# Presentation: 411150

## PAT for BiologicsEnsuring Quality of Biologically Produced Drugs

- FDA Advisory Committee on Pharmaceutical Sciences
- April 13, 2004
- Parrish Galliher and Elizabeth Fowler
- Xcellerex

## Outline

- Xcellerex View of PAT
- Importance of PAT for Biologics
- Value of PAT
- Implementation of PAT – Xcellerex Program
- Summary

## Xcellerex View of PAT

- Process knowledge gained through process analytics and statistically designed process optimization studies
- Processes designed for quality
- Continual monitoring ensures process control
- Risk based approach to quality; PAT provides data

## Key Issues in Biologics Production

- Biological variation in production of material
- Animal to animal variation
- Cell culture variation
- Biological safety – unknown pathogens
- Unrelated impurities with unknown activities

## Product Risk Management

- Present:	Minimal process change allowed
- 	Process parameters used as surrogates for product quality monitoring
- 	Release and some in-process testing used to ensure product consistency
- Future: 	Real-time monitoring provides increased assurance of process and product quality consistency
- 	Increased process understanding enables risk-adjusted evaluation of process & product data

## Real-Time Process MonitoringBiotechnology Drugs

- Fermentation

- Purification

- Formulation
- Fill Finish

- Present

- Cell growth
- Cell viability
- Metabolic parameters
- (dO2, pH, glucose)

- Process parameters
- (OD, pH, Flow rate, Conductivity)

- API concentration Environment
- Fill volume

- Future

- API content
- API quality
- Impurities
- Bioburden & viruses

- API quality
- Content uniformity
- Excipient uniformity
- Impurity levels
- Sterility

- API concentration
- API quality
- Impurity clearance
- Bioburden & viruses

- Purpose

- Control product quality
- Ensure biosafety

- Control product quality
- Ensure impurity removal
- Ensure biosafety

- Ensure product
- Ensure uniformity
- Ensure safety

## Value of PAT for Biologics

- Ensure product quality remains consistent
- Assess deviation impact in real time
- Avoid costs of processing unreleasable batches
- Data justification of batch release
- Continual process monitoring obviates need for process validation
- Reduce testing requirements at end of process
- Increase process knowledge
- Identify critical steps and parameters that impact quality
- Improve risk assessment validity

## Manufacturing Investment Risk

- Savings via On-Line Bioburden QC
- Assumptions:
- 20 batches attempted/year
- $20,000,000 annual budget, fully loaded
- $1,000,000 cost per batch, fully loaded
- 90% overall batch success rate – 18 batches
- Cost of lost batches: $2,000,000/year

## Xcellerex PAT ProgramProcess Development & Analytics

- _Program Initiative_
- Process Development
- Automation - High throughput screening
- Statistical process optimization
- Process Analytics
- Product Quality – microarray glycosylation analysis
- Process control via non-invasive sensors – pH, DO2, optical density, IR
- On-line environmental monitoring – non-viable particulates

- _Benefit_
- Optimized process from start of clinical manufacturing
- Examine more parameters in less time
- Real time assessment of product quality
- Non-invasive monitoring of process parameters
- Real-time assessment of environmental control

## Xcellerex PAT ProgramManufacturing

- _Benefit_
- Minimize operator errors
- Early detection of deviations
- Protect product quality
- Rapid batch release
- Minimize environmental contamination
- Increase flexibility
- Minimize cross-contamination

- _Program Initiative_
- Automation
- Electronic batch records
- Non-invasive sensors – pH and DO2
- On-line quality assurance
- Controlled environment modules
- Operator separation
- Disposables

## Knowledge Management eFactoryTM

-      **eFACTORY****TM**    Knowledge Management

- Data
- Experiments
- Methods
**PD**

- Data
- Protocols
- Methods
**Quality**

- Doc Approvals
- Doc Revisions
- Change control
**QA Documentation**

- Batch data
- Trending
- BPRs
**Mfg**

- MyProject
- secure portal

## Process Optimization by DOE

** **

**Normal MHB ~ 0.8 MM cells/ml**

**Best condition: 1.9 MM cells/ml**
**Cells still 94% viable!**

## Automation: eBatch RecordPurification

## Statistical Process Control

## Challenges in Applying PAT to Biologics

- Investment in bringing analytics on-line
- Innovation to develop analytical tools to assess critical attributes
- Extensive data accumulation needed during development to identify critical attributes and appropriate limits
- Regulatory uncertainty
- More data may reveal more variation
- Stringency of limits related to criticality of impact

## Regulatory Risk with On-line Analytics

- Data
- How much data is too much data
- Collection interval - Continuous versus intermittent
- How to use the data – speeding release or real-time release?
- Noise
- How to handle spurious spikes in continuous on-line data
- May need extra validation to ignore these
- 		Lost productivity, lower plant output, high mfg. costs

## Continual Environmental MonitoringTotal Particulates during Chromatography Step

- Particulates ≥0.5 μ per ft3 (x 10-3)

## SummaryImpact of PAT

- Measure product quality in process stream
- Increased understand of process – product quality relationship
- Continual process monitoring obviates need for process validation
- Enables science-based decision making in manufacturing
- Reduces batch release time, increases plant capacity
- Lower manufacturing risk and COGS
- Can be a very cost effective investment

## Opportunity

**Process Knowledge**

- Result:  Better Quality & Lower COGS for Entire Industry

**Efficiency**