Brief explanation of ICH Q6 guideline

1. ICH Q6 GUIDELINES
FOR
SPECIFICATIONS

2. Quality Q6 Guidelines can be categorized into two sections
Q6A Specifications: Test Procedures and Acceptance Criteria
for New Drug Substances and New Drug Products: Chemical
Substances
Q6B Specifications: Test Procedures and Acceptance Criteria
for Biotechnological/Biological products

3. Objective of the Guideline
This guideline is intended to assist to the extent
possible, in the establishment of a single set of global
specifications for new drug substances and new drug
products. It provides guidance on the setting and
justification of acceptance criteria and the selection of
test procedures for new drug substances.

4. GENERAL CONCEPTS
1. Periodic or Skip Testing
2. Release vs. Shelf-life Acceptance Criteria
3. In-process Tests
4. Design and Development Considerations
5. Limited Data Available at Filing
6. Parametric Release
7. Alternative Procedures
8.Pharmacopoeial Tests and Acceptance Criteria
9. Evolving Technologies
10. Impact of Drug Substance on Drug Product Specifications
11. Reference Standard

5. Periodic or Skip Testing
Periodic or skip testing is the performance of specified tests at
release on pre-selected batches and / or at predetermined
intervals, rather than on a batch-to-batch basis with the
understanding that those batches not being tested still must
meet all acceptance criteria established for that product. This
concept may be applicable to, for example, residual solvents
and microbiological testing, for solid oral dosage forms.
Release vs. Shelf-life Acceptance Criteria
The concept of different acceptance criteria for release vs.
shelf-life specifications applies to drug products only; it
pertains to the establishment of more restrictive criteria for the
release of a drug product than are applied to the shelf-life.
Examples where this may be applicable include assay and
impurity (degradation product) levels.

6. In-process Tests
In-process tests which are only used for the purpose of
adjusting process parameters within an operating range, e.g.,
hardness and friability of tablet cores which will be coated and
individual tablet weights, are not included in the specification.
Design and Development Considerations
The experience and data accumulated during the development
of a new drug substance or product should form the basis for
the setting of specifications. It may be possible to propose
excluding or replacing certain tests on this basis.
Some examples are: microbiological testing for drug
substances and solid dosage forms ,particle size testing

7. Limited Data Available at Filing
It is recognized that only a limited amount of data may be
available at the time of filing, which can influence the process
of setting acceptance criteria.
When only limited data are available, the initially approved
tests and acceptance criteria should be reviewed as more
information is collected, with a view towards possible
modification. This could involve loosening, as well as
tightening, acceptance criteria as appropriate.
Parametric Release
Parametric release can be used as an operational alternative to
routine release testing for the drug product in certain cases
when approved by the regulatory authority. Sterility testing for
terminally sterilized drug products is one example.

8. Alternative Procedures
Alternative procedures are those which may be used to
measure an attribute when such procedures control the quality
of the drug substance or drug product to an extent that is
comparable or superior to the official procedure.
Example: for tablets that have been shown not to degrade
during manufacture, it may be permissible to use a
spectrophotometric procedure for release as opposed to the
official procedure, which is chromatographic.
Pharmacopoeial Tests and Acceptance Criteria
References to certain procedures are found in pharmacopoeias
in each region.

9. Impact of Drug Substance on Drug Product Specifications
In general, it should not be necessary to test the drug product
for quality attributes uniquely associated with the drug
substance.
Example: it is normally not considered necessary to test the
drug product for synthesis impurities which are controlled in
the drug substance and are not degradation products.
Reference Standard
A reference standard, or reference material, is a substance
prepared for use as the standard in an assay, identification, or
purity test. It should have a quality appropriate to its use.

10. 1. Specifications: Definition and Justification
1.1 Definition of Specifications
A specification is defined as a list of tests, references to
analytical procedures, and appropriate acceptance criteria
which are numerical limits, ranges, or other criteria for the tests
described. It establishes the set of criteria to which a new drug
substance or new drug product should conform to be
considered acceptable for its intended use. "Conformance to
specifications" means that the drug substance and / or drug
product, when tested according to the listed analytical
procedures, will meet the listed acceptance criteria.

11. 1.2 Justification of Specifications
When a specification is first proposed, justification should be
presented for each procedure and each acceptance criterion
included. The justification should refer to relevant development
data, pharmacopoeial standards, test data for drug substances
and drug products used in toxicology and clinical studies, and
results from accelerated and long term stability studies, as
appropriate.
This justification may consider theoretical tolerances for a
given procedure or acceptance criterion, but the actual results
obtained should form the primary basis for whatever approach
is taken.
Presentation of test results in graphic format may be helpful in
justifying individual acceptance criteria, particularly for assay
values and impurity levels.

12. 2. Universal Tests / Criteria
2.1 New Drug Substances
The following tests and acceptance criteria are considered
generally applicable to all new drug substances.
a) Identification: eg; IR , HPLC , HPTLC , GC ,GC/MS etc.
b) Description: properties like color , odour , state, etc.
can be determined
c) Assay: content uniformity
d) Impurities : organic & inorganic impurites ,residual
solvents
2.2 New Drug Products
3. Specific Tests / Criteria
3.1 New Drug Substances
a) Physicochemical properties: pH of an aqueous solution,
melting point / range, and refractive index

13. b) Particle size: solid or suspension drug products
c) Polymorphic form : Polymorphism may also include solvation
or hydration products (also known as pseudopolymorphs) and
amorphous forms. Differences in these forms could, in some
cases, affect the quality or performance of the new drug
products. Physicochemical measurements and techniques are
commonly used to determine whether multiple forms exist.
Examples of these procedures are: melting point (including
hot-stage microscopy), solid state IR, X-ray powder
diffraction, thermal analysis procedures (like DSC, TGA and
DTA), Raman spectroscopy, optical microscopy, and solid state
NMR.

