Introduction to PAT

1. Introduction to PAT

2. Current State of Pharmaceutical Manufacturing • Conventional pharmaceutical manufacturing is generally accomplished using batch processing with laboratory testing conducted on collected samples to evaluate quality.

3. 20th Century Process Validation • Establishing documented evidence that provides a high degree of assurance that a specific process will consistently perform as intended.

4. Desired State • Product quality and performance achieved and assured by design of effective and efficient manufacturing processes. • Product specifications based on mechanisticunderstanding of how formulation and process factors impact product performance • Continuous "real time" assurance of quality

5. US drug products are of high quality, BUT.. • The introduction of new technologies has not been facilitated in • the US market slowing innovation, and modernisation of cGMP • resulting in: • An increasing burden on FDA resources: • Handling ~ 4,000 manufacturing supplements submitted yearly • FDA inspectors unable to meet statutory biannual GMP inspection requirement • Lower scrutiny of non-domestic industry • Cost implications for the industry from: • Low manufacturing and QA efficiency

6. Overall • The current approach to risk is probably delivering as much as is reasonably possible in respect of Safety, Efficacy • But at significant cost from a : • Regulatory perspective • Manufacturing perspective • Cost ultimately borne by the consumer • Regulatory uncertainty has had a negative impact on innovation • In an environment where customer awareness of different industry sector’s performance is changing their expectation of the industry’s deliverables

7. PAT Guidance • Released September 29, 2004 • Scientific principles and tools supporting innovation • PAT Tools • Process Understanding • Risk-Based Approach • Integrated Approach • Regulatory Strategy accommodating innovation • PAT Team approach to Review and Inspection • Joint training and certification of staff

8. Process Analytical Technology - Defined • System for designing, analyzing, and controlling manufacturing • through timely measurements (during processing) of critical quality and performance attributes of raw and in-process materials and processes, with the goal of ensuring final product quality. • The term analytical in PAT • includes chemical, physical, microbiological, mathematical, and risk analysis conducted in an integrated manner.

9. Understanding the process A process is well understood when: all critical sources of variability are identified and explained. variability (e.g. raw materials) is managed by the process product quality attributes can be accurately and reliably predicted. Timely measurement (i.e. during processing). Control of critical quality and performance attributes. What PAT means

10. What PAT is • An enabling framework • Science based not procedure based. • Risk based • An integrated systems approach • Flexible • Voluntary

11. It is NOT a regulation (CFR). It is NOT mandatory. It is not just adding a new sensor. It is NOT a technique that must be applied throughout. It may be applied to part or all of a process What PAT is not.

12. Why PAT? What is wrong? • Most processes are fixed with variable materials, resulting in variable quality of product. • Most processes are not well understood. • Existing procedural approach has created a “climate of fear” stifling innovation.

13. The Potential Benefits • Reduced scrap • Improved quality of product (every time, by design) • Faster production • Quicker development, faster scale up • Encourages innovation • Reduced regulatory burden • Real-time release

14. Process Control System in a PAT Context • Often requires new sensors (NIR, RAMAN, acoustics ...) for direct measurement of product attributes (e.g. moisture content, particle size, content uniformity, etc.) • New multi-variate data analysis performed “at-line” or “in-line” • Data records are “different”. • Feedback/feedforward within and between phases.

15. Multivariate Data Analysis

16. How the process might change • More design of experiments during development to understand the process. • More data may be collected to continuously analyse it. • Process may be modified during its life, without revalidation. • Equipment may be added/removed/changed without validation. • Move from batch to continuous processing

17. The FDA • The FDA have trained a few inspectors (4), more(50) are being trained. • The FDA are encouraging draft submissions. • The FDA wish to establish an open dialogue during development of a PAT process. (No more hiding data) • The Pat principle is very well supported by other regulatory agencies (e.e. EMEA) • One NDA has been Pat based (Aventis)

18. PAT, Process Control, MVDA and Eurotherm ? Multi-variate data Analysis Tools Eurotherm NIR etc. Sensor(s) Plant

19. And Finally… • The goal of PAT is to understand and controlthe manufacturing process • to ensure appropriate control of all relevant critical attributes of in-process materials (e.g., using process endpoints)to allowthe process to manage the inherent variability of material attributes that can impact the quality of the output • Proactive science-based approach. Continuous validation (every lot is a validation lot) versus discrete 3-lot exercise.

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