# Presentation: 080932

## CONTINUOUS QUALITY VERIFICATION(CQV) G.K.Raju, Ph.D.Pharmaceutical Manufacturing Initiative (PHARMI),MIT Program on the Pharmaceutical Industry,Massachusetts Institute of Technology

**July 2001**

##   Objective: To Describe the Opportunity to Improve 
Pharmaceutical Manufacturing Performance

**  ****Objective:**** To Describe the Opportunity to Improve **
**Pharmaceutical Manufacturing Performance**

**MIT Pharmaceutical Manufacturing Initiative**** **

**Research**

**Development**

**Manufacturing**

**Marketing**

## Pharmaceutical Manufacturing  

**Research**

**Development**

**Manufacturing**

**Marketing**

** ****Bulk**
**Active**

**      ****Bulk**
**Formulation**

**Filling &**
**Finish**

**Packaging**

**Inbound**
**Logistics**

**Outbound**
**Logistics**

## HORIZONTAL 

**APPROACH**

**STUDYING PHARMACEUTICAL MFG:**
**VERTICAL VS. HORIZONTAL APPROACH**** **

** ****Bulk**
**Active**

**    ****Bulk**
**Formulation**

**Filling/**
**Tableting**

**Packaging/**
**Finishing**

** ****Bulk**
**Active**

**    ****Bulk**
**Formulation**

**Filling/**
**Tableting**

**Packaging/**
**Finishing**

_**Plant A**_

**Bulk**
**Active**

**     ****Bulk**
**Formulation**

**Filling/**
**Tableting**

**Packaging/**
**Finishing**

_**Plant B**_

_**Plant A**_

_**Plant B**_

**VERTICAL **
**APPROACH**

## THE HORIZONTAL APPROACH

**Bulk**
**Active**

**    ****Bulk**
**Formulation**

**Filling/**
**Tableting/**
** ****etc.**

**Packaging/**
**Finishing**

**Bulk**
**Active**

**    ****Bulk**
**Formulation**

**Filling/**
**Tableting/**
** ****etc.**

**Packaging/**
**Finishing**

_**Company A**_

_**Company B**_

_**Company C**_

**THE HORIZONTAL APPROACH**

**PHARMACEUTICAL MANUFACTURING**** **

## DESCRIBING THE OPPORTUNITYIN ROUTINE MANUFACTURING

**CONTINUOUS QUALITY VERIFICATION (CQV)**

## WHICH PROCESSES?

**WHICH PROCESSES?**

**PROCESS CYCLE TIMES**** **

**In Process Development**

**In Routine Manufacturing**

_**Biggest Impact Here?**_**Time-to-market****Enabling****Potent Products**

_**Place for**__** **__**Validation?**_**Potent Products****Difficult Processes****High Volume Products****Products with Tough QC Tests****Generic Competition **

