1. Regulatory Requirements with Relevance for Quality of API
Beijing, March 2010
Jean-Louis ROBERT
National Health Laboratory
L – 1011 LUXEMBOURG
CHMP co-opted member
Chair CHMP/CVMP QWP

2. Topics addressed General considerations – CTD-Q
Manufacturing: API starting materials
Impurities
Related substances
Residual solvents
Genotoxic impurities
Residual metal catalysts/reagents
Stability
EU Assessment Policy: known active substance
Conclusion
Back-up: References relevant guidelines
Application file CTD-Q structure
Decision tree identification/qualification impurities
Example of structure of genotoxic impurities

3. S.1 General Information S.1.1 Nomenclature S.1.2 Structure
S.1.3 General Properties
Physicochemical properties
Properties affecting pharmacological efficacy
…………..

4. S.2 Manufacture (1) S.2.1 Manufacturer(s)
S.2.2 Description of Manufacturing Process and Process Controls
Flowchart
Sequential procedural narrative
Scale, range, yield……..
S.2.3 Control of Materials
API starting material
Information on all materials of biological origin, incl. viral safety

5. S.2.3 Manufacture: API starting material (2)
API starting material incorporated as a significant structural fragment into the structure of the AS
Proposal and justification by the applicant
Full characterisation
Description of a one step synthesis not acceptable, unless described in the European Pharmacopoeia (CEP or compliance with EP monograph to be demonstrated)
Name of supplier has to be submitted
Detailed description of the synthesis and GMP compliance (ICH Q7) should go together.

6. S.2.3 Manufacture: API starting material
only flow chart
detailed
description AS
SM3 AS SM AS n AS SM

7. Example: Ibuprofen N-Butyl-Ibuprofen as an impurity of Ibuprofen
(n-butylbenzene present in starting material isobutylbenzene)
Isobutyl-benzol
Ibuprofen

8. Résolution test

10. S.2 Manufacture (2)
S.2.4 Controls for Critical Steps and Intermediates
Tests and acceptance criteria to be provided
S.2.5 Process Validation and/or Evaluation
Sterilisation process
S.2.6 Manufacturing Process Development
Changes in manufacturing occurring during development (pre-clinical, clinical, commercial)
Development of e.g. a design space, real time release testing

11. S.3 Characterisation
S.3.1 Elucidation of Structure and other Characteristics
Full elucidation or with reference to a pharmacopoeial standard
S.3.2 Impurities
Classification of Impurities
Organic impurities, Inorganic impurities, Residual solvents
Drug substance impurities:
Process (synthetic) and drug related impurities (degradation);
Drug product impurities:
Degradation products

12. Impurities: General Considerations
The ICH guidelines Q3A (R), [Q3B (R)], Q3C are the general basis for the control of impurities in active substances and medicinal products
Consideration of chemistry and safety aspects
Glossary
Initial scope: new active substances and corresponding products.
Extension to existing active substances and corresponding medicinal products.
European Pharmacopoeia: general monographs (e.g. Substances for Pharmaceutical Use) and chapters
New synthesis can generate new impurities (imp. profile)
Not necessarily qualified
In addition EU guidelines
Genotoxic Impurities Testing
Residual metal catalysts/ metal reagents

13. Q3A/B(R) and Q6A are complementary
Q3A-B: address the chemistry aspects and
the safety aspects of impurities and
defines different thresholds
reporting,
identification,
qualification.
Q6A: addresses the setting and justification of acceptance criteria and the selection of test procedures

14. Listing of Impurities Each specified identified impurity
Each specified unidentified impurity
Any unspecified impurity with an acceptance criterion of not more than (<) the identification threshold
Total impurities
Residual Solvents
Inorganic impurities

15. Thresholds (active substance)
MDD < 2g MDD>2g
Reporting T > 0.05% > 0.03%
Identificat. T > 0.10% or > 0.05%
1.0 mg per day intake,
whichever is lower
Qualificat. T > 0.15% > 0.05%
1.0 mg per day intake,
whichever is lower

16. Active substances outside of the scope of the ICH guideline
For active substances outside of the scope of ICH guideline:
The applicant should justify adequate thresholds taking into account the nature of the active substance, the maximal daily dose, the duration of therapy, the ability of the analytical methods (current scientific status).
European Pharmacopoeia:
Organic impurities in peptides obtained by chemical synthesis:
Reporting threshold: > 0.1%
Identification threshold: > 0.5%
Qualification threshold: > 1.0%

17. Scientific Discussion on Impurities
Summary of actual and potential impurities (sound scientific appraisal).
Potential impurity: an impurity that can arise during manufacture or storage. It may or may not appear in the new drug substance.
Risk based approach (see also ICH Q9)
Thorough discussion by the applicant based on synthesis, reagents used, stability,...
Summary of laboratory studies conducted to detect impurities
Negative results can be helpful !
Discussion on the impurity profiles found in preclinical and clinical trials: impurities above the qualification threshold have to be qualified.

