Claim & Reasonable ProbabilityUnderstand Product, Control Process & Demonstrate Quality

Roohi B. Obaid & Obaid AliCivil Service Officer

Drugs Regulatory Authority of Pakistan

Claim & Reasonable ProbabilityUnderstand Product, Control Process & Demonstrate Quality

Part BObaid Ali

Warm up exercise

Fundamental Scenarios and Bio-studies or Dissolution Studies

Drug must be available in the blood stream in the same pattern

on which clinical studies have been performed

Similarity & Equivalency?

If a tablet is disintegrated, in which

situations, it will not reach to the blood

If a tablet is dissolved, in which

situations, it will not reach to the blood

Have you ever imagined a situation

where a tablet can come out from the

body as it is?

If so, can it produce effect

Biopharmaceutical Evaluation

From Fiction to Reality

Performance

should be the

same way

No Worse

Performance

should be the

same way

No Worse

No Better

Performance

should be the

same way

Please make it clear

They are not

clinical studies

Nothing to do

with Safety &

Efficacy of

molecule

Evaluating the

Similarity of

Trends

&

Kinetics

Drug Performance

Dosage Form

Drug in solution

Gut wall BloodSite of

ActivityTherapeutic

Effect

Dosage Form

Performance

Pharmacokinetic

Measurement

Clinical/PD

Measurement

Science of Bioequivalence

Developed over the last few decades

Continues to evolve

Specific approaches depend on a number of factors

Can be simple or highly complex

Generic Drug

….. equivalent drug products

that can be substituted at the

pharmacy level for the

reference /innovator drug, and

each other, without any

adjustment in dose or other

additional therapeutic

monitoring

Pharmaceutical Equivalence

Same active ingredient

Same dosage form

Same route of administration

Identical in strength or concentration

What is Substitutability?

Pharmaceutically equivalent

1Bioequivalent

2

Generic Drugs must be

Generics not necessarily identical

Excipients Difference

Manufacturing Differences

Formulation Difference

Shape, color difference

Bioequivalence & Generic Drugs

Pharmaceutical Equivalent & Bioequivalent

Pharmaceutical Equivalence

Does not mean equivalent performance

Label1

CMC2 Bio-

studies

3 Plant GMP

4

Brand Name Drug Generic Drug

1. Chemistry 1. Chemistry

2. Manufacturing 2. Manufacturing

3. Controls 3. Controls

4. Labeling 4. Labeling

5. Testing 5. Testing

6. Animal Studies

7. Clinical Studies 6. Bioequivalence

8. Bioavailability

Bio-studies

Dissolution

Bioavailability Bioequivalence

PK PD

26

Clinical/PD Dose-

Response

Cli

nic

al/P

D R

esponse

Log Dose

27

Plasma

Concentration-Dose

Dose

Pla

sma

Co

nc.

What is Reference/Innovator Drug

Innovator

Brand

Authorized Brand

29

AUC and Cmax 90% Confidence Intervals (CI) must

fit between 80%-125%

To determine rate and extent of absorption of

generic, innovator

From 2009

On healthy human volunteers but use patients if

there is a safety concern (Etoposide, Clozapine)

Male, Female both

Bio-analytical method must be validated

33

• In vivo measurement of

active moiety or moieties

in biologic fluid

• In vivo pharmacodynamic

comparison

• In vivo limited clinical

comparison

• In vitro comparison

Single-dose, two-way

crossover, fasted

Single-dose, two-

waycrossover, fed

Alternatives

1

• Single-dose, parallel, fasted

• Long Half-Life (wash-out) Amiodarone, Etidronate

2

• Single-dose, replicate design

• Highly Variable Drugs

3

• Multiple-dose, two-way crossover, fasted

• Less Sensitive Clozapine(Patient Trials) Chemotherapy Trials

4

• Clinical endpoint study

• Topicals Nasal Suspensions

Urine may be used for measurement when drug cannot

be measured in plasma e.g. Potassium Chloride

Baseline in blood is too high to permit accurate

measurement

Special Case: Alendronate Sodium (5 to 70 mg)

