ICH Quality Guidelines E-Book

• Herausgeber: John Wiley & Sons
• Kategorie: Wissenschaft und neue Technologien
• Sprache: Englisch

Seitenzahl: 1263

Veröffentlichungsjahr: 2017

Beschreibung

Examining the implications and practical implementation of multi-disciplinary International Conference on Harmonization (ICH) topics, this book gives an integrated view of how the guidelines inform drug development strategic planning and decision-making. * Addresses a consistent need for interpretation, training, and implementation examples of ICH guidelines via case studies * Offers a primary reference point for practitioners addressing the dual challenge of interpretation and practical implementation of ICH guidelines * Uses case studies to help readers understand and apply ICH guidelines * Provides valuable insights into guidelines development, with chapters by authors involved in generating or with experience implementing the guidelines * Includes coverage of stability testing, analytical method validation, impurities, biotechnology drugs and products, and good manufacturing practice (GMP)

Leseprobe

Table of Contents

Cover

Title Page

List of Contributors

An Introduction to ICH Quality Guidelines: Opportunities and Challenges

References

1 ICHQ1A(R2) Stability Testing of New Drug Substance and Product and ICHQ1C Stability Testing of New Dosage Forms

1.1 Introduction

1.2 The Fundamental Science That Underpins Stability Testing

1.3 Part II: Practical Application of the ICH Stability Guidance

References

2 Stability Testing: Photostability Testing of New Drug Substances and Products ICH Q1B

2.1 Introduction

2.2 What the Guidance Says

2.3 What the Guidance Does Not Say

2.4 Other Factors to Consider

References

3 ICH Q1D: Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and Products

3.1 Summary

3.2 Introduction

3.3 Definitions

3.4 Applicability

3.5 Designs

3.6 Data Evaluation

3.7 Practical Examples

3.8 Effect of Matrixing Upon Shelf‐Life Estimations

3.9 Conclusion

References

4 ICH Q1E Evaluation for Stability Data

4.1 Introduction

4.2 The Effect of Environmental Factors on Pharmaceutical Stability

4.3 Multifactor Stability Studies

4.4 Data Evaluation and Statistical Considerations

4.5 Concluding Remarks

References

5 Q2(R1) Validation of Analytical Procedures: Text and Methodology

5.1 Introduction

5.2 ICH Q2(R1) Validation Criteria

5.3 Comparison of Regulatory Criteria for Method Validation

5.4 Other Chromatographic Tests

5.5 Non‐chromatographic Method Validation

5.6 Traditional Method Validation Versus QbD Alternative

5.7 Future Trends

5.8 Conclusions

References

6 Impurities in New Drug Substances and New Drug Products: ICH Q3A/B: Key Guidelines in the General Impurity Management Process

6.1 Introduction

6.2 Basic Principles

6.3 Reporting and Identification

6.4 Qualification

6.5 Extrapolation of Principles to Out‐of‐Scope Molecules

6.6 Drug Substance Control Strategy Key Points for Consideration

6.7 DP Purity: Key Points for Consideration

6.8 Conclusions

References

7 ICH Q3C Impurities: Guideline for Residual Solvents

7.1 Introduction

7.2 Objective and Scope of the ICH Q3C Guideline

7.3 Permitted Daily Exposure and Concentration Limits

7.4 Solvent Classification

7.4.2 Class 2 Solvents: Solvents to Be Limited

7.5 Estimating PDE Values: Safety Factors, Allometric Scaling, and Calculation Adjustments

7.6 Analysis and Reporting

7.7 Maintenance and Expansion of the ICH Q3C Residual Solvent Guideline

7.8 Example: Case for Revision of an Existing Residual Solvent Limit

7.9 Example: Case for Addition of a Residual Solvent to the ICH Q3C Guideline List

7.10 Appraisal of the ICH Q3C Residual Solvents Guideline 17 Years After Step 4

References

8 ICH Q3D Elemental Impurities

8.1 Introduction

8.2 Guideline Structure

8.3 Scope

8.4 Safety Assessment of Potential Elemental Impurities

8.5 Element Classification

8.6 Risk Assessment

8.7 Speciation

8.8 Analytical Procedures

8.9 Training Modules

8.10 Case Study

8.11 Overall Conclusions

References

9 ICH Q4: Pharmacopeial Harmonization and Evaluation and Recommendation of Pharmacopeial Texts for Use in the ICH Regions

9.1 Introduction

9.2 Overview of Guidelines

9.3 Initial Process

9.4 ICH Q4B Annexes

9.6 Pharmacopoeial Harmonization Post‐ICH Q4

9.7 Other Initiatives

9.8 Conclusions

References

10 ICH Q5A : Viral Safety of Biotechnology Products

10.1 Introduction

10.2 Overall Approach for Assuring Viral Safety

10.3 Cell Line Qualification

10.4 Qualification of Animal‐Derived Raw Materials

10.5 Testing of In‐Process and Lot‐Release Samples

10.6 Viral Clearance (Removal and Inactivation) Studies

10.7 Summary

References

11 ICH Q5B Analysis of the Expression Construct in Cell Lines Used for Production of Recombinant DNA‐Derived Protein Products

11.1 Introduction

11.2 Expression Construct

11.3 Characterization of the Expression System

11.4 Conclusions

References

12 ICH Q5C Stability Testing of Biotechnological/Biological Products

12.1 Introduction

12.2 Purposes of Stability Studies

12.3 Degradation Pathways of Therapeutic Proteins

12.4 Stability Testing Protocol

12.5 Stability Conditions and Time Points

12.6 Stability/Shelf‐Life Specification

12.7 Approaches Used to Determine Shelf‐Life Data for the Marketing Application

12.8 Summary

References

13 Q5D Derivation and Characterization of Cell Substrates Used for Production of Biotechnological/Biological Products

13.1 Introduction

13.2 Source, History, and Generation of the Cell Substrate

13.3 Cell Bank Characterization

13.4 Summary

References

14 Conduct of Risk Assessments: An Integral Part of Compliance with ICH Q5A and ICH Q5D

14.1 Introduction

14.2 Conduct of a Risk/Benefit Analysis for the Use of a Cell Substrate Known to Be Infected with a Virus Other Than a Non‐endogenous Retrovirus

14.3 Conduct of an Assessment of Viral Clearance Capacity for Endogenous Retrovirus

14.4 Implementation of an Animal‐Derived Materials Assessment Program

14.5 Conduct of an Overall Adventitious Agent Safety Assessment for the Manufacturing Process

14.6 Conclusions

References

15 ICH Q5E Comparability of Biotechnological/Biological Products Subject to Changes in Their Manufacturing Processes: Summary and Analysis of ICH Q5E Guideline

