This document provides an overview of in-process quality control (IPQC) and ICH guidelines Q3 and Q6. It defines IPQC as quality control tests performed during the manufacturing process to ensure quality is maintained. Common IPQC tests for different dosage forms like tablets, capsules, and parenterals are described. Key ICH guidelines Q3 and Q6 regarding impurities and specifications are summarized. ICH aims to harmonize technical requirements internationally to facilitate drug development and registration while maintaining standards of safety, quality, and efficacy.

1. In Process Quality Control
(IPQC) and ICH Guidelines-
Q3 and Q6
Presented by:
Ajinkya.R.Malpe.
Mpharm QA 1st year(2021-22)
Guided by:
Mr.Shailesh.G.Jawarkar.
Subject Teacher(QC&QA)
Department of Quality Assurance
Vidyabharti College of Pharmacy,Amravati.

2. In Process Quality Control(IPQC)
 In Process Quality control(IPQC) is concerned with providing accurate,specific and
definite descriptions of the procedures to be employed,from the receipt of raw materials
to the release of the finished dosage forms.
 In Process Quality Control tests are mostly performed within the production area.
They should not carry any risk for the quality of product.
 In process testing enables easier identification of problems. It sometime identifies a
defective product batch that can be corrected by rework,whereas once that batch has
been completed, this may not be possible.
 Failure to meet in process control specification indicates either that procedure were not
followed or some factor were out of control.
 IPQC is the activity performed between QC and QA which involves-
 To maintain the quality of the product.
 To control the procedure involved in manufacturing.
 To monitor all features which affect the quality.
 To detect errors when occured by others.

3. Instrument Used in IPQC Department
Friability testing apparatus
 Disintegration apparatus.
 Dissolution apparatus.
 Analytical balance
 Muffle furnace.
 Friability testing apparatus.
 Bulk density apparatus.
 Tablet hardness tester.
 Infra red moisture content measuring apparatus.
 UV spectroscopy.
 Abbe Refractometer
 TLC kit
 Karl Fischer Titrimeter
Bulk Density apparatus

4. Tablet Hardness Tester
Moisture measuring apparatus
Abbe Refractometer TLC Kit Karl Fischer Instrument(Coulometer)

5. IPQC TESTS
IPQC
TESTS
PHYSICAL/CHE
MICAL
Identity
Test
Quality
Test
Purity
Test
Potency
Test
BIOLOGICAL/
MICROBIOLOGIC
AL

6. Identity Test: These tests are qualitative chemical method used to confirm the actual presence
of compound. Ex-colour formation,precipitation.
Quality Test: These tests are physical method used to measure accurate the characteristics
properties of drug. Ex-absorbance,refractive index.
Purity Test: These tests are designed to estimate the levels of all known and significant
impurities and contaminants in the drug substance under evaluation.
Ex-Tests for clarity of solution,acidity/alkalinity.
Biological and Microbiological Tests: It includes macro and micro biologic assays and tests
for safety,toxicity,pyrogenicity,sterility,antiseptic activity and antimicrobial preservative
effectiveness tests.
Biological testing of drugs can be qualitative and quantitative in nature.
It utilizes intact animals,animal preperations,isolated living tissues.
OFFICIAL QUALITATIVE BIOLOGICAL TEST
Product to be tested
1.Preperation of liver/stomach
2.Antiseptics,Disinfectant
Test name
Antianaemia test
Antibacterial test
OFFICIAL QUANTITATIVE BIOLOGICAL TEST
Product to be tested
1.Insulin
2.Digitalis
Animal
Rabbit
Pigeon

7. OFFICIAL QUALITATIVE MICROBIOLOGICAL TEST:
Microorganism
Lactobacillus plantarum
Drug
1.Calcium pantothenate
Purpose of IPQC:
 To ensure detectable and significance human errors.
 Equipment failure.
 Abnormal Interpretation.
 Adoption of given procedure.
Importance of IPQC:
 To minimize human error.
 To accurate,specific,definite description of the procedure to be employed.
 It is a planned system to identify material equipment processes and operation.
 To detect the error.
 To enforce the flow of manufacturing and packaging operation according to established
route and practice.
 To pinpoint the responsibility.
 To detect any abnormality immediately.

