Introduction to Process Analytical Technology - IFFiff.nu/classicasp/Billeder/arrangementer/2006/2006-02-03_Porcess... · Introduction to Process Analytical Technology PAT ... “The

Introduction to Process Analytical Technology

PAT

PhPh. D. Line Lundsberg. D. Line Lundsberg--NielsenNielsenLundsberg ConsultingLundsberg ConsultingIndustriFarmaceutForeningen, 2. marts, 2006IndustriFarmaceutForeningen, 2. marts, 2006

2Lundsberg Consulting

PAT – Process Understanding

The goal is to understand our processes enabling us fast to develop and produce smart and cost effectively high quality products


Who is strongly involved in PAT, 2006

• Sanofi Aventis (first approval)

• ~10 other approvals (not public – OTC, generic, API, biotech, DP)

• Pfizer (4 b $ savings – PAT a part of the tools)

• GSK (to save inventory 2b$)

• Abbott (Controlling the Porto Rico plants by PAT from US – saved 3 digit million $/year – save inventory 1b$/year)

• AstraZeneca (Plackstadt)

• AstraZeneca (Sødertäljecontrolled 70% by PAT)

• Ge Healthcare• Merck • Wyeth• BMS

• Lilly• Lundbeck• Baxter• Amgen• Novo Nordisk• Watson Pharmaceuticals• Xcellercx• Scherring-Plough• Johnson&Johnson• Amteck• Novartis• Sandoz• Genentech• Biogen• FDA, ICH, ISPE, ASTM,

aaps,…..


Outline

• Why PAT?• What is PAT?• Examples of applying PAT

tools

Why PAT


“The pharmaceutical industry has a little secret: Even as it invents futuristic new drugs, its manufacturing techniques lag far behind those of potato-chip and laundry-soap makers”


Doug Dean, FDA Science Board, Nov 16, 2001

Current Paradigm:

• Utilisation levels - 15% or less

• Scrap and rework - plan for 5-10%

• Time to effectiveness - takes years

• Hesitant to Innovate– Incentive?

• Manufacturing Costs: $90 Billion

Why PAT?

Ray Scherzer, FDA Science Board, Apr 2, 2002


Product focus – the traditional development concept

• Compliance – meet specifications – documentations• 3 validation batches• Trial and error• Limited sampling and analysis• Ignore variations, testing to required specifications• No changes, changes are negative• No link between input and output quality• Budgeted scraps, rework, OOS, investigations

Input Production Output


Pharmas compared to other industries

65

90

95

99

99,999

Yields (%)

25-35

20-25

4-8

4-8

1-3

Cost of Quality (% of COGS)

>99%Car, & electronics

1-4%

2-20%

20-50%

>90%

Mass Productivity (Kg Product/ Kg total ex water)

Pharma-ceuticals

Fine Chemicals

Bulk chemicals

Oil refining

Industry


Cost of manufacturing

25%

12%

30%

12%

5%16%Net Income

TaxOther Expenses

SGA

R&D

COGS

Components of Pharmaceutical Industry Costs

What is PAT


PAT- Process Analytical Technology

A Framework for Innovative Pharmaceutical Development,

Manufacturing, and Quality Assurance

FDA PAT Guide

PAT is a framework – not a set of requirements


Change Focus

Move from product focus to process focus


What is PAT, by definition

• A system for:– designing, analyzing, and controlling

manufacturing– timely measurements (i.e., during processing)– critical quality and performance attributes – raw and in-process materials– processes

• “Analytical” includes:– integrated chemical, physical, microbio-

logical, mathematical, and risk analysis

• Focus of PAT is Understanding and Controlling the manufacturing Process


Designing

Based on– Target product profile– Raw materials and intermediates and their

variability– Systematic compilation of Process

Knowledge (literature, existing, other processes and new)

– Identification of critical quality attributes CQA

– Identification of critical process parameters CPP

– Understanding the process


Analysing

• Analysis of (relevant and appropriate, not necessary on-line, but results has to be used for justification within the production process)

– Raw Materials– Process data– In-process analysis– Critical Control Points

• Prediction of– Process and product quality


Controlling

• Control strategies• Monitoring critical quality attributes and

process parameters• Process signatures• Feed-back control• Feed-forward control• Process performance


