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FDAs current practice and challenges in the evaluation of dissolution profile comparisons in support of minor/moderate product quality changes Om Anand, Ph.D . Division of Biopharmaceutics Office of New Drug Products Office of Pharmaceutical

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FDA’s current practice and challenges in the evaluation of dissolution profile comparisons in support of minor/moderate product quality changes

Om Anand, Ph.D.

Division of Biopharmaceutics Office of New Drug Products Office of Pharmaceutical Quality CDER, US-FDA

M-CERSI Workshop May 21-22, 2019, University of Maryland, Baltimore

This presentation reflects the views of the presenter and should not be construed to represent FDA’s views or policies

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Are these profiles similar?

20 40 60 80 100 120 5 10 15 20 25 30

% Release Time (Hours)

X2 X1

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.

Dissolution Profile Comparisons

Dissolution profiles may be considered similar by virtue of (i) overall profile similarity and (ii) similarity at every dissolution sample time point. Two Approaches to demonstrate the similarity: Model Independent Approach: Similarity Factor (f2) Multivariate Confidence Region Model Dependent Approaches

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Regulatory Application of the Dissolution Profile Comparisons in the Life cycle of a Drug Product

Discovery

Phase II

Approval Market

Nonclinical

Phase I Phase III Post- Market

Diss/ QC- Clinical lots Diss/ stability

Diss/ Biowaiver

Diss/ QbD Diss/ Formul integrity Diss/ Biowaver Diss/ lot release Diss/ QC Diss/ Biowaver Diss/ SUPAC

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Dissolution Profile Comparison

  • +

 =

  • }

100 ] ) T R ( n 1 ( 1 {[ log 50

2

f

5 . 2 t t

n = number of time points R(t) = mean % API dissolved of reference product at time point x T(t) = mean % API dissolved of test product at time point x Minimum of 3 time points (zero excluded) 12 units (each in own dissolution vessel) for each product

Only one measurement should be considered after 85% dissolution of both the products

%RSD at earlier time points (e.g., 15 minutes) ≤ 20% %RSD at higher time points ≤ 10%

“f2 values greater than 50 (50-100) ensure sameness of the two curves and, thus, of the performance of the test (post-change) and reference (pre-change) products.”

Model Independent Approach Using Similarity Factor (f2)

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Similarity Factor (f2)- SUPAC MR Guidance

  • The average difference at any dissolution

sampling time point should not be greater than 15% between the changed drug product and the bio-batch or marketed batch (unchanged drug product) dissolution profiles.

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Is f2 Applicable to All Dosage Forms?

  • Oral simple dosage forms

– Immediate release

  • Oral complex dosage forms

– Modified release (DR, ER) – Combination-IR/IR, IR/MR,MR/MR

  • Non-oral dosage forms

– Transdermal Drug Delivery Systems – Dug-Device Combination Products

  • Other dosage forms

– For example topical etc.

f2 applicable

f2 metric NOT applicable

f2 applicable f2 applicable

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Cases When f2 Cannot be Used

  • When the percent coefficient of variation is

higher than 20% requirement for earlier time points (i.e., 15 min) or higher than 10% for the other time points the f2 test cannot be used.

  • Alternative methods to estimate profiles similarity

should be used

f2 with Bootstrap method Multivariate approach

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Cases When f2 may not be Used

  • In general, the f2 test should not be used when there is

an IVIVC model available/ established ‘’safe space”

  • The IVIVC model must be used to estimate AUC and Cmax

AUC Ratio Cmax Ratio

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Cases When f2 Cannot be Used cont..

In Vitro Metric Evaluated - Drug Release Rate (mcg/day)

f2 metric cannot be used to estimate the similarity of drug release rate data ( mg/day etc.).

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Case Studies

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Case study 1: Discriminating method

BCS class 2 drug product

f2 = 76*

20 40 60 80 100 10 20 30 40 50 60

% Release Time (Minutes) Test 1 Test 2

Very rapid dissolution, f2 should not be calculated Method not discriminating/ drug particle size In an in vivo study Test 1 and Test 2 were found not bio-equivalent

*Applicant calculated

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Case study 1: Discriminating method…

BCS class 2 drug product- New method

f2 = 40

Method discriminating/ drug particle size

20 40 60 80 100 10 20 30 40 50 60

% Release Time (Minutes) Test 1 Test 2

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Case study 1: Discriminating method…

f2 limitations: f2 has no application for very rapid dissolution. The outcome of f2 test is uncertain if the method is not discriminating. Lesson learnt: For a meaningful/reliable calculation

  • f

f2, the dissolution method should be discriminating/meaningful.

