Impurity of drug Subatances

1. PRESENTATION ON
IMPURITIES IN DRUG
SUBSTANCES
Presented By
Mohammad Nur Sharif
The ACME Laboratories Limited-API Project
Senior Executive- R&D Analytical

2. REFERENCE
 Q3A(R2)- Impurities in New Drug Substances
 Q3B(R2)- Impurities in New Drug Products
 Q3C(R8)- Impurities: Guideline for Residual Solvents
 Q3D(R1)- Impurities: Guideline for Elemental Impurities
 USP-NF 〈476〉 Control of Organic Impurities in Drug Substances and
Drug Products
 USP-NF 〈232〉 Elemental Impurities—Limits
 USP-NF 〈467〉 Residual Solvents
 Online Platform

3. OBJECTIVES
 The impurities in pharmaceuticals are unwanted that remain with the
Active Pharmaceuticals Ingredients (APIs) or develop during
formulation or upon aging both API and formulation. The presence
of 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 to on reporting,
identifying, qualifying & source information on impurities in new
drug substances.

4. WHAT IS IMPURITY
 ICH defines impurities as substance in API that are not the API
itself
 Or any component in drug substances that is not the chemical entity
 Or for drug product that is not the drug substances or an excipient

5. DEFINITIONS
 Impurity: Any component of the new drug substance that is not the chemical
entity defined as the new drug substance.
 Impurity Profile: A description of the identified and unidentified impurities
present in a new drug substance.
 Chemical Development Studies: Studies conducted to scale-up, optimize, and
validate the manufacturing process for a new drug substance.
 Enantiomeric Impurity: A compound with the same molecular formula as the
drug substance that differs in the spatial arrangement of atoms within the molecule
and is a non-superimposable mirror image.

6. DEFINITIONS
 Extraneous Contaminant: An impurity arising from any source extraneous to the
manufacturing process.
 Herbal Products: Medicinal products containing, exclusively, plant material
and/or vegetable drug preparations as active ingredients. In some traditions,
materials of inorganic or animal origin can also be present.
 Intermediate: A material produced during steps of the synthesis of a new drug
substance that undergoes further chemical transformation before it becomes a new
drug substance.
 Reagent: A substance other than a starting material, intermediate, or solvent that
is used in the manufacture of a new drug substance.

7. DEFINITIONS
 Solvent: An inorganic or an organic liquid used as a vehicle for the preparation of
solutions or suspensions in the synthesis of a new drug substance.
 Starting Material: A material used in the synthesis of a new drug substance that
is incorporated as an element into the structure of an intermediate and/or of the
new drug substance. Starting materials are normally commercially available and
of defined chemical and physical properties and structure.
 Ligand: An agent with a strong affinity to a metal ion.
 PDE: Abbreviation for permitted daily exposure.

8. DEFINITIONS
 Potential Impurity: An impurity that theoretically can arise during
manufacture or storage. It may or may not actually appear in the new drug
substance.
 Identified Impurity: An impurity for which a structural characterization has
been achieved.
 Unidentified Impurity: An impurity for which a structural characterization
has not been achieved and that is defined solely by qualitative analytical
properties (e.g., chromatographic retention time).
 Qualification Threshold: A limit above (>) which an impurity should be
qualified.

9. DEFINITIONS
 Specified Impurity: An impurity that is individually listed and limited with a
specific acceptance criterion in the new drug substance specification. A specified
impurity can be either identified or unidentified.
 Unspecified impurity: An impurity that is limited by a general acceptance
criterion, but not individually listed with its own specific acceptance criterion, in
the new drug substance specification.
 Identification Threshold: A limit above (>) which an impurity should be
identified.
 Reporting Threshold: A limit above (>) which an impurity should be reported.

10. DEFINITIONS
 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.
 Degradation Profile: A description of the degradation products observed in the
drug substance or drug product.
 Permitted Daily Exposure: The maximum acceptable intake per day of residual
solvent in pharmaceutical products.

