process validation – key areas leading to 483’s · pdf fileprocess validation...

Dept. of Health and Human ServicesFood and Drug Administration

Center for Dug Evaluation and Research

Office of Compliance

Process Validation – Key Areas Leading to 483’s

Joseph C. Famulare Deputy Director, Office of Compliance FDA/CDERPharmaceuticalManufacturing.comWebcast, March 26, 2009

DHHS, FDA, CDER Office of Compliance

Overview

Process Validation Stages

Regulatory Consequences


PV Guidance

Draft – November 2008 http://www.fda.gov/cder/guidance/8019dft.pdf

Comments accepted through 03/16/09 at Regulations.gov for docket FDA-2008-D-0559


Guidance Background

Completed under auspices of CGMPs for the 21st Century initiative implementation phase in 2004 (CPQ)

foster innovation and advance the science of the pharmaceutical manufacturing.

Aligns Process Validation activities with the product lifecycleApproach aligns with Pharmaceutical Quality System (PQS) initiativesBuilds on the concepts delineated in the 1987 Guideline


The Question of Process Validation

Do I have confidence in my manufacturing process? Or, more specifically, what scientific evidence assures me that my process is capable of consistently delivering quality product?

How do I demonstrate that my process works as intended?

How do I know my process remains in control?


The process of process validation

Series of activities taking place over the lifecycle of the product/process.

Not a one-time events, but key milestones.


Process Lifecycle Stages

Stage 1, Process Design:Lab, pilot, small scale and commercial scale studies to establish process

Stage 2, Process Qualification:Facility, utilities and equipmentPerformance Qualification (Confirm commercial process design)

Stage 3, Continued Process Verification:Monitor, collect information, assess during commercializationMaintenance, continuous verification, process improvement.


Stage Goals

Stage 1 -functional understanding between parameters (material and process) and quality attributes

Stage 2 - Scientific measurable evidence that product meets specifications consistentlyprocess performance meets acceptance criteria; reproducible

Stage 3 - Maintain or improve control and reduction in product and process variability


Process Design

Propose process steps (unit operations) and operating parameters to be studied.

Identify sources of variability each unit operation is likely to encounter.

Studies to identify multivariate interactions


Input Variability

Manufacturers should understand the sources of variation, detect the presence and measure degree of variation, understand its impact on the process and ultimately product attributes, andmanage it in a manner commensurate with risk it represents to the process and product.


Process Design & Managing Variability

Lab scale, small scale, pilot scale studies

Designed experiments

Modeling

Mechanisms for managing variability is part of the control strategy

e.g., may choose advanced manufacturing technologies that employ detection, analysis and control feedback loops to react to input variability.


Process Design Outputs & Process Qualification

Master production and control records Overall control strategyOperational limits/rangesSpecificationsProcess Qualification: provides confirmation that the process design is functional for commercial scale manufacturing.Transfer process design knowledge to production, i.e., technology transfer


Process Qualification

Two Aspects

1. Qualification of equipment, utilities and facilitiesConsider user requirements, use risk analysis to identify studies/ tests needed and chose criteria to assess outcomes

2. Performance qualificationPerformance qualification protocol(s)


Performance Qualification ProtocolsMust go beyond just a particular number of batches madeCriteria, including statistical, that—if met—leads to the conclusion that process consistently produces a quality productLeverage previous experience and knowledge if the data is relevant to the commercial scale processTypically will include:

Commercial batches manufactured with the qualified utilities, facilities, production equipment, approved components, master production andcontrol record, and trained production personnel in place.

Usually run at target/nominal operating parameters within provenacceptable range or design space.

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


On What Basis Can Commercial Distribution Begin?

Before commercial distribution begins, a manufacturer is expected to have accumulated enough data and knowledge about the commercial production process to support post-approval distribution.

Initial Process Qualification


Continued Process Verification

Process Validation during commercial manufacturing

Activities to continually assure that the process remains in a state of control.


Trend/Assess Data, Monitor

Evaluate periodically (at least annually per 21 CFR 211.180(e)) to determine the need for changes in drug product specifications or manufacturing and control procedures

Analyze data gathered from monitoring processes

Timely monitoring of critical operating and performance parameters

Investigate problems for root cause and implement corrective action.


