing history, including stability testing, should demonstrate that the product will meet the specifications in this guidance when using the standard dissolution test conditions.
Excipients
Should be consistent with the design of IR drug products. Excipients should be included in normal quantities that are consistent with the product’s labeled function. Large quantities of excipients, such as sweeteners and surfactants, may be problematic.

22. Standard Dissolution Test Conditions
General Chapter <711>
Basket Method (USP apparatus 1)
Stirring rate = 100 RPM
100 RPM has been found to be discriminatory for the basket method.
500 mL of 0.01M HCl aqueous media
No surfactant in media
37±0.5°C
B. Paddle Method (USP apparatus 2)
Stirring rate = 75 RPM
75 RPM can be discriminatory while minimizing coning effects seen with lower rates.

23. Specifications
For BCS class 1 products, a single point dissolution specification of Q=80% in 30 minutes.
For BCS class 3 products, a single point dissolution specification of Q=80% in 15 minutes.
BCS class 3 products that meet the more stringent specifications will better ensure that:
bioavailability of the drug is not limited by dissolution
rate-limiting step for drug absorption becomes gastric emptying
For ANDAs, these criteria should apply unless supported by data on the dissolution performance of the reference-listed drug.

24. Disintegration instead of Dissolution
For drug products in both BCS classes 1 and 3, USP disintegration testing can be used in lieu of the dissolution test if the product is shown to meet a dissolution specification of Q=80% in 15 minutes.
For USP disintegration test,
Completely disintegrate within 5 minutes (via USP apparatus in 0.01M HCl)
May serve as a surrogate for routine release and stability dissolution testing.
The approved dissolution method should be retained as the primary method and the approved disintegration method as an alternate method.
Note for SUPAC where dissolution testing is needed, you should use the approved dissolution method.

25. Thank you! Questions ?????