Organic Impurities present in Pharmaceuticals and Food Products

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TheOrganic Impurities in Pharmaceuticals:

The impurities in drug are unwanted chemicals that remains with the active pharmaceutical ingredients (API), develop during formulation and upon aging of API/drug products.The presence of these unwanted chemicals even in trace amount may influence the efficacy and safety of pharmaceutical products.

These impurities often posses unwanted pharmacological or toxicological effects by which any benefits from their administration may be outweighed [1]. The composition of impurities allows one to draw conclusions regarding the manufacturing of the products and its adulteration, which is becoming widespread in all countries of the world therefore, it is necessary to strictly control the quality of pharmaceutical products and to determine the concentration of foreign impurities at all stages of production from raw materials to finished medicinal forms [1, 2].

Impurities in drugs are originated from various sources and phases of the synthetic process and preparation of pharmaceutical dosages forms. However majority of the impurities are characteristics of the synthetic route of the manufacturing process. Since there are several possibilities of synthesizing a drug, it is possible that the same product of different sources may give rise to different impurities. According to the international conference on harmonization (ICH) of technical requirements for registration of pharmaceuticals for human use, impurities are classified as organic impurities, inorganic impurities and residual solvents. Organic impurities may arise from starting materials, by products, synthetic intermediates and degradation products. Inorganic impurities may derived from the manufacturing process and are normally known and identified as reagents , ligands, inorganic salts, heavy metal, catalysts, filter aids and charcoal etc. Residual solvents are the impurities introduced with solvents [1, 2, 3, 4, 5 and 6].

Of the above three groups, the no. of possible inorganic impurities and residual solvents is limited. These are easily identified and their physiological effects and toxicity are well known. For this reason the limits set by the pharmacopoeias and the ICH guidelines can guarantee that the harmful effects of these impurities do not contribute to the toxicity or the side effects of the drug substances. The situation is not so simple with the organic impurities. Especially in the case of drugs prepared by multi-step synthesis, their number and the variety of their structures are almost unlimited and highly dependent on the route and reaction conditions of the syntheses and several other factors such as the purity of the starting material, method of isolation, purification, conditions of storage etc. In addition to this, toxicity is unknown or not easily predictable. For this reason the ICH guideline set threshold above which the identification of the impurity is obligatory. Drug registration authorities require not only the identification of the impurities above these thresholds but also a rationale should be presented explaining the origin of the impurities [1, 2 and 7].

Sources of Organic Impurities:

Organic impurities may arise during the manufacturing process and/or storage of the drug substance. They are derived from drug substance synthetic processes and degradation reactions in drug substances and drug products. Synthetic process related impurities can be derived from starting materials, intermediates, reagents, ligands, and catalysts used in the chemical synthesis, as well as by-products from the side-reactions of the chemical synthesis [8]. Degradation products are derived from the chemical degradation of drug substances and drug products under storage or stress conditions. They may be identified or unidentified, volatile or non-volatile, and include the following [6]:

A) Impurities Originating from Drug Substance Synthetic Processes:

Most small molecule drug substances are chemically synthesized. Chemical entities, other than the drug substance, that are involved or produced in the synthetic process can be carried over to the final drug substance as trace level impurities. These chemical entities include raw materials, intermediates, solvents, chemical reagents, catalysts, by-products, impurities present in the starting materials, and chemical entities formed from those starting material impurities (particularly those involved in the last steps of the synthesis). These impurities are usually referred to as process impurities [8]. The goal of process impurity identification is to determine the structures and origins of these impurities. This knowledge is critical for improving the synthetic chemical process, in order to eliminate or minimize process impurities [9].

• Starting Materials and Intermediates:

Starting materials and intermediates are the chemical building blocks used to construct the final form of a drug substance molecule. Unreacted starting materials and intermediates, particularly those involved in the last a fewsteps of the synthesis, can potentially survive the synthetic and purification process and appear in the final product as impurities [10, 11]. For example, in the synthesis of tipranavir drug substance, the “aniline” is the intermediate in the last step of the synthesis. Because the similarity between the structures of the “aniline” and the final product, it is difficult to totally eliminate it in the subsequent purification step. Consequently, it appears in the drug substance at around 0.1% [12].

• Impurities in the Starting Materials:

Impurities present in the staring materials could follow the same reaction pathways as the starting material itself, and the reaction products could carry over to the final product as process impurities. Knowledge of the impurities in starting materials helps to identify related impurities in the final product, and to understand the formation mechanisms of these related process impurities [8, 11 and 12]. One such example is the presence of a 4-trifluoromethyl positional isomer in 3-trifluoromethyl-a-ethylbenzhydrol (flumecinol), due to the presence of 4-trifluoromethylbenzene impurity in the starting material, 3-trifluoromethylbenzene. A second example involves a 2-methyl analogue present as a trace impurity in tolperisone, due to the presence of 2-methylpropiophenone in the starting material, 4-methylpropiophenone [7].

• Reagents, Ligands and Catalysts:

These chemicals are less commonly found in APIs; however, in some cases they may pose a problem as impurities [6, 7].

