DEVELOPING SPECIFICATION FOR DRUG SUBSTANCE AND DRUG PRODUCT AS PER ICH Q6A Q6B AND Q3(A )AND Q3(C )

1. DEVELOPING SPECIFICATION
PRESENTEDBY : NAMRATA BAWASKAR
M PHARM(QA)
SUBJECT : QUALTY CONTROL QUALITY
ASSURANCE
ALL INDIA SHRI SHIVAJI MEMORIAL SOCIETY’S
COLLEGE OF PHARMACY ,PUNE

2. CONTENT
• SPECIFICATION
• TYPE OF SPECIFICATION
• ICH Q6A GUIDELINE
• ICH Q6B GUIDELINE
• ICH Q3A(R2) GUIDELINE
• ICH Q3C GUIDELINES
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3. WHAT IS SPECIFICATION
• A SPECIFICATION IS DEFINED AS A LIST OF TESTS,
REFERENCE TO ANALYTICAL PROCEDURES , AND
APPROPRIATE ACCEPTANCE CRITERIA WHICH ARE
NUMERICAL LIMITS , RANGES, OR OTHER CRITERIA FOR THE
TESTS DESCRIBED .
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4. JUSTIFICATIONOF SPECIFICATIONS
• Justification required for
1. Each procedure,
2. Each acceptance criterion included in the specification.
• Justification should refer to:
• Setting and justifying specifications by
• Batches from: - 1) Primary stability 2)Scale-up, -3) Validation.
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1. Relevant development data,
2. Pharmacopoeias standards,
3. Test data of batches used in toxicology and clinical studies
4. Results from accelerated and long term stability studies,
5. Reasonable range of expected analytical and manufacturing
variability.

5. TYPE OF SPECIFICATION
active and inactive starting material
packaging materials
for intermediate and bulk products
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6. Q6A
GUIDELINES
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7. UNIVERSAL TEST/
CRITERIA
NEW DRUG SUBSTANCE
NEW DRUG PRODUCTS
SPECIFIC TEST/
CRITERIA
NEW DRUG SUBSTANCE
NEW DRUG PRODUCTS
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8. 1. Universal Tests / Criteria
A. New Drug Substances
The following tests and acceptance criteria are considered generally
applicable to all new drug substances.
a) Identification: e.g. IR , HPLC , HPTLC , GC ,GC/MS etc.
b) Description: properties like colour , odour , state, etc. can be determined
c) Assay: content uniformity
d) Impurities : organic & inorganic impurities ,residual solvents
B. New Drug Products . SAME
2. Specific Tests / Criteria
A. New Drug Substances
a) Physicochemical properties: pH of an aqueous solution, melting point / range,
and refractive index
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9. b) Particle size:
solid or suspension drug products
c) Polymorphic form :
• Polymorphism may also include solvation or hydration products (also
known as pseudo polymorphs) 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.
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10. 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
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11. 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 pharmacopoeia procedures.
B. New Drug Products:
The following tests are applicable to tablets (coated and uncoated) and
hard capsules, oral liquids, and parenteral. One or more of these tests may
also be applicable to soft capsules and granules.
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12. SOLIDDOSAGEFORM
• Dissolution
• Disintegration
• Hardness/friabili
ty
• Uniformity of
dosage units
• Water content
• Microbial limits
ORALLIQUID
• Uniformity of dosage
units
• Ph
• Microbial limits
• Antimicrobial
preservative content
• Extractables
• Alcohol content
• Dissolution
• Particle size distribution
• Redispersibility
• Rheological properties
• Reconstitution time
• Water content
PARENTRAL
• Uniformity of dosage units
• Ph
• Sterility
• Endotoxins/Pyrogens
• Particulate matter
• Water content
• Antimicrobial preservative
content
• Extractables
• Antioxidant preservative
content
• Functionality testing of
delivery systems
• Osmolarity
• Particle size distribution
• Redispersibility
• Reconstitution time
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13. DISSOLUTION
• Dissolution is considered product-specific. The method and limits should
be appropriate for the proposed product.
• Single-point measurements are normally considered to be suitable for
immediate-release dosage forms.
• For modified-release dosage forms, appropriate test conditions and
sampling procedures should be established.
- multiple time point sampling should be performed for extended-release
dosage forms
- two-stage testing (using different media in succession or in parallel, as
appropriate) may be appropriate for delayed-release dosage forms.
• For immediate-release drug products where changes in dissolution rate
have been demonstrated to significantly affect bioavailability
• Dissolution specs at release and shelf-life should be identical. It is useful
to have the parameters (medium, apparatus, speed) in specs.
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14. 14
• The limits should be expressed as “Q”, which also implies three stage
testing as per harmonized texts. Ideally the stages are expressed in the specs
(i.e. S1 all individual values Q+15%) There should be a discussion if the
time is > 45 minutes.
• For products containing water insoluble APIs, it is recommended to have a
two tire dissolution limit.

