Impurities in pharmaceutical products: How, Why, Characterize and Acceptance criteria

ABSTRACT:

The purpose of this article is to provide a practical framework that is applicable to the identification, categorization and control of impurities. This guidance emphasizes considerations of both safety and quality risk management in establishing levels of impurities that are expected to pose negligible risk. It outlines recommendations for assessment and control of impurities that reside or are reasonably expected to reside in final drug substance or product, taking into consideration the intended conditions of human use. This article will describe How, Why, Characterization and control for determining the impurities based on their properties.

Keywords: impurities, acceptance criteria process-related impurities (PRIs), degradation-related impurities (DRIs), Classification, Permitted Daily Exposure(PDE), residual solvents.

INTRODUCTION:

There are number of possible reasons for impurities in pharmaceutical products which are involved either related to process-related impurities (PRIs) or degradation-related impurities (DRIs).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.

Control and determination of these impurities at parts-per-million or parts-per-billion levels are significant challenges for analysts. When developing synthetic routes to APIs, it is the primary responsibility of laboratory personnel to identify the stages in which impurity generation can occur. The analyst must also identify and determine the impurities and control them at the stages of formation.

DISCUSSION:

CLASSIFICATION OF  IMPURITIES IN PHARMACEUTICALS:

According to the definitions of International Council for Harmonization (ICH), Food and Drug Administration (FDA), and USP, impurities are classified into DRIs, PRIs, residual solvents, and heavy metals as shown in below¹:

DETERMINATION OF  IMPURITIES IN PHARMACEUTICALS:

The below Flow chart represents ² the various steps was involved to characterize the impurities in a Drug.

STRATEGIES TO ESTABLISH ANALYTICAL METHODS AND ACCEPTANCE CRITERIA OF PRIs AND DRIs:

Analytical methods and acceptance criteria of process-related impurities (PRIs) and degradation-related

impurities (DRIs) according to the requirements of ICH as shown in  below¹

     CLASSIFICATION OF ELEMENTAL IMPURITIES AS PER  ICH Q3W:

·      Class 1: The elements in this class As, Cd, Hg&Pb, are human toxicants; testing should only be applied when the risk assessment identifies.

·       Class 2: Elements in this class are generally considered as human toxicants are route-dependent.

Ø  Class 2A: The elements in this class Co, Ni and V have relatively high probability of occurrence in the drug products.

Ø  Class 2B: The elements in this class Ag, Au, Ir, Os, Pd, Pt, Rh, Ru, Se and Ti have a reduced probability of occurrence in the drug product related to their low abundance and low potential, they may be intentionally added during the manufacture.

·     Class 3: The elements in this class Ba, Cr, Cu, Li, Mo, Sb and Sn have relatively low       toxicities.

ELEMENTS TO BE CONSIDERED IN A RISK ASSESSMENT:

     Elements level is a critical quality attribute for a drug substance or a drug product. Elements control is one of the most important tasks in a process scale up. Below data Adapted from International Conference on harmonization guideline for elemental impurities Q3D current Step 4 versions (December 16, 2014)³

Element	Class	If intentionally added (all routes)	If not intentionally added
			Oral	Parental	Inhalation
Cd	1	Yes	yes	yes	Yes
Pb	1	Yes	yes	yes	Yes
As	1	Yes	yes	yes	Yes
Hg	1	Yes	yes	yes	Yes
Co	2A	Yes	yes	yes	Yes
V	2A	Yes	yes	yes	Yes
Ni	2A	Yes	yes	yes	Yes
Tl	2B	Yes	no	no	No
Au	2B	Yes	no	no	No
Pd	2B	Yes	no	no	No
Ir	2B	Yes	no	no	No
Os	2B	Yes	no	no	No
Rh	2B	Yes	no	no	No
Ru	2B	Yes	no	no	No
Se	2B	Yes	no	no	No
Ag	2B	Yes	no	no	No
Pt	2B	Yes	no	no	No
Li	3	Yes	no	yes	Yes
Sb	3	Yes	no	yes	Yes
Ba	3	Yes	no	no	Yes
Mo	3	Yes	no	no	Yes
Cu	3	Yes	no	yes	Yes
Sn	3	Yes	no	no	Yes
Cr	3	Yes	no	no	Yes