8. IPQC Tests in Different Dosage Form
1.Solid Dosage Form
TABLETS
 Weight variation-It is the test which compares the individual weights of a sample of tablets with
average weight of the selected sample.
 Hardness-It is used to determine the breaking point and structural integrity of a tablet.It is also
called “Crushing strength test”.
 Thickness-It is determined by the diameter of the tablet.It is measured by vernier
caliper/micrometer.
 Friability-It is the tendency of tablet to powder,chip or fragment and this can affect the elegance
appearance of the tablet.
 Content Uniformity-It is measured to ensure a constant dose of drug between individual drugs.
 Disintegration Time- The time required for the tablet to break into particles under the influence
of disintegrating fluid.These test is not performed for controlled and sustained release tablets.
 Dissolution Test- It is performed to check the percentage release from the dosage forms.
 Potency Test-The concentration of the drug in a compounded preparation is checked.
 Blister or strip sealing test

9. CAPSULES
 Weight variation
 Assays-It is an investigative procedure carried out in lab for qualitative assessing or
quantitatively measuring the presence ,amount or functional activity of a target entity.
 Content uniformity
 Dissolution test
 Disintegration test
 Moisture content
 Bloom strength-it is also called gel strength,it is measure of the strength and stiffness of the
gelatin,reflecting the average molecular weight of its constituents and is usually between 30
and 300 bloom.
 Iron test-It is present in raw gelatin as well as water used in manufacture. Excess quantity
of iron can effect the formulation.
 Hardness and flexibility of shell
 Loss on drying- It is used to determine the moisture content of a sample. It refer to the loss
of any volatile matter from the sample.
Samples are weighed before and after treatment,and the weight difference is measured.

10. 2.Semisolid dosage form
SUSPENSIONS
 Appearance-colour,odour,taste.
 Clarity
 Particles size of disperse phase.
 Rheology-It is the branch of physics that deals with the deformation and flow of matter(Non Newtonian flow
of liquids and the plastic flow of solids).
 QC of water being used
 Sedimentation volume-It is a ratio of the ultimate volume of sediment(Vu) to the original volume of sediment
(Vo) before settling.
 Sedimentation rate
 pH of different vehicles before and after mixing.
 Drug content
 Zeta potential-It is the potential difference across phase boundaries between solids and liquids.
It is the measure of the electrical charge of particles that are suspended in liquid. Colloid with
high zeta potential-Electrically stabilized, Low zeta potential- tend to coagulate/flocculate.
 Stability T
est
 Redispersibility
 Compatibility of product and container/closure

11. EMULSIONS
Coulter counter method
 Appearance-Colour,Odour,Taste.
 Drug content
 Rheology
 Stability
 Clarity
 QC of water to be used
 pH of different vehicles
 Compatibility of product/container/closure.
 Breaking and cracking
PARENTERALS
 pH
 Volume check
 Clarity Test(for particulate matter)
By visual method
Coulter counter method
Light obscuration method
 Content uniformity
 Weight uniformity Light obscuration method

12.  Leakage Test(package integrity)
Visual methods
Bubble methods
Dye Test
Vaccum ionization method
Direct inoculation method
 Pyrogen Testing
Rabbit fever response test
Limulus amoebocyte lysate test
 Sterility Test
Membrane filtration method
Direct inoculation method
 Test for packing containers
 For glass containers
Water attack test
Powder glass test
 For plastic containers
Leakage test,collapsibility test,transparency test,water vapour permeability test

13.  Passibility of parenteral preparation from needle.
 Conductivity Test
IPQC during Packaging
 Line clearance must be given before starting packaging operation.
 Directions given to operations people should be easy and clear.
 Print details on labels must be certified
 Leak testing of bottles,ampoules,vials must be performed.
 Details of measuring cups,spoons,droppers etc must be checked.
 No of unit strips,corton,bottles etc must be checked.
 All directions related to quantity of sampling and methods of sampling must be cleared.
 Results must be recorded in standard formats.

14. ICH
 ICH is the “International Conference on Harmonization of Technical Requirements for
Registration of Pharmaceuticals for Human Use”.
 ICH is a joint initiative involving both regulators and research based industry
representatives of the EU,Japan and the US in scientific and technical discussions of the
testing procedures required to assess and ensure the safety,quality and efficacy of
medicines.
Objectives of ICH
 To increase international harmonization of technical requirements to ensure that safe,
effective and high quality medicines are developed.
 To harmonize technical requirements for registration or marketing approval.
 To develop and register pharmaceuticals in the most efficient and cost effective manner.
 Mantaining safeguards on quality,safety and efficacy.
 To promote public health by early availability of drug in the market.
 To prevent unnecessary duplication of clinical trials on humans.
 To minimize the use of animal testing without compromising safety and effectiveness of
drug.
 ICH Location-The Secretariat is based in Geneva.The biennial meetings and conferences
of the ICH Steering committee rotate between the EU,Japan and USA.

