Sri Padmavati Mahila Visvavidyalayam

TOPIC: Impurity and stability studies.

UNDER THE GUIDENCE OF: SUBMITTED BY:

Dr.Shaheen Begum, M.PHARM,PHD Y.Mounika,M.PHARM,1 YEAR,
IPT-Assistant Professor, Roll No: 11
SPMVV-Tirupathi. Pharmaceutical analysis,
SPMVV-Tirupathi
Contents:
1. Introduction
2. Common terms
3. Need to isolate and identify impurities
4. Classification
5. Ich guidelines
6. Regulatory guidelines for impurities
7. Quantification of impurities
8. Decision tree for identification and qualification of impurities
9. References
 Impurity and stability studies

INTRODUCTION:
Impurity:
 In the pharmaceutical world, an impurity is considered as any other organic material, besides the drug
substance, or ingredients, arise out of synthesis or unwanted chemicals that remains with API’s.
 The following definition of impurity is currently under consideration by the regulatory bodies…
Any entity of the drug substance (bulk material) or drug product(final container product) that is not the
chemical entity defined as the drug substance or excipients or other additives to the drug product.
This definition of impurity include degradation products as impurities.
 According to International conference on harmonisation of technical requirements for registration of
pharmaceuticals for human use(ICH), the degradation products are defined as…..
“ A molecule resulting from a change in the drug substance brought about over time. Such changes could
occur as a result of processing or storage”
(Ex: oxidation, aggregation deamidation and proteolysis)
Common Terms of Impurities:
Following terms are used by various regulatory bodies and ICH to describe the impurities:
1. Intermediate
2. Penultimate intermediate
3. By-products
4. Transformation products
5. Interaction products
6. Related products
7. Degradation products
 Intermediate: The compounds produced during synthesis of the desired material or as a part of the
route of synthesis.
 Penultimate Intermediate: It is the last compound in the synthesis chain prior to the production of
the final desired compound.
 By-products: The compound produced in the reaction other than the required intermediates. They can
occur through a variety of side reactions, such as overreaction, incomplete reaction,
demonization and rearrangement, unwanted reactions between starting materials or intermediates
with chemical reagents or catalysts.
 Transformation Products: They are related to theorize and none theorized products that can occur in
are action. They are similar to by-products except that more is known about these reaction products.
 Interaction Products: These products formed either intentionally or unintentionally interaction
between various chemicals involved.
 Related Products: These are chemically similar to drug substance and may even possess biological
activity.
 Degradation Products: They are formed by the decomposition of active ingredient or other
material of interest by the effect of external factors like heat, light and moisture.
The Need to Isolate and Characterize Impurities:
 Impurities are generally assumed to be inferior to API because they might not have the same level of
pharmacologic activity. However, they are not necessarily always inferior. From the standpoint of its usage,
the drug substance is compromised in terms of purity even if it contains another material with superior
pharmacologic or toxicologic properties.
 The control control of low-level impurities impurities is of great importance when a drug is taken in large
quantities; for example, the use of methotrexate(10–20 g) to treat neoplasia or the use of vitamins, notably
vitamin C.
 It is necessary to isolate and characterize a number of impurities and degradation products mentioned
because it is not always possible to unambiguously characterize them with the widely used hyphenated
methods that are frequently the first line of defense.
Classification Of Impurities:
Impurities can be classified into the following categories:
1. Organic impurities (process- and drug-related)
2. Inorganic impurities.
3. Residual solvents.
1) ORGANIC IMPURITITIES : Organic impurities can arise during the manufacturing process and/or storage

of the new drug substance. They can be identified or unidentified, volatile or non-volatile, and include:
 Starting materials
 By-products
 Intermediates
 Degradation products
 Reagents, ligand and catalysts
2.INORGANIC IMPURITIES: Inorganic impurities can result from the manufacturing process. They are

normally known and identified and include:

2.INORGANIC IMPURITIES: Inorganic impurities can result from the manufacturing process. They are

normally known and identified and include:

 Reagents, ligands and catalysts
 Heavy metals or other residual metals
 Inorganic salts
 Other materials (e.g., filter aids, charcoal)
3. RESIDUAL SOLVENTS : Solvents are inorganic or organic liquids used as vehicles for the preparation of

solutions or suspensions in the synthesis of a new drug substance.

