Understanding Critical Material Properties for Pharmaceutical Dosage Forms

Current vs. Desired State

Ken MorrisProfessor of Industrial and Physical Pharmacy

Professor of Chemical Engineering (by courtesy)

Physical and Mechanical Properties of Excipients:

Workshop SummaryApril 5- 7, 2006

The Problem

Pharmaceutical development and manufacturing processes have become so complex that it is increasingly difficult to provide safe and effective drugs at a significantly lower cost to patients.

The science of pharmaceutical product development and manufacturing is not as advanced as in other industries such as the chemical industry, the aircraft industry, other engineering industries, etc. where “Quality by Design” concepts are applied more routinely

A paradigm shift is required to change how pharmaceutical products are designed and manufactured once a new molecule is discovered.

The ultimate choice is whether we want to invest in developing science or to have more regulation

Drug vs. Dosage Form• Typically you don’t give the pure drug to the patient?

– Small doses, Unstable, Patient compliance

• The active pharmaceutical ingredient (API) is combined with excipients to produce a dosage form which allows the delivery of a drug in the safest and most efficacious way

• A dosage form relies on two elements:

1- Formula and 2 - Process

• A formula without a process is a pile of powder hence the need for pharmaceutical engineering

API is the Drug, what are Excipients?

• Any component intentionally added to a formulation still present in the final dosage form is an excipient

• Excipients must provide some necessary function in the dosage form manufacturability, stability, performance, or elegance

• Typical functions include: bulking agents, disintegrants, lubricants, binders, buffers, preservatives

• Excipients are selected to either amplify desired properties OR mask undesirable properties of the API to obtain the desired dosage form performance

Preformulation-Materials Sciences in Product Development: e.g., tablets

API and Desired DF

Biopharm-aceutics

Physical chemistry

Mechanical – Micromeritcs

Chemical (stability)

Dosage form and Process recommendation

Formulation recommendation

Preliminary Development Plan

High Shear

Granulator

Fluid Bed Dryer

Tumble

MixerRotary

Tablet

Compression

Co- mil

granulationwet

milling

drying

dry

milling

mixing

tableting

Co- mil

Accela-Cota

coating

Tablet

Imprinter

imprinting

Process combine the Drugand excipients into the

dosage form

Courtesy of Steve Nail, Eli Lilly

Results of functional testsPrototype DFs?

Variability of API attributes?

What are the likely excipients?

What are the known API attributes?

What are the possible critical API attributes (CAs)?

What is the intended process?

What is the intended DF?

API/RM Property Selection Rationale/Process (ASTME55.02 in cmte)

Define CAs

Review CAs

So what’s the problem? Variability is still the Enemy

ProcessRM Input Product

Adapted from Rick Cooley, Eli Lilly, and Jon Clark CDER-FDA

variable

FIXED!!???

You CANNOT have a constant output from a fixed process and variable input

Adjustable!

Variability

“Formulation Specific” IVIVCPeak Concentration Vs. % Dissolved in vitro

Clarke et al. J. Pharm. Sci. 66: 1429, 1977

% Dissolved in 40 minutes

20 40 60 80 100

Pe

ak C

on

cen

tra

tio

n (

ug

/10

0ml)

12

14

16

18

20

22

24

26

28

30

A

B

H

I

D

F

JC

G

E

Different filler

Current vs. Desired State:in light of FDA enabling initiatives

Currently one can only either process to “erase” RM variability or reject much material if it isn’t

“exactly” with in spec (very expensive).

The Desired State includes process solutions but also allows control to a desired endpoint!

• But: the process has to be “designed” to allow incorporation of the variability and you have to monitor critical control points!

NIPTE, April 2006

Understanding Product Variability: Where Understanding Product Variability: Where are we?are we?

σσσσσ2

nIntreactio

2

Process

2

Excipients

2

API

2

Product

APIVariability

ExcipientsVariability

ProcessVariability

Product??

R. Christian Moreton, Ph.D - Idenix Pharmaceuticals, Cambridge, MA

Making progress New ground

Getting there

NIPTE, April 2006

Sources of Excipient VariabilitySources of Excipient Variability• Scale – capacity of the equipment train• Variability of raw materials (often of natural origin)

• Conditions during growing season• Conditions at harvest• Variation in growing season year upon year

• Changes in raw material source due to• Drought• Flood• War• Accident

• Weather at the time of manufacture• Hot or cold - Dry or humid

R. Christian Moreton, Ph.D - Idenix Pharmaceuticals, Cambridge, MA

Associated Frustrations of Excipient Suppliers

• Can’t make a different product for EVERY Industry, Client, Product

• Lack of understanding of what variables are critical for a given use

• Lack of methods to determine many critical variables

• AND Customers don’t always know what they want/need anyway

The Kicker!!

There is No Pharmaceutical Excipient Industry

Majority of Pharmaceutical Suppliers are Chemical Industry subsidiaries

Small fraction of Parent ProductionVarying degrees of dedicated R&DSpecifications-drivenGlobal Market and Manufacturing BaseDistributors and Repackagers

“No general purpose New Chemical Excipients for oral solid dosage forms since the early ‘70’s”

(Moreton RC, Eur Pharm Rev Sep 1997)

Pharmaceutical Materials Science traditionally focused ONLY on SOLUBILITY

• Which is of course vital, but we know there’s more– Handling– Compaction– Flow– Size– Shape– MW– etc...

