# Presentation: 181160

## PHARMACEUTICAL MANUFACTURING:NEW TECHNOLOGY OPPORTUNITIES.. G.K.Raju, Ph.D.Executive Director,Pharmaceutical Manufacturing Initiative (PHARMI),MIT Program on the Pharmaceutical Industry,Massachusetts Institute of Technology

**November 16****th**** 2001**

## OUTLINE

**OUTLINE**

**MIT Pharmaceutical Manufacturing Initiative **
**Process Development**
**Blending: On-line blend uniformity**
**So what?**
**Routine Manufacturing**
**Where is the time spent “on average”?**
**Looking beyond the “average”**
**So what?**
**Pharmaceutical Manufacturing: **
**The New Technology Opportunity**

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

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

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

**Research**

**Development**

**Manufacturing**

**Marketing**

## Pharmaceutical Manufacturing:

**Context of Experiences..**

_**FDA**_
*Food & Drug*
*Administration*

_**MIT:**_
- MIT Pharma Mfg Initiative
- (PHARMI)

**G.K. Raju, Ph.D.**

_**Purdue Univ:**_
- Dept of Industrial & Physical Pharmacy

_**CAMP**_

***Consortium ***
***For The ***
***Advancement Of ***
***Manufacturing For***
***Pharmaceuticals***

## Pharmaceutial Manufacturing 

_**RESEARCH**_

_**DEVELOPMENT**_

_**MANUFACTURING**_

**TIME**

**SPACE**

**Pharmaceutial Manufacturing **

## Pharmaceutial Manufacturing Performance 

** ****ACTIVE**

**      ****FORMULN**

**FILL**

**PACK**

** ****ACTIVE**

**      ****FORMULN**

**FILL**

**PACK**

** ****ACTIVE**

**      ****FORMULN**

**FILL**

**PACK**

_**RESEARCH**_

_**DEVELOPMENT**_

_**MANUFACTURING**_

**TIME**

**SPACE**

**Pharmaceutial Manufacturing Performance **

**COST**

**QUALITY**

**TIME**

**SAFETY**

## OUTLINE

**OUTLINE**

**MIT Pharmaceutical Manufacturing Initiative **
**Process Development**
**Blending: On-line blend uniformity**
**So what?**
**Routine Manufacturing**
**Where is the time spent “on average”?**
**Looking beyond the “average”**
**So what?**
**Pharmaceutical Manufacturing: **
**The New Technology Opportunity**

## Pharmaceutial Manufacturing Performance 

**      ****FORMULN**

**FILL**

**PACK**

** ****ACTIVE**

**      ****FORMULN**

**FILL**

**PACK**

** ****ACTIVE**

**      ****FORMULN**

**FILL**

**PACK**

_**RESEARCH**_

_**DEVELOPMENT**_

_**MANUFACTURING**_

**TIME**

**SPACE**

**Pharmaceutial Manufacturing Performance **

***Blending***

## 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

## OUTLINE

**OUTLINE**

**MIT Pharmaceutical Manufacturing Initiative **
**Process Development**
**Blending: On-line blend uniformity**
**So what?**
**Routine Manufacturing**
**Where is the time spent “on average”?**
**Looking beyond the “average”**
**So what?**
**Pharmaceutical Manufacturing: **
**The New Technology Opportunity**

## 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 Performance

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

##   Large (Factor of 10-15) reduction in cycle time 

**Opportunity in Process Development**

-   **Large** (Factor of 10-15) **reduction in cycle time**
- 	in blend process development
-   Large **variability** reduction in blend
- 	process development **time**
-   Independence of organization/product
- 		-> predictability

_**SUMMARY**_

## OUTLINE

**OUTLINE**

**MIT Pharmaceutical Manufacturing Initiative **
**Process Development**
**Blending: On-line blend uniformity**
**So what?**
**Routine Manufacturing**
**Where is the time spent “on average”?**
**Looking beyond the “average”**
**So what?**
**Pharmaceutical Manufacturing: **
**The New Technology Opportunity**