Problem with plasma detection because of low

concentration & re-distribution from bone

Pharmacodynamics Approach

Generic topical corticosteroid, ability to produce

vasoconstriction

Special Case: Tretinoin Acne Gel

Problem with plasma detection, endpoint related to

healing region is considered

Special Case:

Highly Variable Drugs

3 period bio-studies TRR, RTR, RRT

BioWaivers

IV solutions, Oral solutions, BCS class 1, old drugs

with no bio-equivalency problem

Oral Solution

Must not contain an excipient that may significantly

affect absorption of API

e.g. Prednisolone sodium phosphate oral solution

Inactive must not have safety issue

Solid Oral Dosage

Dissolution testing on all strengths

Strength proportionality must be similar to the biostrength

In-vivo BE must be established for higher strength

But for safety lower strength

E.g. Terazosin HCl 1, 2, 5 & 10 mg strength, 2 is acceptable

Highly Soluble, Highly Permeable, Rapidly Dissolving

e.g. Ofloxacin

Dissolution e.g. Omeprazole

Use of dissolution data for biowaiver of non-bio strength

Two stage dissolution testing

(acid medium & buffered medium)

Dissolution as a tool

Batch to batch

consistency

Quality Assurance

Formulation development

Bio-waiver In vitro BE

studies

Alcohol induced dose

dumping

Post-approval manufacturing

changes

Dissolution Method Development

Dissolution

Material Attributes

Process Parameters

Formulation Variables

REMEMBER

Dissolution

method is

product specific

Dissolution Method Development

Product Specific

Method Development Evaluation of

method

Discriminating

Ability

Acceptance

Criteria

1

2

3

Evaluation of

method

1

Solubility ProfileApparatus Selection

Dissolution/Release Media

Rotation speed Sink conditionsSupportive data for surfactant

selection

Discriminating

Ability

2

Differentiates DP manufactured under

target conditions vs. formulation with

meaningful variations for the most

relevant manufacturing variables

Acceptance

Criteria

3

Bioequivalence batches

85% of drug is dissolved or

where plateau of drug dissolved is

reached

Selection of time points should be where Q=80% of drug is dissolved

Common Deficiencies in Regulatory Submissions

Dissolution method development not

included in application

Failure to demonstrate

discriminatory power (information lacking on CMA &

PP)

Data not supportive of proposed

acceptance criteria

Common Deficiencies in Regulatory Submissions

No dissolution data for lower

strength waivers,

multi-media testing for MR

products

No method transfer report on site change after method

validation

Dissolution data collected on aged lots

Individual dissolution data is not submitted

Dissolution Failure

Formulation had not been properly validated (FDA 2008)

Therapeutic failure reported in 2007

Tropol XL (Sandoz) approved in 1992

Metoprolol Succinate Tabs ER Recall due to dissolution

What should we learn?

What do you think?

Recalled due to dissolution

2009 Ethex (KV Pharmaceuticals)

2014 Wockhardt & Ranbaxy

Sometimes Math does not favor

ADHD

• Mallinckrodt

• Methyl Phenidate HCltab

• 18, 27, 36, 54 mg dose

Failure

• Fasting & fed had two different behavior in extended release

Sometimes Math does not favor

BupripionHCl tab

• Study on low dose and waiver on high dose

Failure

• Desired kinetics was not achieved

Teva

• FDA asked to stop distribution in sep 2012

Sometimes Math does not favor

Bupripion(Wellbutrin)

IR Tab of SKB 1985

Bupripion SR Tab 1996

& XL Tab 2003

Based on evidence

demonstrating BE with

low strength

In 2006, Generic

version Mfg by

Impax/Tevawere

approved

85 post marketing

reports from Jan-Jun 2007

Experienced undesirable

effects

Increased side effects,

Decreased therapeutic

effect

Re-switched on brand

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Sometimes Math does not favor

Temporal relationship

under question

FDA re-examined BE data

Conducted study

Withdrawal of Teva drug in Mar 2013 against Sep 2012 FDA

advice

Also generic of Actavis

withdraw their version

A new challenge

General rule will not

work always

Its life, please care

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