# Presentation: 672191

## CASSS CONFERENCESan Francisco, CAJanuary 10, 2000

**ICH UPDATE - QUALITY**
**Yuan-yuan Chiu, Ph.D.**
**Acting Director**
**Office of New Drug Chemistry**
**CDER, FDA**

## DISSCUSION AREAS

**Background**
**Guidelines issued as Step 4 or 5 documents in 1999**
**Guidelines under development**
**Guidelines under revision or maintenance**
**Future of ICH**

## ICH MEMBERS

_**Regulatory Agencies**_**:  FDA, EU/EMEA & MHW**
**	****      ****[TPP and WHO; Pharmacopeias in 1998]**
_**Trade Associations**_**:  PhRMA, EFPIA and JPMA**
**                            ****[EFTA;  IGPA and WSMI in 1998]**

** **
**   **

## ICH STRUCTURE/MEETINGS

**Conferences:  ****Brussels (1991), Orlando (1993), **
**               ****Yokohama (1995) and Brussels (1997)**

_**STEERING CMTE**_
**Members**
**Observers**
**ICH Secretariat**
**(IFPMA)**
**ICH  Coordinators**

_**EWGs**_
**Topic Leaders**
**Deputy Topic Leaders**
**Observers**
**Topic Rapporteur**
**Regulatory Rapporteur**

## HARMONIZATION TOPICS

**Q - Quality**
**S - Safety (preclinical)**
**E - Efficacy (clinical safety and efficacy)**
**M - Multi-disciplinary**

## ICH PROCESS

**Step 1:  Concept Paper; Guideline Development **
**	****  ****Through EWG Scientific Consensus**
**	**
**Step 2:  EWG and Steering Cmte Guideline “Sign Off”**
**Step 3:  Public Comments Requested and Reviewed;**
**	****  ****Draft(s) Revised by Regulators**
**	**
**Step 4:  Regulatory Parties of EWG and Steering Cmte **
**	****  “****Sign Off”;  Finalized ICH Guideline**
**Step 5:  Implementation in Three Regions**
**	**

## ICH QUALITY TOPICS

**Q1****	****	****Stability**
**Q2****	****	****Analytical Procedures**
**Q3****	****	****Impurities**
**Q4****	****	****[Pharmacopeia]**
**Q5****	****	****Biotechnological/Biological products**
**Q6****	****	****Specifications**
**Q7****	****	****GMPs**
**M4****	****Common Technical Document**

## Guidelines Finalized: Stability

**Q1A****	****Stability Testing of New Drug ****	****	****	****	****Substances and Products            ****	****	****	****Step 4 (Oct ‘93), Step 5 (Sep ‘94)**
**Q1B****	****Photostability Testing of New Drug ****	****	****	****Substances and Products****	****	****	****	****	****Step 4 (Nov ‘96), Step 5 (May ‘97)**
**Q1C****	****Stability Testing for New Dosage Forms****	****	****Step 4 (Nov ‘96), Step 5 (May ‘97)**

## Guidelines Finalized: Analytical

**Q2A****	****Validation of Analytical Procedures: ****	****	****Definitions and Terminology****	****	****	****	****Step 4 (Oct ‘94), Step 5 (Mar ‘95)**
**Q2B****	****Validation of Analytical Procedures:****	****	****	****Methodology****	****	****	****	****	****	****	****Step 4 (Nov ‘96), Step 5 (May ‘97)**

## Guidelines Finalized: Impurities

**Q3A****	****Impurities in New Drug Substances****	****	****	****Step 4 (Mar ‘95), Step 5 (Jan ‘96)**
**Q3B****	****Impurities in New Drug Products****	****	****	****Step 4 (Nov ‘96),  Step 5 (Nov ‘97)**
**Q3C****	****Impurities: Residual Solvents****	****	****	****	****Step 4 (Jul ‘97), Step 5 (Dec ‘97)**