## PROCESS A WITH QC TESTS

** ****WEIGHING**

**           ****WET**
**GRANULATION**

**STEP**

**FB DRY**

**   ****STEP**

**BLEND**

**  ****ENCAPSULATE**

**SIEVE**

** ****API**
** ****MICRO**

** ****Particle Size**

** ****Description**
** ****ID**
** ****Assay**
** ****CU**
** ****Impurity**
** ****Dissolution**
** ****MICRO**

**QC****1**

**QC****3**

**QC****4**

**DRY MIX**

**QC****2**

** ****LOD**

## PROCESS A WITH CYCLE TIMES

** ****WEIGH**

**     ****WET**
**GRANULN**

**Processing**

**FB DRY**

**   ****STEP**

**BLEND**

**  ****ENCAPSULATE**

**SIEVE**

** ****API**
** ****MICRO**

** ****Particle **
**   ****Size**

** ****Description**
** ****ID**
** ****Assay**
** ****CU**
** ****Impurity**
** ****Dissolution**
** ****MICRO**

**QC****1**

**QC****3**

**QC****4**

**DRY **
**MIX**

**QC****2**

** ****LOD**

**7 DAYS**

**13 DAYS**

**< 3 DAYS**

## PROCESS B WITH QC TESTS

**CHEMICAL **
**WEIGHING**

**   ****BLEND **

**  ****FILL CAPSULES**

**   ****BOTTLE**
**PACKAGING**

** ****API**
** ****OVI**

** ****Description**
** ****ID**
** ****Assay**
** ****CU**
** ****Impurity**
** ****Dissolution**

**QC****1**

**QC****2**

## PROCESS B WITH CYCLE TIMES

**CHEMICAL **
**WEIGHING**

**   ****BLEND **

**      ****FILL**
** ****CAPSULES**

**   ****BOTTLE**
**PACKAGING**

** ****API**
** ****OVI**

** ****Description**
** ****ID**
** ****Assay**
** ****CU**
** ****Impurity**
** ****Dissolution**

**QC****1**

**QC****2**

**7 DAYS**

**14 DAYS**

**17 DAYS**

## PROCESS C WITH QC TESTS

**WEIGHING**

**GRANULATION**

**FB DRY**

**STEP**

**BLEND**

**  ****FILM**
**COATING**

**COMPRESS**

**   ****BOTTLE**
**PACKAGING**

** ****API**

** ****Particle Size**
** ****LOD**

** ****Description**
** ****ID**
** ****Assay**
** ****CU**
** ****Impurity**
** ****Dissolution**

**QC****1**

**QC****2**

**QC****2**

## PROCESS C WITH CYCLE TIMES

**WEIGHING**

**GRANULATION**

**FB DRY**

**STEP**

**BLEND**

**  ****FILM**
**COATING**

**COMPRESS**

**   ****BOTTLE**
**PACKAGING**

** ****API**

** ****Description**
** ****ID**
** ****Assay**
** ****CU**
** ****Impurity**
** ****Dissolution**

**QC****1**

**QC****2**

**21 DAYS**

**6 DAYS**

**14 DAYS**

## PROCESS D WITH QC TESTS

**CHEMICAL **
**WEIGHING**

**GRANULATION**

**Processing**

**STEP**

**   ****BLEND 1:**

**  ****BLEND 2:**
**   ****PRE-**
**  ****BLEND**

**FINAL**
**BLEND**

**  ****FILM**
**COATING**

**COMPRESS**

**   ****BOTTLE**
**PACKAGING**

** ****API**

** ****Particle Size**
** ****LOD**

** ****Description**
** ****ID**
** ****Assay**
** ****CU**
** ****Impurity**
** ****Dissolution**

**QC****1**

**QC****2**

**QC****3**

## PROCESS D WITH CYCLE TIMES

**QC****1**

**      ****BLEND 2:**
**   ****PRE-BLEND**

**CHEMICAL **
**WEIGHING**

**GRANULATION**

**PROCESSING**

**STEP**

**   ****BLEND 1:**

**FINAL**
**BLEND**

**COMPRESS**

**QC****2**

**QC****3**

**15 DAYS**

**10 DAYS**

**20 DAYS**

**15 DAYS**

**60 DAYS**

** ****Description**
** ****ID**
** ****Assay**
** ****CU**
** ****Impurity**
** ****Dissolution**

** ****Particle Size**
** ****LOD**

** ****API**

## PROCESS D WITH QC TESTS:Cycle Times including BULK ACTIVE

**QC****1**

**      ****BLEND 2:**
**   ****PRE-BLEND**

**CHEMICAL **
**WEIGHING**

**GRANULATION**

**STEP**

**   ****BLEND 1:**

**FINAL**
**BLEND**

**COMPRESS**

**QC****2**

**QC****3**

**15 DAYS**

**10 DAYS**

**20 DAYS**

**15 DAYS**

**60 DAYS**

**    ****21-90 DAYS**

**PROCESSING**

## PROCESS D WITH QC TESTSCycle Times

## WHAT DRIVES THE QC TESTING TIMES?

** ****Sampling**
** ****Batching**
** ****Other Products**
** ****Waiting**
** ****Coordinating**

** ****Other Products**
** ****Other Paperwork**
** ****Waiting**
** ****Coordinating**

**2%**

**TEST**

## WHICH PROCESSES?

**WHICH PROCESSES?**

**PROCESS CYCLE TIMES**** **

**In Process Development**

**In Routine Manufacturing**

_**Biggest Impact Here?**_**Time-to-market****Enabling****Potent Products**

_**Place for**__** **__**Validation?**_**Potent Products****Difficult Processes****High Volume Products****Products with Tough QC Tests****Generic Competition **

