Pharmaceutical Product Quality Assurance Through CMC Drug Development Process

Pharmaceutical Product Quality Assurance Through CMC Drug Development Process
Presented by Darlene Rosario (Aradigm)

21 October 2003 Meeting of the Advisory Committee for Pharmaceutical Science
Presentation Outline
Purpose Pharmaceutical product quality is built-in Quality system development Registration requirements Validation Role of QC tests Pre-approval inspection Conclusions
2
IPAC-RS for ACPS 21 October 2003
Purpose of Presentation
To demonstrate that product development assures that the final product is of appropriate quality
Pharmaceutical Product Quality Cannot 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
Building-in of Quality Starts Early. Development 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 products performance identification of drug products critical characteristics (which would be monitored on a batch-by-batch basis) demonstration of drugs safety and efficacy ultimately leads to the review and approval of the drug
Relationship between Safety, 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
Drug Development Process

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D t rm eSa t ee in fey a dD sa e n o g
Ev lu t a ae Effe t e e Lo k civ n ss. o fo Sid Effe t r e cs.
V rifyEffe t e e e civ n ss, Mno A v r o it r d ese R a t n fr o Lo g e cio s m n Te U rm se
La eSc le rg a M n fa t rin a u cu g -------------D rib t n ist uio -------------Ed c t n u aio
7 %o IN s 0 f D
3 %o IN s 0 f D
2 %o IN s 7 f D
2 %o IN s 0 f D
Quality is Always Part of the Picture Built-In and Built-Up

Quality Control and Quality Assurance Less established Fully established
Pre-IND
Phase I
Phase II
Phase III
Commercial Manufacturing
Specification/Manufacturing Development for the Product
QA & QC* Systems Evolve During Drug Development

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 9
Examples of QA & QC Considerations During 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)
10
Chemistry Manufacturing Controls Evolve 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.
11
Examples of CMC Considerations During 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
12
Process 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. IPAC-RS for ACPS 21 October 2003
13
Validation
14
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
15
Validation is Always Part of the Picture

Pre-IND Phase I Phase II Phase III
Commercial Manufacturing
Specification Development Ongoing Validation (DOE, IQ, OQ, PQ, PV)*
Final process validation Re-validation

* DOE = Design of Experiment IQ = Installation Qualification OQ = Operational Qualification PQ = Performance Qualification PV = Process Validation
16
The extent of IQ, OQ, PQ, validation, etc. depends on complexity of product 6 sigma target
Role 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 wellunderstood and well-controlled manufacturing process
17
Pre-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
18
Conclusions
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
19
IPAC-RS Members

Acknowledgements
Kos Pharmaceuticals Nektar Therapeutics Novartis Novo Nordisk Pfizer Schering-Plough
Aradigm AstraZeneca Aventis Boehringer Ingelheim Eli Lilly GlaxoSmithKline IVAX
Members of IPAC-RS DDU Working Group IPAC-RS Secretariat

20

Pharmaceutical Product Quality Assurance Through CMC Drug Development Process

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How does pharmaceutical quality assurance start?

How does pharmaceutical quality assurance start?

What are the stages of drug development?

What are the stages of drug development?

Pharmaceutical Product Quality Assurance Through CMC Drug Development Process

Presented by Darlene Rosario (Aradigm)

IPAC-RS for ACPS 21 October 2003

IPAC-RS for ACPS 21 October 2003

Pharmaceutical Product Quality Cannot Be Tested in - It Is Built in

IPAC-RS for ACPS 21 October 2003

Building-in of Quality Starts Early. Development Builds-in Quality

Relationship between Safety, Efficacy and Quality

IPAC-RS for ACPS 21 October 2003

Drug Development Process

A ss sse Sa t a d fey n B lo ic l io g a A t it civ y

%of all n d g ew ru s th p at ass

Ev lu t a ae Effe t e e Lo k civ n ss. o fo Sid Effe t r e cs.

V rifyEffe t e e e civ n ss, Mno A v r o it r d ese R a t n fr o Lo g e cio s m n Te U rm se

La eSc le rg a M n fa t rin a u cu g -------------D rib t n ist uio -------------Ed c t n u aio

IPAC-RS for ACPS 21 October 2003

Quality is Always Part of the Picture Built-In and Built-Up

Specification/Manufacturing Development for the Product

IPAC-RS for ACPS 21 October 2003

QA & QC* Systems Evolve During Drug Development

Process optimization continues through the development process, leading to

Examples of QA & QC Considerations During Drug Development

Evolution of QA and QC systems

IPAC-RS for ACPS 21 October 2003

Chemistry Manufacturing Controls Evolve During Drug Development

IPAC-RS for ACPS 21 October 2003

Examples of CMC Considerations During Drug Development

Process Registration Requirements

IPAC-RS for ACPS 21 October 2003

Validation is Always Part of the Picture

Specification Development Ongoing Validation (DOE, IQ, OQ, PQ, PV)*

Final process validation Re-validation

IPAC-RS for ACPS 21 October 2003

The sum of all release parameters confirms the batch quality

IPAC-RS for ACPS 21 October 2003

Aradigm AstraZeneca Aventis Boehringer Ingelheim Eli Lilly GlaxoSmithKline IVAX

Members of IPAC-RS DDU Working Group IPAC-RS Secretariat

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