dissolution testing role in drug product lifecycles …...2016 ispe annual spring conference 10 –...

2016 ISPE Annual Spring Conference

10 – 11 April 2016, Shanghai

Dissolution Testing – Role in

Drug Product Lifecycles from

Development to Commercial

Quality, and Manufacturing

Speaker : Amy R. Barker, Ph.D.

Company: Eli Lilly and Company


OUTLINE

• Background about the Dissolution Test

• Biopharmaceutical Classification System (BCS)

• Dissolution method development and Quality Control (QC) methods

• Method Specifications and Trending

• Biowaiver Guidance Summaries

• Conclusions


DISSOLUTION TEST

Uses of the Dissolution Test

• Predict in vivo performance

• Formulation development

• Drug formulation decisions and design

• Tool for supporting process changes (post approval manufacturing

changes)

• Quality control

• Batch to batch comparison data for manufacturing

• Quality control testing

• Regulatory decisions

• Waive in vivo testing (bioequivalence (BE) study requirement)

• As BE documentation for scale up post approval changes (SUPAC)

• To improve understanding for modified release products (predicts dose

dumping in presence of alcoholic beverages)


DISSOLUTION APPARATUS

Many approved types

of dissolution

apparatus (1-7)

Apparatus 1

Pictured example is Agilent

Apparatus 2


BCS CLASSIFICATION

A classification system that differentiates drugs based on their

solubility and permeability (biopharmaceutics classification

system guidance, multiple global guidances exist)

• Rapid dissolution is an important factor in determining potential

for biowaiver in place of in vivo studies

• Solubility and permeability characteristics of the drug substance

are also required

Goals of the BCS Guidance Documents:

• To waive in vivo study requirements when the risk of non-

bioequivalence is low

• To improve the efficiency of drug development and the review

process by recommending a strategy for identifying expendable

clinical bioequivalence tests.


BCS CLASSIFICATION

Amidon GL, Lennernas H, Shah VP, Crison JR. A theoretical basis for a biopharmaceutic drug classification: the

correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm Res. 1995;12:413. doi:

10.1023/A:1016212804288.


SOLUBILITY AND

PERMEABILITY

SOLUBILITY DETERMINATION • pH-solubility profile of test drug in aqueous media with a pH range of 1 to 6.8.

• Shake-flask or titration method.

• Analysis by a validated stability-indicating assay.

PERMEABILITY DETERMINATION • Extent of absorption in humans:

• Mass-balance pharmacokinetic studies.

• Absolute bioavailability studies.

• INTESTINAL PERMEABILITY METHODS: • In vivo intestinal perfusions studies in humans.

• In vivo or in situ intestinal perfusion studies in animals.

• In vitro permeation experiments with excised human or animal intestinal tissue.

• In vitro permeation experiments across epithelial cell monolayers.

DISSOLUTION DETERMINATION • USP apparatus I (basket) at 100 rpm or USP apparatus II (paddle) at 50 rpm.

• Dissolution media (900 ml): 0.1 N HCl or simulated gastric fluid, pH 4.5 buffer, and pH

6.8 buffer or simulated intestinal fluid.

• Compare dissolution profiles of test and reference products using a similarity factor (f2).


DEFINITIONS

High solubility – highest therapeutic dose is soluble in less than or equal to 250 mL

Low solubility – highest therapeutic dose is not soluble in less than or equal to 250

mL

Highly absorbed – greater or equal to 85% (or 90%) absorbed when highest dose

administered orally

Rapidly dissolving product - Not less than 85% of the labelled amount is released

within 30 minutes or less

Very rapidly dissolving product - Not less than 85% of the labelled amount is

released within 15 minutes or less

Reference product - Approved product that will be used in comparisons

Test product - Product intended for submission


PHARMACOPOEIA

Dissolution general chapters are harmonized across EP, JP, and

USP

Ch.P. differs from the harmonized chapters

• Sizes of basket, paddle, and vessel

• Differences in the staging approach

• Differences in the term “Q”

• Only 12 units may be evaluated in Ch.P.


DISSOLUTION METHOD

DEVELOPMENT

Method development is well summarized in USP <1092>

• Earliest assessments should include selection of media, volume, and apparatus

• The method should be developed in parallel with formulation development and

should discriminate between critical process parameters

• Other important considerations include deaeration, sinker requirements, test

timepoint, analytical method for quantitation

• Sample treatment is a final aspect of method development and includes filtration,

centrifugation, dilutions, and stability

Method validation should include all aspects as required in ICH Q2(R1)

• Range should be evaluated from below the lowest potential specification and

concentration to above the 100% of the highest concentration of drug product

• Validation should be performed in and out of matrix for appropriate properties

• Intermediate precision may hold off until after early development work

• Method robustness should be performed prior to QC deployment


CHARACTERISTICS OF A

“GOOD” QC METHOD

Method should be reproducible and robust and capable of being transferred

between laboratories

Specification timepoints should be at a part of the curve where the slope is lower