11. CLASSIFICATION OF IMPURITIES

12. AIMS TO CONDUCT IMPURITY STUDY
Regulatory requirements Scientific and technical requirements
 Quality and safety of products
 Method validation, i.e., specificity
 Acceptance criteria determination
 Expiry date, retest date, and shelf-life evaluation
 Stability and storage conditions study
 Threshold limits evaluation, i.e., threshold of
toxicological concern (TTC), permitted daily
exposure (PDE), etc.
 Synthetic and production processes
optimization
 Formulation development and optimization
 Efficacy improvement
 ADME and toxicology study
 Manufacturing of reference materials
 Stability improvement
 DPIs and pathways prediction
 Cost consideration

13. REPORTING IMPURITY CONTENT OF BATCHES
 Quantitative results should be presented numerically, and not in general terms
such as “complies”, “meets limit” etc
 Below 1.0%, the results should be reported to two decimal places (e.g.,
0.06%, 0.13%)
 Above 1.0%, the results should be reported to one decimal place (e.g., 1.3%).
 Impurities should be designated by code number or by an appropriate
descriptor, e.g., retention time.
 If a higher reporting threshold is proposed, it should be fully justified.
 All impurities at a level greater than (>) the reporting threshold should be
summed and reported as total impurities.

14. STRATEGIES TO ESTABLISH ANALYTICAL METHODS
AND ACCEPTANCE CRITERIA OF PRIs AND DRIs
 Steps for the determination of potential degradation products, including a science-
based risk assessment, can been addressed as below:
 Stress studies of API.
 Accelerated stability studies or kinetically equivalent shorter-term stability
studies.
 Validation/verification by long-term stability studies of both the drug substance
and formulated drug product.
 An integrated scheme in accordance with the requirements of ICH for the
establishment of analytical methods and acceptance criteria of PRIs and DRIs is
proposed as demonstrated in Figure

16. LISTING OF IMPURITIES IN
SPECIFICATIONS
 Organic 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

17. NEW DRUG SUBSTANCE:
THRESHOLDS
Maximum
Daily Dose1
Reporting
Threshold2,3
Identification
Threshold3
Qualification
Threshold3
 2g/day 0.05%
0.10% or 1.0 mg per
day intake (whichever
is lower)
intake (whichever is lower)
0.15% or 1.0 mg per day
intake (whichever is lower)
> 2g/day 0.03% 0.05% 0.05%
 Notes on Attachment
1 The amount of drug substance administered per day
2 Higher reporting thresholds should be scientifically justified
3 Lower thresholds can be appropriate if the impurity is unusually toxic

18. THRESHOLDS FOR DEGRADATION
PRODUCTS IN NEW DRUG PRODUCTS
 Reporting Thresholds * Identification Thresholds
Maximum
Daily Dose1
Threshold2,
3
 1 g 0.1%
> 1 g 0.05%
Maximum Daily
Dose1
Threshold2, 3
< 1 mg
1.0% or 5 µg TDI, whichever is
lower
1 mg - 10 mg
0.5% or 20 µg TDI, whichever
is lower
>10 mg - 2 g
0.2% or 2 mg TDI, whichever is
lower
> 2 g 0.10%

19. THRESHOLDS FOR DEGRADATION
PRODUCTS IN NEW DRUG PRODUCTS
 Qualification Thresholds
Maximum Daily
Dose1
Threshold2, 3
< 10 mg
1.0% or 5 0µg TDI,
whichever is lower
10 mg - 100 mg
0.5% or 200 µg TDI,
whichever is lower
>100 mg - 2 g
0.2% or 3 mg TDI,
whichever is lower
> 2 g 0.15%
Notes on Attachment
1 The amount of drug substance
administered per day
2 Thresholds for degradation products are
expressed either as a percentage of the
drug substance or as total daily intake
(TDI) of the degradation product. Lower
thresholds can be appropriate if the
degradation product is unusually toxic.
3 Higher thresholds should be
scientifically justified.

21. SOURCES OF IMPURITIES IN
PHARMACEUTICALS
The different sources of impurities in pharmaceuticals are listed below:
1) Raw material used in manufacture
2) Reagents used in manufacturing process
3) Method/ process used in manufacture or method of manufacturing
4) Chemical processes used in the manufacture
5) Atmospheric contamination during the manufacturing process
6) Intermediate products in the manufacturing process
7) Defects in the manufacturing process
8) Manufacturing hazards
9) Inadequate Storage conditions
10) Decomposition of the product during storage
11)Accidental substitution or deliberate adulteration with spurious or useless materials