15.1 Introduction

15.2 General Principles and Scope of the ICH Q5E Guideline

15.3 Manufacturing Process

15.4 Determination of Comparability: Methods and Considerations

15.5 Conclusions

References

16 ICH Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances

16.1 Introduction

16.2 Scope of the ICH Q6A

16.3 ICH Q6A General Concepts

16.4 ICH Q6A Guidelines

16.5 ICH Q6A Decision Trees

16.6 Process Capability and Specification Setting

16.7 Probability‐Based Specification Limits

16.8 ICH Q6A and Quality by Design Initiatives (ICH Q8, Q9, Q10, and Q11)

16.9 Conclusion

References

17 ICH Q6B Specifications: Test Procedures and Acceptance Criteria for Biotechnological/Biological Products

17.1 Introduction

17.2 Principles to Be Considered in Establishing Specifications

17.3 Content of Specifications

17.4 Reference Standards

17.5 Method Validation

17.6 Process Controls

17.7 Raw Materials

17.8 Case Study: Early‐Stage Therapeutic Monoclonal Antibody

17.9 Case Study: Late‐Stage Plasmid Product

17.10 Conclusions

References

18 Process‐Related Impurities in Biopharmaceuticals: A Deeper Dive into ICH Q6B

18.1 Introduction

18.2 Controlling Process‐Related Impurities

18.3 General Methodology for Deriving Limits for Process‐Related Impurities

18.4 Assessment of Impurities and Control Strategies

18.5 Evaluation of Process Capability and Capacity for Removing Impurities

18.6 Safety Margin and Determining the Need for Clearance and Specification Testing

18.7 Conduct of the Risk Assessment for Elimination of Specification Testing

18.8 Case Studies of Interrelationship between Impurity, Risk Assessment, and Need for Specification Testing

18.9 Summary and Conclusions

Acknowledgments

References

19 ICH Q7 Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients (APIs)

19.1 Introduction and Principles on Which ICH Q7 Is Based

19.2 Key Features of ICH Q7A

19.3 Quality Management

19.4 Buildings and Facilities

19.5 Process Equipment

19.6 Documentation and Records

19.7 Materials Management

19.8 Production and In‐Process Controls

19.9 Packaging and Identification Labeling of APIs and Intermediates

19.10 Storage and Distribution

19.11 Laboratory Controls

19.12 Validation

19.13 Change Control

19.14 Rejection and Reuse of Materials

19.15 Complaints and Recalls

19.16 Contract Manufacturers (Including Laboratories)

19.17 Agents, Brokers, Traders, Distributors, Repackers, and Relabeling

19.18 Cell Culture/Fermentation (CCF)

19.19 APIs for Use in Clinical Trials

19.20 ICH Q7A Q&As

19.21 Conclusions

References

20 Q8(R2): Pharmaceutical Development

20.1 Introduction

20.2 Overview of ICH Q8(R2) Pharmaceutical Development

20.3 Utilizing Prior Knowledge to Facilitate QbD in Formulation Development

20.4 Conclusion

References

21 ICH Q9 Quality Risk Management

21.1 Introduction

21.2 Quality Risk Management (QRM)

21.3 QRM and GMP

21.4 Integration of QRM into Industry and Regulatory Operations

21.5 ICH Q9 and Other QRM Initiatives

21.6 Case Studies

21.7 Conclusion

References

22 ICH Q10 Quality Systems: ICH Q10 Implementation at Genentech/Roche

22.1 Introduction

22.2 PQS Considerations

22.3 PQS Documents

22.4 Innovation and Continual Improvement

22.5 Auditing, CAPAs, and Management Oversight

22.6 PQS Enablers

22.7 Benefits of ICH Q10 Implementation and Future Opportunities

Acknowledgments

References

23 ICH Q11: Development and Manufacture of Drug Substance

23.1 Introduction

23.2 The Q11 Guidance: Its Genesis and Birth Right

23.3 Manufacturing Process and Development

23.4 Communicating the Drug Substance Development “Story”

23.5 Control Strategy Development

23.6 The Established Control Strategy

23.7 Process Validation

23.8 Selection and Justification of Starting Material for Drug Substance Commercial Manufacturing

23.9 Summary/Conclusions

References

24 ICH M7: Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk

24.1 Introduction

24.2 ICH M7

24.3 Conclusions

References

Index

End User License Agreement

List of Tables

Chapter 01

Table 1.1 Origin of extraneous contaminants that may influence stability.

Table 1.2 Climatic zones.

Table 1.3 Predicted shelf life for refrigerated storage.

Table 1.4 Typical stability protocol.

Table 1.5 Example early‐phase protocol for drug substance.

Table 1.6 Typical protocol for drug substance intended for long‐term storage at ambient/controlled room temperature.

Table 1.7 Typical quality attributes critical to stability performance for oral and parenteral products.

Table 1.8 Typical quality attributes critical to stability performance for different types of inhalation products.

Table 1.9 Example “global” protocol.

Chapter 02

Table 2.1 Additional tests to consider when evaluating photosensitivity.

Table 2.2 Advantages and disadvantages of Option 1 and Option 2.

Table 2.3 Methods of measuring light power.

Chapter 03

Table 3.1 Example of a bracketing design.

Table 3.2 Matrix designs for two strengths.

Table 3.3 Matrix design for 3 strengths and 3 packs.

Table 3.4 Degree of reduction in bracketing and matrixing.

Table 3.5 Example 1: A matrixed design for conventional tablets 1 mg.

Table 3.6 Example 2: A matrixed design for conventional tablets 200, 400, and 600 mg.

Table 3.7 Example 3: A design for metered‐dose inhaler with four strengths.

Table 3.8 Example 2: A matrixed design for conventional tablets, new API.

Table 3.9 Effects of matrixing upon shelf‐life estimations.

Chapter 04

Table 4.1 Accelerated stability data obtained for “product D.”

Table 4.2 Kinetic expressions for some common solid‐state degradation processes.

Table 4.3 Degradation product data obtained for product G.

Table 4.4 Degradation product data obtained for product H.

Chapter 05

Table 5.1 Definitions provided by ICH Q2(R1) and other statutory agencies.

Table 5.2 ICH Q2(R1) [1] requirements for different methods.

Table 5.3 Global regulatory criteria for method validation.

Chapter 06

Table 6.1 Reporting, identification, and qualification thresholds for DS and DP.