(but not zero)

Deaeration instructions should be specified

Filter adsorption characteristics should be available

Method should be discriminating to critical process parameters, material properties,

and formulation

Method should not be overly dependent on analytical technique or common

laboratory variables such as common reagent suppliers, instrument make/model,

or typical environmental variables


METHOD SPECIFICATIONS

Specifications should be clinically relevant

• Clinically relevant specifications take into account the manufacturing

process, product attributes, and in vivo data

• The specifications are defined to assure a consistent safety and efficacy

profile

Critical

Quality

Attributes Biopharmaceutics

In vivo

Performance

Design Space Method monitoring Clinical Performance


DISSOLUTION TRENDING

Dissolution data should be used as a tool in quality control

• Demonstrate consistent manufacture

• Demonstrate similarity of product from different manufacturers

• Demonstrate comparability between different API and excipient materials

• Similarity calculation

Control Chart Example Example similarity curve


BIOWAIVERS

Biowaivers are intended to reduce the need for in vivo bioequivalence

establishment

When biowaivers are applied, in vitro data are intended to provide a

reasonable comparison for the test product to the reference product

Multiple countries provide guidance for potential application of biowaivers

in place of in vivo bioavailability/bioequivalence studies

• Guidance documents are intended as recommendations for sponsors of

applications

• They are administrative instruments not having force of law

• Alternate approaches may be acceptable if they are supported by adequate

justification

• Additional documentation may be requested as part of submission reviews


FDA BCS/WAIVER

GUIDANCE

BCS based biowaivers are requested based on dissolution, solubility, and intestinal

permeability

• Rapid or very rapid dissolution may help sponsors justify requests for biowaivers

• BCS I and III drug substances are candidates for biowaivers as long as excipients are

comparable and differences do not impact in vivo absorption of the active ingredient

• Dissolution profile similarity should be demonstrated (enzymes are permitted for

gelatin capsule formulations)

• Apparatus should be USP

• Multiple media pH

• Minimum of 12 tested units

• F2 comparison calculation (not required for profiles that achieve 85% at 15 minutes in all

media)

Biowaivers are not applicable for narrow therapeutic range drugs or products

designed to be absorbed in the oral cavity


SUPAC IR

Scale Up and Post Approval Changes for Immediate Release Dosage Forms

(SUPAC IR)

• Applications for changes of:

• The components or composition;

• The site of manufacture;

• The scale-up/scale-down of manufacture;

• The manufacturing (process and equipment) of an immediate release oral

formulation

Guidance contents

• Definitions for levels of changes

• Associated supporting chemistry data required for each level of change

• In vitro or in vivo requirements based on the change level

• Documentation requirements


SUPAC IR

Any level 1 or 2 change for an IR product may leverage dissolution testing which may

be adequate in lieu of BE tests

Site changes that are level 3 may be able to leverage dissolution testing in place of BE

tests

All other level 3 changes will require both dissolution and BE data unless a validated

in vitro in vivo correlation (IVIVC) is available


SUPAC MR

Leveled changes are also applicable to SUPAC Modified

Release (MR)

• Level 1 changes require dissolution comparisons between pre- and

post-change products

• Level 2 changes require compendial method dissolution comparisons

between pre- and post-change products

• Multi-media study is required

• F2 comparisons are required

• In vivo BE study may be waived

• Level 3 changes require BE studies unless IVIVC data or BCS

biowaiver are available


HEALTH CANADA

BCS GUIDANCE

Health Canada defines guidance – BCS System Based Biowaiver

• Applications

• Comparative bioavailability to support BE of subsequent-entry products

• Bridging studies for formulations different from those in the pivotal clinical trials

• Supporting post-approval changes

• Supporting drug identification number applications

• Defines data requirements and acceptance criteria

• High solubility drug substance

• Only intended for immediate release solid oral dosage forms

• Must be BCS class I or III

• The drug substance cannot be a critical dose drug


EMA GUIDANCE

Guideline on the Investigation of Bioequivalence – sets criteria under which

bioavailability studies are not required

• Waiver for additional strength

• The same active substance and excipient combinations must be employed

• Dissolution profiles must be comparable by f2 if applicable (product is not IR)

• BCS based biowaiver

• BCS may act as a surrogate for in vivo studies if in vitro data provide sufficient

comparability

• Active ingredient is BCS class I or III

• Complete dissolution is achieved either by very rapid dissolution (>85% in 15 minutes) or

similarly rapid (85% in 30 minutes) for both test and reference

• Excipients must be similar (and must be the same for those that may impact bioavailability)