18. Impurities to be specified - Rationale for the inclusion or exclusion of impurities
Scientific knowledge/understanding about the manufacturing process of the active substance
Knowledge about how an impurity is generated
Establishment of a control strategy
Specifications of AS starting materials
Control of impurities at intermediates rather than on final AS
Identification of critical process parameters influencing the impurity profile
Process controls
Purification steps: influence on the impurity profile of the final active substance
Knowledge about the degradation pathway

19. Reminder: Control Strategy (ICH Q10)
A planned set of controls, derived from current product and process understanding, that assures process performance and product quality. The controls can include parameters and attributes related to drug substance and drug product materials and components, facility and equipment operating conditions, in-process controls, finished product specifications, and the associated methods and frequency of monitoring and control.
Consider each unit operation but also an overall control strategy.

20. Acceptance criteria for impurities
Acceptance criteria should be based on
Relevant development data
Test data for the active substance used in toxicological and clinical studies
Results from long term and accelerated stability data
Range of expected analytical and manufacturing variability
Actual results obtained should form the primary basis for establishing the acceptance criteria
They should not be higher than the qualification level

21. Reporting impurities content of batches
Results to be provided for batches used for clinical, safety and stability testing, as well as batches representative of the proposed commercial process.
To be reported: > Reporting threshold.
Batches: detailed information to be provided.
Identity / size
Date and site of manufacture
Manufacturing process
Impurities content, single, total
Use of batches
Reference to analytical procedure used

22. New Impurities
Decision Tree for Identification and Qualification (ICH-Q3A R2)
Description of considerations for the qualification and identification of impurities when thresholds are exceeded.
Recommendation what to do when new impurities appear during later stage of development or after authorisation.

23. Residual Solvents: Q3C Residual Solvents: Q3C
Defines safety limits for solvents (class 1, 2, 3 and (4) solvents)
Option 1 based on concentration
Option 2 based on MDD and PDE
When the acceptance criteria are identical to the safety limits (as indicated in the NfG): no justification is needed (option 1).

24. Residual Solvents: Q3C Class 1 solvents
In all cases, the limit of a class 1 solvent in the final active substance should comply with the requirements of the NfG, even if initially not used as a solvent.
e.g. benzene: - use as starting material (synthesis)
- present as contaminant e.g. toluene
- by-product from a chemical reaction

25. Residual Solvents: some comments CHMP position paper
Class 2 solvents
As a principle:
Should be routinely controlled either in an intermediate or in the active substance;
Last step of the synthesis:
Routine control in the final active substance
Prior to the last step:
If <10% present in a suitable intermediate or in the active substance, need not be controlled routinely.

26. Genotoxic Impurities
Joint SWP-QWP “Guideline on the Limits of Genotoxic Impurities”
published 2006
came into effect on 1 January 2007
Basis: ICH Q3A/B guideline:
“For impurities known to be unusually potent or to produce toxic or unexpected pharmacological effects, the quantification - detection limit of the analytical procedures should be commensurate with the level at which the impurities should be controlled”.

27. Genotoxic Impurities Scope New active substances
New applications for existing active substances, where assessment of the route of synthesis, process control and impurity profile does not provide reasonable assurance that no new or higher levels of GTIs are introduced as compared to products currently authorised in the EU containing the same active substance (idem variations)
No need for retrospectively application to authorised products, unless there is a specific cause for concern.

28. Genotoxic Impurities Principles
Identifications guided by existing genotoxic data or the presence of structure alerts
Genotoxic compounds with sufficient evidence for a threshold-related mechanism
Genotoxic compounds without sufficient evidence for a threshold-related mechanism
Threshold of Toxicological concern:
TTC value: 1.5 µg/day

29. Genotoxic impurities Pharmaceutical considerations
Try to avoid genotoxic reagents
Limitations (if possible) at an intermediate rather at the end active substance
Introduction of a specific purification step (destruction of genotoxic impurity)
Assessment from the applicant justifying the potential presence or non presence of the genotoxic impurity
Discussion/collaboration with safety experts important.