PERMITTED DAILY EXPOSURES (PDEs) FOR ELEMENTAL IMPURITIES:

Directive ICH Q3D sets out a list of 24 elements divided into four categories (classes 1, 2A, 2B and 3), in relation to their toxicity and their probability of occurrence and the maximum permitted daily exposure (PDE: Permitted Daily Exposure) for each impurity according to the administration route (µg / day). Below data Adapted from International Conference on harmonization guideline for elemental impurities Q3D Current Step 4 versions (December 16, 2014) ³

Element	Class	Oral PDE µg/day	Parental PDE µg/day	Inhalation PDE µg/day
Cd	1	5	2	3
Pb	1	5	5	5
As	1	15	15	2
Hg	1	30	3	1
Co	2A	50	5	3
V	2A	100	10	1
Ni	2A	200	20	5
Tl	2B	8	8	8
Au	2B	100	100	1
Pd	2B	100	10	1
Ir	2B	100	10	1
Os	2B	100	10	1
Rh	2B	100	10	1
Ru	2B	100	10	1
Se	2B	150	80	130
Ag	2B	150	10	7
Pt	2B	100	10	1
Li	3	550	250	25
Sb	3	1200	90	20
Ba	3	1400	700	300
Mo	3	3000	1500	10
Cu	3	3000	300	30
Sn	3	6000	600	60
Cr	3	11000	1100	3

 

CLASSIFICATION OF RESIDUAL SOLVENTS AND THEIR ASSESSMENTS^5,6:

Residual solvents are used in manufacture either to enhance the yield or determine characteristics of the substances such as crystal form, purity and solubility. There is no therapeutic benefit from residual solvents. Since there is no therapeutic benefit from residual solvents should be removed to the extent possible to meet product specifications, good manufacturing practices, or other quality-based requirements. ICH Q3C and USP <467> are harmonized in their approach with a salient exception: whereas ICH Q3C applies only to new drug products, USP <467> applies the same requirements to all new and existing drug products⁴.

Residual solvents classes	Assessment
Class 1(Solvents to be avoided)	known human carcinogens
	strongly suspected human carcinogens solvents particularly known to have ozone-depleting properties.
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 man; no health-based exposure limit is needed.

LIMIT OF RESIDUAL SOLVENTS:

CLASS 1: SOLVENTS TO BE AVOIDED:

Class 1 residual solvents should not be used in the manufacture of drug substances, excipients, dietry ingredients because of their unacceptable toxicities deleterious environmental effects.

 

However if their use in order to produce an official products with a significant therapeutic advance is unavoidable, their levels should be restricted as shown in below table, unless otherwise individual monograph. The solvent 1,1,1-trichloroethane is included in below table because it is a severe environmental hazard. The sated limit is 1500 ppm is based on a review of safety data⁴. 

Solvent	Concentration Limit(ppm)	Concern
Benzene	2	Carcinogen
Carbon tetrachloride	4	Toxic and environment hazard.
1,2-Dichloroethane	5	Toxic
1,1-Dichloroethene	8	Toxic
1,1,1-Trichloroethane	1500	Environmental hazard.

CLASS 2: SOLVENTS TO BE LIMITED:

Class 2 residual solvents should be limited in drug substances, excipients, dietry ingredients because of the inherent toxicities of these residual solvents.PDEs are given to the nearest 0.1mg/day and concentrations are given to the nearest 10ppm⁴. 

