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Q U A L I T Y C O N T R O L F O R R E G U L AT E D E N V I R O N M E N T S

UNIVERSITY OF HOUSTON

Overview of Validation

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Validation Overview

DefinitionHistoryBuilding BlocksElementsDocumentationComponentsValidation ProcessProject Validation – The big picture

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Fact:We are working in a cGMP environment

Does not stand for “continually Generate Mounds of Paper”

We are bound by Federal Regulations: 21CFR Part 210, 211 (Drugs) 21CFR Part 600 (Biologics) 21CFR Part 820 (Medical Devices) 21CFR Part 11 (Electronic Records and Signatures)

It’s the Law

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Fact:We are working in a cGMP environment

Current Good Manufacturing Practices A set of current, scientifically sound methods,

practices or principles that are implemented and documented during product development and production to ensure consistent manufacture of safe, pure, and potent products

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cGMP Overall Summary

cGMP needs to be in place for products used in clinical IND studies

cGMP reflects and are consistent with good product development

Follow general approaches and principles that are broadly applicable

Tailor cGMP application to product, process, and facility Assess risks and take appropriate actions

Emphasize Product Quality

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What is Validation?

“Establishing documented evidence which provides a high degree of assurance that a specific process consistently products a product meeting pre-determined specifications and quality attributes” -FDA 1987

State of Control

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Key Words

DocumentedConsistentlyPre-determinedHigh Degree of Assurance

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What is Validation – Simple Definition

Prove that each process involved in producing the product can be shown to be both doing the right job and doing the job right

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Goal of Validation

Ensure that quality is built into the system at every step, and not just tested for at the end

Interesting side-note hypothetical IF we were able to test every single product for all of

its important attributes before sending it off to the customer, validation would not be required

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Think of it another way

It is documented evidence of something you already know!

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Building Blocks

Quality AssuranceQuality Control – MicrobiologyQuality Control – AnalyticalEngineeringProcess DevelopmentManufacturingInformation TechnologyCalibrationFacilities/MaintenanceValidation

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Lifecycle Timeline

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Step-wise Approach to Application of Regulatory Requirements

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The Flow from Controls to Quality

Man, Materials, Methods, Machine, Environment

Validation & Qualification

Ongoing vigilance via QA & QC

A Quality Product

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Historical Basis for Validation

Assumptions concerning virus inactivation resulted in ten deaths and 200 children becoming paralyzed, from a supposedly “inactivated” polio vaccine.

Assumptions about sterilization caused severe infections among burn victims given supposedly sterile solutions.

Validation eliminates assumptions and relies on experimental proof!

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History

1906 The Jungle, Upton Sinclair, FD Act1937/1938 107 death “Elixir” / FD&C Act1962 Thalidomide, Frances Kelsey1978 GMP Validation Rule 211.110,..1651987 Aseptic Processing Guideline (2004)1987 Process Validation Guideline (2004)1993 Guideline on Cleaning Validation

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History

1993 Guide to Inspection of High Purity Water Systems

1994 ICH Quality Guidelines1997 Computer Systems, 21CFR Part 11

(rescinded in 2003)2005 Biotechnology Guidelines on Process

Validation2006 FDA withdraws 7 regulations2006 FDA formally adopts ICH Q7A

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Validation Elements

DQ – Design Qualification Does the design satisfy requirements?

IQ – Installation Qualification Are all systems properly installed?

OQ – Operational Qualification Does everything work when switched on?

PQ – Performance Qualification Qualifying Performance leads to Validation

PV – Process Validation Sum total

Design Qualification19

Documents that the needs of the end user are met with the functional characteristics of the piece of equipment

User Requirements

FunctionalSpecification

s

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FDA Definitions

Installation Qualification (IQ) Establishing confidence that the process equipment

and ancillary systems are compliant with appropriate codes and approved design intentions and that the manufacturer’s recommendations are suitably considered

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FDA Definitions

Operational Qualification (OQ) Establishing confidence that the process equipment

and sub-systems are capable of consistently operating within established limits and tolerances

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IQ, OQ, PQ ?