• Residual solvents in pharmaceuticals are defined as organic volatile chemicals that are used in the
manufacture of drug substances.
Synthesis Related Impurity :Impurities in pharmaceutical compounds are mainly formed through the
synthesis process as the product is contaminated by raw materials, solvents, intermediates and by-products.
A general idea of these impurities is given below:
1)Organic Impurities:
These types of impurities form during the manufacturing process or during storage of the drug substance. The
sub- types of these impurities are given below.
a)Starting Materials or Intermediate Impurities: During multistep synthesis process there are high chances
of impurities formed as by products, intermediates are produced. So, special care is needed. It results in
unreacted starting material in the final product.
Example: In the synthesis of Baclofen, the last step carried out with β-(p-chlorophenyl) gutarimide, which on
reaction with NaOH/sodium hypochlorite solution at room temperature yields a potential impurity p-
chlorophenyl glutaric acid, which has to be evaluated
b)Degradation products:Product degradation happens during the synthetic process, storage, formulation of
dosage form and aging. Authoritative examples for impurities from degradation products are penicillin and
cephalosporin. Another degradation pathway is shown in Hydrochlorothiazide through which it degrades to the
disulfonamide in its synthesis

c)By-products:In organic chemistry 100% pure product is not generally formed as there is always a chance of
having by-products. By products can be formed through variety of side reactions, such as incomplete reaction,
rearrangement, dimerization, over reaction, isomerization or unwanted reactions between starting materials .
Example: diacetylated paracetamol may forms as a by-product In the case of paracetamol production
2)Inorganic Impurities:
Inorganic impurities are also obtained from the manufacturing processes which are used in bulk drug
formulation. They are normally known and identified.
a)Enantiomeric impurities:Single enantiomeric form of a chiral drug provides greater chemical entity. It also
helps to provide better therapeutic Index. Conversely, the pharmacokinetic profile of ofloxacin (R-isomeric form)
and levofloxacin (S-isomeric form) are similar, suggesting the lack of advantages of single isomer .
b)Reagent, Ligands and Catalysts:These impurities are pretty rare. Proper care during the manufacturing process
avoids the chance of these kinds of impurities.
c)Heavy Metals:Water is essential during manufacturing process and it is the main source of heavy metals, like
Ar, Cd, Cr, Na, Mg, Mn, etc. These can be avoided by the use of demineralization plant, reverse osmosis technique
that produces mineral free water.
d)Other Materials (Filter Aids, Charcoal):The filters or filtering aids are routinely used in the bulk drugs
manufacturing plants and sometimes activated carbon is also used which acts as a source of impurity. For that
reason regular monitoring of fibres and black particles are needed to avoid the contamination.
3)Residual solvents :
They are potentially undesirable substances which either hazardous to human health or modify the properties of
certain compounds. The residual solvents also affect physicochemical properties like crystalline of bulk drug,
which affect the dissolution properties, colour changes in finished products.
ICH classified these substances in to four types:
a)Class I solvents:These solvents are either avoided or restricted to a limit in the manufacture of excipients and
drug substances because of their unacceptable toxicity or their deleterious effects. These are generally
carcinogens.
b)Class II solvents:As Class II solvents are inherently toxic, their usage should be limited in pharmaceutical
Industry. These are generally Non-genotoxic, animal carcinogens and possible neurotoxicants.
c)Class III Solvents:As they are less toxic and possess lower risk to human health than class I or class II
solvents, they do not have any serious health hazard. According to several data‘s, long term toxicity is generally
not reported.

4)Formulation-related impurities:
Drug substance varies with conditions that lead to its degradation or other chemical reactions. Solutions and
suspensions are prone to degradation due to hydrolysis. Water used in formulation contribute to not only its
impurity but also provide stimulation for process like hydrolysis and catalysis.
 The formulation related impurities can be classified as follows:
i. Method related
ii. Environmental related
 The primary environmental factors that can reduce stability can be sub classified
i. Exposures to adverse temperatures
ii. Light-especially UV light
iii. Humidity
 Dosage form related
i. Mutual interaction amongst ingredients
ii. Functional group- related typical degradation
a) Ester hydrolysis
b) Hydrolysis
c) Oxidative degradation
d) Photolytic cleavage
e) Decarboxylation