Establish Process History & Process Monitoring

Measurements of process variabilityOnly have estimates for new processes

Measurements of process performance over time

Will reveal opportunities for improving the process and the control strategy to better detect and reduce variability


Changes to the Process

U.S. Statutory and GMP References: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 specifications or manufacturing or control procedures are needed”

Q10 – A formal change management system should be in place for commercial manufacturing with appropriate science and risk-based assessments.


Periodic Evaluation

Re-validation – not using this term in the revised Process Validation Guidance

Production phase (continual verification) monitoring will evaluate quality indicator data, changes and adverse trends and should be used to periodically decide if new studies, e.g., conformances batches or other verification experiments, need to be done.


Continuous Processing

Use of PAT systems to detect input and output variability of the material and react in real time to prevent sub-quality product

Scale-up issues may not be as relevant as with batch manufacturing.

Combination of real time detection of material attribute quality (particle size, uniformity) as well as process drift or change in performance (e.g. flow rates, power)

Monitoring quality on a continuous basis.


Continuous Processing

Continuous processing utilizing PAT systems allows product testing requirements to be moved up stream. Superior statistical power obtained by advanced technologies which provide parameter monitoring and material interrogation at frequent intervals.Performance criteria in protocols and studies for continuous processing are likely to be different than those for batch manufacturing.


Summary

Lifecycle approach links product/process development to the commercial manufacturing process, and maintains the process in a state-of-control during routine production.

Consistent with Pharmaceutical Quality Systems (PQS) Q10 Annex 1 - Opportunity to:

increase use of risk based approaches for regulatory inspections; facilitate science based pharmaceutical quality assessment; optimise science and risk based post-approval change processes to maximise benefits from innovation and continual improvement; enable innovative approaches to process validation; establish real-time release mechanisms.


Truth & Consequences

UNITED STATES DISTRICT COURTUnited States of America )

Plaintiff, )v. )

_________________ ) Civil Action No.

corporation, )and )

______________________ )Individuals )

Defendants,CONSENT DECREE FOR PERMANENT INJUNCTION



COMPLAINT FOR PERMANENT INJUNCTIONAdulterated Drugs

13. The United States Food and Drug Administration’s inspections of the Defendant’s facilities have established that the drugs manufactured by the Defendants are adulterated..., in that the methods used in, and the facilities and controls used for, the manufacture, processing, packing, labeling, holding, and distribution of drugs and components are not in compliance with CGMP.




15. Failure toA…follow the responsibilities and procedures

applicable to the quality control unit B…establish control procedures to validate the

performance of those manufacturing process that may be responsible for causing variability in the characteristics of in-process material and the drug product




Failure toC…make written records of investigations into unexplained

discrepancies [or] ..of a batch or any of its components to meet specifications

D…review and approve drug product production and control records by the quality control unit to determine compliance with all established, approved written procedures before a batch is released or distributed

E...review and approve changes to written procedures by the quality control unit




Failure toF...G…follow written procedures and process

control procedures in the execution of production and process control functions



CONSENT DECREE OF PERMANENT INJUNCTION

Upon entry of this decree, Defendents …are permanently restrained and enjoined …from directly of indirectly, doing or causing: the manufacture, processing, packaging, labeling, holding, introduction or delivery for introduction into interstate commerce at or from any of the [Defendant] facilities, of any drug…, unless and until:



CONSENT DECREE OF PERMANENT INJUNCTION

unless and until:C…Defendants establish and follow scientific product

development and manufacturing process design procedures at all facilities to control all significant variables (including material attributes and processing parameters) affecting in-process materials and final drug product specifications and quality attributes


Protecting the Public Health

“The FDA requires companies to manufacture drugs in accordance with the current good manufacturing practice standards and to comply with FDA approval requirements.”

“Consumers need to be confident that drugs meet our manufacturing requirements for identity, strength, purity, and quality, and have been evaluated by the FDA for safety and efficacy.”

Janet Woodcock, M.D., Director Center for Drug Evaluation and Research (CDER).

process validation – key areas leading to 483’s · pdf fileprocess validation...

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