# Presentation: 149801

## Life Cycle Management for Process and System ControlAn Industry ProposalTobias Massa, Ph.D.Executive DirectorGlobal Regulatory Affairs

- Advisory Committee for Pharmaceutical Sciences  Manufacturing Subcommittee
- July 20, 2004

## 
Utilization of science and risk-based quality management systems to 
enable post-approval change and improvement.

	Represents collective recommendation of the following organizations:
EFPIA
JPMA
PhRMA

**Utilization of science and risk-based quality management systems to**** **
**enable post-approval change and improvement.**
**	**
**	****Represents collective recommendation of the following organizations:**
**EFPIA**
**JPMA**
**PhRMA**

**Life Cycle Management****An Industry Proposal for ICH Q10**

## 
	Define the type of activities which a manufacturer may take, using risk 	management processes (Q9) when appropriate, to
monitor and evaluate quality of products, processes and systems appropriately
make and manage improvements/changes appropriately
	in order to demonstrate that Industry understands the manufacturing 	process, controls the process appropriately and can manage post-approval 	changes effectively based on product and process knowledge (Q8).

	To create a guideline against which these aspects of a manufacturer’s 	quality systems can be inspected. 

**	****Define the type of activities which a manufacturer may take, using risk ****	****management processes (Q9) when appropriate, to**
**monitor and evaluate quality of products, processes and systems appropriately**
**make and manage improvements/changes appropriately**
**	****in order to demonstrate that Industry understands the manufacturing ****	****process, controls the process appropriately and can manage post-approval ****	****changes effectively based on product and process knowledge (Q8).**
**	****To create a guideline against which these aspects of a manufacturer’s ****	****quality systems can be inspected. **

**Life Cycle Management****An Industry Proposal for ICH Q10**

**Monitor and evaluate processes with feedback loops, to measure, analyze, plan, act and review which:**
**Identify trends**
**Demonstrate control **_**or**_** the need for action**
**Manage and rectify undesirable occurrences (e.g deviations, complaints, audit and inspection findings, root cause analysis.)**
**Implementation and monitoring of corrective and preventive actions**
**Handle desired occurrences (improvements)**
**Manage/implement change and monitor the effect of change.**

**Life Cycle Management****An Industry Proposal for ICH Q10**

## Life Cycle ManagementAn Industry Proposal for ICH Q10

_**The outcome:**_
**Gives Industry the opportunity via a harmonized standard to realize the full potential of Q8 and to utilize Q9. **
**Encourages and motivates Industry to improve and optimize processes, equipment, facilities, systems and procedures.**
**Gives Regulators the confidence that Industry can be responsible for greater self-management of improvements and changes.**
**Companies with good quality management systems**
**Well controlled processes and products.**
**Quicker and more secure availability of products in the marketplace.**

## FDA Quality Concerns (C. 2001)

- Dealing w/ multi-factorial systems; weak causal links established
- DOE’s used very little by pharma manufacturing
- Don’t understand impact of raw material variability,  so same suppliers and processes are used
**Variability ******** increased risk ******** more compliance**
***Testing ***to document quality
- Quality assurance based on documentation; not quality by design
- Manufacturers produce 2 products today; 1 for the patient and 1 for the FDA (paperwork)
**Quality can not be tested into products, it needs to be “built-in” ****(QUALITY BY DESIGN)**
- Ajaz Hussain, Deputy Director, OPS, CDER (2001)

## Typical GMP Process

- Raw Material

- Product

- Process Variables

- Any variability here

- Shows up here

## Deming on Variability and Inspections

-    Depending on inspection is like treating a symptom while the disease is killing you. The need for inspection results from _**excessive variability**_ in the process. The disease is variability. Ceasing dependence on inspection means you must _**understand your processes**_ so well that you can _**predict the quality of their output from upstream activities and measurements**_. To accomplish this you must have a thorough _**understanding of the sources of variation**_ in your processes and then _**work toward reducing the variation.**_ Ceasing dependence on inspection forces you to reduce variability.
- Deming, 1950

## Key Observations In Deming’s Comments

- “...must understand your processes...”
- “...predict the quality ...from upstream activities and measurements...”
- “...work toward reducing the variation...”
- Isn’t this Quality by Design?

## FDA The Desired State  

- Product quality and performance are ensured through the ***design**** *of effective and efficient manufacturing processes
- Product and process specifications are based on a ***mechanistic understanding*** of how formulation and process factors affect product quality and performance
***Continuous*** product and process ***improvement****** ***
- Relevant ***regulatory policies and procedures*** are tailored to ***reflect**** *current level of ***scientific knowledge and associated risk***
***Risk-based regulatory approaches*** recognize:
- the level of scientific understanding of how formulation and manufacturing process factors affect product quality and performance
- the capability of process control strategies to prevent or mitigate the risk of producing a poor quality product
- Moheb Nasr (DIA, June 2004)

## Life Cycle Management How does it work?

- Design quality into development of process and controls
- Use data rich experiments to identify critical to quality attributes of process
- Development data (including failures and validation protocol/data) in application:  Pharmaceutical Development and Manufacturing Science Report
- We have to figure out how to share these data with regulators!!!
- Validation (consistency run ??) protocol
- Validation summary
- Interim specifications
- Comparability protocol
- CONTINUOUS IMPROVEMENT--Supplements without Prior Approvals

## Process Control and Capability Cycle 

- Development History

- Integrated Validation Master Plan
- process • product • systems

- Process Flow Document

- Technology Transfer

- Qualification

- Validation

- Execute & Monitor

- Technical Evaluations
- process • product

- Countermeasures
- process • product

- Quality (GMP) Evaluations
- quality systems

- Countermeasures
- quality systems

- Site Quality Plan

## Slide 14

## 21st Century Quality Approach

- Raw Material

- Product

- Process Variables

- Combination of feed forward and feedback control of CPP’s provides even greater control of critical quality attributes

## Q10 is only part of the solution!!

- Regulators regulate regionally, Manufacturers commercialize globally.
- Multiple regional regulations governing manufacturing changes are not harmonized--each region (US, EU, Japan, others) has unique regulations.
- Differences include regulatory filing mechanism for same change, review cycles, data requirements and interpretation of same data.
- Result is resistance to change and logistical hurdles that could be avoided.

##                 Why harmonized standards for Quality Systems?

- Product A

- Submitted and reviewed

- A1

- A2

- A3

- A4

- Process Improvement proposed & submitted

- Differences in specs, in-process controls, shelf life = 4 “products”

- One CMC dossier

- Time

**A5**

**A6**

**A6**

**A7**

- 2 processes running 3-5 “products”
- Logistical nightmare

**A8**

- Change requested by authority

- Change
- submitted

**A9**

##                       Why harmonized standards for Quality Systems?

- Change in API which affects 3 formulations

**A logistical impossibility !!!**