CONFIDENTIAL ©2014 PAREXEL INTERNATIONAL CORP. ALL RIGHTS RESERVED.

Cost Effective Process Validation

Lifecycle Management

Carmen Medina, MPH, Ph.D. ( c )

Vice President, Technical Services

Former FDA Investigator

http://www.ivtnetwork.com/sites/default/files/1_Process_Validation_Problems_and_Recommendations.pdf

Cliff Campbell, B.E.

Cliff Campbell Consulting Ltd.

cliffcampbellconsulting@gmail.com

Current Standards

• FDA’s January 2011, Guidance for the Industry, Process Validation: General Principles and Practices – Aligns with product lifecycle concepts included in International

Conference on Harmonization –ICH Guidelines • Q8(R2) Pharmaceutical Development

• Q9 Quality Risk Management

• Q10 Pharmaceutical Quality System

– Promotes a 3-Stage Approach • Stage 1 – Process Design

• Stage 2 – Process Qualification

• Stage 3 – Continued Process Verification

Understand sources of variation// Detect degree of variation//Understand impact of variation//Control variation commensurate with risk it represents

Current Standards

• European Medicines Agency (EMA), March 2012 Guideline on Process Validation – Aligns with product lifecycle concepts included in International Conference on

Harmonization –ICH Guidelines

• Q8(R2) Pharmaceutical Development

• Q9 Quality Risk Management

• Q10 Pharmaceutical Quality System

– Promotes Continuous Process Verification • Risk-based, real-time verification

• Identification of CPPs, CQAs, etc.

• Deepen knowledge of process and heighten control of variability

Understand sources of variability // Detect degree of variability //Understand impact of variability //Control variability commensurate with risk it represents

Current Standards

• cGMPs – 21 CFR 211

• 100: Product and Process Controls

• 110: In-process Sampling and Testing

• 113: Validation of Sterilization Processes

• 160: Scientifically Sound Specs + Sampling

• 180 (e): Annual Product Reviews

• 198: Complaint Files

– Revised Compliance Policy Guide 7132c.08 / Sec. 490.100

– Promotes Continuous Process Verification and Control • Risk-based, real-time verification

• Identification of critical parameters in the process

• Monitor changes

• Evaluate status of control scheme at least annually

• Establish 360 °feedback loop

PV Context

The purpose of a Unit Operation

is to deliver or protect a

predefined subset of the

Target Product Profile

ΣUO: ______

ΣCQA: ______

ΣCPP: ______

Cost-effective Approach

• Life Cycle Phases for New and Legacy Processes: One-time effort • New products

• Formalize Interface with Product Development • Forgo traditional three batch requirement • Understand elements of early stage Process Qualification

• Design control strategy early in the scale-up stage • Design Space: EMA defines it as a combination and interaction of inputs and process

parameters that assure quality. Provides flexibility; reduces deviations and changes.

• Legacy Products • Leverage what you have and know • Historical assessment of variability • Redefine outputs such as set points, CPPs, KPPs, CQAs, etc. • Address variations in batch sizes • Establish predictive models

• Contract Manufacturing Arrangements

• Quality Agreement • Co-development of Validation Master Plan (one batch focus with controls)

Process Validation: A Product Life-cycle Management Program

Key constituents of this program:

Process Design: – Lab, pilot, small scale and commercial scale studies to establish

process

Process Qualification: – Facility, utilities and equipment

– Confirm commercial process design

– Includes technology transfer

Commercialization: – Monitor, collect information, assess

– Maintenance, continuous verification, process improvement.

8

Cost-effective Approach

Process Validation: A Product Life-cycle Management Program

Key Process Qualification Outputs: • Commercial batch(es) manufactured with the qualified utilities,

facilities, production equipment, approved components, master production and control record, and trained production personnel in place.

• Usually run at target/nominal operating parameters within proven acceptable range or design space.

• Extensively tested, i.e., combination of samples analytically tested and increased process control monitoring beyond typical routine QC levels.

• Concerted decision to “release the process” for routine commercial manufacturing

9

Cost-effective Approach

Process Characterization

Review of each process step to determine the outputs

Materials

Methods People

Environment

Equipment

Measurement

Input Process Output

Process Characterization

The Agency recognizes that terminology usage can vary and expects

that each manufacturer will communicate the meaning and intent

of its terminology and categorization to the Agency.

PV Postcards

Process Characterization

• Design of Experiments (DOE) methodologies are often used to limit the number of required experiments and to determine the effects of parameter interactions

• Process Characterization studies focus on parameters that were deemed critical through risk assessment

• Pre-approved acceptance criteria is NOT required for process characterization studies

• Studies are performed using lab-scales models

• Results should be summarized in process characterization reports.