Chemical reagents, ligands, and catalysts used in the synthesis of a drug substance can be carried over to the final products as trace level impurities. For example, carbonic acid chloromethyl tetrahydro-pyran-4-yl ester (CCMTHP), which is used as an alkylating agent in the synthesis of a ß lactam drug substance, was observed in the final product as an impurity. Many chemical reactions are promoted by metal based catalysts. For instance, a Ziegler-Natta catalyst contains titanium, Grubb’s catalyst contains ruthenium, and Adam’s catalyst contains platinum. In some cases, reagents or catalysts may react with intermediates or final products to form by-products. Pyridine, a catalyst used in the course of synthesis of mazipredone, reacts with an intermediate to form a pyridinium impurity [8].

• By-Products of the Synthesis:

The selectivity of a chemical reaction is rarely 100%, and side-reactions are common during the synthesis of drug substances. By-products from the side reactions are among the most common process impurities in drugs [6]. By-products can be formed through a variety of side reactions, such as incomplete reaction, overreaction, isomerization, dimerization, rearrangement, or unwanted reactions between starting materials or intermediates with chemical reagents or catalysts [8].

• Products of over-reaction:

In many cases the least or previous steps of the syntheses are not selective enough and the reagents attack the intermediate not only at the desired site. For e.g. in the synthesis of nanodralone decanoate, the last step of the synthesis is the decanoylation of the 17 –OH group. In the course of overreaction the reagents also attacts the 4ene- 3 oxo group leading to an enol ester- type impurity (3, 17β- dihydroxyestra-3, 5- diene disdecanoate) [7, 9].

• Products of side reactions:

Some of the frequently occurring side reactions ( which are unavoidable in drug synthesis) are well- known to the synthetic chemist; other which lead to trace level impurities have to be detected and elucidated during impurity profiling. The formation of diketopiperazine derivative is a typical side reaction in peptide synthesis [7].

•Impurities originated from reaction solvents:

Some solvents which are the part of the reaction act as a source of impurities. For e.g. Methylene chloride, which is often used as the solvent of friedel- craft acylation of benzene or phenyl derivatives. Impurities in the solvents can also be source of impurities. For e.g. 2-hydroxytetrahydrofuran is an impurity in tetrahydrofuran, which is often used as the solvent of Grignard reagents [7].

B) Impurities Originating from Degradation of the Drug Substance:

Impurities can also be formed by degradation of the end product during manufacturing of bulk drugs. However, degradation products resulting from storage or formulation to different dosage forms or aging are common impurities in the medicines [6]. The definition of degradation product in the ICH guideline is a molecule resulting from a chemical change in the substance brought about by overtime and/or action of e.g. Light, temperature, pH or water or by reaction with excipient and/or the intermediate container closure system [7, 13]. For example in the case of aspartame, in the presence of moisture, hydrolysis occurs to form the degradation products i.e. L- aspartyl- L- Phenyalanine and 3-benzyl-6-carboxymethyl 2, 5-diketopierazine.Third degradation product is also known, β-L- aspartyl-L-phenylalanine methyl ester. Aspartame degradation also occurs during prolong heat treatment [7].

Enantiomeric Impurities:

The majority of therapeutic chiral drugs used as pure enantiomers are natural products. The high level of enantioselectivity of their biosyntheses excludes the possibility of the presence of enantiomeric impurities [6]. In the case of synthetic chiral drugs, the racemates which is usually marketed, if the pure enantiomer is administered, the antipode is considered to be an impurity. The reason for its presence can be either the incomplete enantioselectivity of the syntheses or incomplete resolution of the enantiomers of the racemate [3, 14]. Although the ICH guideline excludes enantiomeric impurities, pharmacopoeias consider them as ordinary impurities [7].

A single enantiomeric form of chiral drug is now considered as an improved chemical entity that may offer a better pharmacological profile and an increased therapeutic index with a more favourable adverse reaction profile. However, the pharmacokinetic profile of levofloxacin (S- Isomeric form) and ofloxacin (R- isomeric form) are comparable, suggesting the lack of advantages of single isomer in this regard [6, 7].

Typical examples of drugs containing enantiomeric impurities:

a) Dexchlorophenarmine maleate (R enantiomer impurity allowed NMT 0.5%)

b) Timolol maleate (R enantiomer impurity allowed NMT 1%)

c) Clopidogrel sulphate (R enantiomer impurity allowed NMT 1%) (Vishweshwar et al., 2002)

In general, an individual API may contain all of the above-mentioned types of organic impurities at levels varying from negligible to significant [6].

Pharmacopoeial Status:

The quality of a chemical active substance with respect to organic impurities is controlled by a set of tests within a pharmacopoeial monograph. Individual monographs are periodically updated to keep pace with scientific progress and regulatory developments. Following the revised ICH Q3A impurity testing guideline major pharmacopoeias will continue publishing new or revised relevant monographs and general chapters. Active substances found to contain an organic impurity not detected by the relevant pharmacopoeial tests prescribed below are not of pharmacopoeial quality, unless the amount and the nature of this impurity are compatible with GMP [15].

