ICH Developments

1. Our Motto
“Start to Finish
Every Thing in Between”
J. Ramniwas

2. Our Motto : “Start to Finish,
every thing in Between”
Updating on the latest developments
in ICH guidelines and applying learning
from recent experiences to speed-up
DMF filing process
By:
J.RAMNIWAS ( CEO)
SAI PHARMA SOLUTIONS INC. VADODARA(GUJARAT) INDIA
10/13/2012 J. Ramniwas 2

3. Our Motto : “Start to Finish,
every thing in Between”
Outline
 Introduction
 Latest Development in ICH Guidelines
 Speed up of DMF filing Process
 Specific Analytical Method Validation Requirements in US
 Challenging Areas in Analytical Validations
 Effective Sourcing Strategies
 Vendor Qualification Requirements
 Method Transfer Requirements at various sites
 Out of Trend and Out of specification issues
 Conclusion
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4. Our Motto : “Start to Finish,
every thing in Between”
INTRODUCTION
 Evolutionary changes in ICH Guidelines
 Science and Risk based Approach
 Quality by Design(QbD)
Design(QbD)
 Question Based Review( QbR)
 Paradigm shift in DMF filing
 Harmonization in Regulatory Process
 Pharmaceutical Development(ICH –Q8)
 Quality Risk Management( ICH-Q9)
ICH-
 Pharmaceutical Quality System(ICH-Q10)
System(ICH-
 Development and Manufacture of Drug Substances(ICH -Q11)
Substances(ICH-
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5. Our Motto : “Start to Finish,
every thing in Between”
The 2003 ICH Quality Vision
Industry parties and regulatory authorities of the ICH Quality met in
Brussels in July 2003 and agreed on the ICH Quality vision “A
harmonised pharmaceutical quality system applicable across the
lifecycle of the product emphasizing an integrated approach to risk
management and science”.
In order to develop a modern pharmaceutical quality system,
discussions on two topics, 1) Pharmaceutical Development (Q8) and
2) Quality Risk Management (Q9) started. The guidelines on the two
topics were published in 2006 in the three ICH regions.
(Pharmaceutical Quality System(Q10) reached final stage in
June’2008)
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6. Our Motto : “Start to Finish,
every thing in Between”
New vision and ICH Quality Guidelines
Q8~Q11
A harmonized pharmaceutical quality system
applicable across the lifecycle of the product
emphasizing an integrated approach to risk
management and science
Q8: Pharmaceutical Development
Q9: Quality Risk Management
Q10: Pharmaceutical Quality System
Q11: Drug substance development and
manufacturing (step 2)
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7. Our Motto : “Start to Finish,
every thing in Between”
Expected Outcome
For Industry
o Establishment of Quality Management System from
development to post-marketing
For regulatory authority
o Improvement of the approval review system by
integration of the review and the GMP inspection
oTo concentrate on higher risk products
oThe establishment of effective, efficient and streamlined
quality regulations
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8. Our Motto : “Start to Finish,
every thing in Between”
Latest Development in ICH Guidelines
Additional Q8/Q9/Q10 Points to Consider added on
the ICH website
(At Seville in November 2011, the ICH Quality
Implementation Working Group )
1. Criticality of Quality Attributes and Process Parameters
2. Control Strategy
3. Level of Documentation in Enhanced(QbD) Regulatory
Submissions
4. Role of Models in Quality by Design (QbD);
5. Design Space
6. Process Validation/Continuous Process Verification
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9. Our Motto : “Start to Finish,
every thing in Between”
Latest Development in ICH Guidelines
Q3D : Guidelines for Metallic Impurities
(Limiting metal impurities qualitatively and
quantitatively in drug products and ingredients) (July ‘2009)
The latest meeting of the group was in June 2011.
Current status of the discussion:
– The guideline will cover all products including biotech products,
but will exempt herbals, radiopharmaceuticals and conventional vaccines.
– The guideline will cover PDE and control strategy,
but will not cover testing strategy and analytical methods.