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Case study 2: site change

Alternate Manufacturing Site Low solubility drug

20 40 60 80 100 10 20 30 40 50 60

% Release Time (Minutes) Pre Change Post change

f2 = 46

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Case study 2: site change…

f2 < 50, was justified and found acceptable

  • Previously, a PK study showed no difference in BA between

a tablet vs. suspension formulations of the same drug. Plasma levels peaks in approximately four hours.

  • The dissolution profile of the post-change batch was within those
  • bserved for the tablet and suspension.
  • Slightly faster dissolution and the lower value of f2 should not

have affect on the efficacy/safety of the drug product.

  • Based on totality of information provided, the change in the site

was accepted even though the dissolution was faster and the f2 was slightly lower than 50.

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Case study 2: site change…

f2 limitations: f2 similarity may have limited application for very rapid dissolving products. Lesson learnt: An f2 value less than 50 does not necessarily

indicate lack of similarity. Risk-based assessment on the potential effect of the proposed change(s) on bioavailability should be conducted.

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Case study 3: Multiple process changes

Post approval, multiple, Level 1 changes in the process to improve the stability of the drug product Low solubility drug

20 40 60 80 100 20 40 60 80 100 120

% Release Time (Minutes) Pre Change Post change

f2 = 58

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Case study 3: Multiple process changes..

The Applicant was asked to provide dissolution data with additional time points at early phase

20 40 60 80 100 20 40 60 80 100 120

% Release

Time (Minutes)

Pre Change Post change

f2 = 40

Based on the totality of the information and potential effect of the manufacturing changes on the bioavailability, the Application was asked to conduct a BE study.

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Case study 3: Multiple process changes …

BE study results Based on the BE study results, the Applicant withdrew the supplement

500 1000 1500 2000 2500 2 4 6 8 10 12 14 16 18 20 22 24 % Mean Concentration (ng/mL) Time (Hours)

T R

Ratio* 90 % CI# Cmax 146 135 156 AUC 0-t 110 103 114

*Point estimate of Geometric mean ratio # 90% Geometric Confidence Interval using log transformed data

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Case study 3: Multiple process changes..

f2 limitations: the selection of sampling time points (both

number and sampling time distribution) are critical for a robust conclusion on the similarity results.

Lesson learnt: To evaluate the similarity of the drug product

performance, it is important to assess the totality of the

  • information. f2 values are only one part of the total information.
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The use of f2 in “Safe Space”

“Safe Space”

Operating Space /Target

If “Safe Space” [all batches are assumed to be bioequivalent] is established, through IVIVC, BE studies, IVIVR, virtual BE studies etc. Similarity in the dissolution profiles is not needed, if the dissolution profiles are with in the “safe space”.

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Case study 4: Site and process change..

Manufacturing site change and minor changes to the manufacturing

  • procedure. No change in the IR formulation. Drug substance has

very low aqueous solubility

f2 = 38

20 40 60 80 100 10 20 30 40 50 60

% Release Time (Minutes)

Pre Change Post Change

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Case study 4: “Safe Space”

20 40 60 80 100 10 20 30 40 50 60

% Release Time (Minutes) Pre Change Post Change Bio-Test 1 Bio-Test 2

Bio-Test 1 and Bio-Test 2 were bioequivalent

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Case study 4: change with in the “safe space”…

f2 limitations: “Safe space” supersedes f2 similarity testing. Lesson learnt: An f2 value less than 50 does not necessarily

indicate lack of similarity. If product changes are occurring with in the “safe space’, an f2 value less <50 is superseded by “safe space” boundaries.

