snehal khedkar | april 2008 1 |1 | pharmaceutical development with focus on paediatric formulations...

Snehal Khedkar | April 20081 |

Pharmaceutical Development with Focus on Paediatric formulations


WHO/FIP TRAINING WORKSHOP

Hyatt Regency HotelSahar Airport Road, Andheri East,

Mumbai, India28 April 2008 – 2 May 2008


Partnering Healthcare Globally

Ipca Laboratories LimitedIpca

Greetings from


Practical problems in developing FDCs & Bilayer tablets

Presenter: Snehal Khedkar

Email: [email protected]




What are Fixed Dose Combinations??? What are Fixed Dose Combinations???



Fixed Dose combination (FDC)“ A combination of two or more actives in a fixed ratio of doses.”

Source: WHO Technical report series, No. 929, p.no-107, 2005

Examples of FDCs in WHO’s list of essential drugs

Anti- Infective: Sulfamethoxazole + Trimethoprim

Anti-Tuberculosis: Rifampicin + Isoniazid

Antiviral: Stavidine + Lamivudine + Neviparine

Antimalarial : Artesunate + Amodiaquine



Patient Convenience

Patient Adherence

Monotherapy prevented

Least probability of developing drug resistance

Validated theory with other infectious diseases like TB, Leprosy, AIDS.

Reduced Pill Burden

Rationale.…


Rationale.…

Hypertension

Heart Disease

Diabetes

Hyperlipidemia

Obesity

Co-morbidConditions

Treat different ailments in the same patient (co-morbidity), at the same time and with one pill

Allows for synergistic combination


DiabetesTuberculosis

Hypertension

Malaria

Allergy/Asthma

AIDS

UlcersPain

POLY -PHARMACY

Rationale.…

Combination drugs that targetthe same indication


Stomach Irritation

WeightGain

Nausea

SIDE EFFECTS

Reduced by using one drug of the combination for this purpose

Amiloride may prevent hypokalemia caused by hydrochlorthiazide

Rationale.…


“Manufacturing challenges:

Product Formulation issues

Manufacturing issues

Challenges in Development of FDCs


Product Formulation issues ……

IR +SR (Use of OCRS)

Bilayer/ Trilayer

Different release kinetics

e.g. Rabeprazole + Domperidone

)20 + 30 mg(

Solutions…

Dilution for low dose drug

Drug loading / Adsorption on excipients

Problems…

e.g. Metformin + Glibenclamide

(400 mg + 2.5 mg)

- Content uniformity

- Assay

Disproportionate doses


Solutions… Hygroscopicity

Problems…

e.g. Metformin + Glipizide

Metformin- Poorly compressible Needs residual moisture

Glipizide - Degrades in moisture

Separate granulation

Coat the Glipizide particles

Altered solubility/ stability

e.g. Atorvastatin + Ramipril + Aspirin

Synergistic action Atorvastatin -is acid labile

Aspirin- Undergoes alkaline hydrolysis

Suitable excipients

Product Formulation issues ……


Drug Delivery Systems for FDCs…..Drug Delivery Systems for FDCs…..

Matrix system

Multilayered tablets (bi/tri)

Compression coated

Tab-in-tab

In-lay technology


Delivery systems to formulate FDCs…..Delivery systems to formulate FDCs…..

Multiple unit system

Beads / coating Particulate / Coating (MUPS)

Multicompartment capsules

Capsule within capsuleCapsule – coatedMini-tab in capsules


Dual Release Drug Absorption Systems

Multi-layered tablets

Bilayer, Trilayer & Tab -in -Tab

One or more than one drug combination with

different release patterns

Incompatibility, stability issue can be

resolved


Multilayered Tablets…..Multilayered Tablets…..

Bilayer Tabletting

+

Release of both drugs starts

immediately

Ease of manufacturing

Elegance to the product


Multilayered Tablets…..Multilayered Tablets…..

Trilayer tabletting

+

+

Two incompatible drugs

Inert layer

Combination of incompatible drugs

Combination of different release profiles

Elegance to the product


100,000 tablets 200,000 layersseveral days

Problems in layered tablets…..Problems in layered tablets…..

Lack of proper bonding of two layers

Stress due to high compression force degrades certain actives e.g. ramipril


Crystal lattice ruptures

Probable cause of increase in impurities


Tablet-in- Tablet Technology…..