15. ICH Members
 EU
 EFPIA(European Federation of Pharmaceutical IndustriesAssociations)
 MHLW(Ministry of Health,Labour and Welfare,Japan)
 JPMA(Japan Pharmaceuticals ManufacturesAssociation)
 US FDA
 PhRMA(Pharmaceutical research and Manufacturers association)
 Observers: WHO,TPP
 International Federation of Pharmaceutical manufacturer’s association.
Steps of ICH Harmonization
Step 1-Building scientific consensus.
Step 2-Agreeing on draft text.
Step 3-Consulting regional regulatory agencies.
Step 4-Adopting harmonized guidelines.
Step 5-Implementing guidelines in ICH regions.

16. ICH guidelines: Types
1.Quality guidelines
2.Safety guidelines
3.Efficacy guidelines
4.Multidisciplinary guidelines

17. ICH Q3(Q3A-Q3D)
 Q3A(R2)-Impurities in New Drug Substances.
 Q3B(R2)-Impurities in New Drug Products.
 Q3C(R5)-Guidelines for Residual Solvents.
 Q3D-Guideline for Elemental Impurities.
ICH defines impurity as substances in the API that are not theAPI itself OR
Any component of drug substance that is not the chemical entity.
Definitions
 Impurity: Any component of the new drug product that is not the drug substance or an
excipient in the drug product.
 Impurity Profile: A description of the identified and unidentified impurities present in a drug
product.
 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.
 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. For example-
light, temp, pH, water, or by reaction with an excipient and/or the immediate container
closure system.

18. Degradation Profile: A description of the degradation products observed in the drug substance of drug
product.
Identified Degradation Product: A degradation product for which a structural characterization has been
achieved.
Unidentified Degradation Product: A degradation product for which a structural characterization has not
been achieved and that is defined solely by qualitative analytical properties (eg. chromatographic retention
time).
Qualification Threshold: A limit above (>) which a degradation product should be qualified.
Reporting Threshold: A limit above(>) which a degradation product should be reported.
Identification Threshold: A limit above(>) which a degradation product should be identified.
Types of Impurity
1.Organic- These impurities mainly arise during the synthesis, purification(manufacturing process) and or
storage of the drug substance. Ex-starting materials,Intermediate,degradation products, reagents,ligand
and catalysts.
2.Inorganic-These impurities derive from the manufacturing process and excipients Generally,excipients
contain high levels of heavy metals.
Sometimes they might present in the product during processing or they leached from packing material.
Ex-Fe,Ni,Cd,Cr,Cu,Arsenic,Bismuth,Lead(Heavy metals),Inorganic salts
Other materials-filter aids,charcoal.

19. 3.Residual solvents-They are potentially undesirable substances.They modify the properties of
certain compounds or may be hazardous to human health
The residual solvents also affect physiochemical 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 synthesis of a new drug substance.
Classification of Residual solvents:
1. CLASS 1 solvents(solvents to be avoided)
 Human carcinogens
2. CLASS 2 solvents(solvents to be limited)
 Non genotoxic animal carcinogenic
3. CLASS 3 solvents(solvents with low toxic potential)
 Low toxic potential to man

20. Class 1 solvents: solvents to be avoided
Should not be employed in the manufacture of drug substances,excipients and drug product.
If unavoidable then limited should be restricted as shown
Class 2 solvents: solvents to be limited
Limited because inherent toxicity.
PDEs are given to the nearest 0.1mg/day and concentrations are given to the nearest 10 ppm.
Solvent Conc. Limit(ppm) Concern
Benzene 2 Carcinogen
Carbon tetrachloride 4 Toxic and env. hazard
1,2-Dichloroethane 5 Toxic
1,1-Dichloroethane 8 Toxic
1,1,1-Trichloroethane 1500 Env. hazard
Solvent PDE(mg/day) Conc.limit(ppm)
Acetonitrile 4.1 410
Chlorobenzene 3.6 360
Chloroform 0.6 60

21. Class 3 solvents: solvents with low toxic potential
Regarded as less toxic and of low risk to human health.
Considered that amounts of these residual solvents of 50 mg per day or less/5000ppm or less
would be acceptable without justification.
Cumene 0.7 70
Cyclohexane 38.8 3880
1,2 Dichloroethene 18.7 1870
Dichloromethane 6.0 600
Acetic acid 2-Butanol
Heptane 3-Methyl-1-butanol
Acetone Butyl acetate
Isobutyl acetate Methylethyl ketone
Anisole tert-Butylmethyl ether
Isopropyl acetate 2-Methyl-1-propanol
1-Butanol 2-Dimethyl sulfoxide
Methyl acetate Pentane

