the importance of raw material quality risk management in ... · the importance of raw material...

B Carlin Sindusfarma 2013 1

The importance of raw material quality risk

management in QbD and its impact on the

regulated sector

A importância do gerenciamento se risco de

qualidade de materias primas no QbD e seus

impactos no setor regulado

Professor Brian A Carlin

Director Open Innovation FMC BioPolymer

Chair IPEC Americas QbD Committee

Chair IPEC Americas Excipient Composition Committee

Member USP Excipient Committee

[email protected]


International Pharmaceutical

Excipient Council


IPEC: Total Excipient Control

D Schoneker Pharma Times 45(3) 54-56 March 2013


Quality by Design: FDA 21st century cGMP

• Desired state

•A maximally efficient, agile, flexible pharmaceutical manufacturing sector that reliably produces high quality drug products without extensive regulatory oversight. Janet Woodcock, M.D. Director CDER

• From Quality by Inspection to QbD

•2σ to 6σ

• New Manufacturing Technologies

• Batch to continuous manufacturing

•Eliminate scale-up


QbD Distance Learning

www.qbd-dmu.co.uk


FDASIA 2012/ANSI 363 Excipient GMP


Raw Materials in QbD

• Quality of Design

•Good raw materials will not rescue a bad design

•Good design minimises but cannot eliminate raw material impact

•Excipient risk must be managed

• Raw materials & components in other regulated sectors

•Do not underestimate complexity of Pharma excipients

•Do not underestimate complexity of Pharma finished products

•Do not underestimate variability of Pharma excipients

• Specification of raw materials

•Pharmacopoeial compliance is not fitness for purpose

• Design of Experiments vs Control Strategy

• Compliance & supply chain security alone are insufficient to manage excipient risk.


A Good Design?

• 1910: Launched

• 1911: Rammed & holed by cruiser

• 1918: Rammed & sank U-103

• 1934: Rammed & sank Nantucket lightship

• 1935: Retired after 257 transatlantic crossings

• RMS Olympic (“Old Reliable”)


Rearranging the deckchairs on Titanic does

not impart resistance to icebergs!

QbD: Compliance ≠ Quality


Raw Materials/Components

in Regulated Sectors

Industry Components Specification Sigma

Airlines Individually

engineered

Composition

Performance

Tolerances

6σ

Chemical

(solution)

Molecular Composition

Purity

6σ

Actives

Reagents

Food

(semisolid)

Complex

variable

mixtures

Nominal Composition

Purity

Performance

6σ

Pharma

(solid)

Mass

produced

particulates

Nominal Composition*

Purity*

*pharmacopoeial

2-3σ

Excipients

(+ small scale

fixed processes)


Engineered Systems are not perfect

B Carlin Sindusfarma 2013 12 http://rmc.nasa.gov/archive/rmc_v/presentations/oconnor%20osma%20risk%20is%20part%20of%20nasa%20mission.pdf

Incógnitas Desconhecidas


Black Swan Theory….

the extreme impact of certain

kinds of rare and unpredictable

events (outliers) and humans'

tendency to find simplistic

explanations for these events

retrospectively, after the fact.


http://mastermindmaps.wordpress.com/2010/11/22/black-swans/

Nassim Nicholas Taleb "The Black Swan:

The Impact of the Highly Improbable.” 2nd Ed. Random House Trade Paperbacks (May 2010)

C of A

Not on C of A


Excipients & ICH Q9 Risk Assessment

http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q9/Step4/Q9_Guideline.pdf


Unknowns Add to System Complexity

System

•States

•Parameters

Inputs Outputs

Known

Variability

Unknowns

???


Excipient Unknown Unknowns

• Composition

• Functionality/Performance

• Relevance of Pharmacopoeial Attributes

•Fitness for purpose?

• Unspecified excipient attributes

•Controlled? Notified?

• True variability of specified attributes

• Criticalities in the Finished product

Carlin B, J Excipients & Food Chem 3 (4) 2012 143-153

http://ojs.abo.fi/index.php/jefc/article/view/190/176


Application Criticalities

• Criticality = Point of transition from one state to another:- not in ICH definition

• Excipients may unexpectedly affect CQAs if there is a criticality in the application

• Criticalities not built in by design •Unanticipated, interactions •Not always intrinsic to an excipient •Variable (scale-dependent?) •Non-linearities, discontinuities, tipping points

• Disproportionate impact if minor excipient variability interacts with a criticality!


Explosive Percolation

The probability

Ppath that there is

a path between

opposite sites of a

L L square lattice.