Installation Qualification (IQ) A process used to document that the piece of equipment was

supplied and installed properly and that appropriate utilities, i.e., electrical, steam, gas, etc. are available to operate the equipment according to the manufacturers specifications.

Operational Qualification (OQ) A process designed to supply the documented evidence that a

piece of equipment operates as it is intended through all anticipated operational ranges.

Performance (Process) Qualification (PQ) Verifies that a process / piece of equipment performs as it is

intended to in the manufacturing process and produces product (in process or final) meeting predetermined specifications.

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Example of a protocol for the IQ component of validating apH meter

As with all other SOP’s this document will contain an Objective, scope, and responsibilitySection.

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Typical information in an IQ protocol

Name and description of equipment, including model numbers

Identification, including model and serial numbersLocation of the equipmentAny utility requirements, i.e. electrical voltage,

steam or water pressure, etc.Any safety features of the equipment, including

alarms, interlocks, or relief valves.That all documentation, including manufacturers

contact information, spare parts inventory, operational manual, and installation drawings are available on site.

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OQ ProtocolExample of a protocol for the OQ component of validating apH meter

As with all other SOP’s this document will contain an Objective, scope, and responsibilitySection.

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OQ ProtocolExample of a protocol for the OQ component of validating anautoclave

As with all other SOP’s this document will contain an Objective, scope, and responsibilitySection.

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Typical OQ Protocol Components

ObjectiveResponsibilityEquipment required (Calibration verification

& Traceability)SOP(s) usedEquipment IdentificationParameters measured (Specifications)Documentation

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FDA Definitions

Process Performance Qualification Establishing confidence that the process is effective

and reproducibleProduct Performance Qualification

Establishing confidence through appropriate testing that the finished product produced by a specified process meets all release requirements for functionality and safety

The PQ is documented evidence that the product or output of the equipment or process meets all pre-determined criteria

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Unbreakable Rule

The scope of the Validation Project PLUSThe criteria for the Acceptance of the

Validation Data

Must be set BEFORE Validation starts

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The OQ and PQ Confusion

Having an OQ and a PQ is not required for all systems

The OQ verifies operationThe PQ verifies output

Example: An OQ for an incubator used for media plates in QC-

Micro verifies the temperature mapping characteristics of a unit

The PQ is actually verification that the media can support growth at that temperature

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Validation Documentation

Validation Master PlanBasis of DesignSOPs – specific for validation equipmentPolicies – General Corporate PhilosophyProtocols – DQ/IQ/OQ/PQFinal Reports – DQ/IQ/OQ/PWChange Control – Equipment, Systems, and

SoftwareRe-validation

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Validation Components

Upper Managements SupportRe-validationChange ControlComputer / Software ValidationCalibrationPreventive Maintenance$$$$ and Time

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Utility Validation

Purified WaterWFIClean SteamCCANitrogenVacuumHVACBack-up Generator

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Equipment / Systems

AutoclavesDry Heat OvensStopper / Vial WashersGlassware WashersBioreactorsProcess EquipmentQC EquipmentAnalytical Equipment

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Specialty Studies

Cleaning ValidationComputer / SoftwareContainer Closure IntegritySteam-in-Place (SIP)Clean-in-Place (CIP)Shipping ValidationStability Studies

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Analytical Method Validation

We need to be certain that the measurements we’re making are giving us meaningful, accurate, precise, and quality information about whatever we’re measuring

AMV ensures that our measurements, assays, and tests performed on raw materials, in-process materials, final product, stability samples, or microbiological samples is performing as it should (i.e. to our stated expectations/specifications)

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Process Validation

Establishing documented evidenceProvides a high degree of assuranceSpecific ProcessConsistently producesProduct meets pre-determined specificationsProcess QualificationProduct Qualification