Tablet-in- Tablet Technology…..

Tab-in-Tab

Elegance to the product Improved product stability Minimal incompatibility


A new platform technology for decreasing the mechanical shear on double compressed products which can lead to decrease in unknown/process related impurities.

Release of both drugs starts immediately

Inlay Technology…..Inlay Technology…..


Dosing regimen based on weight to age data

Optimised dose ratio i.e. 1 : 3

Rationale: To ensure that patients take both drugs together in the right dose, with a particular attention paid to paediatric needs (dose ratio, age-adapted strengths, optimized pharmaceutical formulation)

Ref: WHO Bulletin, Vol 84, No. 12 Dec. 2006, 921-1000

Artesunate + Amodiaquine HCl

Case study……Artemisinin based FDCs


AMODIAQUINE. HCl ARTESUNATE

ACID –DEGRADED ARTESUNATE

Chemical incompatibility..…


Bilayer technologyBilayer technology

A’sunate

(Optionally coated)

A’quine

Limited contact

Degradation problem solved

Technology Used ……


Sr. No.

ParametersRemark

1API

i. Particle size distribution

Increase in effective surface area

ii. Storage Protect Artesunate from moisture

2Granulation Point Wet mass (mixing time)= Improved wetability

3Moisture ContentLess than 1%w/w (Measured on IR moisture balance at 65ºC)

Improvement in compaction properties

4Hardness of TabletsLowHigh

Layer separation Decrease in Solubility/ Dissolution

Critical Process Parameters ……


Characterization of impurities

Stability Indicating Assay

Related Compounds

Dissolution Profile

Content Uniformity

OVI / Residual Solvents

Impurity profile study

Drug : Excipients compatibility study

Evaluation studies ……


Physical and /or chemical incompatible drugs

Artesunate + Amodiaquine

Drugs with different biological half lives

Loratidine + Pseudoephedrine

Multiple release formulations

Bilayer Antidiabetic drug combinations

Zolpidem tartarte ER

Metformin ER +Glicazide MR + Pioglitizone IR

Inlay

Trilayer

To prevent side effects Lamotrigene MR tablets

Mumps – multiple unit particulate system

Filled in hard gelatin capsule

Compressed within a tablet

(Metoprolol Succinate XL)

Some of IPCA’s Unique Products*…..

*For Indian Market


The starting formulation may be based onINTUITION

but the ending formulation must be based onSCIENCE

Science means: There will be no weak eye in the pharmaceutical development chain


Validation

Tech. Transfer

RegulatoryEvaluation

Development

Identification

Divisions

ProductDevelopment

Medical Marketing

R&D AnalyticalResearch

Pharmacology Evaluation

Regulatory Affairs

R&D Production Validation team

R&D Production Q.A.

Research & Development (Formulations)…..New Product Introduction


Pre-formulation Establish Drug : Excipients compatibility

Development lots Mini experimental trials to decide the formula / process

Process optimization Fine tuning to avoid scale-up problem Process qualification To define critical processing steps

(Scale-up batch) and test parameters usually mimics production conditions

Pivotal batch Samples are used to perform the bio-

equivalence study / clinical trials.

Product development For PAI visit report & Submission

Development Program Timelines…..

3

4

2

4

2

StabilityStudies

~ 15 Months for Product Development, by Following ICH Guidelines

Months Stages Activities


Technology Transfer…..

R&D Development

More effective as we movepoint of intersection to the left

Manufacturing& Quality

0

100

Launch / CommercializationEarly Development

% I

nvo

lved

i n D

e ve l

opm

ent

• Master Manufacturing Document

• Development Report

• Specifications

• Validation Protocols/SOPs

• Onsite training & technical Presentation


Product Quality Design…..

Existing knowledge & new scientific data generated in the process

Interaction of input variables & process parameters that provides Quality Product

Includes Input material controls, Process controls & FPP control tests

Design space

Knowledge space

Control strategy

Development of ‘ASSURED QUALITY

PRODUCT’

DESIGN SPACE

CONTROL STRATEGIES


BECAUSE

Knowledge space & resulting design space & process understanding

CONSTANTLY EVOLVES……!!

snehal khedkar | april 2008 1 |1 | pharmaceutical development with focus on paediatric formulations...

Documents

snehal khedkar email

development of fdcs

indication slide

synergistic combination

lay technology slide

excipients problems

examples of fdcs

combination drugs