In the limit of infinite L,

Ppath becomes a step

function, jumping from 0 to

1 at pc. Such a situation

where one goes from the

impossible (Ppath=0) to the

inevitable (Ppath=1),

without ever visiting the

improbable, is called a "0-1

law" in mathematics. In

physics, this phenomenon

is called a "phase

transition."

http://www2.imperial.ac.uk/~mgastner/percolation/percolation.html


Examples of Criticalities

• Percolation thresholds

•Disintegrant in insoluble/hydrophobic matrix

•No wicking without contiguous network

•Non-linear tablet hardness-force profile

•Contiguous high density regions within compact

• Conflicting technological objectives

•Overgranulation

•Lubrication vs Compaction vs Dissolution

• Unidentified Critical Material Attributes

•especially with “non-critical” excipients in ‘”simple” formulations (what can go wrong?)

Percolation theory - a novel approach to solid dosage form design

Leuenberger H et al Int J P’ceutics 38 (1987) 109-115


Known Knowns

Attributes known to both parties

and specified.

e.g.: C of A or Pharmacopoeial

attributes

Unknowns Compromise Risk Assessment

Unknown Knowns

Unspecified Attributes which can

impact finished product

performance including CQAs.

e.g.: Variability of high volume continuously

manufactured excipients not reflected

in C of A data

e.g.: Unspecified attributes

Unknown Unknowns

.

e.g.: Attribute not critical in itself but critical

if variability impacts finished product

sensitivity or weakness

e.g.: Unspecified attributes

Known Unknowns

Undisclosed raw material

impacts, not fed back to supplier

for control or improvement of

excipient fitness

e.g.: Failure to specify fitness for purpose

requirements

(composition/functionality)

Known to Supplier

Kn

ow

n t

o U

ser

Yes No

Ye

s

No

Excipient interaction with finished

product criticality leading to

unanticipated modes of failure


Jim Michaels NIPTE/FDA Mtg 13th June 2012


Excipient “non-

critical”

Excipient not in DOE

Scale-up

Limited Excipient

experience

No functional

Spec

Suboptimal Product or

Failures

Beware “Non-critical” Excipients

DOEs are only as good

as the considered

factors

Impact of excluded

factors will not be

evaluated


Control Strategy, Not DOE,

for Managing Excipient Risk

Excipient in

DOE (or Production)

Redesign

Product or

Specify

Excipient

Product

NOT

Robust

No Evidence

of Problem

CQA

Affected?

is NOT

evidence of

no problem!

Yes

No


Binomial Probability of Excipient Related Adverse Event

Excipient Reliability

Trials=#excipients x #batches x #products

99%

99.9%

99.99%


Dr. Laura Birou, Director of North America-IIAPS

International Institute For Advanced Purchasing and Supply

[email protected] 239-405-2800

Xavier University Global Outsourcing Conference – 2012

mailto:[email protected]


Cost of Poor Quality

($90bn @ 5-10% = $4.5-9bn*)

The Tip of the Iceberg

J DeFeo

Quality Progress 29-37 May 2001

*Pavlovic K, Božanic V

Int J Qual Res 6(1) 23-28 2012

Not including

regulatory costs!


Closing the Excipients Knowledge Gap

Supplier

Knowledge

Industry,

Academic, &

Regulatory

Knowledge

Shared

Understanding

Collaboration crucial

to identify:

impact of variability from

previously unspecified raw material

attributes both in new product

development and commercial

manufacturing

AND

existence of criticalities in

commercial formulations and their

susceptibility to both known and

unknown raw material attributes

(elimination of failures)


The Central Role of the Supply Chain in

Developing Process Understanding

Why ….. What does the supplier have to contribute ??

• Knowledge of the product itself

• Knowledge of how the product was created

• Knowledge of the how the product will behave in unexpected circumstances

• Knowledge of the how the product can be changed or improved

• Knowledge of how to specify the product

• Knowledge of the risks associated with the product

G Mahboubian-Jones FDA-Xavier Conference 2012


Collaboration on new critical material attributes


Benefits of Excipient Understanding

• Adequate specification of excipients reflecting shared understanding and fitness for purpose in application.

• Regulatory recognition of supplier-user partnerships jointly reducing excipient-related risks through mutual due diligence.

Brian Carlin NIPTE/FDA Mtg 13th June 2012

Jeff Medwid NIPTE/FDA Mtg 13th June 2012


Excipient Risk Management

• Excipient Unknowns more likely to cause product failure

• Pharmaceutically aligned excipient suppliers can identify potential failure modes related to their excipients IF they know what you are doing

• User-supplier joint due-diligence provides lowest risk basis for approval

the importance of raw material quality risk management in ... · the importance of raw material...

Documents