Table 6.2 Thresholds for antibiotics: DS and DP.

Chapter 07

Table 7.1 Class 1 solvents included in Q3C(R5).

Table 7.2 Class 2 solvents included in Q3C(R5).

Table 7.3 Class 3 solvents included in Q3C(R5).

Table 7.4 Physiological parameter values used in calculation of PDEs.

Table 7.5 Solvents listed in Q3C(R5) but not assigned a PDE.

a

Chapter 08

Table 8.1 Permitted daily exposures for elemental impurities.

Table 8.2 Elements to be considered in the risk assessment.

Table 8.3 Formulation composition and excipient source.

Table 8.4 Typical processing operations used in drug product manufacture and their potential impact and associated cGMP controls.

Table 8.5 Case study formulation.

Table 8.6 Formulation composition.

Table 8.7 Proposed testing.

Chapter 09

Table 9.1 General chapters identified for harmonization.

Table 9.2 General chapters with some specific implementation guidelines.

Table 9.3 Current harmonization status of pharmacopoeial general chapters (USP, 2016).

Table 9.4 Current harmonization status of pharmacopoeial excipient monographs (USP, 2016).

Chapter 10

Table 10.1 Tests performed on cell banks.

Table 10.2 Examples of detector cell lines used in

in vitro

virus screening assays.

Table 10.3 Hemagglutinin characteristics of some virus types.

Table 10.4 Susceptibility of various laboratory animals to viruses.

Table 10.5 Panels of PCR tests recommended for different production cell types.

Table 10.6 Viral detection tests performed on “unprocessed bulk.”

Table 10.7 Downstream purification steps with viral clearance capability.

Table 10.8 Particle size ranges for model viruses from different families.

Chapter 11

Table 11.1 Summary of testing expectations per ICH Q5B.

Chapter 12

Table 12.1 Common degradation pathways for therapeutic proteins and associated analytical methods.

Table 12.2 Commonly used accelerated and stress conditions for biologics.

Table 12.3 Long‐term stability data for a hypothetical drug product held at the recommended storage condition.

Table 12.4 Possible outcomes for shelf‐life determination from statistical analysis of data from three hypothetical product lots.

Table 12.5 ANOCOVA test of the hypothesis of equal slopes for % purity versus time for three hypothetical drug product lots.

Table 12.6 ANOCOVA test of the hypothesis of equal

y

‐intercepts for % purity versus time for three hypothetical drug product lots.

Table 12.7 Summary of analysis of individual lots with root mean square error (

s

Assay

).

Table 12.8 Pooled slope estimate (

b

) and standard error of the slope (

s

b

).

Chapter 13

Table 13.1 Cell bank adventitious agent testing for a Chinese hamster ovary production cell.

Chapter 15

Table 15.1 Hierarchy of comparability testing.

Table 15.2 Case study 1: comparability protocol tests and acceptance criteria.

Chapter 16

Table 16.1 ICH Q6A general concepts.

Table 16.2 ICH Q6A additional specific tests for APIs.

Table 16.3 Additional specific tests for drug products (solid oral dosage forms).

Table 16.4 Additional specific tests for drug products (liquid/semisolid dosage forms).

Table 16.5 Overview of requirements for extractable/leachable testing.

Table 16.6 Process capability and out‐of‐specification (OOS) outcomes.

Chapter 17

Table 17.1 Analytical methods used for determining structure of therapeutic proteins.

Table 17.2 Quality attributes and tests typically associated with a therapeutic protein product.

Table 17.3 Drug product specifications for an early‐phase monoclonal antibody product derived from CHO cells.

Table 17.4 Evolution of DS specification for a plasmid product.

Chapter 18

Table 18.1 Examples of scoring of severity, occurrence, and detectability during a risk assessment to determine the need for specification testing.

Table 18.2 Toxicology‐based permissible daily exposures (PDEs) for process reagents.

Table 18.3 Determining the need for clearance testing.

Table 18.4 Hypothetical process capacity to remove process‐related impurities.

Chapter 19

Table 19.1 Application of this guidance to API manufacturing (from ICH Q7A).

Chapter 20

Table 20.1 Technical specifications for an immediate release tablet as part of QTPP.

Table 20.2 Process technology for granulation or tablet manufacturing and potential parameters to be considered in‐process selection.

Table 20.3 Composition of the MCC‐based roller compaction formulation.

Table 20.4 Platform data output and PLS regression model performance.

Table 20.5 Platform and test compound property comparison.

Table 20.6 Results from roller compaction of the test formulation including CIPA predictions from the platform.

Chapter 21

Table 21.1 Quality risk management definitions.

Table 21.2 Risk identification techniques.

Table 21.3 Risk reduction tools.

Table 21.4 Pros and cons of principal risk‐based tools.

Table 21.5 Rank ordering of shelf‐life limiting attributes (SLLA).

Table 21.6 SRA output.

Chapter 22

Table 22.1 GSP document implementation.

Table 22.2 Inspection focus areas and elements.

Table 22.3 Potential opportunities to enhance science‐ and risk‐based regulatory approaches.

Chapter 24

Table 24.1 Impurities classification with respect to mutagenic and carcinogenic potential and resulting control actions.

Table 24.2 Tests to investigate the

in vivo

relevance of

in vitro

mutagens (positive bacterial mutagenicity).

Table 24.3 Acceptable intakes (AIs) or permissible daily exposures (PDEs) for mutagenic carcinogens.

Table 24.4 Acceptable intakes for alkyl bromides.

Table 24.5 Acceptable intakes for an individual impurity.

Table 24.6 Acceptable total daily intakes for multiple impurities.

Table 24.7 Purge values.

List of Illustrations

Chapter 01

Figure 1.1 Factors potentially affecting product stability.

Figure 1.2 Free energy diagram for a degradation reaction.

Figure 1.3 Components of the Arrhenius plot.

Figure 1.4 Calculation of

t

90

for a specific degradation reaction, using a high and low estimate for activation energy (

E

a

).

Figure 1.5 Automated system for rapid stability screening.

Figure 1.6 Example degradation “map.”

Figure 1.7 Statistical calculation of shelf life.

Figure 1.8 Aspects of stability testing during the development lifecycle.

Chapter 02

Figure 2.1 ICH Q1B flowchart.

Figure 2.2 Spectral power distribution of a xenon lamp that simulates outdoor or window‐filtered sunlight.

