# Presentation: 843604

## Establishing Dissolution Specification Current CMC Practice

**Vibhakar Shah, Ph.D.**
**Office of New Drug Chemistry**
**Office of Pharmaceutical Science**
**Center for Drug Evaluation and Research, FDA**
**Advisory Committee for pharmaceutical Science**
**May 3-4, 2005**

## Outline:

**Overview of Current Practice**
**CMC Assessment**
**ICH Q6A Principles**
**Case Study Example**
**Extended-Release Oral Suspension**
**Original Drug Development strategy**
**Dissolution Results**
**Critical Issues**
**Recommendations**
**Improvements**
**Dissolution Results: Post-Improvements **
**Concluding Remarks**

## Current Practice:

- Establishing dissolution specification(s) is a _**shared**_ responsibility between the Office of New Drug Chemistry (**ONDC**) and the Office of Clinical Pharmacology and Biopharmaceutics (**OCPB**)

## CMC Assessment:

_**Scientific Analysis and Assessment**_:
- Physico-chemical properties of the formulation components: drug substance(s) and excipients
- Solubility
- pKa
- particle size distribution
- Polymorphic forms
- Others
- Impact of these physico-chemical properties on
- Processibility of the formulation components
- Safety, efficacy, (BA/BE, dissolution), and stability of the drug product
- Manufacturing processes, especially those having potential to influence the release profile of the drug substance
- Control strategy of critical process parameters
- In-process testing

## CMC Assessment:

- Relationship of in-process testing to critical quality attributes (e.g., dissolution) of the drug product:
- Particle size distribution
- Release rate
- Compression force, tablet hardness, friability etc.
- Development and validation aspects of the proposed in-vitro dissolution method (e.g., UV, HPLC etc.):
- Chromatographic parameters
- Specificity, linearity, accuracy, precision, ruggedness, etc.
- Release time point intervals
- Available in-vitro dissolution data from development, clinical, bio-, and primary stability batches for a **discerning trend** on storage
- The proposed shelf-life of the drug product on the basis of the stability data analysis of dissolution as well as other DP attributes

## OCPB Assessment:

- Results of in-vivo studies (PK, food effect, etc.)
- Results of IVIVC studies
- Development/optimization of the proposed in-vitro dissolution method:
- Dissolution medium (Components)/Medium pH
- Release time point intervals (e.g., 1, 3, 6, 12 Hr)
- Apparatus

## CMC Assessment:

- 	**In ****coordination**** with OCPB, appropriate dissolution specifications (test method and acceptance criteria) that are **_**reflective**_** of the dissolution data from various batches (clinical, bio-, stability) of the drug product are recommended.**

## ICH Q6A Principles:

- Quality Attributes with potential relevance to dissolution within ICH Q6A:
- Particle size (DS): Decision Tree #3
- Polymorphic content (DS): Decision Tree #4
- Polymorphic change (DP): Decision Tree #4
- From the forgoing discussion (CMC assessment) it should be apparent that ICH Q6A principles for setting specifications (e.g., dissolution) are well integrated in the quality assessment of the drug product

## ICH Q6A

**ICH Q6A**
**Decision Tree #3**
_**Drug Substance**_
**Particle Size Distribution**
**Acceptance Criteria**

## ICH Q6A

**ICH Q6A**
**Decision Tree #4**
_**Drug Substance**_
**Polymorphic Content**
**Acceptance**
**Criteria**

## ICH Q6A

**ICH Q6A**
**Decision Tree #4**
_**Drug Product**_
**Polymorphic Change**
**Acceptance Criteria**

## Case Study ExampleExtended-Release Oral Suspension

## Extended-Release (ER) Oral Suspension:  

- 505(b)(2) application:
- _Safety_ and _efficacy_ of the proposed active ingredients for the proposed indication established through immediate release products available under the Tentative OTC Monograph for the same indication
- Therefore, no clinical trials required
- Proposed Dose:
- Single dose (Q12h) to patients **6 years** of age or older
- Equivalent to the nominal OTC monograph doses, given Q6h X 2