22. Solvents for which no Adequate Toxicological Data was found
Thresholds
1,1-Diethoxypropane Methyl isopropylketone
1,1-dimethoxymethane Methyl tetrahydrofuran
2,2-Dimethoxypropane Petroleum ether
Isooctane Trichloroacetic acid
Isopropyl ether Trifluoroacetic acid
Maximium Daily
Dose
Reporting
Threshold
Identification
Threshold
Qualification
Threshold
</=2g/day 0.05% 0.10% OR
1 mg/day intake
(whichever is
lower)
0.15% OR
1mg/day intake
(whichever is
lower)
>/=2g/day 0.03% 0.05% 0.05%

23. ICH Q6
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.
Objectives of the Guidelines:
a) The 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.
b) It provides guidance on the setting and justification of acceptance criteria and the selection
of test procedures for new drug substances
Reference Standard
A reference standard or reference standard 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.

24. Q3 Guidelines
1.Specifications:Definition and Justification
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 shuld
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.
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 ans long term stability studies,as appropriate.
 Presentation of test results in graphic format may be helpful in justifying individual
acceptance criteria,particularly for assay values and impurity levels.

25. 2.Universal Tests/Criteria
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 colour,odour,state etc. can be determined.
c) Assay: HPLC for both assay of the new drug substance and quantitation of impurities.
d) Impurities: organic and inorganic impurities,residual solvents.
2.2New Drug Products
Same as above
3.Specific Tests/Criteria
3.1New Drug Substances
a) Physiochemical properties: pH of an aqueous solution,melting point/range and refractive index.
b) Particle size: solid or suspension drug products.
c) Polymorphic form: Polymorphism may also include solvation or hydration products(also called as
pseudopolymorphs) and amorphous forms.
Differences in these forms could,in some cases,affect the quality or performance of the new drug
products.
Physiochemical measurements and techniques are commonly used to determine whether multiple
forms exist.

26. 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
spectroscopy and solid state NMR.
d)Tests for chiral new drug substances: identity tests,impurity tests and assay 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. eg-Karl Fischer titration.
f)Inorganic impurities: may be determined by other appropriate procedures.eg-atomic absorption
spectroscopy.
g)Microbial limits: There may be 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.-Staphlococcus aureus,Escheria
coli,Salmonella,Pseudomonas aeruginosa).
These should be suitably determined using pharmacopeial procedures.
2. New Drug Products
1. The following tests are applicable to tablets(coated and uncoated) and hard capsules. One or more of
these tests may be applicable to soft capsules and granules.
a) Dissolution
b) Disintegration

27. 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
j) Rheological properties
k) Reconstitution time
l) Water content

28. 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
j) Functionality testing of delivery systems
k) Osmolarity
l) Particle size distribution
m) Redispersibility
n) Reconstitution time

29. Q6B Guidelines
Objective: This guidance document provides general principles on the setting and
justification,to the extent possible,of uniform set of international specifications for
biotechnological and biological products.
1) PRINCIPLES FOR CONSIDERATION IN SETTING SPECIFICATIONS
1. Characterization
a) Physicochemical properties-include a determination of composition,physical properties and
primary structure of the desired product.
b) Biological activity
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-When the antibody is the desired product,its immunological
properties should be fully characterized. Ex-ELISA,Western-blot
d) Purity,impurities and contaminants
e) Quantity-usually measured as protein content,should be determined by appropriate assay.

30. 1.2 Analytical Considerations
1. Reference standards and reference materials
2. Validation of analytical procedures
1.3 Process Controls
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.
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. Raw materials and excipients specifications
The quality of the raw materials,excipients as well as container/closure systems should meet
pharmacopoeial standards,appropriate for their intended use.
4. Pharmacopoeial Specifications
5. Release Limits vs Shelf life limits

31. This concept pertains to the establishment of limits which are tighter for the release than for
the shelf life of the drug substance/drug product.
1.6 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.
 Specifications are linked to preclinical and clinical studies.
 Specifications should account for the stability of drug substance and drug product.
3.SPECIFICATIONS
1. Drug Substance Specification
Generally,the following tests and acceptance criteria are considered applicable to all drug
substances
 Appearance and description

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

33. THANK YOU!