15. 15Additional considerations are required when there is a BCS-based
biowaiver:
• BCS Class 1 (e.g. emtricitabine, stavudine, zidovudine, levofloxacin,
ofloxacin): The test and comparator products must be at least rapidly
dissolving. (NLT 85% in 30 minutes)
• BCS Class 3 (e.g. abacavir sulphate, lamivudine, ethambutol,
isoniazid, pyrazinamide): The test and comparator products must be
very rapidly dissolving (NLT 85% in 15 minutes).
• Dissolution limits must meet the biowaiver requirements.

16. 16• Setting of Dissolution Specifications
• The Q value is recommended to be set on the basis of the bio-batch
dissolution result (mean value of 12 units) minus 10%.
• Usually the time points 15, 30 or 45 minutes would be sufficient, but
other time points may be used if justified.
Dissolution of the Biobatch Specification Setting
≥ 95% in 15min Q=85% in 15 minutes
≤ 95% and ≥ 85% in 15min Q=75%, 80% or 85% whichever is closer to Q=biobatch result
-10% at 15 minutes
≥ 85% after 30min Q=75%, 80% or 85% whichever is closer to Q=biobatch result
-10% at 30 minutes
≥ 85% after 45min Q=75%, 80% or 85% whichever is closer to Q=biobatch result
-10% in 45 minutes
≤ 85% after 45min Q=75% in 45 minutes
≤ 75% after 45min Dissolution specification should be based on more than one
time point

17. DISINTEGRATION
For rapidly dissolving (dissolution >80% in 15 minutes at pH 1.2, 4.0 and 6.8)
products containing drugs which are highly soluble throughout the physiological
range (dose/solubility volume < 250 mL from pH 1.2 to 6.8), disintegration may
be substituted for dissolution.
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Un coated tablet) NMT 15 min, in water with disc 37 °C ± 2°C
Coated tablet NMT 30 min, in water with disc for film coated tab, and NMT 60 min, other
than film coated tablet
Enteric coated tab Intact for 1 hr in 0.1 N HCl & disintegrate within 2 hr in mixed 6.8 phosphate
buffer. According to USP 1 hr in simulated gastric fluid, then in simulated
intestinal fluid.
Dispersible/soluble Within 3 min in water at
25°C ±1°C (IP)
15-25°C (BP)
Orodispersible Within 1 min
Effervescent tab 5 min in 250 ml water at 20 – 30 °C (IP) 5 min in 200 ml water at 15 – 25 °C
(BP
Buccal & sublingual Not applicable but dissolve within 15 – 30

18. HARDNESS/FRIABILITY
• It is normally appropriate to perform hardness and/or friability testing as an
in-process control. Under these circumstances, it is normally not necessary
to include these attributes in the specification.
• Chewable tablets: acceptance criteria should be included in the
specification.
• Friability limit is NMT 1 %
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Water content
• A test for water content should be included when appropriate. The
acceptance criteria may be justified with data on the effects of hydration or
water absorption on the drug product.
• In some cases, a Loss on Drying procedure may be considered adequate;
however, a detection procedure which is specific for water (e.g., Karl
Fischer titration) is preferred.

