process validation for pharmaceutical -life science organization
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Process Validation for Pharmaceutical -Life Science Organization for API-DrugsTRANSCRIPT
Process Validation Regulatory Requirements for Biologics
Conference on PROCESS VALIDATION
for Biopharmaceutical ManufacturingOctober 8-9, 2003
Philadelphia
Elizabeth Leininger, Ph.D.
Process Validation from a Regulatory Perspective
Regulatory Guidance DocumentsRegulatory Expectations– Purpose of Process Validation– Validation Life Cycle – Validation Approached
General Observations
Process Validation: Requirement of cGMP for Finished Pharmaceuticals (21CFR 210 and 211)
Written ProceduresProcess ControlControl Procedures Validate Performance
→ To assure that the drug products have identity, strength, quality, and purity they purport or are represented to possess
Assurance of Product Quality
Selection of quality parts and materialsAdequate product and process designControl of the processIn-process and end product testing
Quality Assurance Goal: Production of articles that are fit for their intended use
Quality, safety and effectiveness must be designed and built into the productQuality cannot be inspected or tested into the finished productEach step of the manufacturing process must be controlled to maximize the probability that the finished product meets all quality and design specifications
→ Process Validation key element in assuring that these quality assurance goals are met
Validation
Establishing DOCUMENTED EVIDENCE which
provides a high degree of assurance that a specific
process will CONSISTENTLY PRODUCE a product
meeting its PRE-DETERMINED SPECIFICATIONS
and QUALITY ATTRIBUTES.
(US FDA Guidance on General Principles of Process Validation, May, 1987)
A Validated Process
Consistently produces a product– Control of the process– Minimize product failure– Meet cGMP
Consistently meets pre-determined specifications and quality attributes– Quality built into the product– Suitable for its intended use
Regulatory Guidance DocumentsFDA Guideline on General Principles of Process Validation (May 1987)ICH Q7A: Good Manufacturing Practice for Active Pharmaceutical Ingredients, Section 12 (Validation)Annex 15 to the EU Guide to Good Manufacturing Practice (Qualification and Validation)EudraLex (volume 2B) Part II - Concerning Chemical, Pharmaceutical and Biological Documentation for: Biological Medicinal Products (Section 1.5 Production, 1.8 Process Validation)
Validation Requirements from Guidance Documents
Critical Parameters/attributes should be identified during the development stage, and the ranges necessary for reproducible operation should be defined.Critical process parameters should be controlled and monitored.Specifications should already be set and approved prior to the start of the process validation at full scale.Testing to the pre-approved specifications is done with valid assays. Specifications under Change Control
Validation Requirements from Guidance Documents (cont.)
Impurity profile must be confirmed.All equipment, facilities and systems are qualified before the Process Validation startsBatches should be the same size as the intended commercial scale.A sufficient number of runs should be analyzed, the number is based on the complexity of the process.Validation lots must meet specification
Process Validation ProgramPROPOSE, DEFINE & IDENTIFY
Evaluation StudiesDevelopment Studies
CONFIRMValidation Studies– Process Validation Protocol– Critical Process Parameters defined and documented
» Locked Process– Defined Impurity Profile– Approved Specifications– Valid Assays – Defined number of lots
Process Validation Development Cycle:Small Scale & Pilot Plant Activities
•Define Processunit operations/process steps
•Define operating parameters/process variable
•Identify key/critical operatingparameters
•Define product characteristics& quality attributes
Evaluation Studies
DevelopmentStudiesLaboratory ModelsPilot Scale
Analytical MethodsDevelopment
Process Validation Development Cycle: Commercial Scale Activities
Validation protocol
At least 3 consecutive commercial scale lots
Pre-approved specificationsValid analytical assays
Qualified facilities,equipment &
systems
Meet established criteria and specifications
Validation report
Validated manufacturingprocess
Pre-clinicalDiscovery
BLA
Process Validation Program[Slide by Chris Joneckis, CBER, FDA (Sept 2003)]
Clinical (IND) Post-Approval
Source/starting material characterization
Raw materials qualification
Evaluation studies for clearance of viruses/ impurities-control of production scale
Vaccine/toxin inactivation on production scale
Change ControlMonitoring/Trending(Statistical Process Control PC)
Accumulated manufacturing experience
EquipmentIQ, OQ, PQ
Development Studies
Consistency Lots – “validation study”
Analytical Methodsand Assay Qualification