## Pharmaceutial Manufacturing Performance 

** ****ACTIVE**

**      ****FORMULN**

**FILL**

**PACK**

** ****ACTIVE**

**      ****FORMULN**

**FILL**

**PACK**

** ****ACTIVE**

**      ****FORMULN**

**FILL**

**PACK**

_**RESEARCH**_

_**DEVELOPMENT**_

_**MANUFACTURING**_

**TIME**

**SPACE**

**Pharmaceutial Manufacturing Performance **

_**Which Products?**_**High Volume****Complex****Liquid**

## 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 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**

## Pharmaceutial Manufacturing Performance 

** ****ACTIVE**

**      ****FORMULN**

**FILL**

**PACK**

** ****ACTIVE**

**      ****FORMULN**

**FILL**

**PACK**

** ****ACTIVE**

**      ****FORMULN**

**FILL**

**PACK**

_**RESEARCH**_

_**DEVELOPMENT**_

_**MANUFACTURING**_

**TIME**

**SPACE**

**Pharmaceutial Manufacturing Performance **

_**Which Products?**_**High Volume****Complex****Liquid**

## 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 **

## Pharmaceutial Manufacturing Performance 

** ****ACTIVE**

**      ****FORMULN**

**FILL**

**PACK**

** ****ACTIVE**

**      ****FORMULN**

**FILL**

**PACK**

** ****ACTIVE**

**      ****FORMULN**

**FILL**

**PACK**

_**RESEARCH**_

_**DEVELOPMENT**_

_**MANUFACTURING**_

**TIME**

**SPACE**

**Pharmaceutial Manufacturing Performance **

_**Which Products?**_**High Volume****Complex****Liquid**

## 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**

## OVERALL CYCLE TIMES:QC TESTING TIMES  ARE SIGNIFICANT

## CYCLE TIME COMPONENTS

## ON-LINE TECHNOLOGY IMPACTSDOMINANT CYCLE TIMES

**On-line LIF, NIR, Data Analysis, etc.**

## WHAT DRIVES THE QC TESTING TIMES?

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

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

**2%**

**TEST**

## ON-LINE QC TESTING 

**IN ROUTINE MANUFACTURING**

** ****Quality testing is Discontinuous**
** ****QC testing times are large **
** ****QC Cycle Times > Process Cycle Times**
** ****OFF-LINE NATURE of test drive time**

_**ON-LINE**_** QC TESTING **
**CAN GREATLY IMPACT **
**OVERALL CYCLE TIMES**

## OUTLINE

**OUTLINE**

**MIT Pharmaceutical Manufacturing Initiative **
**Process Development**
**Blending: On-line blend uniformity**
**So what?**
**Routine Manufacturing**
**Where is the time spent “on average”?**
**Looking beyond the “average”**
**So what?**
**Pharmaceutical Manufacturing: **
**The New Technology Opportunity**

## Pharmaceutial Manufacturing Performance 

** ****ACTIVE**

**      ****FORMULN**

**FILL**

**PACK**

** ****ACTIVE**

**      ****FORMULN**

**FILL**

**PACK**

** ****ACTIVE**

**      ****FORMULN**

**FILL**

**PACK**

_**RESEARCH**_

_**DEVELOPMENT**_

_**MANUFACTURING**_

**TIME**

**SPACE**

**Pharmaceutial Manufacturing Performance **

**COST**

**QUALITY**

**TIME**

**SAFETY**

## PHARMACEUTICAL MANUFACTURING:LOOKING BEYOND THE “AVERAGE”

**0**

**100**

**200**

**300**

**400**

**500**

**600**

**700**

**800**

**LOT NUMBER**

**OVERALL CYCLE TIMES **

**Lots  without Exceptions**

**Lots  with Exceptions**

***NEED FOR FUNDAMENTAL TECHNOLOGY***

## OUTLINE

**OUTLINE**

**MIT Pharmaceutical Manufacturing Initiative **
**Process Development**
**Blending: On-line blend uniformity**
**So what?**
**Routine Manufacturing**
**Where is the time spent “on average”?**
**Looking beyond the “average”**
**So what?**
**Pharmaceutical Manufacturing: **
**The New Technology Opportunity**