## PROCESS E WITH QC TEST POINTS 

** ****WEIGH**

** ****DRY MIX**

**    ****WET **
** ****GRANULN**

**   ****WET GRANULN**

**FL BED DRY**

**MILL**

**MILL**

**STORE**

**DRY**

**   ****SIFT**

** ****WET GRAN**

**MIX**

**MIX**

**COAT**

**STORE**

**MILL**

**SIFT**

**STORE**

**BLEND**

**BLEND**

**BLEND**

**BLEND**

**STORE**

**BOTTLE FILL**

**DRY**

**MIX**

**MIX**

**GRANUL**

**DRY**

**MILL**

**MILL**

**ACTIVE**

**INITIAL GRANULATION STAGE**

**SECOND GRANULATION STAGE**

**COATING  STAGE**

**EXCEPIENT PREPARATION STAGE**

**SIFT&BLEND STAGE**

**BLEND&FILL STAGE**

**QC****4**

**QC****3**

**QC****2**

**QC****1**

**LOD**

**LOD**

**LOD**

## PROCESS E WITH QC TEST TIMES 

**ACTIVE**

**      ****FIRST **
**      ****GRAN **

** ****SECOND**
** ****GRAN**

**QC****1**

**7 days**

**COAT **

**SIFT&**
**BLEND **

**BLEND**

**QC****4**

**QC****3**

**QC****2**

**FILL**

**7 days**

**7 days**

**3 days**

**< 1 **
**day **

**< 1 **
**day **

** ****1-2**
** ****days **

**< 1**
** ****day **

**< 1 **
**day **

**< 1 **
**day **

## WHICH PROCESSES?

**WHICH PROCESSES?**

**TOWARDS PARAMETRIC RELEASE**** **

**In Process Development**

**In Routine Manufacturing**

_**Biggest Impact Here?**_**Time-to-market****Enabling****Potent Products**

_**Place for**__** **__**Validation?**_**Potent Products****Difficult Processes****High Volume Products****Products with Tough QC Tests****Generic Competition **

## PROCESS F: LIQUID LINE

**WEIGH**

**pH ADJ**

**COMPOUND**

**FILTER**

**   ****FILL**

**  ****STOPPER**

**CAP**

**LABEL/PKG**

**    ****TERMINAL**
**STERILIZATION**

**WEIGH**

**WEIGH**

**VIALS**

**STOPPERS**

**WFI**

**BUFFER**

**WASH**

**WASH**

**AUTOCLAVE**

**DEPYROGEN**

**SEALS**

** ****Appearance**
** ****ID**
** ****Assay **
** ****Impurity**
** ****Fill Vol, Osmolarity, Partic.**
** ****Endotoxin**
** ****STERILITY TESTING**

** ****ENVIRO. MONITORING**

** ****BIOBURDEN**

** ****WFI TESTING**
** ****Endotoxin**
** ****TOC**

** ****ID**

** ****ID**

** ****pH**

** ****Visual Check**

** ****Wt Check**

** ****QC Check**

** ****QC Check**

** ****QC Check**

## PROCESS F: LIQUID LINE WITH CYCLE TIMES

** ****10 days**

** ****7 days**

** ****ENVIRONMENTAL MONITORING**

** ****BIOBURDEN TESTING**

** ****17-20 days**

** ****7 days**

** ****3-4 days**

** ****STERILITY TESTING**

** ****WFI TESTING**

**   ****3-4 months**

## PERCEIVED PROCESS CYCLE TIMES:SUMMARY

## CYCLE TIME COMPONENTS

## ON-LINE TECHNOLOGY IMPACTSDOMINANT CYCLE TIMES

**On-line LIF, NIR, Pattern Recognition, etc.**

##  Quality Monitoring is Discontinuous

-  Quality Monitoring is Discontinuous
-  QC testing times are approximately = 1 month
-  Factor of 20-25 opportunity in cycle time: Process
-  Factor of 20-25 opportunity in cycle time: QC
-  QC Cycle Times >= Process Cycle Times
-  Time is driven by off-line nature of test
-   Exception is MICRO test

