# Presentation: 690427

## Lifecycle Approach to Process Validation

- DIA Annual Meeting – June 29, 2005
- Grace E. McNally
- CDER Office of Compliance
- Division of Manufacturing & Product Quality
- 301-827-8941

## Validation Requirement

**Process Validation is an Enforceable Requirement**
** **Finished Dosage Form Products
**21 CFR 211.100  **
**21 CFR 211.110**
- 21 CFR 211.113
- 21 CFR 211.42
- 21 CFR 211.63
- 21 CFR 211.165
- 21 CFR 211.180

## Validation Requirement

**Process Validation is an Enforceable Requirement**
- Active Pharmaceutical Ingredients
- Statutory CGMP provisions of 501(a)(2)(b) of the Food Drug and Cosmetic Act
- No regulations
- GMP guidance available - ICH Q7A

## Goal of Process Validation

- Drug product meeting the needs of the patient, i.e., safe and effective; and has the identity, strength, purity, and quality characteristics it is represented to possess.
- Achieved through proper product development and proper process validation.

## Process Validation Lifecycle

## Design

- First principle: Quality by Design
- GMP requirements for Process Design
- 211.42	Design of Facility
- 211.63	Design of Equipment
- 211.100	Design of Production and 				Control Procedures
- 211.160	Design of Laboratory Controls

##  Design

- Propose process steps (unit operations) and process variables (operating parameters) that need to be studied.
- Identify sources of variability each unit operation is likely to encounter.
- Consider possible range of variability for each input into the operation.
- Evaluate process steps and variables for potential criticality.
- Select process steps and variables for test in representative models.

## Design

- Development studies to identify critical operation parameters and operating ranges
- Designed experiments
- Lab scale, pilot scale and/or full scale experimental batches to gain process understanding
- Establish mechanisms to limit or control variability based on experimental data
- Aim for a “robust process”, i.e., one that can tolerate input variability and still produce consistent acceptable output.

## Confirm

- Transfer developmental knowledge to Production, i.e., technology transfer.
- Batch record and operating SOPs in place, equipment and facilities equivalency established.
- Raw materials approved.
- Measurement systems qualified (QC lab as well as production floor test instrumentation).
- Personnel training completed.
- Environment controlled as necessary.
- Execution of Conformance Batches with appropriate sampling points and sampling level.
- First evidence that process can function at commercial scale by Production personnel.
- Demonstrates reproducibility.
- Reasonable measure of protection to consumer.

## Confirm

- Full sample and data analysis
- Data may confirm process as-is, point to major process design change(s) or suggest process improvement(s).
- Implement changes via approved change control procedures.
- Assess need for additional conformance batch(es) or limited testing. Amount/degree of additional work commensurate with the significance of the change and its impact on product quality.

## Monitor

- Routine Commercial Manufacturing
- Monitor critical operating and performance parameters
- Utilize appropriate tools, e.g., Statistical Process Control
- Monitor product characteristics (e.g., stability, product specifications)
- Monitor state of personnel training and material, facility/equipment and SOP changes
- Investigate OOS for root cause and implement corrective action.

## Assess

- Analyze Monitoring Data
- Trend data:  e.g., Real time, Monthly, Quarterly review
- Evaluate need to increase level of monitoring/sampling, or decreased monitoring based on accumulated data
- Periodic evaluation (at least annually) per 21 CFR 211.180(e)
- –To determine **the need** for changes in drug product specifications or** manufacturing and control procedures**
- Study OOS and OOT (out of trend) data in the aggregate.
- Assess impact of process and product changes made over time.
- Feed back into design stage for significant process shifts or changes

## Change Control

**Statutory and GMP References:**
- Section 506A(b) FD&C Act, “Manufacturing Changes”, post marketing report – **requires validation of the effects of a change on the identity, strength, quality, purity and potency**
- 21 CFR 211.100(a) “...written procedures, **including any changes**, shall be drafted, reviewed and approved...”
- 21 CFR 211. 180(e) – Annual review to determine whether **changes in specification or manufacturing procedures are needed”**

## Outcome

- 1) maintain state of control
- 2) maintain or improve product quality
- 3) improve process efficiency and capability.

## Validation Guidance

**1987 - ***Guideline on General Principles of Process Validation*
- Under Revision
**Compliance Policy Guide 7132c.08**
*	**Sec. 490.100 Process Validation Requirements for Drug Products and Active Pharmaceutical Ingredients**** ****Subject to Pre-Market Approval*
**www.fda.gov/ora/compliance_ref/cpg/cpgdrg/cpg490-100/html**

## 1987 Guideline

- Very general
- Covers proper design, controls, monitoring
- Emphasis on qualification, testing, documentation
- Reflects current policy

## 1987 Guideline - Need For Revision

- Industry perceptions
- FDA interpretation
- GMP 21st Century Initiative
- 1996 proposed amendments
- Encourage innovation

##  New Concepts/Emphasis

- Life-cycle concept
- Process design
- Risk assessment
- Process knowledge
- Process capability

## New Concepts/Emphasis

- PAT
- Conventional processes
- Documentation
- Life-cycle continues
- Process improvement
- Change Control

## Compliance Policy Guide 7132c.08

*Sec. 490.100 Process Validation Requirements for Drug Products and Active Pharmaceutical Ingredients**** ****Subject to Pre-Market Approval*
- Issued on 3/12/2004
- Replaces CPG 7132c.08, dated 8/30/1993

## CPG  7132c.08

**Purpose**
- Explains the enforcement policy regarding the **timing** of the completion of certain process validation activities for products covered by this CPG

## CPG  7132c.08

**Validated Manufacturing Process**
- A validated manufacturing process has a high level of scientific assurance that it will reliably produce acceptable product

## CPG  7132c.08

**Proof of Validation**
- Proof of validation is obtained through rational experimental design and the evaluation of data, preferably beginning from the process development phase continuing through the commercial production phase.

## CPG  7132c.08

**Prior to Commercial Distribution**
- Manufacturer has accumulated enough data and knowledge about the commercial process to support post-approval distribution

## CPG  7132c.08

**Prior to Commercial Distribution**
- The data normally includes
- Satisfactory product and process development
- Scale-up studies
- Equipment and system qualification
- Successful completion of initial conformance (validation) batches

## CPG  7132c.08

**Prior to Commercial Distribution**
- Prior to the manufacture of the conformance batches, the manufacturer should have identified and controlled all critical sources of variability

## CPG  7132c.08

**Conformance Batches**
- Must be completed prior to commercial distribution of the approved product
- Except as noted in the CPG

## CPG  7132c.08

**Differences between 2004 and 1993 CPG**
- Recognition of roll of emerging advanced engineering principles and control technologies in ensuring batch quality
- Deletes reference to 3 validation (or conformance) batches
- Clarifies the importance of post-market information gathering
- Adds reference to Q7A guidance for APIs