• We lack the Materials Science tools in place for traditional materials

NIST/NIPTE workshop Bruno Hancock 16

Where do we start? Scale of scrutiny

QUANTUM

BULK TABLET

SINGLE TABLET

MOLECULAR(CRYSTA

L)

PARTICULATE Scale-up

Blending, granulation

, compressio

n

Crystallization, spray drying, lyophilization

Crystal structure

NIST/NIPTE workshop Bruno Hancock 17

Predictive approaches

• Atomic/Molecular

• Particle

• Bulk Powder

• Dosage Form

NIST/NIPTE workshop Bruno Hancock 18

Where are we?• Lack of MSE knowledge for our materials

makes 1st principles prediction/design a long term goal

• Empirical methods give relative values but rely on anecdotal data

• We have NO reliable mixing rules!!• Standard methods don’t exist or aren’t

agreed upon for determination of many properties

• Lack of an excipient physical and mechanical properties database prevents Bayesian prior knowledge approaches

Enter NIPTE and NIST:Standards, Measurement Science, and Property Prediction

Anne ChakaChief, Physical and Chemical Properties DivisionChemical Science and Technology Laboratory

Second half:Ram D. Sriram“Manufacturing Metrology and Standards for the HealthCare Enterprise”Leader, Design and Process Group Manufacturing Systems Integration Division Manufacturing Engineering Laboratory

NIST MissionNIST Mission

To promote U.S. innovation and industrial competitiveness To promote U.S. innovation and industrial competitiveness by advancingby advancing

measurement science,measurement science,standards, andstandards, andtechnologytechnology

in ways that enhance economic security and improve our in ways that enhance economic security and improve our quality of lifequality of life

NIST Measurements and StandardsNIST Measurements and Standards

Measurement Research 2,100 publications/years

Standard Reference Data90 types available; 5,000 units sold/ year

Standard Reference Materials>1,200 products available; 30,000 units sold/year

Calibrations and Tests3,200 items calibrated/year

Laboratory Accreditation826 accreditations

Standards Committees390 NIST staff, 450 committees

Metrology Training Courses25 per year

Collaborative Effort Between NIPTE and NIST• In any product design project, the first step ought to be to

fully characterize the materials that go into the product.• Properties of excipients, which form the biggest part of

pharmaceutical dosage forms, are not well defined and characterized.

• It is also not well understood how intrinsic properties of these excipients impact processing or manufacturing

• This is an area of fundamental research for NIPTE – without this understanding, one cannot really do “Quality by Design”

• NIST’s mission is to advance measurement science, standards and technology

• This project is a perfect example of collaboration for these two organizations for the advancement of science in a critical area of mutual interest

The Needs• Methods for quantifying potentially critical attributes Methods for quantifying potentially critical attributes

(NIST-NIPTE collaboration)(NIST-NIPTE collaboration)

• Database of physical and mechanical properties of our Database of physical and mechanical properties of our excipients and their grades (all partners)excipients and their grades (all partners)

• Models for the drug product manufacturers to use to Models for the drug product manufacturers to use to create a production or design space that can create a production or design space that can accommodate reasonable variation in the RMs accommodate reasonable variation in the RMs (NIPTE)(NIPTE)

• QbD implementation in the companies to take full QbD implementation in the companies to take full advantage of the above! (everyone, FDA has done its advantage of the above! (everyone, FDA has done its part)part)

The Benefits of getting to the Desired State

• Less uncertainty in demands and less wasteLess uncertainty in demands and less waste

• Meaningful, reliable analytical methods based on Meaningful, reliable analytical methods based on materials understanding for determination of materials understanding for determination of potentially “critical” attributes potentially “critical” attributes

• Pharmaceutical Scientists and Engineers then Pharmaceutical Scientists and Engineers then “choose” their desired materials and build the “choose” their desired materials and build the appropriate design space appropriate design space

• Ability to identify “value added” changes Ability to identify “value added” changes

• Ability to recognize and meet the need for new and/or Ability to recognize and meet the need for new and/or niche productsniche products

Progress and Next Steps • Planning committee established: Ann Chaka

(NIST) and Gerald Thone (FMC) cochairs. • Charge: to develop a plan for the next steps

leading to a NIST-FDA-NIPTE industry CRADA

• Establish Steering Cmte with industry Champions• Establish working groups• Organize follow up workshops with more stake

holders • ID expertise in other fields that might help our

effort• Investigate the limits of testing devices

Next Steps• Start by investigating a “simple” tertiary

system: market drug, carrier-MCC, Mg- stearate and gradually increase complexity

• Round-robin testing at various companies• Investigate the limits of testing devices • Consider models and mixing rules• Combine to do particle design to lead to

the optimal behavior• Map out the various stages where

variability could occur

Acknowledgements

NIPTE

OPS-CDER-FDA