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Process Validation

Cell culture parametersMixing StudiesHold StudiesBioburden/Endotoxin ControlQualification lotsPurification Studies

Impurity removal Contaminant removal Viral safety

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Change Control

System to Ensure State of ControlValidated Equipment and SystemsEmergency ChangesSOP – document changes and approval

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Revalidation

Key to maintaining “State of Control”Change Control componentRoutine timing depends on

System/EquipmentScaled-down validationFrequency

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Preventive Maintenance Program

Scheduled maintenance program to maintain validated “State of Control”

DocumentationRationaleTrained Personnel

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Validation Costs

Validation is expensiveSaves time and money in the long run

Throughput is increased due to a reduction in rejects and reworks

Lower utility and raw material costs Fewer complaints Quality

Upper Managements supportValidationLine between too much and not enoughUse Quality Vendors

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Type of Pharma/Biotech Projects

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Quality Attributes A refresher

Identity 21 CFR 211.84 (d) at least one test shall be conducted to verify the identity of each component of a drug product. Chemical, biological, Immunological Raw materials, In-process intermediates, final products.

Safety 21 CFR 600.3 (p) safety as the relative freedom from harmful effect to persons affected, directly or indirectly, by a

product when prudently administered, taking into consideration the character of the product in relationship to the condition of the recipient at the time. Activity of active ingredients Activity of the excipients or additives Activity of process related impurities

Efficacy Effectiveness of the product in achieving its medicinal purpose (therapeutic, prophylactic, diagnostic). Gathered at

phase II and Phase III trials. Potency

21 CFR 600.3 (s) specific ability or capacity of the product, as indicated by its appropriate laboratory tests or by adequately controlled clinical data obtained through the administration of the product in the manner indicated to effect the given result.

Purity 21 CFR 600.3 (r) relative freedom from extraneous matters in the finished product, whether or not harmful to the

recipient or deleterious to the product. Cleaning Procedures

Stability 21 CFR 211.137 (a) to assure that a drug product meets applicable standards of identity, quality, and purity at the time

of use; it shall bear an expiration date determined by stability testing. Drugs may use accelerated time studies, biologics must use real time studies.

Consistency The ability of the product and/or process to reliably possess specified quality attributes on an ongoing basis. 3

consecutive batches of product meeting predetermined specifications is accepted as proof that a process is consistent. However, in NDA data from up to twenty batches may be submitted.

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CASE STUDYAn example of a facility / process validation

Remicade® (infliximab) is a chimeric mAb* directed against TNF-α.

Approved in 1998 (US) and 1999 (EU) to treat Crohn’s disease, and RA.

Produced by Centocor, Inc. in Malvern, PA

* Contains mouse variable domains and human constant domains (IgG1)

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Antibodies

Proteins 2 heavy Chains 2 Light Chains Disulfide Bonds

Variable region Recognizes antigen

Constant region Effecter function Classes & subclasses

Ig G class

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Production of Remicade®

BLA approved in August 1998 (FDA), 1999 (EMEA).

First site for bulk manufacture was Leiden, The Netherlands.

Process was transferred to Malvern, PA in April 2002*.

Process changes, including larger bioreactors, external spin filters, and a change in media components were introduced to meet increased demand.

Not only did a new facility have to be validated, but also the changes to the manufacturing process had to be validated.

Necessary to demonstrate that product produced under these new conditions had same quality attributes as product produced in Leiden.

An unanticipated consequence of increased product yield was a change in chromatography conditions due to product breakthrough under old conditions.

Minor changes can have unanticipated consequences on product quality!

A new facility for production of remicade is being constructed in the Republic of Ireland and should be on line in 2007

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Changes in Production Process in Malvern, PA

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Example of a 1000 L Bioreactor with an external spin filter used in the production of Remicade® in Malvern, PA

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Remicade Production

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These tanks are used for the holding of material from the bioreactors prior to product capture and initial chromatography.

What performance aspects of these tanks do you think need to be validated?

