# Presentation: 357856

## 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

- IPAC-RS for ACPS 21 October 2003

## Presentation Outline

- Purpose
- Pharmaceutical product quality is built-in
- Quality system development
- Registration requirements
- Validation
- Role of QC tests
- Pre-approval inspection
- Conclusions

- IPAC-RS for ACPS 21 October 2003

## Purpose of Presentation

- To demonstrate that product development assures that the final product is of appropriate quality

- IPAC-RS for ACPS 21 October 2003

## 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

- IPAC-RS for ACPS 21 October 2003

## 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 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

- IPAC-RS for ACPS 21 October 2003

## 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

- IPAC-RS for ACPS 21 October 2003

## Drug Development Process

- IPAC-RS for ACPS 21 October 2003

## Quality is Always Part of the Picture - Built-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*

- IPAC-RS for ACPS 21 October 2003

## 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 of the results

- 9

- IPAC-RS for ACPS 21 October 2003

## 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)

- IPAC-RS for ACPS 21 October 2003

## 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.

- IPAC-RS for ACPS 21 October 2003

## 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

- IPAC-RS for ACPS 21 October 2003

## 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

## Validation

- IPAC-RS for ACPS 21 October 2003

## 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

- IPAC-RS for ACPS 21 October 2003

## Validation 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 Development*

- Final process validation

- Re-validation

- The extent of IQ, OQ, PQ, validation, etc. depends on complexity of product
- 6 sigma target

- IPAC-RS for ACPS 21 October 2003

## 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 well-understood and well-controlled manufacturing process

- IPAC-RS for ACPS 21 October 2003

## 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

- IPAC-RS for ACPS 21 October 2003

## 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

- IPAC-RS for ACPS 21 October 2003

## Acknowledgements

- 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

- IPAC-RS for ACPS 21 October 2003