Materials qualification
“ValidatedProcess”
Product Characterization
DevelopmentStudies
validation Study
CommercialScale
PilotScale
LaboratoryModel
CommercialScale
Evaluation
MaintenancecGMPMonitor
Change Control
Validation Life Cycle[Slide (modified) by Chris Joneckis, CBER, FDA (Sept 2003)]
Qualified“ValidatedManufacturingProcess”
Revalidation(propose)
(identify)
(confirm)
(monitor)
Validation Life CycleProcess and product experience– Define your process– Define your product– Data driven– Identify what’s critical
Process Validation– Documented evidence of defined
process under control– Known quality of product – Confirm what you established
State of Validation– Maintain thru change control– Trending and monitoring– Revalidation
→Validation must be comprehensive and continuous
Development Reports(documentation of critical
process parameters)
Validation Reports
Change Control
Process Validation Approaches
ProspectiveConcurrentRetrospective
Generic Clearance StudiesModular Clearance Studies
Process Validation Approaches:Prospective Validation
Validation conducted and completed prior to the distribution of either a new product, or product made under a revised manufacturing process, where the revisions may affect the product’s characteristics
Process Validation Approaches:Concurrent Validation
Validation which includes all elements of validation except that the replicate production runs can occur in conjunction with release of product distributionCreated by CBERLimited applicationHeighten testing– Increase frequency and or additional testing
Process Validation Approaches:Retrospective Validation
Validation of a process for a product already in distribution based upon accumulative production, testing and control data
Process Validation Approaches:Generic Clearance Study
Generic Clearance Study: virus clearance is demonstrated for steps in the purification of a model mAb and extrapolated to another mAb following the same purification and clearance scheme as the model mAb. (PTC mAb, 1997)
Modular Clearance Study: virus clearance is demonstrated on individual purification steps (modules) and identical modules can be extrapolated. (PTC mAb, 1997)
Process Validation ObservationsFDA Inspections and 483s
Conference on PROCESS VALIDATION
for Biopharmaceutical ManufacturingOctober 9, 2003
Philadelphia
Elizabeth Leininger, Ph.D.
Process Validation 483sDocumentation
Site Master Validation Program does not identify production steps to be validatedProgram does not specify time frames for completion of validation protocolsProcess validation limited to retrospective studies; no prospective or concurrent studiesValidation protocols were not consistently written according to established proceduresValidation studies are executed prior to approval of the protocol
Process Validation 483sDocumentation
Validation Reports includes acceptance criteria that were not contained in the Validation Protocol No definition of what constitutes an acceptable validationProtocol deviations were not always documented, investigated, and/or correctedValidation studies are not given independent, final approval by QA
Process Validation 483sChromatography
No validation for column load volumes for…No assurance column packing procedure adequately validatedMaximum number of uses of purification column not validatedNo data to support the between run hold times of the purification column
Process Validation 483sProcessing
No established validated time limit for processing…Production time limits have not been established for inoculum fermentationNo usage limit has been established for ultrafilters used for…No validation data to support mixing times used during addition of excipientsNo hold time studies were conducted for buffers and rinse solutions used in production
Process Validation 483sAssays
Bioburden method used in both validation and routine monitoring not validatedMethod used to assess protein concentration of active ingredient not validatedHPLC method used for release and stability testing before validation was completeSystems used to identify water, environmental, and bioburden monitoring isolates not validatedAn impurities profile has not been established for th active ingredient
Process Validation 483sEquipment
Installation/Operation Qualification of the process equipment is lackingInadequate qualification of vessels used for storage and transport of sterile bulk productInadequate validation of decontamination of fermentersand media tanks: validation study did not result in all acceptance criteria being metStorage/hold time for cleaned production equipment has not been validated
Acknowledgments
I would like to give thanks and acknowledgement to many colleagues whom have contributed to this presentation by providing input via discussions, previous presentations and hands-on experience with process validation.
