Thirunellaivenkateshwaranichq8andq9areview

ICH Q8 and Q9 – A Review

T.G. Venkateshwaran, Ph.D., Associate Director, Global Regulatory Affairs – CMC September 10, 2007

ICH Q8 and Q9 – Discussion Topics n

Background  Quality by Design

n

ICH Q8 and Q9 and their relationship to Pharmaceutical Stability

n

Applications of Risk Management to understanding Pharmaceutical Stability Drug Substance Drug Product

n

Conclusions/Path Forward

ICH Q8, Q9 - A review - AAPS Stability Workshop, September 2007

Pharmaceutical Quality Assessment Systems – Elements of QbD ICH Q8: Pharmaceutical Development

+

ICH Q9: Quality Risk Management

+

ICH Q10: Quality Systems

Quality by Design : Systematic Approach to Pharmaceutical Development and Lifecycle Management

ICH Q8, Q9 - A review - AAPS Stability Workshop, September 2007

ICH Q8- Pharmaceutical Development To design a quality product and manufacturing process and deliver consistent performance (safety and efficacy) n Collation of knowledge establishing the rationale for type of dosage form, formulation proposed is suitable for the intended use, process and product understanding n Aspects of drug substance(s), excipients, container closure systems and manufacturing processes that are critical to product quality n

Stability is a Critical Quality Attribute – Its understanding is

critical to the development of a quality product

ICH Q8, Q9 - A review - AAPS Stability Workshop, September 2007

ICH Q9 – Quality Risk Management

Quality Risk Management is a systematic process for the assessment, control, communication and review of risks to the quality of the drug product across the product lifecycle

QRM is a tool that enables focus on product/process attributes that are critical to stability and is useful throughout the lifecycle of the product

ICH Q8, Q9 - A review - AAPS Stability Workshop, September 2007

System Definition

System Description

Risk Analysis

Risk Assessment

ICH Q9 – Quality Risk Management*

Hazard Identification

Risk Management Risk Analysis Tools •PRA

Risk Estimation

•FMEA Risk Evaluation Acceptable? Yes

•FMA No

Monitoring and Re-evaluation

Control and Mitigation

Communication

*: Risk Assessment and Risk Management Pharmaceutical Industry – ICH Q8,in Q9the - A review - AAPS Stability Workshop, Clear and Simple – James L. Vesper, 2006 September 2007

•HAZOPS •Etc

Pharmaceutical Stability API/Drug Substance + Excipients n

Formulation

Drug Product

Packaging

Finished Product

Stability of a pharmaceutical depends on API – Physical and Chemical Stability Compatability of the API with excipients Compatability of the drug product with the packaging systems Environmental conditions – conditions for storage (light, humidity and temperature) and time of exposure ICH Q8, Q9 - A review - AAPS Stability Workshop, September 2007

Pharmaceutical Stability – Use of Risk Assessment During Development n

API Development – Physical and Chemical Characteristics of API are investigated in

early stages – Understand characteristics of the API that are important to the stability of the molecule and need to be controlled, For eg: Crystallinity of an API Understand and control manufacturing process so that there is a

control of organic and inorganic impurities, For eg: Formation of enantiomers Understand the impact of the environment and container closure

system on API stability and take measures to protect the API, For eg: Use of a protective packaging in the case of API susceptible to light

ICH Q8, Q9 - A review - AAPS Stability Workshop, September 2007

Pharmaceutical Stability – Use of Risk Assessment During Development n

Characteristics of the Drug Product Y Intravenous drug product API is manufactured using a semi-synthetic process

n

Control of API quality ensures quality of drug product produced

n

Mechanism of degradation identified and QbD principles used to control levels of degradant in API and stability enhancement of API/DP

ICH Q8, Q9 - A review - AAPS Stability Workshop, September 2007

Pharmaceutical Stability – Use of Risk Assessment During Development n

Identified critical quality attributes of API by studying parameters that affect drug product purity profile and drug product stability

n

Risk assessment (FMEA) performed on each unit operation of the API manufacturing process

n

Critical processing parameters identified as  Control of raw materials/intermediates  Control of synthetic parameters to prevent oxidative degradation

during the manufacturing process  Control of crystallization (Large impact on API stability and little

effect on oxidative degradative content)  Control of isolation conditions (handling/storage)

ICH Q8, Q9 - A review - AAPS Stability Workshop, September 2007

Pharmaceutical Stability – Effect of Scale-up on Crystallization Scale-up leads to poor crystallinity

•

Laboratory scale process produced high-quality crystals – Simple, anti-solvent process for with minimal controls – Crystal size consistent

•

Upon scale-up crystal quality and size changed, purity not impacted – Bulk drug batches started failing long term stability – Process sent back to the lab

ICH Q8, Q9 - A review - AAPS Stability Workshop, September 2007

API Y – API Process Flow Crude API Antisolvent Antisolvent addition addition

Dissolve in solvent

Hold Hold for for X X hours hours

Clarification Filtration

Distill Distill to to amorphous amorphous foam foam

Pre-parental API

Dissolve Dissolve in in Solvent Solvent B, B, nucleation nucleation Verify precipitation

ICH Q8, Q9 - A review - AAPS Stability Workshop, September 2007

Crystallization Trajectory Established Early Induction time = nucleation time + aging time 8000