19. WEIGHT VARIATION
• This term includes both the mass of the dosage form and the content of the
active substance in the dosage form
• A pharmacopoeia procedure should be used.
• In general, the specification should include one or the other but not both.
• If appropriate, these tests may be performed in-process;
• The acceptance criteria should be included in the specification. A test and limit
for weight variation may be established in lieu of content uniformity testing;
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IP/BP LIMIT USP
80 mg or less 10 % 130 mg or less 80 mg
80 mg-250 mg 7.5 % 130 mg -324 mg
250 mg or more 5 % 324 mg or more
For tablet For capsule
IP LIMIT
Less than 100 mg 10 %
100 mg or more 7.5 %

20. ORAL LIQUID
Uniformity of dosage units
• Content uniformity
• Mass uniformity
pH :Acceptance criteria where applicable and proposed range justified.
Microbial limits
• TAMC, • TYMC, • Specified micro organism
Antimicrobial preservative content
• Acceptance criteria based on levels to maintain microbiological product
quality throughout shelf life.
• The lowest specified concentration should be controlled by antimicrobial
preservative effectiveness test
• Antimicrobial preservative effectiveness. should be demonstrated during
development, scale-up, throughout the shelf life.
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21. ANTIOXIDANT PRESERVATIVE CONTENT
• Release testing should be performed
• Shelf life testing may be unnecessary where justified by development and
stability data.
EXTRACTABLES
Where development and stability data show no significant evidence of
extractables elimination of this test may be proposed.
• Where data demonstrate need acceptance criteria for oral solutions: - rubber
stopper - cap liner - plastic bottle
• Data should be collected as early in development process as possible.
ALOCHOL CONTENT
• Where it is declared quantitatively on the label in accordance with pertinent
regulations, the alcohol content should be specified. It may be assayed or
calculated.
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22. 22Dissolution
• It may be appropriate for insoluble drug substance
• Single-point measurements - Immediate-release dosage forms
• Multiple-point measurements - Modified-release dosage forms Particle size
distribution
• PSD may be appropriate for oral suspensions
• Developmental data should be considered for either a dissolution procedure or a
particle size distribution procedure for these formulations
Particle size distribution
• testing may also be proposed in place of dissolution testing, justification
should be provided.
• Mean, upper and/or lower particle size limits should be well defined.

23. Redispersibility
• For oral suspensions which settle on storage (produce sediment),
acceptance criteria for redispersibility may be appropriate. Shaking may be
an appropriate procedure.
Rheological properties
• For relatively viscous solutions or suspensions, it may be appropriate to
include rheological properties (viscosity/specific gravity) in the
specification.
Reconstitution time
• should be provided for dry powder products which require reconstitution
• The choice of diluent should be justified
• Data generated during product development may be sufficient to justify
skip lot testing, or elimination of this attribute from the specification may be
proposed.
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24. 24
Sterility:
• This approach may be proposed for terminally sterilized drug products
• Data generated during development and validation
Endotoxins/Pyrogens:
• Endotoxins-using a procedure such as the limulus amoebocyte lysate test (LAL
test)
• Pyrogenicity testing may be proposed as an alternative to endotoxin testing where
justified
Particulate matter:
• Limits for visible particulates (foreign matter) and / or clarity of solution, as well
as for sub-visible particulates as appropriate.
PARENTRAL TEST

25. Water content:
• For non-aqueous parenteral, and for parenteral products for reconstitution
• Loss on drying is generally considered sufficient.
• In certain cases a more specific procedure (e.g., Karl Fischer titration) may
be preferable.
Extractables:
• More important for parenteral products than for oral liquids
• where development and stability data show evidence that extractables are
consistently below the levels that are demonstrated to be acceptable and
safe, elimination of this test can normally be accepted.
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26. 26Functionality testing of delivery systems:
• For pre-filled syringes, autoinjector cartridges, or the equivalent
• These may include control of syringability, pressure, and seal integrity
(leakage), and/or parameters such as tip cap removal force, piston
release force, piston travel force, and power injector function force.
• Skip test applicable, if justified.
Osmolarity:
• When the tonicity of a product is declared in its labelling, appropriate
control of its osmolarity should be performed.
• Skip test applicable, if justified.