5)Metabolite impurities:
By products formed by drugs after instigation in body are generally known as Metabolite impurities. Metabolite
impurities can be formed during metabolism as the API and drug product in the body is exposed to various
enzymes .
Examples: asenapine N-oxide, asenapine desmethyl, and ciprofoxacin ethyl diamino impurity, which are
formed as process impurities, but are also metabolites of the same process.
ICH guidelines :
The ICH is an International Conference on Harmonization of Technical Requirements for Registration of
Pharmaceuticals for Human Use. It was created in 1990. ICH is a joint initiative involving both regulators and
research-based industry representatives of the European Union, Japan and the USA in scientific and technical
discussions of the testing procedures required to assess and ensure the safety, quality and efficacy of medicines.
Goal of ICH:
 Ensure a timelier introduction of new medicinal products and their availability to patients.
 Work towards more economical use of human, animal and material resources.
 Maintain safeguards on quality, safety and efficacy, and regulatory obligations to protect public health.
 Share knowledge about revised ICH Procedures and Med-DRA development
 Understand the background for ICH reforms
 Discuss the status of active electronic and pharmacovigilance topics
 Discuss the status of evolving safety and quality topics
ICH Topics Considerations:
 Q - Quality Topics
 S - Safety Topics
 E - Efficacy Topics
 M - Multidisciplinary Topics
Terminology – Adapted from ICH:
 Selection of batches
 Container closure system
 Testing Frequency
 Storage condition
 Bracketing & Matrixing
 In-use stability testing
 Variation
 On-going Stability Studies
ICH SATABILITY GUIDELINES:
S.NO TYPES TOPICS
1 Q1A(R2 Stability Testing of New Drug Substances & Products
2 Q1B Stability Testing : Photo stability Testing of New Drug Substances & Products
3 Q1C Stability Testing for New Dosage Forms
4 Q1D Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and
Products
5 Q1E Evaluation for stability data
6 Q1F Stability Data Package for Registration Applications in Climatic Zones III and IV
7 Q2(R1) Validation of Analytical Procedures Text and Methodology
8 Q3A(R2) Impurities in New Drug Substances

9 Q3B(R2) Impurities in New Drug Products

10 Q3C(R4) Impurities: Guideline for Residual Solvents

11 Q4B Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH regions
12 Q5A(R1) Viral Safety Evaluation of Biotechnology Products Derived from Cell lines of Human or
Animal origin
13 Q5B Quality of Biotechnology Products: Analysis of the Expression
Construct in Cells used for Production of R-DNA Derived Protein Products
14 Q5C Quality of Biotechnology products: Stability testing of Biotechnological/ Biological
products
ICH STABILITY GUIDELINES…
S.NO TYPES TOPICS

16 Q5E Comparability of Biotechnological/ Biological products subjects to chances in their

Manufacturing process

17 Q6A Specifications: Test procedures and Acceptance criteria for New Drug Substances &
New Drug Products: Chemical substances

18 Q6B Specifications: Test procedures and Acceptance criteria for Biotechnological/

Biological products

19 Q7 Good Manufacturing Practice guide for Active Pharmaceutical Ingredients

20 Q8(R Pharmaceutical Development

2)

21 Q9 Quality Risk Management

22 Q10 Pharmaceutical Quality System

The various regulatory guidelines regarding impurities are as follows:
1. ICH guidelines “stability testing of new drug substances and products"- Q1A
2. ICH guidelines “Impurities in New Drug Substances”- Q3A
3. ICH guidelines “Impurities in New Drug Products”- Q3B
4. ICH guidelines “Impurities: Guidelines for residual solvents”- Q3C
5. ICH guidelines “Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and
New Drug Products: Chemical Substances”-Q6A
6. US-FDA guidelines “NDAs -Impurities in New Drug Substances”
7. US-FDA guidelines “ANDAs – Impurities in New Drug Substances”
8. Australian regulatory guideline for prescription medicines, Therapeutic Governance Authority
(TGA), Australia.-
Quantification of impurities in drug substance and drug products:
 Impurity quantification in pharmaceutical dosage forms Identification and quantification of impurities in drug
compounds is a crucial task in pharmaceutical process development for quality and safety.
 Related components are the impurities in pharmaceuticals which are unwanted chemicals that remain with the
active pharmaceutical ingredients (APIs), or develop during stability testing, or develop during formulation or
upon aging of both API and formulated APIs in Medicines
 The presence of these unwanted chemicals even in small amounts may influence the efficacy and safety of the
pharmaceutical products.
 Various analytical methodologies were employed for the determination of related components in
pharmaceuticals.
 Analytical methods for impurities estimation should be stability indicating to monitor the stability of
pharmaceutical dosage forms during the investigational phase of drug development, and once the drug is
marketed, the ongoing stability studiesmust be conducted/ performed.
 The purpose of stability testing is to provide evidence on how the quality of a drug substance or drug product
varies with time under the influence of a variety of environmental factors such as temperature, humidity and
light, enables to establish a retest period/shelf life for a drug substance and a recommended storage
condition.
 Methods can be developed which measure the amount of drug remaining, the amount of drug lost (or the
appearance of degradation products), or both.
 The development of these methods for pharmaceuticals can be approached from several avenues. Related
components, related substances, and related impurities are synonyms for the term impurities; the use of
above terms at different phrases means one and the same (i.e. impurities).
Decision tree for identification and qualification of impurities.
REFERENCE:
1) GOOGLE(Slide share)
2) Text book of pharmaceutical analysis by K A Connors.
3) Dnyaneshwar Bharat Kadlag; A review on stability development guidelines and impurities profile
consideration in solid oral dosage form ,2020
4) Partha Pratim Mahata; Pharmaceutical impuries:A review, 2015
5) Luca Ginnari Satriani; Impuries in drug substance and drug product: Regulatory aspects,2022