The PAT Framework will enable

• Focusing on Process Understanding• Creating an environment that facilitates

rationale science, risk, and business decisions

• Providing a flexible and less burdensome regulatory approach for well understood processes

• Only controlling critical quality and process parameters

• Managing the variability in manufacturing processes

Input Production Output


A Process is understood when

• All critical sources of variability are identified and explained

• Variability is managed by the process

• Product quality attributes can be accurately and reliable predicted


PAT production framework

On-line control of critical parameters

Feed back Process control

loop

Raw materialsProduct

Adjustment

Production processes

Monitoring of critical parameters

Adjustment


Result of the “new” way of thinking

• A focus on process understanding will reduce/remove validation burden

• No process validation - each batch process is a validation

• If anything goes wrong, we know what it is• Room for natural variation (e.g. raw material)• Reduction in OOS and failure investigations• Quality of end product can be predicted• Expected regulatory relief• Cost reduction!!!


Note!

• Transfer of laboratory methods to on-, in-, or at-line methods may not necessarily be PAT

• A “PAT” technology used in the lab may not necessarily be PAT


PAT is multi functional

• Chemists• Pharmacist• Process Engineers• Quality expert• Analytical chemist• Chemometician (statistician)• Regulatory• Development• Manufacturing


PAT Tools

• Integrated Systems Approach • Risk Based Approach• Systematic approach• Related tools – LEAN, Six Sigma• Multivariate tools for design, data acquisition

and analysis• Process analyzers• Process control tools• Continuous improvement and

knowledge management tools• Real Time Release


Obstacles in implementing PAT

• Understanding ”Process Understanding”• Holistic approach• Not only a R&D, production or support issue• Organisational challenges: Has to involve

– R&D– QA– RA – Productions– Engineering– QC

• Need top management support• Change management: Changing the way we

normally work and co-operate together• The development and implementation strategy

for new products has to be reworked…

Examples


What Can Be Measured Using PATAPI/Raw Materials

• Chemical Interactions• Particle Size Distribution• Polymorphism• Reaction Rate & Endpoint• Concentration/Composition/Uniformity• Identification• Drying Rate & Endpoint• Adequacy of a Cleaning Process• Etc.


What Can Be Measured Using PATDrug Product

• Particle Size Distribution• Blending Homogeneity & Endpoint• Granulation Rate & Endpoint• Drying Rate and Endpoint• Drying Temperature & Relative Humidity• Drying Airflow Rate• Tablet Identity• Tablet Uniformity/Potency• Dissolution Rate• Tablet Weight• Tablet Thickness• Tablet Hardness• Tablet Coating Thickness & Quality• Coating solution viscosity & specific gravity• Etc.


Example 1, Solid dosage forms

• Sticking of blend to tablet punches• Creates damages tablets• Scrap!

• Why?

• Lack of process understanding• What is critical to the product and to

the process?


Tablet Sticking during Production


Vision System Theory

The Vision system takes an individual digital image of every particle of a dispersed sample then measures the size and shape from the image to produce a distribution

Glass Slide

Particles of sample

TelevisionCamera


Magnesium Stearate - Japan vs. Brazil

Japanese material has 202 % the surface area of the Brazilian material

Brazil magnesium stearate

Japan magnesium stearate


Sticking versus Dissolution Issues

• Mg stearate supplier was changed to increased surface area material, for all products following the successful work to eliminate sticking.

• New “Good” supplier material caused low and variable dissolution in a capsules product

• One PSD does not fit all– Some plants now uses one grade of material

for capsules and another grade for tablets

• Very robust processes with optimal material


Example 2, Blend homogeneity

• How to avoid segregation? • When is a blend homogenate?• What is critical for our blend process