22. 1) RAW MATERIALS EMPLOYED IN
MANUFACTURE
 Impurities known to be associated with these chemicals may be carried through the
manufacturing process and contaminate the final product.
 Example
Rock salt--------→ Calcium Sulphate (CaSO4) + Magnesium Chloride (MgCl2)= NaCl
prepared Rock salt contains small amounts of Calcium sulphate and Magnesium chloride. Thus
Sodium chloride prepared from this source will contain traces of Calcium and Magnesium
compounds.
Impurities such as Arsenic, Lead and Heavy metals are present in raw materials and hence are
found in substances. So, it is necessary to use pure chemicals and substances as raw materials
for the manufacturing process.
Calcium sulphate
and Magnesium
chloride

23. 1) RAW MATERIALS EMPLOYED IN
MANUFACTURE
 Example:
 Copper sulphate may be prepared by the action of sulphuric acid on copper turnings:
 Cu+ 2 H2SO4------------------------→ CuSO4 + 2 H2O + SO2
Copper turnings are known to have Iron and Arsenic as impurities. If Large quantities of
impurities are present in the raw material (e.g. Copper turnings), they may enter the final
product. (CuSO4.5H2O)
Due to this I.P. prescribes limit of tolerance for Arsenic as impurity to be not more than 8 parts
per million in copper sulphate. Similarly it prescribes a limit of Iron as impurity.

24. 2) REAGENTS USED IN THE MANUFACTURING
PROCESS
 If reagents used in the manufacturing process are not completely removed by washing,
these may find entry into the final products.
 Example:
Ammoniated mercury may be prepared by adding a solution of Mercuric chloride to dilute
ammonia solution.
HgCl2+ 2NH4OH-------------→NH2HgCl + NH4Cl + 2 H2O
Soluble soluble Ammoniated mercury (ppt) soluble
The precipitate of Ammoniated mercury (Final Product)contains ammonium hydroxide. Thus,
this precipitate is washed with cold water to remove ammonium hydroxide.
If it is not removed completely by washing with water, the final product may contain in it
Ammonium hydroxide as impurity.

25. 3) METHOD OR THE PROCESS USED IN THE
MANUFACTURE
 Many drugs and chemicals (usually organic) are manufactured from different raw materials,
by using different methods or processes.
 Some impurities are incorporated into the materials during the manufacturing process.
 The type and amount of impurity present in the drug/ chemical varies.
 In certain drugs , a multiple-step-synthesis procedure is used , which produces intermediate
compounds.
 The purification of intermediates is also important, otherwise the impurities present in the
intermediate will get incorporated in the final product.
 Usually side reactions occur during the synthesis.
 Impurities of the product side reactions also occur in the substances. This may introduce
new impurities due to contamination by reagents and solvents at various stages of the
process as described below:
a) Reagents employed in the process
b) Reagents added to remove other impurities
c) Solvents
d) Action of solvents and reagents on reaction vessels

26. 3) METHOD OR THE PROCESS USED IN THE
MANUFACTURE
a) Reagents employed in the manufacturing process:
 Soluble alkali in Calcium carbonate arises from sodium carbonate used in the process.
 Calcium carbonate is obtained by interaction of a soluble calcium salt and a soluble
carbonate and therefore the product will contain traces of soluble alkali, which the washing
process has failed to remove.
b) Reagents added to remove other impurities:
 Potassium bromide contains traces of Barium, which is added in the manufacturing process
to remove excess of sulphate.

27. 3) METHOD OR THE PROCESS USED IN THE
MANUFACTURE
C) Solvents: Water is the cheapest solvent available and has been used wherever possible.

28. 3) METHOD OR THE PROCESS USED IN THE
MANUFACTURE
d) Action of solvents and reagents on reaction vessels:
 During manufacturing process, some of the solvents and reagent may undergo reaction
with metals of reaction vessel and may dissolve these metals, which appear as impurities in
the final product.
 Example:
 Iron is known to contain Arsenic impurity.
 The inorganic compounds manufactured in Iron vessel will contain Arsenic and Iron as
impurities.
 Thus IP has prescribed limit test for Arsenic and Iron for most inorganic compounds.
Iron vessel

29. 4) CHEMICAL PROCESS USED IN THE
MANUFACTURE
 For the synthesis of drugs, many chemical reactions such as Nitration, Halogenation, Oxidation,
reduction, hydrolysis are involved.
 In these chemical processes, different chemicals are used.
 Tap water is generally used in the various processes and it is often having Cl-,Mg+2, Ca+2 ions,
which are generally found in the substance which is being manufactured.