## Drug Product Formulation:  

- Two different **active** ingredients: **DS1** and **DS2**
**DS1** is anchored to a drug carrier support and coated separately with semipermeable polymer to prevent dose dumping and to impart extended release (**ER)** profile
**DS2 **binds to the drug carrier support *in-situ* during the manufacturing process, but it is _not coated_
- Both active ingredients along with other excipients are suspended in aqueous based solution
**Concerns**:
- Safety implications due to potential dose dumping
- Efficacy implications due to insufficient rate and extent of release of the actives

## Drug Development Strategy:

- Demonstrate bioavailability of the drug product formulation (6% coating of **DS1**) to a _reference drug_, an immediate-release (IR) Solution, containing the same two active ingredients
- Formulate three experimental drug product formulations, each differing only by the coating level of semipermeable polymer on **DS1**:
**Low **(2% w/w): 		**Fast** release formulation
**Medium **(5.5% w/w): 	**Intermediate** release formulation
**High **(9% w/w): 		**Slow** release formulation
- Establish IVIVC for each active among these three experimental formulations
- Establish dissolution specifications for both actives based on generated dissolution profiles from the _**slow**_ and _**fast**_ release drug product formulations

## NDA Submission Data:

- Manufactured five formulations of the DP containing **DS1** coated with varying levels of semipermeable polymer: 2% (low), 5.5% (medium), 9% (high) as well as 6% and 10%
- Performed following PK studies:
- Multi dose bioavailability (BA) study with IR solution and Single dose food effect study
- DP Formulation containing **DS1** with 6% polymer coating
- Single dose IVIVC study:
- DP Formulations containing **DS1** with 2%, 5.5% and 9% polymer coating
- In-vivo results from 4 Batches (PK studies) and in-vitro dissolution data from nine batches (4 PK and 5 stability)

## Applicant’s Claims:

- Level A IVIVC _established_ for both the actives of the ER suspension
- The mean and individual Level A IVIVC models for **DS2** met the FDA validation criteria and can be used for setting dissolution specifications and biowaivers
- The mean and individual Level A IVIVC models for **DS1** _failed_ the FDA validation criteria in that the predicted values had a larger error than recommended
- However, if the dissolution criteria remain within the dissolution profiles tested in IVIVC study, the **DS1** results can serve as a mapping study for the formulation

## Agency’s Findings of PK Results:

**BA and Food Effect Studies: **(6% coating of **DS1**):
- Systemic exposures of both actives were favorable between the ER suspension and multiple dose of reference IR solution
- Observed no food effect for both actives
**IVIVC Study: **(2%, 5.5% and 9% coating of **DS1**):
**DS1:**
- Failed to establish in-vivo in-vitro correlation (IVIVC)
- Observed more than 20 % of difference in Cmax for formulations of fast and slow dissolution profile
**DS2:**
- Level “A” IVIVC established, but* *failed to validate the IVIVC
- The formulations used in IVIVC study were found bio-inequivalent, i.e., Cmax of the formulations used in the IVIVC study were different by more than 20%
- The proposed dissolution specification and the approach to set a dissolution specification based on IVIVC by mapping was found _unacceptable_

## Stability Results Analysis:

- Contradictory release profiles observed between drug product formulations containing 6% and 9% coated **DS1**
**DS2** showed more decrease in dissolution than **DS1**
- Observed **substantial** (up to 20%) **decrease** in dissolution (% release) at **1 hr**, **3 hr**, and **6 hr** time points **for both actives** from their corresponding initial values among bio- and primary stability batches at all storage conditions
- The decrease in dissolution was most notable at **3 hr** and **6 hr** time points
- The decrease in dissolutions is minimum at **12 hr** time point
- The decrease in dissolution for both actives levels off by nine months on storage