_**SUMMARY**_

## DESCRIBING THE OPPORTUNITYIN PROCESS DEVELOPMENT

**CONTINUOUS QUALITY VERIFICATION (CQV)**

## THE VERTICAL APPROACH

_**THE VERTICAL APPROACH**_

***Blending***
***Drying***
***Granulation***

***Fermentation***

***Rapid ***
***Microbial***
***Detection***

***Flow***
***Tableting***
***Transport***

## BLENDING UNIT OPERATION

**Bulk**
**Active**

**    ****Bulk**
**Formulation**

**Filling &**
**Finish**

**Packaging**

**Bulk**
**Active**

**    ****Bulk**
**Formulation**

**Filling &**
**Finish**

**Packaging**

**Bulk**
**Active**

**    ****Bulk**
**Formulation**

**Filling &**
**Finish**

**Packaging**

_**Company A**_

_**Company B**_

_**Company C**_

_**VERTICAL ANALYSIS I:**_
**BLENDING UNIT OPERATION**

***Eg. Blending***

## WHICH PROCESSES?

**WHICH PROCESSES?**

**PROCESS CYCLE TIMES**** **

**In Process Development**

**In Routine Manufacturing**

_**Biggest Impact Here?**_**Time-to-market****Enabling****Potent Products**

_**Place for**__** **__**Validation?**_**Potent Products****Difficult Processes****High Volume Products****Products with Tough QC Tests****Generic Competition **

## FOCUS

**  ****Explore the Potential Impact of On-line Monitoring Technology on Blending Process Development**

**MIT Pharmaceutical Manufacturing Initiative**** **

## Blending Operation Model

**Blender**
** ****cleaning**

**Undermixed**
**mix-longer**

**Homogeneous**
**Next batch**

**Discarded**
**Next batch**

## LIGHT INDUCED FLUORESCENCE SYSTEM

**LIGHT INDUCED FLUORESCENCE SYSTEM**
**FOR THE DETERMINATION OF THE **
**HOMOGENEITY OF DRY POWDER BLENDING**

**PHARMACEUTICAL MANUFACTURING:**
**LIF FOR ON-LINE MONITORING OF BLENDING**

## LIF VERIFICATION STUDIES

- Established a correlation between LIF assessment of
- homogeneity and thief-sampling with off-line analysis

## PROCESS D: BLENDING PROCESS DEVELOPMENT

**PROCESS D: ****BLENDING PROCESS DEVELOPMENT**

**CHEMICAL **
**WEIGHING**

**GRANULATION**

**Processing**

**STEP**

**   ****BLEND 1:**

**  ****BLEND 2:**
**   ****PRE-**
**  ****BLEND**

**FINAL**
**BLEND**

**  ****FILM**
**COATING**

**COMPRESS**

**   ****BOTTLE**
**PACKAGING**

** ****OFF LINE QC TEST**

** ****ON LINE SENSOR**

##  Blending Operation: Two Technologies, Two Approaches

** ****Blending Operation: Two Technologies, Two Approaches**
***Process Development, Validation and Manufacturing***

**OFF  LINE**

**ON  LINE**

## Blending Data Collected from CAMP Companies 

**Blending Data Collected from CAMP Companies **

**Operation Characteristics**

## Results

**Results**

**Blending Performance**
***Process Development and Validation***
***6% no wait between blends***

** ****1 Blend**

**2 Blends**

**3 Blends**

**Best**

**Med.**

**Worst**

**  ****2.32**

**13.19**

**25.82**

**0.36**

**1.31**

**2.57**

**4.96**

**23.45**

**43.40**

**0.68**

**1.93**

**3.56**

**8.45**

**30.65**

**56.17**

**1.07**

**2.41**

**4.46**

**Time (days)**

## Blending Performance

**Blending Performance**
**Process Development and Validation**

## APPROACH TO LEARNING:

**Consequences on Process Development & Commercial Production**

##  Process development can be on the critical path

-  Process development can be on the critical path
-  Factor of 10-15 reduction in cycle time in blend
- 	process development (maybe more..)
-  Variability reduction in blend process dev. time
-  independence of organization/product -> predictability...
-   Benefits not restricted to use of new on-line sensors
-  improvement data analysis of existing sensor data
-  use of this for experimental design