Figure 2.3 Relative spectral power distributions of various representative fluorescent lamps plotted from published CIE data. F2 represents a cool white fluorescent source that is compliant with ICH Q1B Option 2; F7 represents a typical “broadband” fluorescent source; and F11 represents a triphosphor or three‐band cool white fluorescent source. The inset shows the spectral power distribution of one source (F2) relative to daylight (D65).

Figure 2.4 The effect of sample quantity.

Figure 2.5 A possible pack to test a single layer of tablets in a pack.

Figure 2.6 The effect of sample positioning.

Figure 2.7 Power distribution within an Option 1 cabinet.

Figure 2.8 Impact of different illuminances (rate) on extent of degradation.

Figure 2.9 Effect of light source.

Figure 2.10 Color fade of blue capsules in light—effect of humidity. Capsules contained 0.147% indigo carmine. Delta

E

represents the total color change from initial as determined by tristimulus colorimetry.

Figure 2.11 Effect of film coat color on tablet temperature. Typical temperature difference (°C) between a black sample and colored samples (after Boxhamer).

Figure 2.12 Effect of photo exposure on tablet hardness.

Figure 2.13 Assessment of the need for phototoxicity testing.

*

“Otherwise”: data do not support low potential for phototoxicity or have not been generated (assay/test/evaluation not conducted).

#

A “negative” result in an appropriately conducted

in vivo

phototoxicity study supersedes a positive

in vitro

result. A robust clinical phototoxicity assessment indicating no concern supersedes any positive nonclinical results. A positive result in an

in vitro

phototoxicity test could also, on a case‐by‐case basis, be negated by tissue distribution data (see text). In the United States, for products applied dermally, a dedicated clinical trial for phototoxicity on the to‐be‐marketed formulation can be warranted in support of product approval.

$

Clinical evaluation could range from standard reporting of adverse events in clinical studies to dedicated clinical photosafety trial.

§

Tissue distribution is not a consideration for the phototoxicity of dermal product.

Chapter 04

Figure 4.1 A graphical representation of Equation 4.7 in which log(degradation rate) varies linearly with 1/

T

and %RH and with no temperature–humidity interaction effects.

Figure 4.2 Arrhenius plot obtained for drug product A in which the effect of temperature appears to be essentially independent of relative humidity and log

k

appears to increase proportionally with relative humidity.

Figure 4.3 Log

k

versus relative humidity for product A, obtained at constant temperature (70°C), in which log(degradation rate) appears to be linearly proportional to the relative humidity.

Figure 4.4 Log

k

versus relative humidity obtained at constant temperature (60°C), in which log(degradation rate) appears to be linearly proportional to the water vapor pressure.

Figure 4.5 Relationship between degradation rate and oxygen headspace level for “product B.”

Figure 4.6 The humidity and temperature sensitivity of about 60 products.

Figure 4.7 The rate of change of the humidity inside packaging depends on packaging permeability, the moisture sorption properties, and the amount of the material inside the packaging.

Figure 4.8 The humidity inside 60 cc HDPE bottles, containing a 1 g silica desiccant and variable numbers of tablets.

Figure 4.9 Accelerated stability data from product D (Table 4.1) presented as an Arrhenius plot. The points clustered at A are 80°C/40% RH data, B are 70°C/75% RH data, C are 70°C/10% RH data, D are 60°C/40% RH data, and E are 50°C/75% RH data. The dotted lines are the Arrhenius plots expected at different relative humidity levels based on Equation 4.7.

Figure 4.10 Predicted long‐term degradation behavior for product D when three different strengths are packaged in 30 count HDPE bottles and stored at 30°C/75% RH. The log

A

,

E

a

, and

B

information from the accelerated stability study (Table 4.1 and Figure 4.11) can be used to transform the “%RH in packaging” information into degradation information.

Figure 4.11 Extent of degradation observed after 1 month’s storage at 80°C/40% RH when API “E” is mixed with microcrystalline cellulose in different ratios; approximately 40 different mixtures were measured. The curve‐labeled “model” shows the levels predicted in Equation 4.17.

Figure 4.12 Degradation versus time curves obtained for product F at different temperatures, but under constant relative humidity. (a) The raw data. (b) The same data but with the time axis adjusted showing that the data from different conditions lie on the same overall shaped curve.

Figure 4.13 Degradation versus time curves obtained for product F under different temperature and humidity conditions. (a) The raw data. (b) The same data but with the time axis adjusted showing that the data from different conditions do not lie on the same overall shaped curve.

Figure 4.14 Degradation versus time curves obtained for product G. (a) The data rounded to 2 decimal places. (b) The same data rounded to 1 decimal place.

Figure 4.15 Degradation versus time curves obtained for product H. (a) The data rounded to 2 decimal places. (b) The same data rounded to 1 decimal place.

Chapter 05

Figure 5.1 Analytical factor evaluation.

Figure 5.2 Fishbone diagram for GC‐FID method factors with enlarged method section.

Chapter 06

Figure 6.1 Examples of how ICH Q3A [1] and ICH M7 [5] interact for assessment of impurities in the DS. The examples are divided into two scenarios, one dealing with potential impurities (scenario 1) and one dealing with actual impurities (scenario 2). Indicated on the

y

‐axes are the ranges for (relative/absolute) amounts of impurities/degradants in the DS, as well as the various thresholds (TH). The TTC in this context relates to the relevant acceptable intake level as defined in ICH M7 [5], the 1.5 µg/day level being the most conservative one.

Figure 6.2 Example for qualification of a known impurity in case the clinical batch and the batch for supportive toxicity studies are different.

Figure 6.3 Adapted qualification process scheme incorporating details of ICH M7 and of other sections that may not be based on guidelines of the existing ICH Q3A and Q3B schemes.

Figure 6.4 Illustration of factors that affect the revenue of a product.

Chapter 08

Figure 8.1 ICH Q3D risk assessment process.

Figure 8.2 Potential sources of elemental impurities in finished drug products.

Figure 8.3 Primary potential sources of EIs in drug substance (DS).

Figure 8.4 Mycophenolic acid.

Figure 8.5 Potential risk associated with excipients based on material source.

Figure 8.6 Summary of results from Jenke et al. [24] review.

Figure 8.7 Visible comparison of nozzles before and after use.

Figure 8.8 Relationship between product risk assessment outcomes and control strategy.

Figure 8.9 Modified IPEC questionnaire.

Figure 8.10 Daily dose calculator.

Figure 8.11 Relationship between training modules and EI risk assessment process.

Figure 8.12 Preliminary risk assessment.

Figure 8.13 API manufacturing process.

Figure 8.14 Manufacturing process.

Figure 8.15 FMECA.