## OVERALL CYCLE TIMES:QC TESTING TIMES  ARE SIGNIFICANT

## Average Cycle time  		             95 days
Std dev(Cycle time)			          > 100 days
Exceptions increase cycle time by       > 50 %
Exceptions increase variability by        > 100%
Capacity Utilization of “System”           LOW     

**Std dev**(Cycle time)**	****	****	****          ****>**** ****100 days**
**Exceptions** increase cycle time by**       ****>**** ****50 %**
**Exceptions** increase variability by        **>** **100%**
**Capacity Utilization** of “System”           **LOW     **

**PERFORMANCE MEASURE**

**VALUE**

**Pharmaceutical Manufacturing:****Impact of Exceptions**

***(Detailed Analysis of 2 Products)***

***NEED FOR FUNDAMENTAL TECHNOLOGY***

## OUTLINE

**OUTLINE**

**MIT Pharmaceutical Manufacturing Initiative **
**Process Development**
**Blending: On-line blend uniformity**
**So what?**
**Routine Manufacturing**
**Where is the time spent “on average”?**
**Looking beyond the “average”**
**So what?**
**Pharmaceutical Manufacturing: **
**The New Technology Opportunity..**

## Pharmaceutial Manufacturing Performance 

** ****ACTIVE**

**      ****FORMULN**

**FILL**

**PACK**

** ****ACTIVE**

**      ****FORMULN**

**FILL**

**PACK**

** ****ACTIVE**

**      ****FORMULN**

**FILL**

**PACK**

_**RESEARCH**_

_**DEVELOPMENT**_

_**MANUFACTURING**_

**TIME**

**SPACE**

**Pharmaceutial Manufacturing Performance **

_**Which Products?**_**High Volume****Complex****Liquid**

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

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

***Assay***
***Fermentation***

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

## Pharmaceutial Manufacturing Performance 

** ****ACTIVE**

**      ****FORMULN**

**FILL**

**PACK**

** ****ACTIVE**

**      ****FORMULN**

**FILL**

**PACK**

** ****ACTIVE**

**      ****FORMULN**

**FILL**

**PACK**

_**RESEARCH**_

_**DEVELOPMENT**_

_**MANUFACTURING**_

**TIME**

**SPACE**

**Pharmaceutial Manufacturing Performance **

_**Which Products?**_**High Volume****Complex****Liquid**

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

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

***Assay***
***Fermentation***

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

## PHARMACEUTICAL MANUFACTURING:The New Technology Opportunity..

- New Technology Can Be A Huge Win For:
**INDUSTRY**
**FDA**
**SOCIETY**
- But We Can Only Capture Its Potential If We Work Together In a **“Win-Win”** Mode
- If We Don’t We All **Lose**..
- Lets Find A Way To **All Win**..

## Pharmaceutical Manufacturing:

**Context of Experiences..**

_**FDA**_
*Food & Drug*
*Administration*

_**MIT:**_
- MIT Pharma Mfg Initiative
- (PHARMI)

**G.K. Raju, Ph.D.**

_**Purdue Univ:**_
- Dept of Industrial & Physical Pharmacy

_**CAMP**_

***Consortium ***
***For The ***
***Advancement Of ***
***Manufacturing For***
***Pharmaceuticals***

## ACKNOWLEDGEMENTS

- Consortium for the Advancement of Manufacturing of Pharmaceuticals (CAMP)
- Professor Charles Cooney (MIT)
- Professor Stephen Byrn (Purdue)

## NOTE ON CONTEXT

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