30. Genotoxic impurities SWP – QWP Q&As Revision 1 issued June 2008
The aim of the Q&As document is to provide clarification and harmonisation of interpretation of the Guideline on the Limits of Genotoxic Impurities
Addresses 7 key areas

31. Genotoxic impurities “Cause for concern”:
If a manufacturing procedure for API remains essentially unchanged, a re-evaluation with respect to the presence of potentially genotoxic impurities is generally not needed. However, new knowledge may indicate a previously unknown “cause for concern”.
e.g. mesylate salt

32. Metal Catalysts/Metal Reagents
Recommendation of acceptable concentration limits for the residues of metal catalysts or metal reagents that may be present in pharmaceutical substances or in drug products.

33. Metal Catalysts/Metal Reagents
EMEA/145858/2006
General considerations
Same principles as for Residual Solvents ICH Q3C
Conservative approach compared to food additives
3 classes
Class limit for class 1B
Reporting similar to ICH Q3C
Implementation 5 years (for existing products)

34. Metal Catalysts/Metal Reagents
Concept
Class 1 Metals: metals of high toxic potential
Known carcinogens
Class 2 Metals: metals with low toxic potential
Nutritional trace metals, common in food and food additives
Class 3 Metals: metals with no significant toxicity
Ubiquitous in environment, plants and animals
No need for health based exposure limit
Difference is made between oral, parenteral and inhalation exposure (class 1)

35. Metal Catalysts/Metal Reagents
Expectation:
The relevant residual metal should be controlled with a suitable method
Pharmacopoeial heavy metal test generally not acceptable
Further discussion at international level ongoing both on the methodology and the limits

36. Setting Specifications – Considerations Control of Impurities
Drug substance:
Identification of process parameter(s) (CQP) in the synthesis influencing the generation of a specific impurity in the final product: introduction of a specific in-process control: tightening of pH range.
Introduction of a specific purification step e.g. to limit a potential genotoxic impurity below TTC (degradation of this impurity).

37. Synthesis Indinavir Sulfate

38. Setting specification: GTI (case centralised authorised product)
Final AS
Intermediate II +
Compound III
Compound IV
suspected GT
comp. III < 10 ppm
(detection limit)
< TTC
(target)

39. S.4 Control of Drug Substance
S.4.1 Specification
S.4.2 Analytical Procedures
S.4.3 Validation of Analytical Procedures
S.4.4 Batch Analyses
S.4.5 Justification of Specification

40. S.5 Reference Standards of Materials
Full characterisation
Pharmacopoeial standards

41. S.6 Container Closure System
Brief description of bulk container closure system

42. S.7 Stability (1) S.7.1 Stability summary and Conclusions
S.7.2 Post-approval Stability Protocol and Stability Commitment
S.7.3 Stability Data

43. S.7 Stability (2) EU in climatic zone I/II
Storage conditions according to ICH
Guidelines:
ICH 1A (R2): new active substances
CHMP: existing active substances derived from ICH guideline
In principle no difference in requirements between new active substances and existing active substances.

44. Stability: Storage conditions
General case
* It is up to the applicant to decide whether long term stability studies are performed at 25°C ± 2°C/60% RH ± 5% RH or
30°C ± 2°C/65% RH ± 5% RH. In the latter case, no additional data under intermediate conditions will have to be generated.
Study
Storage condition
Minimum time period covered by data at submission
Long term*
25°C ± 2°C/60% RH ± 5% RH or
30°C ± 2°C/65% RH ± 5% RH
New AS. 1 year
Exi. AS: 6 mo. (opt. a and b)
Intermediate
6 months
Accelerated
40°C ± 2°C/75% RH ± 5% RH

45. Stability: Storage conditions
Refrigerator
Freezer
Study
Storage condition
Minimum time period covered by data at submission
Long term
25°C ± 2°C/60% RH ± 5% RH or
New AS. 1 year
Exi. AS: 6 mo. (opt. a and b)
Accelerated
25°C ± 2°C/60% RH ± 5% RH
6 months
Study
Storage condition
Minimum time period covered by data at submission
Long term
-20°C ± 5°C
New AS. 1 year
Exi. AS: 6 mo. (opt. a and b)

46. Stability: Further Considerations
Retest period to be defined
Pharmacopoeial substances: monographs cover synthetic and degradation products: if no retest date, batch has to be controlled immediately prior to be manufactured in the medicinal product.

47. Declaration Storage Conditions (CPMP)
Testing conditions where stability has been shown
Required label
Additional label, where relevant
25°C/60%RH
alt. 30°C/65%RH
40°C/75%RH
None
Do not refrigerate or freeze
25°C/60%RH +
30°C/60%RH (interm)
or 30°C/65%RH
Do not store above 30°C
Do not store above 25°C
5°C±3°C
Store at 2-8°C
Do not freeze
Below 0°C
Store in freezer

48. Setting Specifications: future position paper
Harmonisation approach for residual solvents, heavy metals, genotoxic impurities
Last step of the synthesis
Prior to the last step of the synthesis
…..