In all cases, dissolution criteria should be based on approved specifications

for the reference product

• Dissolution profiles must contain a sufficient number of timepoints

• IR products must contain a 15 minute comparison to assure complete dissolution prior

to gastric emptying (if complete release in 15 minutes, further profile comparison

calculations are not required)


JAPAN GUIDANCE

Dissolution may be used to evaluate the similarity of pharmaceutical properties, to

detect differences between products, and to determine the need for a bio-waiver and

BE studies

• Dissolution should be performed at 3 different pH levels (between 1.2-7.5)

as well as in water

• For generic drugs

• In vivo tests are also expected and dissolution assists in determining if a special

population is necessary for BE studies

• Dissolution tests support in vivo equivalence

• For formulation change and additional strengths

• Changes are characterized (Levels A-D)

• Change allowances A-C are similar to SUPAC

• Level D is for rapidly dissolving products

Amendments to the Guideline for Bioequivalence Studies of

Generic Products and Other Guidelines


Paddle Method, 900 mL, 37 °C, 12 vessels per each condition

Testing Period: 2 hrs for pH 1.2, 6 hrs for the other medium (can be ended when reference product shows >85% dissolved)

Agitation

Speed

Acidic API

Basic API

Neutral API

Film-coated Product

Insoluble API

50 rpm

• pH1.2

• pH 5.5 - 6.5

• pH 6.8 - 7.5

• Water

• pH 1.2

• pH 3.0 - 5.0

• pH 6.8

• Water

• pH 1.2

• pH 4.0

• pH 6.8

• Water

• pH 1.2 + surfactant



100 rpm • Most discriminating pH from the above*

* Test at 100 rpm can be skipped if both reference and test products show average %

dissolved of >85% at 50 rpm in 30 min using the specified medium.

DISSOLUTION TEST REQUIRED

FOR LEVEL B CHANGE ( E X A M P L E )

Total 5 conditions 5 conditions 8 conditions


SIMILAR GLOBAL REQUIREMENTS FOR

BIOWAIVERS

High solubility should be established

In vitro dissolution should be similar based on f2 calculation between reference and

test batches (n=12 units per batch)

Dissolution method must be validated

Dissolution should be evaluated at multiple pH values

Product should have a wide therapeutic window

Materials employed in manufacturing must be similar


GLOBAL REQUIREMENTS

THAT DIFFER

Specific media requirements for dissolution profile comparisons

Leveled decision trees are defined for some countries

Number of reference and test batches (and the way in which they are established)

Allowance for use of enzymes to overcome capsule crosslinking


GUIDANCE FOR GENERICS

Multiple guidance documents provide information about dissolution as a tool for

generic drug development

• When a compendial method is available for a product, it should be

employed for in vitro testing of a generic product

• FDA publishes a dissolution method list as a second tier if a compendial

method is not available

• Any other method employed should be validated and demonstrate

discriminating capability including solubility, media pH profiles, and sink

conditions

• Comprehensive dissolution data are required as part of generic

submissions and are published in regulatory guidance


CRITICAL IN VITRO DATA

Dissolution method must be validated and demonstrated to be discriminating

Comprehensive dissolution data

• A minimum of 12 units per evaluated batch

• Test product

• Reference product

• Multiple pH media based on regulatory guidance

• Solubility data across the pH range

Supporting solubility data should be presented

Supporting intestinal permeability data may be requested to support a biowaiver

depending on BCS classification


CONCLUSIONS

Dissolution testing is a critical method to help demonstrate in vitro equivalence of

products

• Alternate strengths

• Post approval process changes

• Generic markets

Global guidance documents provide recommendations for deciding on BE studies

versus requesting biowaivers

Biowaivers may be granted based on BCS classification in combination with

provision of critical dissolution comparisons and supporting BCS classification data


REFERENCES

FDA Guidance for Industry: immediate release solid oral dosage forms: scale-up and post-

approval changes

FDA Guidance for Industry: dissolution testing of immediate release solid oral dosage forms

FDA Guidance for Industry: bioavailability and bioequivalence studies for orally administered

drug products – general considerations

FDA Guidance for Industry – waiver of in vivo bioavailability and bioequivalence studies for

immediate release solid oral dosage forms based on a biopharmaceutics classification system

Health Canada – BCS system based biowaiver

EMEA – Guideline on the investigation of bioequivalence

WHO – Multisource (generic pharmaceutical products: guidelines on registration requirements

to establish interchangeability

http:///www.nihs.go.jp/drug/DrugDiv-E.html - Amendments to the guideline for

bioequivalence studies of generic products and other guidelines


ACKNOWLEGEMENTS

Jeffrey Gelwicks, Ph.D.

David Sperry, Ph.D.

Erin Wang

The ISPE Annual Spring Conference Planning Committee


Thank you!