QbD AND PAT - CURRENT STAT US OF THE PHARMACE UTICAL INDUSTRY

The 2013 University of Heidelberg QbD/PAT Conference past October coincidentally marked the 10th anniversary of the publication of the draft PAT Guidance and the 50th anniversary of the introduction of Good Manufacturing Practice.

Surprisingly, after 10 years active involvement with both PAT and QbD, the industry's manufacturing sectors are still seen as failing to perform at manufacturing levels commensurate with society's current expectation.

Plainly, in spite of PAT and QbD, current Good Manufacturing Practice is largely incapable of delivering Good Manufacturing Performance.

That being so the conference took a holistic overview of how the principles of PAT and QbD which have evolved in many application areas in the interim, might be more effectively deployed to close the gap between Practice and Performance across the manufacturing spectrum by redefining the Practice/ Performance Equation from:

• API manufacture
• particle engineering
• formulated product manufacture
• setting meaningful specifications
• designing and implementing controllable processes

to enable continuous verification to consistently deliver:

•  right first time performance
• high levels of equipment utilisation
• significant product lead time reduction
• inventory reduction

The EU experience and regulatory perspective with regard to NIRS and the often associated PAT and Real Time Release (RTR) testing was subject of a lecture by Dr Lina Ertle from the French National Drug and Health Products Safety Agency (ANSM).

Recommendation

Munich, Germany4 June 2024

Qualified Person IMP Pre-Course Session

The use of NIRS in pharmaceutical industry for qualitative and quantitative analysis is being submitted for approval across the EU. The range of submissions received to date can be typically broken down into the following classes:

• NIR for Blend uniformity, PAT application
• NIR at line, alternative method for batch release
• Drug product specifications - Film coated tablets - low dosage form
• Impurity level based on Drug Substance parameters, RTRT
• Drug substance specifications
• Dissolution based on DS parameters, RTRT
• Drug product specifications (abstract) Film coated tablets
• MSPC for granulation unit operation monitoring
• MSPC for drying unit operation, monitoring

All these submissions had to develop interdependent, applications specific models, defining what it was all about. The level of data required in the dossier depends on the models used: low-impact model for process understanding, medium-impact model for on-going verification and highimpact model for real time release testing. Low-Impact Models are typically used to support product and/or process development (e.g. formulation optimisation). Medium- Impact Models can be useful in assuring quality of the product but are not the sole indicators of product quality (e.g. most design space models, many in-process controls). Finally, if prediction from the model is a significant indicator of quality of the product (e.g. a chemometric model for product assay, a surrogate model for dissolutions) it can be considered a High-Impact Model.

These new developments represent significant challenges for both regulators and applicants. Consequently there is no standard approach, so as "All roads lead to Rome". There is no preferred approach but strong expectations based on previous submissions. Therefore all applicants are clearly advised to:

• Clearly define the scope
• Justify all assumptions and claims regarding criticality, scale, design space, and control strategy
• Provide supportive and comprehensive data, in tabulated format
• For any clarification, seek advice from EU PAT team

Additionally reference was made to the introduction of a new general chapter 2.9.47 (Demonstration of uniformity of large sample sizes) in the Ph. Eur. which may provide a reference point to the transition from current 3 batch validation to continuous verification.

What's coming in the next 25 years?

So what are the major issues that will shape the industry over the next 25 years? This question was answered by Dr Ajaz Hussain who was formerly with the FDA and who gave the presentation in lieu of FDA's CDER Director Dr Janet Woodcock who was unfortunately unable to give it herself. Whatever happens in the industry the macro trend of all macro trends - today's worldwide economic crisis - will have a lasting effect driving industry and regulators, nationally and globally, to do more with less in a climate of ever increasing society expectation.

Some of the major areas of change will be:

• Continuous manufacturing - Current manufacturing practices will be abandoned in favour of cleaner, flexible, more efficient processes.
• Molecular medicine is going to be extremely powerful and will revolutionize treatment as our understanding of disease at a molecular level develops.
• Political turmoil - Advances in science and technology will inevitably have an increasing influence in the approval of new drugs resolving some of the many conflicts that can be experienced today.
• Drug regulation will grow less intrusive and less complex - Current regulation is formulated to deal with uncertainties in manufacturing, safety and efficacy around drugs. The more we can make those predictable, the less regulation we will need. One of the most turbulent sectors in the coming years will be toxicology and risk prediction; improving those aspects of clinical trials would reduce the time spent testing and the money spent monitoring trials.
• Electronic health records (EHRs) and clinical trial networks deliver a much more efficient, reliable clinical trials system worldwide. When that happens networks like the Sentinel Initiative and other vigilance networks will be able to find out what's happening with medicines in the real world, allowing regulators and companies to quickly respond to reported drug problems.

In preparation for improving manufacturing performance consistent with compliance with cGMP FDA's recent enforcement actions clearly have identified a need for scientifically justifiable process performance measures based on statistical relationships between Process Performance and Pharmaceutical Quality.

This part of the presentation included outlines of the current status of their initiatives in this area from the perspective of:

• CGMP statistical references
• Bioequivalence
• Use of Consensus Standards for Pharmaceutical Manufacturing quality

Using recent enforcement actions as examples Dr Woodcock predicts that in 25 years time "we'll look back in horror at how we managed drug safety in the early 2000s."

Dr John O'Reilly from Roche, Ireland, presented a business and safety case in which he covered the implementation of a Mid-IR PAT System for the control of an extremely hazardous large scale reaction. This reaction required strict, metered control of the borohydride addition to a predetermined reaction endpoint monitored so far by sampling and by time-consuming remote analysis. In addition

• yields and reaction times varied significantly.
• the introduction of mid-IR in vessel spectroscopy as PAT system enables now the safe operation of the borohydride addition and the on-line control to the reaction end point.This end point is now determined in real time from the process status, while delivering significantly increased yield in a consistent time envelope.
• the yield saving was € 800.000,- per annum, complimented by improved operator safety levels and staff reduction.

What manufacturing benefits Real Time Release (RTR) testing can generate demonstrated Conor McSweeney from Pfizer Global Supply in Ireland. His presentation gave an extensive overview of Real Time Release (RTR) activity in Pfizer.

Recommendation

Hamburg, Germany5-7 November 2024

GMP meets Development

Probably the most challenging statement was: "Though QbD can be an enabler for RTR - it is not necessary - product and process understanding however is necessary".

The rational behind this statement was elaborated in a range of case studies covering legacy and new products. As an added benefit to RTR, Concor McSweeney emphasized that RTR analysers can be used as out of trend indicators. They show out of trend situations in processes well before a product really went out of specification. In addition he addressed different Regulatory expectations and Queries.

According to Conor McSweeney the business benefits of applying RTR at Pfizer are lower manufacturing costs, cycle time reduction as well as increased assurance of quality for patients.

Author:
Ken Leiper
... Benson Associates, is an independent Consultant for pharmaceutical quality systems, analytics and Process Analytical Technology (PAT).