6000

4000 A/S added immediately after nucleation

A/S added before nucleation 2000

A/S added after aging

Aging

0 0

20

40

60

80

100

120

Time (min) ICH Q8, Q9 - A review - AAPS Stability Workshop, September 2007

140

Operating area

0% solvent content

Antisolvent Add’n Time (min)

Antisolvent Add’n Time (min)

Response Surface Curves: Solvent Content Operating area

5% solvent content Induction Time (h)

Induction Time (h)

Antisolvent Add’n Time (min)

•

•

10% solvent content

Response surface model for crystallinity as a function of antisolvent add’n rate & induction time at constant mixing speed Acetone content shows a significant impact on crystal quality – Antisolvent add’n time and induction time also important *Degree of crystallinity determined by DSC and particle size measurement

Induction Time (h)

ICH Q8, Q9 - A review - AAPS Stability Workshop, September 2007

Solvent Level Optimization Model prediction of solvent level for optimum crystallinity and yield c Yield/ crystallinity ‹ +10% confidence limit z -10% confidence limit 1. 0 0

90 88

0. 9 0

86

0. 8 0

Crystallinity

84

Yield

82 80 78 76 74

70 68

0. 6 0 0. 5 0 0. 4 0

Higher crystallinity

0. 3 0

In-process control limit set for solvent concentration of NMT “x” v%

72

0. 7 0

Ease of solvent removal

0. 2 0 0. 1 0 0. 0 0

0

1

2

3

4

5

6

7

8

Solvent content (V%)

9

10

0

1

2

3

4

5

6

7

Solvent content (V%) ICH Q8, Q9 - A review - AAPS Stability Workshop, September 2007

8

9

10

Modified Process with Controls Dissolve Dissolve API API in in solvent solvent

Age Age crystals crystals NLT NLT “y”h “y”h Verify precipitation

Clarification Clarification

Distill Distill to to amorphous amorphous foam foam

Stepwise Stepwise antisolvent antisolvent add’n add’n

Hold Hold “z” “z” hh

Design Space for OD control •

• •

Crystallize Crystallize

Filtration Filtration •

Criteria not met

Solvent NMT x% v/v

Pre-parental API ICH Q8, Q9 - A review - AAPS Stability Workshop, September 2007

Solvent content in amorphous foam NMT x % Minimum induction time of “y” hours Antisolvent added stepwise at defined rate of addition Minimum hold time of “z” hours

Pharmaceutical Stability – Use of Risk Assessment During Development - Summary n

Experiments demonstrated that API crystallinity impacts API and drug product stability

n

DOE (small scale) to investigate factors affecting crystal quality performed Factors investigated include Induction time, mixing speed and

solvent content Design space for controlling crystal quality developed based on

results of the DOE Manufacturing performed at small scale and stability confirmed

ICH Q8, Q9 - A review - AAPS Stability Workshop, September 2007

Pharmaceutical Stability - Drug Product n

Factors considered during formulation/process development Interaction of API with excipients - Preformulation studies performed to understand interactions (physical or chemical) - Stress degradation studies are performed to identify any impurities formed as a result of API with excipients and also identify potential degradation products of the API

API stability during the drug product manufacturing process. For eg:

degradation product formation and enantiomer formation - Monitored using assays (physical and chemical) as necessary

Understand the impact of the environment and container closure

system on drug product stability and take measures to protect the drug product, For eg: Use of a protective packaging in the case of drug product susceptible to moisture ICH Q8, Q9 - A review - AAPS Stability Workshop, September 2007

Optimization of Container Closure System During Development Identify the attributes of the drug product that could be potentially affected during storage in the package

Identify the risks associated with the failure to meet attributes

Mitigate risks by developing appropriate controls e.g. alternate packaging

ICH Q8, Q9 - A review - AAPS Stability Workshop, September 2007

Example of Drug Product Container Closure System Design Space n

Immediate release dosage form – sensitive to hydrolysis

n

Drug product critical quality attributes are not influenced by environmental factors

n

Level of moisture in drug product controlled during manufacturing

n

A number of packaging materials were investigated during development

n

Based on data during development, understanding of the product/process, permeability of packaging material (MVTR data) and stability data on a packaging material (for eg . PVC/ACLAR), propose to use packaging material of as good or better permeability in application – would this be acceptable?

ICH Q8, Q9 - A review - AAPS Stability Workshop, September 2007

Impact of QbD in Understanding Stability Conclusions ¾ Pharmaceutical Development (Q8) enables us to understand

the impact of various API/drug product properties on stability ¾ Risk management helps to understand the factors and mitigate

the risk of stability failure – This can be by design change or by establishing controls upstream in the process ¾ In combination principles of ICH Q8 and Q9 help develop

stability programs that are based on sound scientific principles and help achieve the intended goals – mitigate the risk of stability as a potential cause for product recalls/failures

ICH Q8, Q9 - A review - AAPS Stability Workshop, September 2007

Acknowledgements Michael O’Brien Subodh Deshmukh Michael Kolb Parimal Desai Richard Saunders Patricia F. Mann T.G. Venkateshwaran Steve Simmons Donald Esherick Ferdinando Aspesi Richard Saunders Shailesh Singh

ICH Q8, Q9 - A review - AAPS Stability Workshop, September 2007