V-blender, on-line NIR monitoring

Rodolfo J. Romañach, UPR-Mayagüez, PRPQA January 24, 2006


Bohle-blender, on-line NIR monitoring

Experimental design for on-line

measurement of powder mixing

using a diode array NIR


On-line NIR monitoring of powder mixing

-10

0

10

20

30

40

50

60

70

80

90

100

0 100 200 300 400 500 600

Rotations

Con

cent

ratio

n / %

On-line results using PLS calibration

On-line concentration of API

On-line concentration of mic. cellulose

On-line concentration of Mg-stearate

Step I: Mixing of API and talcum powder

Step II: Addition of mic. cellulose and otherexcipients

Step III: Addition of Mg-stearate


Example 3, Crystallisation

• Separation of polymorphs• Crystal shape & size• PSD


Crystallisation process

NIR


Crystal forms, Raman


Identification of different polymorphs, NIR

Amorphous

Crystal form α

Crystal form β

Crystal form α and β (1:1)

III

I

I + II

II

Amorphous

Crystal form α

Crystal form β

Crystal form α and β (1:1)

III AmorphousAmorphous

Crystal form αCrystal form α

Crystal form βCrystal form β

Crystal form α and β (1:1)Crystal form α and β (1:1)

III

I

I + II

II


Crystallisation

Lasentec probeFocused beam reflectanse

Probe inserted into crystalliser

Circulating light beam bounces of particles suspended in solvent

Measures crystal diameter


Crystal size during formation

0

200

400

600

800

1000

1200

1:16:00 1:20:48 1:25:36 1:30:24 1:35:12

Reaction Time (hrs)

Part

icle

Cou

nt s

ec-1

0-50 microns

O-10 microns

50-100 microns

> 100 microns

Seed point


Endoscope picture inside crystalliser

Possible benefits

Control of fines or agglomerates in API

Reduced need to mill

Control of particle size


Warming to lower content of fines.

0

500

1000

1500

2000

2500

3000

3500

4000

4500

5000

12:28 12:57 13:26 13:55 14:24 14:52 15:21 15:500

50

100

150

200

250

#/sec, No Wt 0 10 #/sec, No Wt 10 50 #/sec, No Wt 50 100 #/sec, No Wt 100 1000

50-100

0 - 10

10- 50

100- 1000

Temp


Summary

• PAT is a science and risk based framework

• Process Understanding is the heart of PAT• PAT is a tool for managing the variability in

the various manufacturing steps• PAT is a tool for faster product development• PAT is design, analysing and controlling what

is critical• PAT is a tool for production optimisation• PAT is a tool for cost reduction• PAT is a not new but new to pharmaceutical

manufacturing!


Acknowledge

• FDA, Ali Afnan and Chris Watts• Industrial colleagues:

– Ajaz Hussain, Sandoz– Ray Scherzer, GSK– Steve Hammond, Pfizer– Zhihong Ge, Merck– Casper Leuenhagen, Novo Nordisk– Mette Bryder, H. Lundbeck A/S – Lisbeth Thierry-Carstensen, H. Lundbeck A/S – Anette Hansen, H. Lundbeck A/S– Uffe Svare, H. Lundbeck A/S– Michael Hahn, H. Lundbeck A/S– Frank Høien Lendal H. Lundbeck A/S– Gert Mølgaard, NNE


Questions?

More examples


Example 4, controlling reactions

• Conventional samples are taken at “appropriate time” and analysed in lab (take days or weeks)

• But what is happening during reaction?• What is critical to the process?• How can yields be optimised and

impurities minimised?


On-line NIR, IR or Raman

On-line control of critical parameters

Feed back Process control loop

Raw materialsProduct

Adjustment

Production processes

Monitoring of critical parameters

Adjustment


No samplingNo operator exposureAccurate end pointControl of impurities

Mid-IR to Monitor and Control Reactions

Curves generated using peak heights at 2-point baseline:Blue – starting material at 2239 cm-1Red – starting material at 930 cm-1Green – product at 1308 cm-1


Typical reaction monitoring techniques - NIR

• NIR is a strong tool for controlling end-point reaction

• Note NIR does not see every thing, e.g. not generation of impurities

Progress of reaction Reaction

complete


On-line Raman, monitoring Catalytic Hydrogenation Reaction

ReactantIntermediateProduct

Documents

Introduction to Process Analytical Technology - IFFiff.nu/classicasp/Billeder/arrangementer/2006/2006-02-03_Porcess... · Introduction to Process Analytical Technology PAT ... “The