Chapter 09

Figure 9.1 Pharmacopoeial harmonization process.

Figure 9.2 ICH Q4 implementation considerations.

Chapter 10

Figure 10.1 Safety testing triangle for biologicals. .

Figure 10.2 Electron micrographs of CHO cells demonstrating A‐ and C‐type particles.

Figure 10.3 An example of a viral clearance study. Five steps are investigated: one inactivation step (low pH) and four removal steps. Four model viruses are used (retrovirus, herpesvirus, parvovirus, and adenovirus).

Figure 10.4 ICH Q5A(R1) in practice. Virus entry points are displayed in boxes. The primary threats are those impacting the upstream (cell culture process). Operator and environmental threats are best mitigated through the use of closed processes. HTST, high temperature/short time treatment; UV, ultraviolet irradiation. The downstream process includes viral clearance steps.

Chapter 11

Figure 11.1 Overall strategy for the development of a mAb‐expressing production cell.

Figure 11.2 A schematic component map for a mAb expression vector. Amp R, ampicillin resistance; HC, heavy chain; LC, light chain; mAb, monoclonal antibody; poly A, polyadenylation; Puc, plasmid cloning vector pUC; puro, puromycin.

Chapter 12

Figure 12.1 Structural features of a therapeutic antibody.

Figure 12.2 Representative scheme of Asn deamidation pathway. (Figure is from Wikipedia [27].)

Figure 12.3 Plots of long‐term stability data for three lots of a hypothetical drug product.

Figure 12.4 Linear regression analysis and application of the 90% confidence interval for three drug product lots.

Figure 12.5 Purity monitored over 26 months (assigned shelf life) for a manufactured lot with a release purity outside of the distribution of the three stability lots used to assign the shelf life.

Figure 12.6 Minimum purity release specification to assure meeting a shelf‐life requirement of 24 months. Arrows represent the estimated loss in purity by 24 months on stability and the combined slope and release assay variabilities.

Chapter 13

Figure 13.1 Demonstration of monoclonality using a well plate imaging technology.

Chapter 14

Figure 14.1 Calculation of theoretical maximum viral load per patient dose.

Figure 14.2 Example of a raw materials assessment tool that may be used as part of an ADM assessment program.

Figure 14.3 Some of the elements of an overall adventitious agent safety assessment for a manufacturing process and associated concerns. The arrow indicates the temporal relationship between the various factors (i.e., upstream manufacturing vs. downstream processing and finally patient profile and dosing).

Chapter 15

Figure 15.1 Comparability assessment; possible outcomes.

Figure 15.2 Typical forms of protein heterogeneity [11].

Figure 15.3 Factors influencing comparability complexity: stage of product development and impact of the change to critical product quality.

Chapter 16

Figure 16.1 Schematic showing ICH Q6A general concepts.

Figure 16.2 Scanning electron microscopy pictures of polymorphs of a drug substance (showing pronounced differences in habit).

Figure 16.3 ICH Q6A decision tree overview

Figure 16.4 Schematic showing impact of impurities, process capability, and method capability on the allowable API specification variability.

Figure 16.5 Specifications complying with simple acceptance criteria.

Figure 16.6 Specifications using acceptance criteria, (a) relaxed acceptance (test for nonconformity) and (b) stringent acceptance (test for conformity).

Chapter 17

Figure 17.1 Four levels of protein structure.

Figure 17.2 Demonstration of size variants using SEC‐HPLC (a) and SDS‐PAGE (b) and charge variants using CEX‐HPLC (c) and cIEF (d).

Chapter 18

Figure 18.1 Safety margin (

S

e

or

S

m

) as a criterion to determine the requirement for clearance and specification testing for PSC reagents at process development (PD), process characterization (PC), process validation (PV), and commercial production stages.

Figure 18.2 Procedure for determining the need for reagent clearance and specification testing at the PD, PC, PV, and commercial production stages.

Chapter 20

Figure 20.1 The

project management triangle

and the three constraints on a project deliverable impacting on product quality (resource, time, and scope).

Figure 20.2 Elements of a pharmaceutical technology platform.

Figure 20.3 Simplification of a platform technology. Knowledge captured in the platform covers quality attributes that are primarily affected by the excipients. API dependent properties (e.g., dissolution, stability) are explored in more detail as a part of an actual NCE product development.

Figure 20.4 Illustration of how the formulation platform is applied to NCE formulation development. Output from the formulation strategy triggers application of the platform.

Figure 20.5 Illustration of the stages during QbD formulation development, leading up to a final formulation that delivers the desired QTTP and is technically feasible to manufacture. Public as well as prior knowledge is utilized in the strategies behind the selection of process technology and excipients, while a platform technology is based solely on in‐house practical experience, that is, prior knowledge. First‐principles models are incorporated throughout all three stages.

Figure 20.6 Selection criteria of process technology based on median volume particle size (

d

50

) of the drug substance (regular shaped crystals) and the relative tablet dose % w/w.

Figure 20.7 Variations in content of uniformity displayed by the relative standard deviation between tablet assays sampled over 100 min of total tableting time. Two tablets have been analyzed for content every 10 min. Maximum allowed content RSD is 4% indicated by a dashed line.

**

Punch‐face adhesion observed.

X

‐axis represents median volume particle size of the API.

Figure 20.8 Illustration of a roller compactor (Gerteis model). 1, powder feeding; 2, compaction; 3, size reduction/milling (granulator).

Figure 20.9 Examples of critical input and output variables for roller compaction (RC) process and their mutual relationship.

Figure 20.10 The principle of dry granulation using roller compaction (RC). Critical process parameters (CPP) and selected in‐process quality attributes (CIPA) are shown. CPPs include force, gap and roll speed, whereas CIPAs preblend and ribbon porosity. Note: Actual rolls on the Mini‐Pactor are inclined.

Figure 20.11 Illustration of the approach taken to develop the MCC‐based RC platform formulation. The granulation knowledge space is constructed through a CCF optimization design. The derived CIPA predictive equations are used to calculate optimal process settings providing granules of acceptable quality. The resulting granulate is compressed into tablets from which the tablet knowledge space is independently generated.

Figure 20.12 Design space regions for the MCC‐based platform formulation at a 28% w/w API intra‐granular load. Stars indicate the process parameter settings applied to the test compound. The design space for the 9% w/w granulate is not shown. OOS, out of specification.

Figure 20.13 Response surface plots of specific crushing strength (SCS) (i.e., hardness normalized against tablet cross sectional area) for the (a) 9% granulate and (b) 28% using the test substance.