27. Q6 (B) GUIDELINES
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
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28. 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
d) Purity, impurities and contaminants
e) Quantity
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29. 2. Analytical Considerations .
• 1 Reference standards and reference materials
2 Validation of analytical procedures
3. Process Controls.
1. Process-related considerations:
2. Raw materials and excipient specifications :
3. In-process acceptance criteria and action limits:
4. Pharmacopoeial Specifications.
5. Release Limits vs. Shelf-life Limits : Statistical Concepts :.
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30. 1.Drug Substance
Specification
Purity and impurities
Potency
Appearance and
description
Identity
Quantity
1.Drug Product
Specification
Appearance and
description
Identity
Purity and
impurities
Potency
Quantity
Additional testing for
unique dosage forms
General tests
specification 30

31. Q3
GUIDELINES
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32. OBJECTIVE
• The impurities in pharmaceuticals are unwanted chemicals that remain with
the active pharmaceutical ingredients (APIs) or develop during formulation
or upon aging of both API and formulation. The presence of these unwanted
chemicals even in trace amount may influence the efficacy and safety of
pharmaceutical product. The control of impurities is currently a critical issue
to the pharmaceutical industry.
• Objective: To makes recommendation to applicant on reporting, identifying
& qualifying information on impurities in new drug substance .
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33. WHATIS IMPURITY…..?
ICH defines impurities as substances in the API that are not the API itself.
OR Any component of drug substance that is not the chemical entity
Or for drug product that is not the drug substance or an excipient .
• ICH Status: Q3A- Q3D Impurities
• Q3A (R2) Impurities in New Drug Substances
• Q3B (R2) – Impurities in New Drug Products
• Q3C (R5) – Impurities : Guideline for Residual Solvents
• Q3D – Impurities : Guideline for Elemental Impurities
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34. DEFINATIONS
1. Impurity: Any component of the new drug product that is not the
drug substance or an excipient in the drug product.
2. Impurity Profile: A description of the identified and unidentified
impurities present in a drug product.
3. Qualification: The process of acquiring and evaluating data that
establishes the biological safety of an individual degradation product
or a given degradation profile at the level(s) specified.
4. Degradation Product: An impurity resulting from a chemical change
in the drug substance brought about during manufacture and/or
storage of the new drug product by the effect of, for example, light,
temperature, pH, water, or by reaction with an excipient and/or the
immediate container closure system.
5. Degradation Profile: A description of the degradation products
observed in the drug substance or drug product.
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35. 6. Identified Degradation Product: A degradation product for
which a structural characterisation has been achieved.
7. Unidentified Degradation Product: A degradation product for
which a structural characterisation has not been achieved and
that is defined solely by qualitative analytical properties (e.g.,
chromatographic retention time)
8. Qualification Threshold: A limit above (>) which a degradation
product should be qualified.
9. Reporting Threshold: A limit above (>) which a degradation
product should be reported.
10.Identification Threshold: A limit above (>) which a
degradation product should be identified.
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36. organic
inorganic
Residual
solvent
TYPES OF IMPURITIES
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37. ORGANIC
•Organic impurities mainly arise during the synthesis,
purification(manufacturing process )and or storage of
the drug substance
•Organic impurities can be classified like...
1. Starting materials
2. Intermediate
3. Degradation products
4. Reagents, ligand and catalyst
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38. INORGANIC
Inorganic impurities derive from the manufacturing process and
excipients.
Generally, excipients contain high levels of heavy metals such as
arsenic, bismuth, cadmium, chromium, copper, iron, lead,
mercury, nickel and sodium.
Sometimes they might present in the product during processing
or they leached from packing material
Heavy metals
Inorganic salts
Other material's like filter aids, charcoal
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39. RESIDUAL SOLVENTS (ICH Q3 C GUIDELINE)
• Residual solvents are potentially undesirable substances.
• They either modify the properties of certain compounds or may
be hazardous to human health. The residual solvents also affect
physicochemical properties of the bulk drug substances such as
crystallinity of bulk drug, which in turn may affect the
dissolution properties, odour and colour changes in finished
products
• Residual solvents are those solvents which are used as vehicles
for the preparation of solution / suspensions in the synthesis of
a new drug substance
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40. OBJECTIVE OF THIS GUIDELINE
• The is to recommend acceptable amounts for residual solvents in
pharmaceuticals for the safety of the patient. The guideline
recommends use of less toxic solvents and describes levels
considered to be toxicologically acceptable for some residual
solvents
• Since there is no therapeutic benefit from residual solvents, all
residual solvents should be removed to the extent possible to
meet product specifications, good manufacturing practices, or
other quality-based requirements. Drug products should contain
no higher levels of residual solvents than can be supported by
safety data.
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41. AS PER THE ICH GUIDELINES, THE SOLVENTS
USED IN THE MANUFACTURING OF DRUG
SUBSTANCES CLASSIFIED IN TO FOUR TYPES
•Class 1 solvents: Solvents to be avoided
•Class 2 solvents: Solvents to be limited
•Class 3 solvents: Solvents with low toxic potential
•Class 4 solvents: Solvents for which No
Adequate Toxicological Data
was Found
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42. A) CLASS I SOLVENTS:
• Solvents to Be Avoided Solvents in Class 1 should not be
employed in the manufacture of drug substances, excipients, and
drug products because of their unacceptable toxicity or their
deleterious environmental effect. However, if their use is
unavoidable in order to produce a drug product with a significant
therapeutic advance, then their levels should be restricted as
shown in Table 1.
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43. Residual solvent
benzene
Carbon tetra
chloride
1,1 dichloro
ethane
1,2 dichloro ethane
1,1,1 trichloro
ethane
Concentration limit
ppm
2 (toxic)
4(toxic)
8(toxic)
5(toxic)
15000(environmental
hazards)
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44. Solvents to Be Limited Class II solvents usage should be
limited in pharmaceutical products because of their
inherent toxicity.
Table 2 lists class II solvents with their daily permissible
exposure.
Class II solvents: 44