49. EU Assessment Policy (known ASs)
From a pharmaceutical quality point of view no difference is made between new active substances and “existing or known” active substances (and their corresponding products).
This is also highlighted in the European Pharmacopoeia where relevant ICH or CHMP guidelines or the policy adopted have been adopted:
Impurities
Residual solvents
Genotoxic impurities (EP policy)
Residual metal catalysts/reagents (EP policy)

50. EU Assessment Policy (known ASs) (2)
Applications for a MA of medicinal products containing existing active substances are assessed according to their own merit (based on quality risk management).
A summary of impurities present in batches of the active substance(s) …………..(and decomposition products arising during storage) as proposed for use in the product to be marketed together with an evaluation of these impurities.
For existing/known active substances, the European Pharmacopoeia general monograph “Substances for pharmaceutical use” is applicable.

51. EU Assessment Policy (known ASs) (3)
Each active substance with regard to impurities has ultimately to be assessed on its own merits. If the impurity profile of the proposed product is different from that of the reference product, this fact is not a ground for rejection of the application if the impurities are considered qualified.
In the development part of the application, it is expected to find a discussion whether the product is likely to have a different impurity profile as compared to the original product.

52. EU Assessment Policy (known ASs) (4)
It is expected that the applicant of a generic product justifies why he considers the impurities in his product safe for the intended use and qualified, either by reference to expected similarity with the originator or by other means e.g. compliance with relevant (V)ICH guidelines.
In the case where the impurity profile of a generic product differs qualitatively from the originator, or where higher amount of impurities are seen, the full qualification or other adequate information about the safety of these impurities will be requested.

53. 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

54. Conclusion
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.!!

55. Back-up slides

56. References - Relevant Guidelines (API)
From a pharmaceutical quality point of view no difference is made between new active substances and “existing or known” active substances (and their corresponding products).
CHMP NfG: Chemistry on new active substances
CHMP NfG: Summary of requirements for Active Substances in the Quality Part of the Dossier
Q3A (R2): Impurities Testing in new drug substances
Q3C: Impurities: Guideline for Residual Solvents
CHMP position paper class 1/class 2 solvents
CHMP NfG: Testing on Genotoxic Impurities
CHMP HfG: Specification limits for residues of metal catalysts or metal reagents

57. 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…….
CHMP NfG: Stability: existing active substances…….
European Pharmacopoeia
General monograph: Substances for pharmacopoeial use
General chapter:
Control of Impurities (5.10)
Residual Solvents (5.4)
EMEA Website: including Q&As

58. Application file: CTD-Q: Drug Substances 3.2.S
S.1 General Information
S.1.1 Nomenclature
S.1.2 Structure
S.1.3 General Properties
S.2 Manufacture
S.2.1 Manufacturer(s)
S.2.2 Description of Manufacturing Process and Process Controls
S.2.3 Control of Materials
S.2.4 Controls for Critical Steps and Intermediates
S.2.5 Process Validation and/or Evaluation
S.2.6 Manufacturing Process Development

59. Applicatin file: CTD-Q: Drug Substances 3.2.S
S.3 Characterisation
S.3.1 Elucidation of Structure and other Characteristics
S.3.2 Impurities
S.4 Control of Drug Substances
S.4.1 Specification
S.4.2 Analytical Procedures
S.4.3 Validation of Analytical Procedures
S.4.4 Batch Analyses
S.4.5 Justification of Specification

60. Application file: CTD-Q: Drug Substances 3.2.S
S.5 Reference Standards of Materials
S.6 Container Closure System
S.7 Stability
S.7.1 Stability Summary and Conclusions
S.7.2 Post-approval Stability Protocol and Stability Commitment
S.7.3 Stability Data

61. Decision Tree for Identification and Qualification
Is impurity greater than identification
Threshold?
No action
Yes No
Structure identified?
Any known human
relevant risks?
Yes
Reduce to save level
Yes
No further
action No No
Yes
Reduce to not
more than (≤)
identification threshold
Yes
Reduce to not
more than (≤)
identification threshold
Greater
than qualification
Threshold? No
action
Yes No No No
Consider patient population and duration of use and consider conducting:
Genotoxicity studies (point mutation, chromosomal aberration)
General toxicity studies (one species, usually 14 to 90 days)
Other specific toxicity endpoints, as appropriate
Any clinically relevant
adverse effects?
Reduce to save level
Qualified
Yes No

62. Examples of Structure of Genotoxic Impurities