Figure 20.14 Summary of the construction and application of the roller compaction platform. POC, proof of concept. At this early stage of NCE formulation development it is known whether the API can be processed by roller compaction at a larger scale.

Figure 20.15 Relationship between ribbon porosity and granule geometric mean size (µm) of five batches each of the 9 and 28% w/w (API) blends described in previous sections. All granulates were subdivided prior to sieve analysis to ensure representative sampling and the most accurate determination of

D

gw

.

Figure 20.16 Scale‐comparable front view of Gerteis’ (a) Mini‐Pactor and (b) Macro‐Pactor roller compactors. The rolls—and thus the ribbons—are four times wider for the Macro‐Pactor as shown in the bottom of the picture.

Figure 20.17 Column charts (top) and scatter plots (bottom), the latter confirming a 1 : 1 relationship between the porosity of ribbons acquired from the Mini‐ and Macro‐Pactor at identical gap and roll force.

Chapter 21

Figure 21.1 Outline of a typical QRM process.

Figure 21.2 Fishbone (cause and effect) diagram highlighting potential hazards (that could lead to a microbiological contamination risks) in an aseptic process.

Chapter 22

Figure 22.1 Diagram of the ICH Q10 pharmaceutical quality system model.

Figure 22.2 PQS document implementation map.

Figure 22.3 Document hierarchy.

Figure 22.4 Innovation and continual improvement document nesting.

Figure 22.5 End‐to‐end development.

Figure 22.6 Flow diagram of change management for clinical development.

Figure 22.7 Discrepancy policy documents nesting.

Figure 22.8 Preliminary assessment of discrepancies.

Figure 22.9 Deviation management process flow.

Figure 22.10 An example of qualitative risk evaluation.

Figure 22.11 Quality risk management process flow.

Figure 22.12 The utilization of four QRAs at different stages of pharmaceutical development of small molecule.

Figure 22.13 An example of the summary of QRA2 used to identify the CMAs and CPPs that impact drug product pCQAs.

Figure 22.14 Components of the product history file.

Figure 22.15 Product and process knowledge management program.

Chapter 24

Figure 24.1 Interrelationship between degradant classes.

Figure 24.2 Potential sources of mutagenic impurities.

Figure 24.3 Decision matrix when evaluating two

in silico

predictions.

Figure 24.4 Synthetic route utilizing allyl bromide and bromopropylamine.

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ICH Quality Guidelines

An Implementation Guide

Edited by

Andrew Teasdale

AstraZeneca, London, UK

David Elder

Consultant (Former GSK), Hertford, Hertfordshire, UK

Raymond W. Nims

RMC Pharmaceutical Solutions, Inc., Longmont, CO, USA

This edition first published 2018© 2018 John Wiley & Sons, Inc.

All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by law. Advice on how to obtain permission to reuse material from this title is available at http://www.wiley.com/go/permissions.

The right of Andrew Teasdale, David Elder, and Raymond W. Nims to be identified as the editors of this work has been asserted in accordance with law.

Registered OfficeJohn Wiley & Sons, Inc., 111 River Street, Hoboken, NJ 07030, USA

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For details of our global editorial offices, customer services, and more information about Wiley products visit us at www.wiley.com.

Wiley also publishes its books in a variety of electronic formats and by print‐on‐demand. Some content that appears in standard print versions of this book may not be available in other formats.

Limit of Liability/Disclaimer of WarrantyIn view of ongoing research, equipment modifications, changes in governmental regulations, and the constant flow of information relating to the use of experimental reagents, equipment, and devices, the reader is urged to review and evaluate the information provided in the package insert or instructions for each chemical, piece of equipment, reagent, or device for, among other things, any changes in the instructions or indication of usage and for added warnings and precautions. While the publisher and authors have used their best efforts in preparing this work, they make no representations or warranties with respect to the accuracy or completeness of the contents of this work and specifically disclaim all warranties, including without limitation any implied warranties of merchantability or fitness for a particular purpose. No warranty may be created or extended by sales representatives, written sales materials or promotional statements for this work. The fact that an organization, website, or product is referred to in this work as a citation and/or potential source of further information does not mean that the publisher and authors endorse the information or services the organization, website, or product may provide or recommendations it may make. This work is sold with the understanding that the publisher is not engaged in rendering professional services. The advice and strategies contained herein may not be suitable for your situation. You should consult with a specialist where appropriate. Further, readers should be aware that websites listed in this work may have changed or disappeared between when this work was written and when it is read. Neither the publisher nor authors shall be liable for any loss of profit or any other commercial damages, including but not limited to special, incidental, consequential, or other damages.

Library of Congress Cataloging‐in‐Publication Data

Names: Teasdale, Andrew, editor. | Elder, David (David P.), editor. | Nims, Raymond W.Title: ICH quality guidelines : an implementation guide / edited by Andrew Teasdale, AstraZeneca, London, United Kingdom, David Elder, Consultant (fGSK), Hertford, Hertfordshire, SG14 2DE, United Kingdom, Raymond W. Nims, RMC Pharmaceutical Solutions, Inc., Longmont, CO, USA.Other titles: International Conference on Harmonization quality guidelinesDescription: First edition. | Hoboken, NJ : Wiley, 2018. | Includes bibliographical references and index. |Identifiers: LCCN 2017013162 (print) | LCCN 2017014318 (ebook) | ISBN 9781118971123 (pdf) | ISBN 9781118971130 (epub) | ISBN 9781118971116 (hardback)Subjects: LCSH: Drug development. | Drugs–Testing. | Drugs–Quality control. | BISAC: MEDICAL / Pharmacology. | TECHNOLOGY & ENGINEERING / Quality Control. | SCIENCE / Chemistry / Industrial & Technical.Classification: LCC RM301.25 (ebook) | LCC RM301.25 .I24 2018 (print) | DDC 615.1/9–dc23LC record available at https://lccn.loc.gov/2017013162