## Guidelines Finalized: Biotechnology/Biological Products

**Q5A****	****Viral Safety Evaluation of ****	****	****	****	****Biotechnology Products Derived from ****	****	****Cell Lines of Human or Animal Origin****	****	****Step 4 (Mar ‘97), Step 5 (Sep ‘98)**
**Q5B****	****Analysis of the Expression Construct in ****	****	****Cells****	****Used for Production of r-DNA ****	****	****	****Derived Protein Products****	****	****	****	****	****Step 4 (Nov ‘95), Step 5 (Feb ‘96)****	**

## Guidelines Finalized: Biotechnology/Biological Products

**Q5C****	****Stability Testing of ****	****	****	****	****	****	****Biotechnological/Biological Products****	****	****	****Step 4 (Nov ‘95), Step 5 (Jul ‘96)**
**Q5D****	****Derivation and Characterization of ****	****	****	****Cell****	****Substrates Used for Production ****	****	****of Biotechnological/Biological ****	****	****	****	****Products ****	****	****	****	****	****	****	****	****Step 4 (Jul ‘97), Step 5 (Sep ‘98)**

## Guidelines Finalized in 1999

**Q6A****	****Specifications: Test Procedures and ****	****	****	****Acceptance Criteria for New Drug ****	****	****	****Substances and New Drug Products: ****	****	****Chemical Substances****	****	****	****	****	****Step 4 (Oct ‘99), Step 5 (pending)**
**Q6B****	****Specifications: Test Procedures and ****	****	****	****Acceptance Criteria for****	****	****	****	****	****Biotechnological/Biological Products****	****	****	****Step 4 (Mar ‘99), Step 5 (Aug ‘99)**

## Q6A/B: Definition of Specification

**A list of tests, references to analytical procedures, and appropriate acceptance criteria which are numerical limits, ranges, or other criteria for the tests described**

## Highlights of Q6B

**Characterization**
**Specifications**
**Process Validation**
**GMP Compliance**

**Strength/Potency**
**Purity**
**Consistency**
**Identity**

## Q6B: Characterization

**Recognize product heterogeneity**
**Desired product, Product-related substances**
**Consider both biological activity and quantity**
**Purity**
**Impurities**
**Product-related impurities, Process-related impurities**
**Contaminates**
**Full characterization > batch QC testing**

## Q6B: Analytical Considerationsand Process Controls

**Distinguish reference standards from reference materials**
**Provide opportunity to eliminate impurity test when supported by suitable studies and verification at production scale**
**Define in-process acceptance criteria and action limits**

## Q6B: Setting Specifications

**Manufacturing data**
**Stability data**
**Analytical data of the preclinical and clinical materials**
**Analytical procedures including reference standard**
**[Impact on safety and efficacy]**

## Q6B: Other Considerationsin Setting Specifications

**Raw materials and excipient specification**
**Pharmacopoeial specifications**
**Release limits versus shelf-life limits**
**Statistical concepts**

## Q6A: Highlights #1

**Periodic or skip testing**
**In-process tests in lieu of release tests**
**Release tests performed during in-process**
**Excluding or replacing certain tests based on experience and data accumulated during development**
**Recognizing limited data available at filing**
**Parametric release**

## Q6A: Highlights #2

**Alternative procedures**
**Pharmacopeial tests and acceptance criteria**
**Evolving technologies**
**Impact of drug substance on drug product specifications**
**Decision trees**

## Q6A:  Decision Trees

**#1:  Establishing acceptance criterion for a    specified impurity in a new drug substance**
**#2:  Establishing acceptance criterion for a degradation product in a new drug product**
**#6:  Microbiological quality attributes of drug substance and excipients**
**#8:  Microbiological attributes of non-sterile drug products **

## Guidelines for Chemical/Biological Drugs under Development

**Q7A:  Good Manufacturing Practice for APIs (Drug Substance)****	****	****Step 1 (Apr ‘98)  **
**M4:  Common Technical Document (CTD-Q,  CTD-S, CTD-E) ****	****	****Step 2 (Oct ‘99)**

## Q7A: Scope

**Chemical manufacturing**
**API derived from plant**
**Extraction from animal**
**Biotech**
**Fermentation**
**Herbal drug preparations (comminuted or powdered)**
**Herbal drug preparations (extracts etc.)**