Solvent	PDE(mg/day)	Concentration Limit(ppm)
Acetonitrile	4.1	410
Chlorobenzene	3.6	360
Chloroform	0.6	60
Cumene	0.7	70
Cyclohexane	38.8	3880
1,2-Dichloroethene	18.7	1870
1,2-Dimethoxyethane	1.0	100
N,N-Dimethylacetamide	10.9	1090
N,N-Dimethylformamide	8.8	880
1,4-Dioxane	3.8	380
2-Ethoxyethanol	1.6	160
Ethylene glycol	6.2	620
Formamide	2.2	220
Hexane	2.9	290
Methanol	30.0	3000
2-Methoxyethanol	0.5	50
Methylbutyl ketone	0.5	50
Methylisobutyl ketone	45	4500(official 1st dec.2020)
Methylcyclohexane	11.8	1180
Methylene Chloride	6.0	600
N-Methylpyrrolidone	5.3	530
Nitromethane	0.5	50
Pyridine	2.0	200
Sulfolane	1.6	160
Tetrahydrofuran	7.2	720
Tetralin	1.0	100
Toluene	8.9	890
1,1,2-Trichloroethene	0.8	80
Xylene(usually 60%m xylene,14%p-xylene and 9%o-xylene  with 17% ethyl benzene)	21.7	2170

CLASS 3: SOLVENTS WITH LOW TOXIC POTENTIAL:

Class 3 solvents are regarded as less toxic and of lower risk to human health than class 1 and class 2 residual solvents. Class 3 includes no solvent known to be a human health hazard at levels normally accepted in pharmaceuticals. However, there are no long- term toxicity or carcinogenicity studies for many of residual solvents in class 3.Available data indicate that they are less toxic in acute or short term studies and negative in genotoxicity studies.

It is considered that amounts of these residual solvents of 50mg/day or less of each solvent (corresponding 5000ppm or 0.5%w/w) would be acceptable for each solvent without justification. Higher amounts may also be acceptable, provided that they are realistic in relation to manufacturing capabilities and good manufacturing practice. If a class 3 solvent limit in an individual monograph is greater than 0.5%, that residual solvent should be identified and quantified⁴.

Acetic acid	Isobutyl acetate
Acetone	Isopropyl acetate
Anisole	Methyl acetate
1-Butanol	3-Methyl-1-butanol
2-Butanol	Methylbutyl ketone
Butyl acetate	Cumene
tert-Butylmethyl ether	2-Methyl-1-propanol
Dimethyl sulfoxide	Pentane
Ethanol	1-Pentanol
Ethyl acetate	1-Propanol
Ethyl ether	2-Propanol
Ethyl formate	Propyl acetate
Formic acid	Triethylamine (official 1st dec.2020)
Heptane

CONCLUSION:

This review provides a perspective on impurities in drug substance and drug product. Impurity profile of pharmaceuticals is receiving an increasing importance and drug safety receives more and more attention from the public and from the media. This article provides the valuable information about the impurities types and its classification, various techniques of isolation and characterization, analytical techniques for the determination, qualification of impurities and critical factors to be considered while preparation of the bulk drugs. Now a day, it is mandatory requirement in various pharmacopoeias to know the impurities present in API’s. Isolation and characterization of impurities is required for acquiring and evaluating data that establishes biological safety which reveals the need and scope of impurity profiling of drugs in pharmaceutical research.

FUNDING:

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

CONFLICT OF INTEREST:

The author declares that he does not have any financial and personal relationships with other people or any other organizations that could inappropriately influence this research work

 QUERY:

Ask if you have any Query visit  http://pharmasolution1.blogspot.com, I revert back to you with solution. To learn more always visit and connect with Pharma solutions by Dr. Ajay

REFERENCES:

1.   Kung-Tien Liu and Chien-Hsin Chen "Determination of impurities in pharmaceuticals". 
2.  Rahman, H. Azmi and N. Wu, “Accrediation in Quality Assurance”, 2006.
3.  International Conference on harmonization guideline for elemental impurities Q3D current Step 4 versions (December 16, 2014).
4. © 2019 The United State Pharmacopeial Convention.
5. Ajay Kumar Singh “Effect of Aqua- Organic medium on lon-dipole type Reactions” in ARJP.
6. Ajay Kumar Singh “A study of alkaline Hydrolysis of ethyl isonicotinate” in ARJP.    

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About the Author:

Dr. Ajay Kumar Singh, M.Sc. (Gold Medalist), Ph.D. is the author and founder of “Pharma Solutions by Dr. Ajay”.

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