– The guideline will be applicable to new products,
but will not be applied to existing products and clinical trials.
– 2 sub-groups (safety assessment and control strategy) working simultaneously.
– The guideline will cover more elements than the EMA guideline (about 30! In total) and intends to cover the general risk of c ontamination with
metal impurities .
 State 2 document expected for June 2012.
 Adoption of the final guideline is not likely before 2014.
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10. Our Motto : “Start to Finish,
every thing in Between”
Latest Development in ICH Guidelines
Q10 Pharmaceutical Quality System
( June’2008 Final Guideline)
Product Life Cycle
1. Pharmaceutical Development
2. Technology Transfer
3. Manufacturing
4. Product Discontinuation
Quality System Elements:
1. Process performance and product quality monitoring
2. Corrective Action and Preventive Action( CAPA)
3. Change Management
4. Management Review of Process Performance and Product Quality
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11. Our Motto : “Start to Finish,
every thing in Between”
Latest Development in ICH Guidelines
Q11 Development and Manufacture of Drug Substances
(Chemical Entities and Biotechnological/Biological Entities)
(May’2011)
CTD sections
1. S 2.2 – Description of Manufacturing Process and Process Controls
2. S 2.3 – Control of Materials
3. S.2.4 – Control of Critical Steps and Intermediates
4. S.2.5 – Process Validation and or Evaluation
5. S.2.6 – Manufacturing Process Development
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12. Our Motto : “Start to Finish,
every thing in Between”
Outlook
• Preparation of an ICH API (chemical and biotechnological
origin) guideline (Q11) taking into account the concepts and
principles described in Q8R (Pharmaceutical Development).
– enhanced/systematic development
– establishment of design space
– establishment of real time release testing
• New Paradigm: combination of enhanced process
understanding, formal use risk management tools and
establishment of an efficient quality system
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13. Our Motto : “Start to Finish,
every thing in Between”
Incremental steps
Pharmaceutical Development (Q8)
Changed Past: Data transfer / Variable output
Paradigm Present: Knowledge transfer / Science
based / Consistent output
Quality Risk Management (Q9)
Past: Used, however poorly defined
Present: Opportunity to use structured
process thinking
Pharmaceutical Quality Systems (Q10)
Past: GMP checklist
Future: Quality Systems across product
life cycle
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14. Our Motto : “Start to Finish,
every thing in Between”
Speed up of DMF Filing Process
References - Relevant Guidelines (API)
• Q6A: Specifications: Test Procedures and
Acceptance Criteria for New Drug
Substances and New Drug Products
• Q2R: Validation of analytical procedures
• Q1A (R2): Stability: new active substances…….
• Q3A (R2): Impurities Testing in new drug substances
• Q3C: Impurities: Guideline for Residual Solvents
• Q3D: Guidelines for Metallic Impurities
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15. Our Motto : “Start to Finish,
every thing in Between”
Speed up of DMF Filing Process
1. Planning aspects
2. Formatting and compilation aspects
3. Review aspects
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16. Our Motto : “Start to Finish,
every thing in Between”
Speed up of DMF Filing Process
1. PLANNING ASPECTS
 Deadline
 Understanding Registration Requirements
 Requirement listing
 Sending Requirements to the respective departments
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17. Our Motto : “Start to Finish,
every thing in Between”
Speed up of DMF Filing Process
2. FORMATTING AND COMPLIATION ASPECTS
 Format
 Compilation
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18. Our Motto : “Start to Finish,
every thing in Between”
Speed up of DMF Filing Process
3. REVIEW ASPECTS
 Recheck the information
 Cross Verification
 Use checklist
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19. Our Motto : “Start to Finish,
every thing in Between”
Speed up of DMF Filing Process
AVOIDING DEFICIENCIES:
 Reporting Identification/ Quantitation thresholds of degradation
impurities are not set as per ICH.