How does cleaning of these tanks between use affect validation?

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Some Questions

A valve used to transfer material from a holding tank to the purification suite jam’s closed. You have a spare valve that is an identical model. Can you change this valve with the spare and continue operations? What if the valve is from a different manufacturer?

You notice that your autoclave loading plan leaves room for additional material. Realizing that increasing that amount of material in the autoclave will shorten the turn around time for the production line you contemplate increasing the amount of material loaded into the autoclave then specified by the loading plan. What should you do? What will be required to implement this change?

An SOP for calibration of a pH meter calls for a two point calibration at pH 4 and pH 7. You notice that a single point calibration at pH 7 produces the same result from pH measurements of your buffer solutions and allows you to take a longer break. Is it Ok to do the one point calibration when the SOP calls for a two point calibration? How would you go about changing the SOP to allow for a one point calibration?

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What documents would provide information concerning the make and model of a particular valve used to regulate the transfer of material from a holding tank to the purification suite?

Your supervisor is concerned that the fermentation vessel is not providing sufficient aeration of the culture to get optimal growth and suggests installing a different kind of baffle in the vessel. How would you demonstrate that this change has no effect on product quality?

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References

Pharmaceutical Manufacturers Association’s (Pharmaceutical Research and Manufacturers of America) Validation Advisory Committee “Process Validation Concepts for Drug Products” Pharmaceutical Technology, September 1985 p 82.

Bismuth, G. Cleaning Validation: A Practical Approach. CRC Press, 2000. ISBN 1574911082. Pharmaceutical Process Validation, 3rd Ed. Edited by Robert Nash and Alfred Wachter, Marcel Decker, 2003. ISBN 082470838-5 Validation of Pharmaceutical Processes: Sterile Products. 1998. 2nd Edition. Edited by Frederick J. Carlton and James Agalloco.

Marcel Decker, 1998. ISBN 0824793846. Validation Standard Operating Procedures: A step by Step Guide for Achieving Compliance in the Pharmaceutical, Medical

Device, and Biotech Industries, Syed Imtiaz Haider, St. Lucie Press, 2002. ISBN 1574443313. Good Manufacturing Practices for Pharmaceuticals: A Plan for Total Quality Control From Manufacturer to Consumer, Sidney J.

Willig. Marcel Decker, 2000. ISBN 0824704258. Voss, J. Cleaning and Cleaning Validation: A Biotechnology Perspective. CRC Press, 1995. ISBN 0939459507. LeBlanc, D.A. 2000. Validated Cleaning Technologies for Pharmaceutical Manufacturing. CRC Press. ISBN 1574911163. Cloud, P. 1998. Pharmaceutical Equipment Validation: The Ultimate Qualification Guidebook. CRC Press. ISBN 1574910795. Juran, Quality Control Handbook, 4th Edition., McGraw-Hill, 1988. DeSain C, Sutton C. (1995). Process development that supports process validation. Pharmaceutical Technology 19 (Oct.): 130-

136, 1995. Garcia T, Wilkinson S, Scott J. The development of a blend-sampling technique to assess the uniformity of a powder mixture.

Drug Development and Industrial Pharmacy 27(4): 297-307, 2001.  Chaloner-Larsson, G., Anderson, R., Egan, A. 1997. A WHO guide to good manufacturing practice (GMP) requirements Part 2:

Validation . World Health Organization, Geneva. www.who.int/vaccines-documents/DocsPDF/www9666.pdf Accessed on October 2nd, 2006.

Brown, F. 1993. Review of accidents caused by incomplete inactivation of viruses. Dev. Biol. Stand. 81: 103-7 Nathanson, N. and Langmuir, A.D. 1995. The Cutter incident. Poliomyelitis following formaldehyde-inactivated poliovirus

vaccination in the United States during the Spring of 1955. II. Relationship of poliomyelitis to Cutter vaccine. 1963. Am. J. Epidemiol. 142:109-40.