## Q7A: Format and Content #1

**1.  Introduction**
**2.  Quality management**
**3.  Personnel**
**4.  Building and facilities**
**5.  Process equipment**
**6.  Documentation and Records**
**7.  Materials management**

## Q7A: Format and Content #2

**8.  Production and in-process controls**
**9.  Packaging and labeling**
**10. Storage and distribution**
**11. Laboratory controls**
**12. Validation**
**13. Change control**
**14. Rejection and reuse of materials**

## Q7A: Format and Content #3

**15. Complaints and recalls**
**16. Contract manufacturers and laboratories**
**17. API agents, brokers, distributors, repackers, and relabellers**
**18. Special biotech consideration**
**19. APIs for clinical trials**
**20. Glossary**

## Q7A- GMP Concept

**GMP controls apply to all steps in the manufacturing process beginning with the use of starting materials**
**Only critical manufacturing steps are subject to process validation**

## Q7A: Special Biotech Consideration

**18.1  General**
**18.2  Fermentation**
**18.3  Harvesting**
**18.4  Purification**
**18.5  Reference to Q5A and Q6B**

## M4:  Common Technical Document

**Objective:  “Develop an ICH guideline to describe the elements for the format and content of that portion of the health **
**registration submission which contains all the data developed from the use of the harmonized ICH guidelines, as well as those individual regional guidelines which did not require harmonization.”**

## ICH M4-Q (CTD-Q) EWG: Participating Groups 

**MHW****	**
**JPMA**
**FDA**
**PhRMA**
**EU**
**EFPIA**

**TPP**
**WHO**
**IGPA**
**USP/EP**
**WSMI**

## CTD-Q:  Regulatory Challenges and Issues

-  **Different Regional Laws and                           ****	****Format/Content Regulations**
** ****Different Approval Processes**
** ****Q7A and other ICH Q Guidelines**

## Standard Format:  EU Dossier

**IB.  SUMMARY  OF  PRODUCT**
**       ****CHARACTERISTICS**

**IC.  EXPERT  REPORTS**

**II.  CHEMICAL, PHARM.,**
**      ****AND  BIOLOGICAL**
**      ****DOCUMENTATION**

**III.  PHARMACO.,**
**        ****TOXICOLOGICAL**
**        ****DOCUMENTATION**

**IV.  CLINICAL**
**        ****DOCUMENTATION**

**V.   SPECIAL**
**       ****PARTICULARS**

**SUMMARY****of the**
**DOSSIER**

**CORE**
**DOSSIER**

**Standard Format:  EU Dossier**

## EU Core Dossier (Part II):  

**Control Test on**
**Finished Product**

**Control Test on**
**Intermediates    **

**Control of      **
**Starting Materials**

**Method of **
**Preparation**

**Composition**

**Composition of Proprietary Product**

**Container**

**Clinical Trial Formula(e)**

**Development Pharmaceutics**

**Pre-formulation studies**

**Explanation of choice of composition**

**Compatibility with container/closure**

**Summary *****in vivo***** BA/BE studies**

**EU Core Dossier (Part II):  **
**Development Pharmaceutics**

## Responsibilities in the EU/FDA

**EU**

**USA**

**CORE**
**DOSSIER**

**EXPERT**
**REPORTS**

**REVIEW**

**NDA/BLA**

**REVIEW**

**REGULATORY**
**DECISION**

**REGULATORY**
**DECISION**

**KEY:**

**TECHNICAL EVALUATION**

**APPLICANT**

**REGULATION AUTHORITY**

**ILLUSTRATIVE**

**Responsibilities in the EU/FDA**
**Drug  Approval  Processes**

## Drug Approval: M4 & Q7A

**CTD-Q+S+E**

**GMPs**

**[DS(Q7) + DP]**

**APPLICATION APPROVAL**

## M4: CTD Modules

**Module I: Administrative Information and ****	****	****	****Product Labeling****	****	****	****	****	****	****A. Module I table of contents****	****	****	****	****B. Documents specific to each region**
**Module II: CTD Summaries****	****	****	****	****	****	****A.  CTD Table of content****	****	****	****	****	****B.  Executive summary of the CTD****	****	****	****C.  Quality tablulated summaries****	****	****	****D.  Nonclinical****	****	****	****	****	****	****	****E.  Clinical**