14. d) Tests for chiral new drug substances: identity tests, impurity
tests, and assays may be needed for both new drug substances
and new drug products, according to the following concepts:
 Drug Substance :1. Impurities
2. Assay
3. Identity
 Drug Product: 1. Degradation products
2. Assay
3. Identity
e) Water content: This test is important in cases where the new
drug substance is known to be hygroscopic or degraded by
moisture.
e.g., Karl Fischer titration

15. f) Inorganic impurities: may be determined by other appropriate
procedures, e.g., atomic absorption spectroscopy.
g) Microbial limits: There may be a need to specify the total
count of aerobic microorganism, the total count of yeasts and
molds, and the absence of specific objectionable bacteria (e.g.,
Staphylococcus aureus, Escherichia coli, Salmonella,
Pseudomonas aeruginosa). These should be suitably
determined using pharmacopoeial procedures.
3.2 New Drug Products
 3.2.1 The following tests are applicable to tablets (coated and
uncoated) and hard capsules. One or more of these tests may
also be applicable to soft capsules and granules.
a) Dissolution
b) Disintegration

16. c) Hardness/friability
d) Uniformity of dosage units
e) Water content
f) Microbial limits
3.2.2 Oral liquids
a) Uniformity of dosage units
b) pH
c) Microbial limits
d) Antimicrobial preservative content
e) Extractables:
f) Alcohol content
g) Dissolution
h) Particle size distribution
i) Redispersibility

17. j) Rheological properties
k) Reconstitution time
m)Water content
3.2.3 Parenteral Drug Products
a) Uniformity of dosage units
b) pH
c) Sterility
d) Endotoxins/Pyrogens
e) Particulate matter
f) Water content
g) Antimicrobial preservative content
h) Extractables
i) Antioxidant preservative content

18. j) Functionality testing of delivery systems
k) Osmolarity
l) Particle size distribution
m) Redispersibility
n) Reconstitution time

19. Objective
This guidance document provides general principles on the
setting and justification, to the extent possible, of a uniform set
of international specifications for biotechnological and
biological products to support new marketing applications.
PRINCIPLES FOR CONSIDERATION IN SETTING
SPECIFICATIONS
1. Characterization
a) Physicochemical properties
b) Biological activity

20. Examples of procedures used to measure biological activity
include:
 Animal-based biological assays, which measure an
organism's biological response to the product;
 Cell culture-based biological assays, which measure
biochemical or physiological response at the cellular
level;
 Biochemical assays, which measure biological activities
such as enzymatic reaction rates or biological responses
induced by immunological interactions.
c) Immunochemical properties
e.g., ELISA, Western-blot

21. d) Purity, impurities and contaminants
e) Quantity
2. Analytical Considerations
2.1 Reference standards and reference materials
2.2 Validation of analytical procedures
3. Process Controls
3.1 Process-related considerations
Adequate design of a process and knowledge of its capability
are part of the strategy used to develop a manufacturing
process which is controlled and reproducible, yielding a drug
substance or drug product that meets specifications.

22. 3.2 In-process acceptance criteria and action limits
The results of in-process testing may be recorded as action
limits or reported as acceptance criteria. Performing such
testing may eliminate the need for testing of the drug substance
or drug product.
3.3 Raw materials and excipient specifications
The quality of the raw materials used in the production of the
drug substance (or drug product) should meet standards,
appropriate for their intended use.
The quality of the excipients used in the drug product
formulation (and in some cases, in the drug substance), as well
as the container/closure systems, should meet pharmacopoeial
standards, where available and appropriate.

23. 3.4. Pharmacopoeial Specifications
3.5. Release Limits vs. Shelf-life Limits
This concept pertains to the establishment of limits which are
tighter for the release than for the shelf-life of the drug
substance or drug product. Examples where this may be
applicable include potency and degradation products.
3.6. Statistical Concepts
Appropriate statistical analysis should be applied, when
necessary, to quantitative data reported.
2. JUSTIFICATION OF THE SPECIFICATION
The following points should be taken into consideration when
establishing scientifically justifiable specifications.
 Specifications are linked to a manufacturing process.
 Specifications should account for the stability of drug
substance and drug product.

24.  Specifications are linked to preclinical and clinical studies.
 Specifications are linked to analytical procedures.
 Specifications should account for the stability of drug
substance and drug product.
3. SPECIFICATIONS
3.1 Drug Substance Specification
Generally, the following tests and acceptance criteria are
considered applicable to all drug substances
o Appearance and description
o Identity
o Purity and impurities
o Potency
o Quantity

25. 3.2 Drug Product Specification
Generally, the following tests and acceptance criteria are
considered applicable to all drug products.
o Appearance and description
o Identity
o Purity and impurities
o Potency
o Quantity
o General tests
o Additional testing for unique dosage forms

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