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Case study 5: variable dissolution

A Modified Release (MR) product. BE Study on higher strength (strength 1), biowaiver request for the lower strength (strength 2),

20 40 60 80 100 2 4 6 8 10 12

% Release Time (Hours)

Strength 1- 0.1 HCl Strength 2- 0.1 HCl

% RSD Time (hours) 1 2 4 6 12 Strength 1 16.8 13.7 8.9 7.1 2.6 Strength 2 13.1 9.5 6.4 4.5 0.9

f2 = 57

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Case study 5: variable dissolution..

% RSD Time (hours) 1 2 4 6 8 Strength 1

11.3 8.8 6.3 5.1 3.9

Strength 2

14.2 11.5 8.8 6 4

20 40 60 80 100 1 2 3 4 5 6 7 8 9

% Release Time (Hours) Strength 1- pH 4.5 Strength 2- pH 4.5

f2 = 63

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Case study 5: variable dissolution..

% RSD Time (hours) 0.5 1 2 4 Strength 1 19.1 15.7 10.8 9.5 Strength 2 16.5 12.6 8.4 3.9

20 40 60 80 100 1 2 3 4 5 6

% Release Time (Hours) Strength 1- pH 6.8 Strength 2- pH 6.8

f2 = 35

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Case study 5: variable dissolution..

  • Investigate the root cause of high variability; and

differences in dissolution profiles in pH 6.8.

  • Response: No specific reasons for the variability

and the differences.

  • BE study was recommended.
  • BE study failed to meet the 90% CI.
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Case study 5: variable dissolution

f2 limitations: Due to high variability in the dissolution data, comparison

  • f

mean f2 profiles is not recommended. what is early timepoint for an ER product? Lesson learnt: In case

  • f

high variability in the dissolution profiles, the root cause of high variability should be determined prior to using alternate approaches to demonstrate the similarity between the profiles.

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f2 values are only part of the total information

f2 value

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Question

20 40 60 80 100 120 5 10 15 20 25 30

% Release

Time (Hours)

X2 X1

Should we use f2 for comparing these dissolution profiles? f2 = 52

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Challenges in the Implementation

  • f Similarity Testing
  • f2 similarity may have limited or no application for

very rapid dissolving products.

  • Selection of sampling time points (both number

and sampling time distribution) are critical.

  • High variability in the dissolution data. An early

timepoint for ER products is not defined.

  • f2 calculations does not consider shape of the profiles.
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Conclusions

  • For a reliable calculation of f2, the dissolution method

should be discriminating/meaningful.

  • To

evaluate the similarity

  • f

the drug product performance, it is important to assess the totality of the

  • information. f2 values are only the part of the total

information.

  • In case of high variability in the dissolution profiles, the

root cause of high variability should be determined and variability in the data should be reduced, if possible, without compromising on the discriminating ability of the method.

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Conclusions

  • An f2 value less than 50 does not necessarily

indicate lack of similarity. The potential effect

  • f the proposed change resulting in differences

in dissolution profiles can be justified including additional data to support the claim

  • f

similarity, as well as supporting statistical analysis (e.g. 90% confidence interval analysis), and ‘safe space’ etc.

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Acknowledgements

  • Thanks To:

– Sandra Suarez Sharp, Ph.D. – Angelica Dorantes, Ph.D. – Haritha Mandula, Ph.D. – Kaushal Dave, Ph.D. – Kimberly W. Raines, Ph.D. – Poonam Delvadia, Ph.D.

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FDA Guidances and Similarity f2 Metric

  • Dissolution Testing of Immediate Release Solid Oral Dosage Forms
  • Waiver of in vivo Bioavailability and Bioequivalence Studies for Immediate

Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System

  • Extended

Release Oral Dosage Forms: Development, Evaluation, and Application of In Vitro/In Vivo Correlations

  • Immediate Release Solid Oral Dosage Forms: Scale-Up and Post-Approval

Changes: Chemistry, Manufacturing, and Controls, In Vitro Dissolution Testing, and In Vivo Bioequivalence Documentation

  • SUPAC-MR: Modified Release Solid Oral Dosage Forms: Scale-Up and Post-

Approval Changes: Chemistry, Manufacturing, and Controls, In Vitro Dissolution Testing, and In Vivo Bioequivalence Documentation Bioavailability and Bioequivalence Studies for Orally Administered Drug Products, General Considerations Several Guidance documents recommend f2 metric to evaluate products sameness

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Thank you!

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