_**SUMMARY**_

## WHAT ARE THE IMPLICATIONS?

**CONTINUOUS QUALITY VERIFICATION (CQV)**

## Consortium for the Advancement of Manufacturing in Pharmaceuticals (CAMP)

**FDA**

_**Pharmaceutical Companies**_

**CAMP**

**Purdue**

**MIT**

** ****Abbott**
** ****Aventis**
** ****Bristol-Myers Squibb**
** ****Johnson & Johnson**

** ****Hoffmann-La Roche**
** ****Glaxo SmithKline**
** ****Wyeth-Ayerst**

**Consortium for the Advancement of Manufacturing in Pharmaceuticals (CAMP)**

**Vendors**

## PROCESS A WITH CURRENT QC TESTS AND NEW POSSIBILITIES

** ****WEIGHING**

**           ****WET**
**GRANULATION**

**STEP**

**FB DRY**

**STEP**

**BLEND**

**  ****ENCAPSULATE**

**SIEVE**

** ****API**
** ****MICRO**

** ****Particle Size**

** ****Description**
** ****ID**
** ****Assay**
** ****CU**
** ****Impurity**
** ****Dissolution**
** ****MICRO**

**QC****1**

**QC****3**

**QC****4**

**DRY MIX**

**QC****2**

** ****LOD**

## Need to Focus on Both Material Flow and Information Flow

**INFORMATION FLOW**

**MATERIAL FLOW**

## Manufacturing Information Management: Has Hardware and Software Components

-  Fast Response
-  On-Line
-  Real-Time
-  Accurate
-  Robust

-  Rapid Rate of Learning
-  Short Cycle Times
-  Benchmarking
-  Modeling
-  Continuous Problem Solving

## HORIZONTAL AND VERTICAL APPROACHES

**Bulk**
**Active**

**    ****Bulk**
**Formulation**

**Filling &**
**Finish**

**Packaging**

**Bulk**
**Active**

**    ****Bulk**
**Formulation**

**Filling &**
**Finish**

**Packaging**

**Bulk**
**Active**

**    ****Bulk**
**Formulation**

**Filling &**
**Finish**

**Packaging**

_**Company A**_

_**Company B**_

_**Company C**_

_**HORIZONTAL AND VERTICAL APPROACHES**_

_***Blending***_
***Drying***
***Granulation***

_***Fermentation***_

***Rapid ***
***Microbial***
***Detection***

***Flow***
***Tableting***
***Transport***

**High Vol**

**Variable**

**Liquids**

## CQV: BENEFITS

-  Data Mining of Process Data
-  Data -> Information -> Knowledge
-  Rationale for New Sensors
-  Variable Categorization: PCCPs, etc.
-  Basis for Specifications, Batch Record Design
-  Basis for Experimental Design,  Etc. ...

## Learning Curve: Cycle Times

- Accelerated Learning Curve Facilitated By
- Continuous Quality Verification

## CQV: SO WHAT?

** ****On-line sensors**** doing the same thing will have **
**only incremental impact**
** ****This impact will still be only incremental **
**	****even if there is an ****MES/EBR system**
** ****Data Warehousing**** focused on exceptions can**
**	****have a large impact**
** ****On-line sensors + EBR + Data Warehousing **
**	****can ****fundamentally change**** pharma. mfg.**

## PRODUCT LIFE CYCLE: OPPORTUNITIES

## Pharmaceutical Manufacturing:Opportunity Areas

***Pharmaceutical Manufacturing:******Opportunity Areas***

- Manufacturing:  		*Cost  -->   Profit** *
- Organizational focus:    *Functional -->  Process*
- Optimization:  		*Local  -->  Supply chain*
- Inventory Management: *JIC  -->   JIT*
- Cost of Quality:  		*Inspection  -->  Prevention*
**	****KEY TECHNOLOGY OPPORTUNITY:**** **
**	****On-line Sensors+EBR+Data Warehousing!**

## ACKNOWLEDGEMENTS

- Professor Charles Cooney (MIT)
- Professor Stephen Byrn (Purdue)
- CAMP

## NOTE ON CONTEXT

*This presentation does not necessarily represent the views of MIT, Purdue or CAMP*
*Some data have been disguised for reasons of sensitivity and confidentiality*