## M4:  CTD Modules

**Module III:  Quality data****	****	****	****	****	****	****	****A.  Table of content****	****	****	****	****	****	****B.  Body of data****	****	****	****	****	****	****C.  Key literature references**
**Module IV:  Nonclinical data****	****	****	****	****	****	****A.  Table of contents****	****	****	****	****	****	****B.  Study reports****	****	****	****	****	****	****C.  Key literature references**

## M4:  CTD Modules

**Module V:  Clinical data****	****	****	****	****	****	****	****A.  Table of content****	****	****	****	****	****	****B.  Study reports**
**Module VI:  Additional regional information****	****	****	****A.  Module VI Table of contents****	****	****	****B.  Information specific to each region****	****	****	**

## CTD-Q History

**DIA Workshop (Brussels) Sep 1988**
**AAPS Workshop (Arlington) Apr 1992**
**DIA Workshop (Noordwijk) Oct 1994**
**AAPS Workshop (Bethesda) Sep 1995**
**DIA Workshop (Philadelphia) Sep 1996**
**ICH 1997 (Brussels) CTD Topic Accepted**

## CTD-Q Document Format (Step 2)

**Scope:  Drug substances and their corresponding drug products as defined **
**in the scope of Q6A and Q6B**

## CTD-Q Document Format (Step 2)

_**Part **_**          **_** Data Module **_
**  ****S              Drug Substance**
**  ****P              Drug Product**
**  ****O             Other Information**
**	****	****(Refer to regional guidances)**
**  ****A             Appendices**

## CTD-Q Document Format (Step 2)

_**Part **_**          **_** Data Module **_
**  ****S              Drug Substance**
**  **_**S1**_**            General Information**
**    ****S1.1       Nomenclature**
**    ****S1.2       Structure**
**    ****S1.3       General Properties**

## CTD-Q Document Format (Step 2)

_**Part **_**          **_** Data Module **_
**   **_**S2**_** ****	****	****Manufacture**
**    ****S2.1****	****Manufacturer(s)**
**    ****S2.2       Description of the Manufacturing ****	****	****	****Process and Process Controls**
**    ****S2.3****	****Control of Materials**
**    ****S2.4****	****Control of Critical Steps and ****	****	****	****	****Intermediates**
**    ****S2.5****	****Process Validation or Evaluation**
**    ****S2.6****	****Manufacturing Process Development**

## CTD-Q Document Format (Step 2)

_**Part **_**          **_** Data Module **_
**   **_**S3**_** ****	****	****Characterization**
**    ****S3.1****	****Elucidation of Structure and/or ****	****	****	****Biological Characterization**
**    ****S3.2          Impurities**
**   **_**S4  **_**	****	****Control of Drug Substance**
**    ****S4.1****	****Specification**
**    ****S4.2****	****Analytical Procedures**
**    ****S4.3****	****Validation or Analytical Procedures**
**    ****S4.4****	****Batch Analysis**
-     **S4.5****	****Justification of Specification**

## CTD-Q Document Format (Step 2)

_**Part **_**          **_** Data Module **_
**   **_**S5**_** ****	****	****Reference Standards or Materials    **
**   **_**S6**__**	**_**	****Container Closure System**
**   **_**S7**__**	**__**	**_**Stability**
**    ****S7.1****	****Stability Summary & ****	****	****	****	****Conclusions**
**    ****S7.2****	****Post-approval Stability Protocol****	****	****and Stability Commitment **
**    ****S7.3****	****Stability Data**

## CTD-Q Document Format (Step 2)

_**Part **_**          **_** Data Module **_
**   ****P**_**	**__**	**_**Drug Product**
**   **_**P1**_** ****	****	****Description and Composition of ****	****	****the Drug Product    **
**   **_**P2**__**	**_**	****Pharmaceutical Development ****	****	****	****Report**