45. Solvent PDE (mg/day) Concentration limit (ppm)
Acetonitrile 4.1 460
Chlorobenzene 3.6 360
Chloroform 0.6 60
Cyclohexane 38.8 3880
1,2-Dichloroethene 18.7 1870
Dichloromethane 6.0 600
Hexane 2.9 290
Cumene 1 0.7 70
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46. CLASS III SOLVENTS:
• Solvents with Low Toxic Potential These are less toxic and possess
lower risk to human health than class I or class II
• Long-term toxicity or carcinogenicity not reported, which is evident
from the available data for the solvents under this category.
• The use of class III solvents in pharmaceuticals does not have any
serious health hazard. Some of the solvents are;
Acetic acid, anisole, butanol, 2butanol, isopropyl acetate, methyl
acetate, butyl acetate, ter-butyl methyl ether, pentene, cumene,
Dimethyl sulfoxide, ethanol, ethyl acetate, formic acid, heptane,
isobutyl ketone, tetrahydrofuran, 1-pentanol, 2propanol, methyl
isobutyl ketone, propyl acetate, 3methyl- 1-butanol, methyl ethyl
ketone.
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47. CLASS IV SOLVENTS:
• Class IV solvents, adequate toxicological data is not available.
The manufacturers should justify the residual levels for these
solvents in pharmaceutical products.
• The solvents under class IV are
1, 1-diethoxy propane, 1-1-dimethoxy
propane,2dimethoxy propane, methyl isopropyl
ketone, isooctane, isopropyl ether, methyl
tetrahydrofuran, petroleum ether, trichloro acetic
acid.
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48. REFERENCES:
• GUIDELINE on Cgmp AND QUALITY OF PHARMACEUTICAL
PRODUCTS By S. Iyer ,D.K.Publication pg. 203.
• PHARMACEUTICAL QUALITY ASSURANCE BY Manohar A.
Potdar, NIRALI PRAKASHAN , pg. 7.5-7.7.
• Impurities evaluation of pharmaceuticals by satinder ahuja
• ICH HARMONISED TRIPARTITE GUIDELINE ON : ICH Q6 A, Q6 B ,
Q3 A (R2).
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49. THANK YOU
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