 Stability Indicating nature of analytical method not proved
 LOD/LOQ limits of impurities/ Degradants not specified
 No adequate justification of proposed limits for impurities
 No adequate justification of expiry date, retest period
 No information on the type of polymorph
 No complete characterization of impurities
 Discussion on Chirality inadequate on chiral substances
 Distorted Mass Balance( Sum of Assay & impurities) during stability
study
 Carry-over of impurities from starting materials in to the API

10/13/2012
Residual Solvents
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20. Our Motto : “Start to Finish,
every thing in Between”
Speed up of DMF Filing Process
Key software skills for effective DMF management
 Proficiency in MS office
 Proficiency in Adobe Acrobat tools. (Especially useful in
preparing eCTD ).
 Proficiency in ISIS draw or Chem sketch software
 training in the use of eCTD software.
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21. Our Motto : “Start to Finish,
every thing in Between”
Speed up of DMF Filing Process
Outlook
• The pharmaceutical quality requirements for the API (AS)
are very much guided by the harmonised ICH guidelines:
Impurities, stability, analytical validation,………
• From a pharmaceutical quality point of view there is no
difference between new ASs and existing/known ASs.
• The section on impurities is one of the most important
section in an application file. Thorough preparation and
presentation of this section is most helpful for the assessor.
• During lifetime of the product, attention has to be paid to
changes in the manufacturing process including change in
suppliers of starting materials.
• Impurities profile depends very much on the route of
synthesis.!!
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22. Our Motto : “Start to Finish,
every thing in Between”
Specific Analytical Method Validation
Requirements in US
PRE-REQUISITES
Suitability of Instrument
• Status of Qualification and Calibration
Suitability of Materials
• Status of Reference Standards, Reagents, Placebo
Lots
Suitability of Analyst
• Status of Training and Qualification Records
Suitability of Documentation
• Written analytical procedure and proper approved
protocol with pre-established acceptance criteria
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23. Our Motto : “Start to Finish,
every thing in Between”
Specific Analytical Method Validation
Requirements in US
PURPOSE OF ANALYTICAL VALIDATION
• Identification of Sources and Quantitation of Potential
errors
• Determination if Method is Acceptable for Intended Use
• Establish Proof that a Method Can be Used for Decision
Making
• Satisfy FDA Requirements
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24. Our Motto : “Start to Finish,
every thing in Between”
Specific Analytical Method Validation
Requirements in US
Verification Versus Validation
• Compendial vs. Non-compendial Methods
– Compendial methods-Verification
– Non-compendial methods-Validation requirement
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25. Our Motto : “Start to Finish,
every thing in Between”
Specific Analytical Method Validation
Requirements in US
Compendial Analytical Procedures
• The Analytical procedures in the USP 25/NF 20 are legally recognized under
section 501(b) of the Federal Food, Drug and Cosmetic Act as the regulatory
analytical procedures for the compendial items. The suitability of these
procedures must be verified under actual conditions of use. When using USP
25/NF 20 analytical procedures, the guidance recommends that information be
p r o v i d e d f o r t h e f o l l o w i n g
characteristics:
– Specificity of the procedure
– Stability of the sample solution
– Intermediate precision
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26. Our Motto : “Start to Finish,
every thing in Between”
Specific Analytical Method Validation
Requirements in US
Regulatory and Compliance Requirement Review
Validation of an analytical method is the process by which
it is established, by laboratory studies, that the
performance characteristics of the method meet the
requirements for the intended analytical applications.
USP 23 General
Information <1225>
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27. Our Motto : “Start to Finish,
every thing in Between”
Specific Analytical Method Validation
Requirements in US
Regulatory and Compliance Requirement Review
The accuracy, sensitivity, specificity, and reproducibility of
test methods employed by the firm shall be established
and documented. Such validation and documentation may
Be accomplished in accordance with 211.194(a)(2)
21 CFR PART 211 - CURRENT GOOD MANUFACTURING PRACTICE
FOR FINISHED PHARMACEUTICALS
Subpart I-Laboratory Controls
211.165 Testing and release for distribution (e)
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28. Our Motto : “Start to Finish,
every thing in Between”
Specific Analytical Method Validation
Requirements in US
Regulatory and Compliance Requirement Review
• The objective of validation of an analytical procedure is
to demonstrate that it is suitable
for its intended purpose
ICH Guideline for Industry
Q2A, Text on Validation of
Analytical Procedures
March 1995
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29. Our Motto : “Start to Finish,
every thing in Between”
Specific Analytical Method Validation
Requirements in US
Regulatory and Compliance Requirement Review
In practice, it is usually possible to design the experimental
work such that the appropriate validation characteristics
can be considered simultaneously to provide a sound,
overall knowledge of the capabilities of the analytical
procedure, for instance: Specificity, Linearity, Range,
Accuracy, and Precision.