Cover image: © Yagi Studio/GettyimagesCover design by Wiley

List of Contributors

Morten AllesøChemical and Pharmaceutical ResearchH. Lundbeck A/SValbyDenmark

Joel P. BercuGilead Sciences, Inc.Foster City, CAUSA

Phillip BormanGSKWareUK

Mette C. BryderChemical and Pharmaceutical ResearchH. Lundbeck A/SValbyDenmark

Jeanine L. BussiereAmgen Inc.Thousand Oaks, CAUSA

Patricia W. CashMedImmuneGaithersburg, MDUSA

David ClaphamDavid Clapham, Independent Pharmaceutical ConsultantHertfordshireUK

John ConnellyApoPharma IncorporatedToronto, OntarioCanada

John G. DaviesMedImmuneGaithersburg, MDUSA

David ElderDavid P Elder ConsultancyHertfordUK

Daniel GalbraithBioOursource Ltd.GlasgowUK

Di GaoAstraZenecaFrederick, MDUSA

Richard HarrisAstraZenecaFrederick, MDUSA

James HarveyGSKWareUK

Per HolmChemical and Pharmaceutical ResearchH. Lundbeck A/SValbyDenmark

René HolmChemical and Pharmaceutical ResearchH. Lundbeck A/SValbyDenmark

Yoen Joo KimMedImmuneGaithersburg, MDUSA

Kim LiAmgen Inc.Thousand Oaks, CAUSA

Zhong LiuMerck & Co. Inc.Kenilworth, NJUSAandCurrently at: Adello BiologicsPiscataway, NJUSA

Robert McCombieGenentech Inc.San Francisco, CAUSA

Raymond Peter MundenMunden ConsultancyRoystonUK

Gordon MunroMunro‐Elbrook AssociatesWelwynUK

Raymond W. NimsRMC Pharmaceutical Solutions, Inc.Longmont, COUSA

Ronald OgilviePfizerSandwichUK

Danny OoiGenentech, a Member of the Roche GroupSouth San Francisco, CAUSA

Mark PlavsicLysogeneCambridge, MAUSA

David PollardMerck & Co. Inc.Kenilworth, NJUSAandCurrently at: Amicus TherapeuticsCranbury, NJUSA

Qiang QinAstraZenecaFrederick, MDUSAandCurrent Affiliation: GlaxoSmithKlineRockville, MDUSA

Jinshu QiuAmgen Inc.Thousand Oaks, CAUSA

Anil RaghaniCoherus BioSciences, Inc.Camarillo, CAUSA

Ramani R. RaghavanMerck & Co., Inc.Rahway, NJUSA

Andy RignallAstraZenecaLondonUK

Scott R. RudgeRMC Pharmaceutical Solutions, Inc.Longmont, COUSA

Timothy L. SchofieldCurrent Affiliation: GlaxoSmithKlineRockville, MDUSAandMedImmuneGaithersburg, MDUSA

Garry ScrivensPfizerSandwichUK

Steven SpanhaakJanssen Pharmaceutica NVBeerseBelgium

Andrew TeasdaleAstraZenecaMacclesfieldUK

Sarah ThompsonAstraZenecaMacclesfieldUK

Larry WigmanGenentech, a Member of the Roche GroupSouth San Francisco, CAUSA

Jianxin YeCurrently at: Amicus TherapeuticsCranbury, NJUSAandMerck & Co. Inc.Kenilworth, NJUSA

Roujian ZhangAstraZenecaFrederick, MDUSA

An Introduction to ICH Quality Guidelines: Opportunities and Challenges

The International Conference on Harmonisation (ICH) of technical requirements for registration of pharmaceuticals for human use was initiated in April 1990. ICH had the initial objective of coordinating the regulatory activities of the European, Japanese, and the United States bodies (along with the pharmaceutical trade associations from these three regions), to discuss and agree the scientific and technical aspects arising from product registration. This was recently supplemented by the addition of Health Canada and Swissmedic, to the core ICH Steering Committee (SC) [1].

At the initial ICH SC meeting the terms of reference were agreed and it was decided that harmonisation initiatives would be divided into Safety (S), Quality (Q), and Efficacy (E), reflecting the main criteria which underpin the approval and authorization of new medicinal products. It was subsequently realised that several topics were multi‐disciplinary (M) in nature.

Thus, ICH’s mission was to realize greater harmonization in both the interpretation and application of requirements for new product registration, with the objective of minimizing repetition/duplication of both testing and reporting, which is routinely performed as part of the development of new medicinal products. Harmonizing these differences via the ICH guidelines would help industry reduce development times, save resources and benefit the patient.

It is difficult not to underestimate the benefits of the ICH initiative in general and the ICH Quality guidelines in particular (and those related Multi‐Disciplinary guidelines), to the CMC community. Although it is fair to state that not all of the guidelines have been equally successful; it is very clear that the majority have been very successful and there is an ongoing recognition of the need to update and maintain the guidance in line with new developments and technological advances. Furthermore, the desire to extend the benefits of harmonisation beyond the ICH regions through collaborative efforts is to be welcomed and brings us a step closer to global harmonisation of these important principles of medicinal product evaluation. As part of the objective to extend its global outreach, ICH recently welcomed new regulatory members from Brazil and South Korea. In addition regulatory authorities from Cuba, Kazakhstan, and South Africa were also agreed as ICH Observers [2].

The success of the ICH guidelines, in many ways has been due to the adoption of overarching principles and a guidance framework describing the main requirements for compliance without being overly prescriptive. Yet while varying levels of detailed information has been included in the different guidelines to facilitate understanding, it has left many seeking further clarification on the practical application of the guidance. The purpose and benefit of this book is that it allows the reader a deeper insight provided through dedicated chapters into the practical aspects of a specific guideline’s application.

Each of the chapters seeks to examine the key requirements of the specific guidelines and then considers the challenges both in interpretation and practical implementation. It is this perspective, looking behind the basic framework; and then examining both the intent and practical guidance that I believe will make this text an essential aid to those involved in CMC matters, both from an industry and regulators’ perspective.

To achieve the intended goal the Editors have pulled together an unrivalled collation of subject matter experts aligned to each chapter, many involved directly in the derivation of the ICH guidelines themselves.

Dr David Tainsh, Chief Product Quality Officer, GSK

References

1

SwissMedic. ICH Meeting in Minneapolis, USA: SwissMedic and Health Canada Included as New Members, July 9, 2014.

https://www.swissmedic.ch/aktuell/00673/02270/index.html?lang=en

. Accessed on February 27, 2017.

2

ICH. Press Release Osaka Meeting, November 17, 2016.

http://www.ich.org/ichnews/press‐releases/view/article/ich‐assembly‐osaka‐japan‐november‐2016.html

. Accessed on April 12, 2017.

1ICHQ1A(R2) Stability Testing of New Drug Substance and Product and ICHQ1C Stability Testing of New Dosage Forms

Andy Rignall

AstraZeneca, London, UK

1.1 Introduction

A core part of the medicines development process is an understanding of the chemical and physical behavior of the active ingredient and the medicinal product into which it is incorporated under the storage and usage conditions they are likely to encounter. The International Conference on Harmonisation of Technical Requirements for the Registration of Pharmaceuticals for Human Use (ICH) stability guidance provides a foundation and framework for this endeavor.