Process Characterization

Cost-effective Approach

• Risk Management • Process mapping

• Justify sampling and testing plans

• Gather data efficiently and quickly

• Analyze data

• Intercept and mitigate variability

• Continuous monitoring using statistical tools

• Leverage key quality systems and metrics

• Establish alert and action limits

• Prospective and retrospective control charts

Process Mapping

Process Legend for any step in a process

Process Parameters:

• CPP = Critical Process Parameter

• CQA = Critical Quality Attribute

• L = Licensed Process Parameter

Equipment or Instrument

Material (Tested by Inspection Plan)

Material (Untested)

◊ In-Process Quality Control Testing

RA3

RA2 RA1 PV Poster

Important Definitions

ICH Q5E states,

Quality Attribute: A molecular or product characteristic that is

selected for its ability to help indicate the quality of the product.

Collectively, the quality attributes define identity, purity, potency,

and stability of the product, and safety with respect to

adventitious agents. Specifications measure a selected subset of

the quality attributes.

Important Definitions

ICH Q8 (R2)states,

Critical Quality Attribute (CQA): A physical, chemical, biological or

microbiological property or characteristic that should be within an

appropriate limit, range, or distribution to ensure the desired

product quality.

Important Definitions

Impact/No impact: Assessment of impact is focused to drug product safety, efficacy, and quality based on scientific knowledge. The statement "No impact to drug product" means that the failure mode is not impacting the safety, efficacy, and quality on the final drug product. Process Performance Attribute (PPA): An in-process measurement that is used to evaluate the performance of the process. Process Performance Attributes are not directly controlled and are typically considered process outputs. An example would be a process step yield measurement. Two types of Process Performance Attributes are defined; critical, and key. Critical Performance Attribute (CPA): A direct measure of the functionality or objective of a step especially as it relates to product quality. Key Performance Attribute (KPA): An attribute that is used to assess process consistency for a particular process step or stage.

Important Definitions

Process Parameter (Operational Parameter): A parameter that can be directly manipulated. Operational parameters are typically considered process inputs. Three types of Process Parameters are defined; critical, key, and non-key (Key and Non-Key are subsets of Non-Critical).

Critical Process Parameter (CPP): A process parameter whose variability has an impact on one or more critical quality attributes and therefore should be monitored or controlled to ensure the desired product quality.

Key Process Parameter (KPP): A process parameter that, when varied within the Characterization Range, has a significant impact on process consistency or on a key or critical performance attribute.

Non-key Process Parameter (Non-KPP): A process parameter that, when varied within the Characterization Range, will not have a significant impact on either process consistency or product quality.

Important Definitions

Set point: A target value of the process parameter during operation, around which the control system regulates the value. Not all process parameters have a set point. The maintenance of the set point by the equipment defines the control range of the process parameter. Control Range: The ability of the control system to regulate a defined set point. Operational Range: A range within the license that defines the optimal process control. In absence of a defined operational range the license range is used for process control. License: The operating value or range for the process parameters that are defined in the TD/ regulatory submission. Within these ranges, the process produces the specified product.

Important Definitions

Evaluated Range: A given process parameter range that has been evaluated for parameter's impact on CQAs. The data may be from development studies, process validations, or commercial-scale studies or excursions.

Impacted CQA: Primary CQA impacted when CPP exceeds the evaluated range. High-Risk: Quality impact is high if the failure has a potential impact on patient health or disrupts the supply of product to the patient.

Low Risk: Quality impact is low if the failure results in no negative impact to patient health and does not disrupt the supply of product to the patient.

Ken Chapman's insights are crucial - a control

strategy must incorporate feedback and response

commitments - otherwise it is merely a

measurement strategy.

Enhanced sampling plan is a direct

extension of the process map.

Executed specification

becomes the protocol.

Risk Management Systems

Organization: multidisciplinary lenses, evaluations and conclusions Design Space for new products Quality Mission / Policy Purchasing Controls / Supplier Management Management Review [211.180(f)] Deviations and Corrective and Preventive Actions Complaint Management Statistical Techniques

Interpretation and appropriate application of quality systems during the entire lifecycle of the product—concept to commerce.

Cost-effective Approach

• Target Low Hanging Fruit • Prioritize and control most costly and risky CQAs, CPPs, CPAs, KPAs, etc.

• Develop predictive models for each process

• Tie to development knowledge

• Quality Triad or grouping that provides the most insight into process fluctuations

• Make PV Lifecycle management the flywheel of QA activities

– Monitor process using pertinent quality metrics

– Establish alert & action limits around key metrics (multidisciplinary

lenses)

Cost-effective Approach

• Monitor, Correct, Improve • Deepen process understanding batch-to-batch

– Identify and measure variation

• Quarterly monitoring

• APRs

• Enhance sampling and testing scheme – May allow for a reduction

– May need to increase

• Develop risk-based, real-time profiles for each process

• Maintain validated state using continuous monitoring of both quality and process metrics – Change control trends

– Deviation Trends and CAPAs

– Complaint Trends

– Equipment Histories

Capability of a Process

Ability of a process to produce a product that

will fulfill the requirements of that product.

The concept of process capability can also be

defined in statistical terms. (ISO 9000:2005)

The level of monitoring and

testing should be sufficient to

confirm uniform product

quality throughout the batch.

Q & A

Thank you