ICH Guideline for Industry
Q2B, Validation of Analytical
Procedures: Methodology
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30. Our Motto : “Start to Finish,
every thing in Between”
Specific Analytical Method Validation
Requirements in US
Today’s Validation Requirements
ICH/USP
GMPs
(legal) FDA
10/13/2012 J. Ramniwas 30

31. Our Motto : “Start to Finish,
every thing in Between”
Specific Analytical Method Validation
Requirements in US
ICH/USP Validation Requirements & Parameters
USP ICH
• Specificity
 Specificity • Linearity
 Linearity and Range • Range
 Accuracy • Accuracy
 Precision • Precision
 Limit of Detection – Repeatability
 Limit of Quantitation – Intermediate Precision
 Ruggedness – Reproducibility
 Robustness • Limit of Detection
• Limit of Quantitation
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32. Our Motto : “Start to Finish,
every thing in Between”
Specific Analytical Method Validation
Requirements in US
483 Observations
There was inadequate method validation specificity data to demonstrate
that each method was capable of distinguishing the active ingredient from
its impurities and degradation products.
Specificity studies did not include the minimum stress conditions of acid
and base hydrolysis, oxidation, thermal degradation and photolysis,
degradation schematic for the active ingredient that identifies the major
degradation products was not included for each product.
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33. Our Motto : “Start to Finish,
every thing in Between”
Specific Analytical Method Validation
Requirements in US
FDA Waning Letter
On addition to the example of modifying both compendial methods and
customer supplied methods, we also observed the use of unvalidated in-
house methods as well as unvalidated modifications to in-house methods.
A statement indicating that the method has not been validated in the
particular formulation was included in the certificate of analysis for…use
of this statement does not absolve…from using valid, accurate, and
reproducible methods.
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34. Our Motto : “Start to Finish,
every thing in Between”
Challenging Areas in Analytical Validations
Man Machine Methods
qualified calibrated characterised
robust documented
skilled qualified suitable
Quality of the
Reference analytical method
Vibrations Time
standards Irradi-
Irradi- Analysts´
Analysts´
ations support
Tempe-
Tempe-
Quality rature Humidity Supplies
Material Milieu Management
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35. Our Motto : “Start to Finish,
every thing in Between”
Effective Sourcing Strategies
1. Proactive Quality Assurance
2. Risk based Approach
3. Communicate Constantly
4. Release Product
5. Measure Capabilities
6. Qualify Supplier
7. Co-investigate Failures
8. Establish Milestones
9. Quality Agreements
10. Embrace Supplier Infrastructure
11. Customize Audits
12. Maintain Control
13. Manage Changes
14. Monitor through Surveillance Program
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36. Our Motto : “Start to Finish,
every thing in Between”
Vendor Qualification Requirements
 Under 21 CFR 211.84, all lots of all components (API and
excipient) must be tested before use for compliance with the
predetermined specifications.
 The supplier's understanding of the GMP requirements
 The conditions under which the starting material is produced
and controlled
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37. Our Motto : “Start to Finish,
every thing in Between”
Vendor Qualification Requirements
 At least one test to verify the identity of each batch of material
 System in place to evaluate suppliers
 Manufacturer can consistently provide material meeting
specifications.
 Full analyses should be conducted on at least three batches
before reducing in-house testing
 Full analysis at appropriate intervals and compare with the
Certificates of Analysis
 Reliability of Certificates of Analysis should be checked at
regular intervals.