## CTD-Q Document Format (Step 2)

_**Part **_**          **_** Data Module **_
**    **_**P3**__**	**__**	**_**Manufacture**
**     ****P3.1****	****Manufacturer(s)**
**     ****P3.2****	****Batch Formula**
**     ****P3.3****	****Description of the Manufacturing ****	****	****Process and Process Controls**
**     ****P3.4****	****Controls of Critical Steps and ****	****	****	****Intermediates**
**     ****P3.5****	****Process Validation or Evaluation**

## CTD-Q Document Format (Step 2)

_**Part **_**          **_** Data Module **_
**    **_**P4**__**	**__**	**_**Control of Excipients**
**     ****P4.1****	****Specifications**
**     ****P4.2****	****Analytical Procedures**
**     ****P4.3****	****Valdn of Analytical Procedures**
**     ****P4.4****	****Justification of Specifications**
**     ****P4.5****	****Excipients (Human/Animal Origin)**
**     ****P4.6****	****Novel Excipients**

## CTD-Q Document Format (Step 2)

_**Part **_**          **_** Data Module **_
**    **_**P5**__**	**__**	**_**Control of Drug Product**
**     ****P5.1****	****Specification**
**     ****P5.2****	****Analytical Procedures**
**     ****P5.3****	****Valdn of Analytical Procedures**
**     ****P5.4****	****Batch Analyses**
**     ****P5.5****	****Justification of Specification**

## CTD-Q Document Format (Step 2)

_**Part **_**          **_** Data Module **_
**    **_**P6**__**	**_**	****Container Closure System**
**    **_**P7**__**	**__**	**_**Stability**
**     ****P7.1****	****Stability Summary & Conclusions**
**     ****P7.2****	****Post-approval Stability Protocol ****	****	****and Stability Commitment**
**     ****P7.3****	****Stability Data**

## CTD-Q Document Format (Step 2)

_**Part **_**          **_** Data Module **_
**    ****O**_**	**_**	****Other Information**
**     ****O1****	****Executed batch records (USA)**
**     ****O2****	****Method validation package (USA)**
**     ****O3****	****Comparability Protocols (USA)**

## CTD-Q Document Format (Step 2)

_**Part **_**          **_** Data Module **_
**    ****A**_**	**_**	****Appendices**
**     ****A1****	****Description of biotech facilities ****	****	****	****and equipment**
**     ****A2****	****Viral safety evaluation**

## Slide 54

## Q1 Stability Guidelines: Revision and New Topics

**Q1A: Revision**
**Q1D: Statistical Analysis and Data**
**Q1E:  Matrixing and Bracketing**

##  ICH Q1A Revision

** ****Low Temperature Storage (5°C, -20°C, & **
**   ****	****below -20****o****C)**
** ****Testing Conditions for Products in Semi-permeable       ****	****Containers (Long Term : 25°C/40% RH,  & ****	****	****Accelerated: 40°C/25% RH)**
** ****Accelerated Studies: Testing Intervals**
** ****Commitment Batches: Clarification**
**• ****Editorial Consistency**
**	****	****	****Step 2 (Oct 1999)**

## Q1 Stability Guidelines: Other Proposed New Topics

**Storage statement in labeling**
**Testing conditions for climatic zones III & IV**
**Site-specific stability data**
**Stability testing of generic drugs**
**Variations and changes**

## Q3A/B Maintenance

**Reporting thresholds (Q3A)**
**Discussions in Q6A Specifications (Q3B)**
**Pass/fail (e.g., 0.1%), principles of rounding (Q3A and Q3B)**
**Editorial consistency (Q3A and Q3B)**
**Step 2 (Oct 1999)**

## Q4: Pharmacopeial Harmonization of General Methods (USP, EP, JP)

**Sterility**
**Residue on ignition & sulfated ash**
**Bacterial Endotoxins **
**Color/Clarity**
**Particulate Matter**
**Extractable volume**

**Dissolution **
**Disintegration**
**Uniformity of mass**
**Uniformity of content**
**Microbial contamination**

## ICH 5:  San Diego, CANovember, 2000