Stability testing was one of the first quality, safety, and efficacy topics harmonized across the ICH territories (Europe, USA, Japan, Canada, and Switzerland) in tripartite guidance. The latest revision of ICHQ1A Stability Testing of New Drug Substances and Products was adopted in 2003 [1]. It forms the parent guideline to a suite of associated guidelines providing more details on recommended stability practice. The guideline provides information on storage conditions and duration and testing requirements that should be used to generate the core stability data package in support of product registration in the ICH regions. To encompass the behavior of different drug delivery platforms and their input drug substances, the guideline contains some flexibility in the requirements. Importantly, the guideline also includes an introductory statement recognizing that alternative stability approaches can be used if scientifically justified. A short annex to the parent stability guideline is embodied in ICHQ1C, which addresses the stability requirements for a new dosage form when an applicant develops a new product variant following an original drug substance and drug product application [2].

As worldwide registration is the goal for many medicinal products, the standardization and simplification of the global supply chain for a new medicine, via harmonized stability and labeling practice, is desirable. While the intent of the guideline is to recommend the data sets required to register new drug substance and products in the three main ICH regions, its content is cited and used much more widely. The ICH guidelines are also referenced in territorial guidance beyond the ICH regions either on a stand‐alone basis or in support of local stability guidance. For example, the World Health Organization (WHO) is a long‐standing observer of the ICH process, leading to the incorporation of much of the content of the ICH into its own stability guidance [3].

The ICH stability guidance not only is intended for registration purposes but also informs stability practice during development, for example, the storage conditions described in the guidance can provide a framework for the development stability protocols used to underwrite the quality, safety, and efficacy of drug product used in clinical studies.

While the guidance embodies a traditional approach to stability protocols, the principles described in terms of the stability performance requirements for pharmaceutical products have also been translated into targets for predictive stability screening tools. These tools can provide assurance that when formal stability studies to support product registration are performed in accordance with ICH guidance, the likelihood of obtaining unexpected results is reduced.

Some stability testing requirements are linked with specific product platforms and are detailed in other guidance. Examples include instructions relating to studies that justify in‐use storage, strategies to demonstrate the suitability of protective secondary packaging, and specific studies to underwrite temperature excursions during storage and transportation.

In the “quality by design” era, where pharmaceutical development practice is guided by science‐ and risk‐based approaches, highlighted in three more recent ICH guidelines on pharmaceutical development [4], risk management [5], and pharmaceutical quality system [6], the focus for stability studies has evolved further to emphasize the importance of generating detailed stability knowledge and understanding. This may include establishing the attributes of the input materials (drug substance and excipient) and any processing parameters that are critical to stability performance. Following identification of the attributes critical to stability, an integrated control strategy should be established to ensure the attributes remain within acceptable limits, thereby assuring that the required stability performance is demonstrated. The use of risk management tools to ensure development activities are focused on the areas that will have the most influence on the control of stability (and therefore quality safety and efficacy) is also a feature.

From a practical perspective, the goal of performing stability testing on products intended for global registration remains challenging, requiring the development of a protocol that will result in a high probability of approval in all major markets. Regions with their own specific stability requirements can make the development of a truly “global” registration protocol more challenging. For example, the guidance on stability study requirements for the registration of drug products in countries forming the ASEAN region of Southeast Asia recommends a different long‐term storage condition compared with the ICH regions [7].

This chapter aims to provide an understanding of the fundamental principles behind stability testing and then demonstrate how the guidance is typically applied during pharmaceutical development.

1.2 The Fundamental Science That Underpins Stability Testing

1.2.1 The Stability Process

Quality, safety, and efficacy must be maintained throughout the shelf life of a medicine, from manufacture to the end of shelf life and when being used by the patient. This can be achieved by developing an understanding of the chemical and physical properties of the product so that it is possible to establish methods to control and monitor the critical parameters and establish the long‐term behavior of the drug substance and medicine.

The regulations require an expiry date on drug products or a retest date on active pharmaceutical ingredient [8]. For drug product, the expiry date defines the period within which the drug product is expected to comply with its approved control specification limits when stored under the recommended conditions. Similarly, a retest date is assigned to drug substance. If a drug substance batch is required for drug product manufacture beyond its labeled retest date, it should be retested to confirm continued compliance with specification prior to use. Stability testing provides the means to investigate how a medicine behaves under different environmental conditions and demonstrate that a pharmaceutical product maintains its fitness for use throughout this labeled shelf life. The stability testing of drug products involves evaluating them on storage over time in the container/closure system intended for use in the clinic or the commercial market.

The stability of a pharmaceutical product is the result of a complex interplay between environmental factors (temperature, humidity, availability of oxygen, and exposure to light), and the intrinsic chemical and physical stability of active ingredients and formulation excipients. The conditions under which these ingredients are processed to form the medicine, and the degree of protection provided by any primary and secondary packaging are also influencing factors.

The stability process involves finding out what degradation pathways are available to a new chemical entity, what steps can be taken to assess the extent of degradation most likely to be encountered under normal storage, and what strategies are available to prevent or limit any observed degradation. Chemical breakdown constitutes a major factor in drug or formulation failure on storage, but physical, biological, and microbiological changes can also be a source of instability.

Chemistry driven changes include changes in product quality or product performance characteristics caused by

Increase in levels of degradation products with potential impact on safety

Potency loss associated with chemical breakdown/reaction of active ingredient with potential impact on efficacy

Change in visual, taste, or odor caused by increased levels of degradation, with potential impact on overall product acceptability

The extent of chemical breakdown does not need to be significant for potential problems to occur, for example, formation of low levels of a breakdown product that gives rise to specific safety concerns or small amounts of a highly colored degradation product affecting visual appearance.

1.2.2 Factors Affecting Stability

Demonstrating stability knowledge and appropriate control involves developing an understanding of the factors that can affect the stability of a medicine and confirming that appropriate controls are in place to assure quality, safety, and efficacy throughout the labeled shelf life. These factors include

The intrinsic stability of the active pharmaceutical ingredient(s)

Input excipient properties and how they affect the stability of the API

The unit operations associated with the manufacturing process

Environmental factors (external, internal, and microenvironment)

The materials and functionality associated with any packaging system

Further factors affecting product stability are outlined in Figure 1.1

Figure 1.1 Factors potentially affecting product stability.

1.2.2.1 Intrinsic Stability of the Active Pharmaceutical Ingredient