 (ICH Guidelines)
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38. Our Motto : “Start to Finish,
every thing in Between”
Vendor Qualification Requirements
Quality Agreements
1. Applicable GMP Standard
2. Certificate of Analysis
3. Change Control
4. Right to Audit
5. Authority Inspections
6. Sub-contracting
7. Retention of samples (final SUBSTANCE)
8. Retention of records/documentation
9. Stability
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39. Our Motto : “Start to Finish,
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Vendor Qualification Requirements
Quality Agreements
10. Complaints
11. Recall
12. Product quality review
13. Storage and distribution
14. Undesirable contaminants
15. HAPIs
16. Qualification / Validation
17. Reprocessing
18. Reworking
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40. Our Motto : “Start to Finish,
every thing in Between”
Vendor Qualification Requirements
Quality Agreements
19. Deviations / OOS (incl. stability)
20. Packaging
21. Labelling
22. Regulatory documents
23. Product release
24. Reference standards
25. Specifications
26. Analytical methods
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41. Our Motto : “Start to Finish,
every thing in Between”
Method Transfer Requirements at various sites
 Sending Unit (SU):
Create the transfer protocol
Execute training
Assist in analysis
Acceptance Criteria
 Receiving Unit (RU):
Qualified instrumentation
Personnel
Systems (Materials, Utilities, SOP's, etc)
Executes the protocol
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42. Our Motto : “Start to Finish,
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Method Transfer Requirements at various sites
METHODS TO BE TRANSFERRED
Assay
Impurities / Degradants
Chiral Purity(If any)
Identification
Cleaning Validation
Micronisation
Microbiological
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43. Our Motto : “Start to Finish,
every thing in Between”
Method Transfer Requirements at various sites
Pre-transfer Activities
 The RU should be provided with and review
analytical methods prior to their transfer.
 The SU and the RU should formally agree
criteria for success before execution of the
transfer protocol.
 The SU should provide training to the RU. This
should include a review of the methods and
transfer protocol, as well as laboratory work, if
possible. Training should be documented.
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44. Our Motto : “Start to Finish,
every thing in Between”
Method Transfer Requirements at various sites
Transfer Protocol
 Objective
 Scope
 Responsibilities
 Materials/Methods/Equipment
 Experimental Design
 Acceptance Criteria
 Documentation
 Deviations
 References
 Signature/Approval Page
 Reference samples, actives, intermediates, and
10/13/2012
finished products
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45. Our Motto : “Start to Finish,
every thing in Between”
Method Transfer Requirements at various sites
Transfer Report
Should include conclusions regarding the
success of the transfer and confirm whether the
receiving site is qualified to perform each
analytical method.
Any deviation should be discussed and justified
in the transfer report.
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46. Our Motto : “Start to Finish,
every thing in Between”
Out of Trend and Out of specification issues
1. No immediate information about OOS by outsourcing
laboratories
2. Use of averaging?
3. Definition of reportable values?
4. Number of retests?
5. Second analyst?
6. Use of outlier testing?
7. What specification limits?
8. Defining testing into compliance?
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47. Our Motto : “Start to Finish,
every thing in Between”
Conclusion
 Keep pace with the latest regulatory developments
 Learn, de-learn and re-learn
de- re-
 Revision in regulatory process
 Rising awareness of quality, efficacy and safety
 See today with the eyes of tomorrow
 Reconfigure of review process to minimize delays
 Risk Assessment
 Doing things right first time
 Short cuts can be a costly affair
 Regulators understand guidelines, rules, laws and
regulations only
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48. Our Motto : “Start to Finish,
every thing in Between”
Thank you for your
attention
J.RAMNIWAS
Founder & CEO
SAI PHARMA SOLUTIONS INC.
(Gateway to Regulatory Affairs, Quality & cGMP Compliance)
Email: jramniwas@saipharmasolutions.com
Phone No: +919558809128
Website: www.saipharmasolutions.com
Our Motto" Start to finish, everything in between".
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