30. 5) ATMOSPHERIC CONTAMINATION DURING THE
MANUFACTURING PROCESS
 In the industrial areas, the atmosphere is contaminated with dust particles and some gases
like Hydrogen sulphide, Sulphur dioxide, and black smoke.
 During the manufacture or purification of the pharmaceutical products, these impurities
enter the final products.
 There are many pharmaceutical products which when manufactured are contaminated with
atmospheric CO2 and water vapor. E.g. NaOH absorbs atmospheric CO2.
 2NaOH + CO2 --------------------------------→ Na2CO3 + H2O
 Due to this reaction, NaOH should not be kept open for a longer time during its
manufacture.
 Therefore, IP has prescribed that Sodium hydroxide should not contain more than 3% of
sodium carbonate.

31. 6) DEFECTS IN THE MANUFACTURING PROCESS
 In many manufacturing processes, there are defects like imperfect mixing, incompleteness,
non-adherence to proper temperature, pressure, pH or reaction conditions, which may give
chemical compounds with impurities in them.
 Example:
 Zinc oxide may be prepared by heating metallic zinc to bright redness in a current of air. The
vapours of Zinc burn to form Zinc oxide which is collected as a fine white powder.
 But if there is less heat or air or both, zinc metal is not completely converted to zinc oxide.
 Thus the final product, Zinc oxide may still contain metallic zinc as impurity.
 So, IP has prescribed a test for Zinc metal in zinc oxide.

32. 7) INTERMEDIATE PRODUCTS IN THE
MANUFACTURING PROCESS
 There are some intermediates which are produced during the manufacturing process.
 Sometimes these intermediates may be carried through to the final product as impurity.
 Example:
Potassium iodide is prepared by reacting Iodine with Potassium hydroxide.
6KOH+ 3I2-------------------- 5KI + KIO3 +3H2O
The resulting solution is first evaporated and then heated with charcoal.
KIO3 + 3C---------- KI + 3CO
 In this process if the intermediate product (KIO3) is not completely converted into KI,
then it may be carried through to the final product as an impurity.

33. 8) MANUFACTURING HAZARDS

34. 8) MANUFACTURING HAZARDS
 Particulate contamination:
 The presence of unwanted particulate matter can arise due to dirt, dust, glass, porcelain
or plastic fragments from sieves, granulating or tableting machines or from product
containers.
 Ware and tare of equipment or improperly cleaned equipment may also cause particulate
contamination.
 Clarity of solutions for injection is particularly important.
 E.g. Metal particles which have been found in eye ointments packed in metal tubes.

35. 8) MANUFACTURING HAZARDS
 Process errors:
 Gross errors arising from incomplete solution of a solute in a liquid preparation must be
detected readily by the normal analytical control procedures.
 Minor errors arise if the manufacturing tolerance for the quantity of active ingredient in
the product has been wide.
 Cross contamination:
 The handling of powders, granules, and tablets in large bulk creates air-borne dust, which
leads to cross contamination of the product.
 So, face masks and special extraction equipment are used to protect operators from
harmful effects of drugs.
 E.g penicillin preparation requires special handling during its manufacture.

36. 8) MANUFACTURING HAZARDS

37. 8) MANUFACTURING HAZARDS
 Microbial contamination:
 Parenteral preparations and ophthalmic preparations require special care against microbial
contamination.
 Many liquid preparations and creams are liable to bacterial and fungal contamination. So care
should be taken.
 E.g. Acacia, senna, tragacanth---→They should be controlled for Salmonellae.
 Packing errors:
 Products of similar appearance such as tablets of same size, shape, colour packed in similar
containers can constitute a potential source of danger.
 Improper labelling or destruction of stock of unused labels also constitutes a major packaging
hazard.

38. 9) STORAGE CONDITIONS
 The chemical substances when prepared have to be stored in different types of containers depending upon:
 Nature of the material
 Batch size
 Quantity
 Many types of materials are used for storage purpose like plastic, polythene, iron vessels, stainless steel and
aluminum.
 Leaching out effect: Alkalis stored in ordinary glass containers extract lead from it, which in found as
impurity in the final product.
 Strong chemicals react with iron containers and extract Iron an impurity in final product.

39. 9) STORAGE CONDITIONS
 Inadequate storage and their effects are as follows:
a) Filth: Stored products may become contaminated with dust, bodies of insects, animal and
insect excreta.
b) Chemical instability: decomposition because of light, traces of acid or alkali, air
oxidation, water vapor, CO2 and traces of metallic ions. e.g light sensitive materials
should be stored in amber colored bottles.
c) Reactions with container materials: e.g salicylic acid ointment must not be stored in
metal tubes.
d) Physical changes: The occurance of changes in the physical form of drug like change in
crystal size can lead to change in efficiency of product.
e) Temperature effect: Chemical and physical changes occur if materials are not stored at
proper temperature.

