Post on 22-Dec-2015
Pharmaceutical Product Quality Pharmaceutical Product Quality Assurance Through CMC Drug Assurance Through CMC Drug
Development ProcessDevelopment Process Presented by Darlene Rosario (Aradigm)
21 October 2003
Meeting of the Advisory Committee for Pharmaceutical Science
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Presentation OutlinePresentation Outline
• Purpose• Pharmaceutical product quality is built-in• Quality system development• Registration requirements• Validation• Role of QC tests• Pre-approval inspection• Conclusions
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Purpose of PresentationPurpose of Presentation
• To demonstrate that product development assures that the final product is of appropriate quality
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Pharmaceutical Product Quality Pharmaceutical Product Quality Cannot Be Tested in - It Is Built inCannot Be Tested in - It Is Built in• Pharmaceutical product quality is assured by
– comprehensive development program– extensive manufacturing and environmental controls – rigorous validation procedures and requirements
• The high quality thus built into the final product is ensured through in-process controls and verified in a series of confirmatory tests before each manufactured batch is released to the market
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Building-in of Quality Starts Early.Building-in of Quality Starts Early.Development Builds-in QualityDevelopment Builds-in Quality
• The chemistry, manufacturing and controls (CMC) aspect of drug development is focused on producing medicines suitable for human use with specified quality, safety and efficacy characteristics
• The drug development program is geared towards – thorough understanding of the drug product’s performance – identification of drug product’s critical characteristics
(which would be monitored on a batch-by-batch basis)– demonstration of drug’s safety and efficacy– ultimately leads to the review and approval of the drug
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Relationship between Relationship between Safety, Efficacy and QualitySafety, Efficacy and Quality
• Every drug product (with its specifications) has been thoroughly tested in clinical trials for safety and efficacy – Specifications for release and stability testing may
be equal to or tighter than the specifications for clinical trial batches
• Therapeutic indication and QC are considerations in establishing specifications
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Drug Development ProcessDrug Development Process
Pre Clinical Testing
Phase I Phase II Phase III FDA Approval
Years 3.5 1 - 2 2 - 4 4 - 6 1.5 Total = 12 - 17
Te
st P
opul
atio
n Laboratory and Animal
Studies
20 to 100 Healthy
Volunteers
100 – 300 Patient
Volunteers
1,000 to 3,000
Patient Volunteers
Review
Post Marketing
Safety Monitoring
P
urpo
se
Assess Safety and Biological
Activity
Determine Safety and Dosage
Evaluate Effectiveness. Look
for Side Effects.
Verify Effectiveness, Monitor Adverse
Reactions from Long-Term Use
Process Large Scale
Manufacturing -------------- Distribution -------------- Education
% o
f all
new
dru
gs
that
pas
s
FILE
IND
70% of INDs
30% of INDs
27% of INDs
FILE
ND
A
20% of INDs
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Quality is Always Part of the Picture - Quality is Always Part of the Picture - Built-In and Built-UpBuilt-In and Built-Up
Quality Control and Quality Assurance
Pre-IND Phase I Phase II Phase III Commercial Manufacturing
Specification/Manufacturing Development
for the Product
Less established Fully established
QA & QC* Systems Evolve During Drug QA & QC* Systems Evolve During Drug DevelopmentDevelopment
• Quality assurance and quality control systems begin being established during early clinical trials and involve:– equipment validation (IQ, OQ, PQ)– manufacturing controls and limits– product specifications
• Process optimization continues through the development process, leading to – identification of critical in-process control parameters
– final product specifications for QC purposes
– final process validation
• Stability– Batches produced by the defined manufacturing process are studied at
different storage conditions to verify consistent quality and performance of the product throughout shelf-life
* QC generally means product testing, and QA an independent review of the results
9
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Examples of QA & QC Considerations Examples of QA & QC Considerations During Drug DevelopmentDuring Drug Development
• Evolution of documentation systems– SOP– change control– OOS system and procedures– trend analysis
• Evolution of QA and QC systems– internal audits– supplier audits– document review (e.g., SOP, batch records, specifications,
data)
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Chemistry Manufacturing Controls Chemistry Manufacturing Controls Evolve During Drug DevelopmentEvolve During Drug Development
• The goal is to have process and product performance determined by the time of validation, although some level of validation occurs along the continuum and eventually leads to the full-scale validation.
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Examples of CMC Considerations Examples of CMC Considerations During Drug DevelopmentDuring Drug Development
• Selection of appropriate technology and raw materials• Optimization
– of formulation and device – of manufacturing process– of specifications and analytical methods
• Careful selection and control of container closure systems• Identification and control of critical manufacturing process
parameters• Process capability established• Technical transfer to larger scale, i.e., scale-up• Process validation
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Process Registration RequirementsProcess Registration Requirements• Sponsor is required to describe how the product was developed• Companies need to optimize, justify and register the entire “recipe”
– ranges• temperatures• mixing times• hold times• etc.
– quantities • active ingredient• excipients
– raw material specifications – in-process limits– in-process methods– product specifications– etc.
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What is Validation?What is Validation?• Documented evidence that the manufacturing process
consistently produces product that meets predetermined specifications – Defines product quality – Developed and validated based on a thorough understanding of
the critical process parameters– Parameters are carefully controlled within the validated ranges to
ensure a consistent manufacturing process.
• Manufacturing process validation consists of successfully manufacturing at least three full-scale batches in succession, which pass all in-process and product quality attributes
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Validation is Always Part of the PictureValidation is Always Part of the Picture
Ongoing Validation
(DOE, IQ, OQ, PQ, PV)*
Pre-IND Phase I Phase II Phase III Commercial Manufacturing
* DOE = Design of Experiment IQ = Installation Qualification OQ = Operational Qualification PQ = Performance Qualification PV = Process Validation
Specification DevelopmentFinal process validation
Re-validation
• The extent of IQ, OQ, PQ, validation, etc. depends on complexity of product
• 6 sigma target
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Role of QC TestsRole of QC Tests• Each batch of orally inhaled and nasal drug products
(OINDP), manufactured by the validated process, is tested to the critical QC attributes as defined during development – Confirms consistent performance
• The Delivered Dose Uniformity test for OINDP is one of several confirmatory QC tests of the finished product– a result of a long and careful development and characterization
process– QC tests confirm the quality built-in through a well-understood
and well-controlled manufacturing process
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Pre-Approval InspectionPre-Approval Inspection
• Confirms Facility is Ready– Sponsor can do what they submit in the NDA
– Process is validated or validation protocols are in place• Validation required prior to launch
– Thorough documentation review
– Quality systems are established and capable
– Confirms specifications are met• Compliance versus Review Division
– Specifications may change based on NDA review
– Tighter than process capability
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ConclusionsConclusions• Pharmaceutical quality is built-in through the entire
drug development process
– validation is key element of ensuring quality
– in-process controls assure quality during manufacturing
– Specifications established based on thorough understanding of process
• The sum of all release parameters confirms the batch quality
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AcknowledgementsAcknowledgements• IPAC-RS Members
– Aradigm– AstraZeneca– Aventis– Boehringer Ingelheim– Eli Lilly – GlaxoSmithKline– IVAX
• Members of IPAC-RS DDU Working Group• IPAC-RS Secretariat
– Kos Pharmaceuticals– Nektar Therapeutics– Novartis– Novo Nordisk– Pfizer– Schering-Plough