## Dissolution Results of DS1

**6%**

**9%**

**5.5%**

**2%**

## Dissolution Results of DS2

## Potential Critical Issues:

- Raw materials Controls (including excipients):
- Particle size distribution control of drug carrier support
- Particle size distribution control of excipients
- Manufacturing Process & In-process controls:
- Binding of DS1 to drug carrier support
- Coating level and coating process for DS1
- Other manufacturing Processes
- Particle size distribution of coated DS1
- Release profile of DS1
- Controls:
- Particle size distribution (PSD)
- Criteria (drug carrier support, coated drug bound carrier support)
- Method (e.g., sieving vs. laser diffraction)
- Dissolution method

## Revised Drug Development Strategy:

- Abandon IVIVC approach to set dissolution acceptance criteria
- Conduct PK studies (BA/BE) on commercial scale bio-batch containing **DS1** at the specified target coating level (rather than a range) and compare it to the reference IR solution
- Manufacture additional three pilot scale primary stability batches of the drug product containing **DS1** at the specified target coating level
- Propose dissolution acceptance criteria based on in-vitro dissolution profiles obtained for both actives from the bio-batch

## Applicant’s Improvements:

**Process Improvements:**
- Specified the target coating level of semipermeable polymer within** ****X±1%**** **for the **DS1**
- Revised coating and subsequent manufacturing processes
- Instituted appropriate process controls to stabilize binding of both actives to the drug carrier support in the suspension
- Manufactured 1 commercial scale bio- and 3 pilot scale stability batches
**Controls:**
- Instituted appropriate particle size measurement method (e.g., laser diffraction) for drug carrier support, and coated drug (DS1) bound carrier particles
- Revised PSD acceptance criteria for drug carrier support, coated drug (DS1) bound carrier support particles and suspension stabilizing excipients

## Agency’s Findings of PK Results: Post-Improvement

- Three PK Studies conducted utilizing DP formulation containing **X±1%** coating of DS1**:**
- BA/BE assessment
- PK at steady state
- Food effect study
- Results**:**
- The PK profiles of DS1 and DS2 from test ER suspension were found similar/comparable to the reference IR solution following single and multiple dose administration
- Food had no effect on bioavailability of both actives

## Post Improvement Stability Results Analysis:

- Observed **stable** and **consistent** release profiles (1hr, 3hr, 6hr and 12hr time points) for both DS1 and DS2 on storage **within** each of the bio- and three primary stability batches
- Observed **no discernible trend** in release profiles of DS1 and DS2 among bio- and primary stability batches at all storage conditions
- Comparable release profiles for both DS1 and DS2 **among** bio- and three primary stability batches

## Post-Improvement Dissolution Results of DS1

## Post-Improvement Dissolution Results of DS2

## Concluding Remarks:

- Identified probable causes of discrepant and inconsistent dissolution results for DS1 and DS2
- Recommended corrective measures to address the issues
- End results:
- Consistent manufacturing process
- Acceptable BA/BE results
- Stable and consistent release profiles without any discernible trend on storage for both drug substances DS1 and DS2
- Dissolution criteria better reflective of the data
- Improvement in the quality of the drug product
- Improvement in assurance against the safety and efficacy concerns

## Concluding Remarks:

- The case study example highlighted:
**Lack of/poor** **understanding** of the raw material properties and manufacturing processes that were critical to be controlled for consistent quality and thereby desired performance (e.g., extended-release/dissolution) of the drug product
**Inadequate** **efforts** invested by the applicant during the **drug development** to understand the **causal links** of dissolution failures

## Concluding Remarks:

- The case study example stresses a **dire** **need** for **improvement** to the existing drug development efforts to understand:
- The relationship between the raw material properties of formulation components and critical quality attributes of the drug product (which and how)
- The effect of raw material properties of formulation components on their processibility for selected manufacturing processes
- The effect of manufacturing processes and associated critical process parameters on the critical quality attributes of the drug product

## Concluding Remarks:

**	****There is ****no substitute**** to a systematic and scientific approach to a drug development for a safe, efficacious and quality drug product.**