40. 10) DECOMPOSITION OF THE PRODUCT
DURING STORAGE
 Chemical decomposition, analysis or breakdown is the separation of a chemical compound
into elements or simpler compounds. It is sometimes defined as the exact opposite of a
chemical synthesis. Chemical decomposition is often an undesired chemical reaction.
 Some substances decompose on storing due to presence of air, light and oxygen. So, the
final product is contaminated.
 Deliquescent substances, absorb water from the atmosphere and get liquefied.
 Decomposition products appear as impurities in the substances.

41. 11) ACCIDENTAL SUBSTITUTION OR
DELIBERATE ADULTERATION WITH SPURIOUS
OR USELESS MATERIALS
 It is possible to avoid accidental substitution by storing the toxic substances together
separately or in a locked cupboard.
 Many pharmaceutical chemicals are adulterated with cheaper substances.
 E.g. The expensive potassium may be adulterated with sodium bromide.

42. ELEMENTAL IMPURITIES
 Elemental impurities: Elemental impurities include catalysts and environmental
contaminants that may be present in drug substances, excipients, or drug products.
These impuri-ties may occur naturally, be added intentionally, or be introduced
inadvertently (e.g., by interactions with processing equip-ment and the container
closure system).

43. ELEMENTS CLASSIFICATION
 Class 1 (As, Cd, Hg, and Pb)
 Human toxicants with limited or no use in pharmaceutical manufacturing
 Class 2
 Toxicity is dependent on the administration route
 Class 2A (Co, Ni, V)
• Relatively high probability of occurrence
 Class 2B (Ag, Au, Ir, Os, Pd, Pt, Rh, Ru, Se, Tl)
• Relatively low probability of occurrence
 Class 3 (Ba, Cr, Cu, Li, Mo, Sb, Sn)
• Relatively low toxicities (high PDEs) by oral administration, but may require
consideration in the risk assessment for inhalation and parenteral routes
• Other elements do not have established PDEs but may need to be considered include: Al, B,
Ca, Fe, K, Mg, Mn, Na, W, and Zn

44. SOURCE OF ELEMENTAL IMPURITIES
 Residual catalysts added in synthesis
 May be present as impurities
 Arising from processing equipment
 Leaching from container/closure systems

45. ICH elements and limits, R/A: Risk Assessment, these are
elements that need to be considered as part of the risk element

46. RESIDUAL SOLVENT (RS)
 Residual solvents in drug substances, excipients, and in drug products (also
referred to as organic volatile impurities or OVIs) are considered impurities that
are not removed during product purification and are possibly left over from the
manufacture of active pharmaceutical ingredients (APIs) or drug substances and
excipients or the formulation of drug products. They can also possibly be formed
during packaging or storage. Drug products should contain no higher levels of
residual solvents than can be supported by safety data.

47. CLASSIFICATION OF RESIDUAL SOLVENTS BY
RISK ASSESSMENT
Residual
Solvent Class
Assessment
Class 1
Solvents to be avoided
Known human carcinogens
Strongly suspected human carcinogens
Environmental hazards
Class 2
Solvents to be limited
Nongenotoxic animal carcinogens or possible causative agents of other irreversible
toxicity, such as neurotoxicity or teratogenicity.
Solvents suspected of other significant but reversible toxicities.
Class 3
Solvents with low toxic potential
Solvents with low toxic potential to humans; no health-based exposure limit is
needed. [NOTE—Class 3 residual solvents have PDEs of 50 mg or more per day.]*

48. LIMITS OF RESIDUAL SOLVENTS

49. EFFECT OF IMPURITIES
 The impurities present in the substances may give following effects:
 Impurities having toxic effects may be injurious to health, if present above certain limits.
 Traces of impurities, may exert a cumulative toxic effect after a certain time.
 Impurities may lower the active strength of the substance.
 Impurity may decrease shelf life of substance.
 Impurity may cause incompatibility with other substances.
 Impurities may cause a physical or chemical change in the properties of the substance, so
making the substance medicinally useless.
 May cause change in color, odour and taste.

51. Any Questions ?