Pharmaceutical: Batch Consistency

The Challenge

A mid-size pharmaceutical manufacturer produces active pharmaceutical ingredients (APIs) for both generic and contract manufacturing markets. Their flagship facility runs 6 multi-purpose batch reactors producing a portfolio of 12 different APIs.

In pharmaceutical manufacturing, consistency isn't just desirable—it's mandated. Every batch must meet strict specifications, and any deviation requires extensive investigation and documentation.

Specific Challenges

• Batch-to-batch variability: Despite following identical procedures, critical quality attributes varied by ±8-12%, close to specification limits
• Investigation burden: 15% of batches required deviation investigations, consuming significant QA resources
• Yield losses: Conservative process parameters reduced yield to ensure quality compliance
• Regulatory scrutiny: Recent FDA observations highlighted need for better process understanding and control

The Regulatory Context

Pharmaceutical manufacturing is governed by extensive regulations. Any new technology must not only improve operations but also satisfy regulators. Key considerations:

21 CFR Part 11 Compliance

FDA regulations require electronic records to be trustworthy, reliable, and equivalent to paper records. Acaysia addresses this through:

• Complete audit trails for all control actions and parameter changes
• Role-based access control with individual user authentication
• Tamper-evident logging with cryptographic verification
• Electronic signatures for critical operations

Process Validation

Implementing advanced control requires demonstrating that the process remains validated. Our approach:

• Staged deployment with extensive documentation at each phase
• Statistical comparison of pre- and post-implementation batches
• Clear operating procedures for system interaction
• Defined fallback procedures maintaining process equivalence

Change Control

All changes followed the facility's established change control procedures:

• Impact assessment on product quality and GMP compliance
• Risk analysis using FMEA methodology
• Qualification protocols (IQ, OQ, PQ)
• Training documentation for all affected personnel

The Solution

Working closely with the facility's quality and validation teams, we implemented Acaysia with full regulatory compliance built in from the start.

Phased Implementation

1. Qualification (8 weeks):
   • Installation Qualification (IQ): Hardware and software installation
   • Operational Qualification (OQ): Functional testing of all features
   • Documentation review and approval
2. Shadow Mode (6 weeks):
   • Model development and validation
   • Comparison of recommendations to actual operator actions
   • No impact on production—pure observation
3. Performance Qualification (4 weeks):
   • Advisory mode with selected products
   • Statistical demonstration of equivalent or better quality
   • Operator training and competency assessment
4. Validated Production:
   • Closed-loop control with full audit trails
   • Continuous monitoring of process capability
   • Periodic revalidation per facility schedule

Quality-Focused Features

• Critical Process Parameter (CPP) monitoring: Real-time tracking of all parameters identified in process validation
• Design Space adherence: Control actions constrained to remain within the validated design space
• Automated batch records: Electronic documentation of all process parameters with timestamps and user attribution

The Results

Dramatic Variability Reduction

The most significant improvement was in batch consistency. For the primary API product, critical quality attribute variability decreased by 67%:

Zero Out-of-Specification Batches

In the 12 months following full deployment, the facility produced zero out-of-specification batches for Acaysia-controlled products—a first in the facility's history for this product line.

Reduced Investigation Burden

With tighter process control, deviation investigations dropped dramatically:

• Major deviations: 12/year → 0/year
• Minor deviations: 45/year → 8/year
• QA investigation hours: -75%

This freed QA resources to focus on proactive quality improvement rather than reactive investigation.

Yield Improvement

With confidence in process control, the team optimized operating parameters within the design space, improving average yield from 82% to 87%—representing approximately $1.2M in additional annual production value.

Regulatory Success

Six months after deployment, the facility underwent an FDA inspection. The Acaysia system was reviewed as part of the inspection with positive results:

Process Understanding

Beyond immediate operational benefits, Acaysia provided deeper process insights:

Root Cause Identification

Analysis of model behavior revealed that much of the historical variability came from subtle interactions between:

• Jacket inlet temperature oscillations during heating ramps
• Mixing patterns affected by fill level variations
• Ambient temperature effects on heat transfer

These insights led to equipment modifications that further improved consistency even in manual operation.

Design Space Exploration

The model enabled safe exploration of operating conditions, leading to an expanded design space filing with the regulatory agency. This provides greater operational flexibility for future optimization.

Lessons for Pharma Deployment

• Engage QA early: Quality and validation teams should be involved from project inception, not after deployment
• Document everything: Comprehensive documentation enables regulatory confidence and smoother inspections
• Focus on consistency first: In pharma, reducing variability is often more valuable than optimizing means
• Build in compliance: Regulatory requirements should drive system design, not be retrofitted
• Train extensively: Operators and QA personnel need to understand the system to maintain it effectively