Two general chapters (<466> & <1086>) of the US Pharmacopoeia (USP) deal with organic impurity testing. Concepts and definitions are clearly described although a somewhat different terminology from that of ICH is used. Until now, one of three types of tests in bulk pharmaceutical chemicals is ordered:

1. A chromatographic purity test coupled with a non- specific assay

2. A chromatographic purity- indicating method that also serves as an assay

3. A specific limit test for known impurities, a procedure that requires reference standards for these impurities [16].

In the future, new and revised USP individual monographs will include tests that actually control specified and unspecified organic impurities. Where different routes of synthesis yield different impurity profile, different analytical procedures will be proposed. All specified impurities will be separately limited, with a further limit of 0.10% for any unspecified (unknown) impurity. Total impurities above the disregard limit should be less than 1.0%. USP also proposes that a suitable test for detecting impurities that may have been introduced from extraneous sources should be employed in addition to tests provided in a specific monograph [14, 15 and 16].

The European Commission decided that the principles and terminology of the revised ICH Q3A should be implemented in the European Pharmacopoeia (EP) monographs of the active substances; both new and already published [17]. A new general chapter concerning the control of impurities in pharmaceutical substances was introduced in the fifth edition of the EP, while a revision of the monograph entitled Substances for Pharmaceutical Use has also been done. According to the policy of EP control of the relevant organic impurities in synthetic drug substances is often accomplished by the test of related substances. Currently, it is a limit test (comparison of the peak areas), but will progressively be changed to utilize a quantitative acceptance criterion [3, 18].

Some individual monographs already satisfy this demand. More tests are ordered, if the general test does not control a given impurity or there are other special reasons [17]. Potential impurities with a defined structure that are known to be detected by the tests in a monograph, but are not known to be present in medicinal substances above the identification threshold, are referred to as detectable impurities. They are limited by a general acceptance criterion [18]. EP individual monographs published in the new format include a separate section in which all impurities (specified and detected) are listed. Unidentified specified impurities are not listed in this section, but their specific acceptance criteria along with appropriate analytical characteristics (e.g., retention time) are reported in the text, wherever it is applicable [14].

However, previous EP monographs not having a related substances test in the new explicit style are to be read and interpreted according to the recent amendments. During the coming years, EP individual monographs now published in the old format will be revised to contain related substances tests and lists on specified and other detectable impurities. Monographs containing tests for related substances based on TLC will also be revised [3, 14, 17 and 18].

Pharmacopoeial Norms for the Enantiomeric Impurities:

B.P 2001 has recommended following norms for the enantiomerically pure drug substance. It describes the way in which the stereochemistry of a substance is identified and/or controlled.

1- Many medicinal substances that contain one or more chiral centres and that are already on the market have been made available for pharmaceutical use as recimic mixtures with little known about the biological activities of the separate isomers.this has been reflected in the monograph in the pharmacopoeia and a test to show that the substance is a recimic mixture has not usually been included unless it was known that at least one of the separate enantiomers was also available commercially. Nevertheless, with increasing concern by regulatory authorities for substances to be made available as single isomers, tests for enantiomeric composition will become more common [10].

Chemical definition (monographs other than those of the European pharmacopoeia)

1-In the case of substances containing a single chiral centre, the descriptor ‘(RS)’-Iis included at the appropriate position in the chemical definition of the substances to indicate a recimic mixture.

2- For substances containing multiple chiral centuries and comprising mixture of all possible stereomers the term ‘all-rec’ has been used, for example Isoaminile. In those few substances existing as diastereomeric mixtures, that is where in one or more centres the stereochemistry is explicit but in other centres it is not, each centre is defined either as the specific (R)- or (S) – configuration , or as recimic (RS)-, respectively.


3- In future, when a monograph describes an enantiomer, it will include both a test for specific optical rotation under identication and atest using methods such as chiral chromatography, to control enantiomeric purity.

4- When both the recimic mixture and the enantiomer are available, the monograph for the recimic mixture will specify a test for angle of rotation together with a cross reference under identification. The test for angle of rotation will normally specify limits of +0.10° to -0.10°in order to limit the presence of optically active impurities and demonstrate equal proportions of the enantiomers.

5- When only the recimic mixture is available, the monograph for the recimic mixture will simply specify a test for angle of rotation [10, 19].

ICH Guideline:

According to ICH Guideline, each impurity must be investigated with respect to both chemistry and safety aspects. The former include identification (structural characterization), reporting and quantitation using suitable analytical procedures, while the latter include a process of acquiring and evaluating data concerning the biological safety of an impurity (qualification). Individually listed impurities, limited with specific acceptance criteria, are referred to as specified and they can be either identified or unidentified.

Unspecified impurities are limited by a general acceptance criterion. A decision tree for the identification and qualification along with the corresponding thresholds, which are dependent on the maximum permitted daily dose (MDD), is given by ICH. Summing up, the following list of organic impurities must be presented in the specification of a synthetic drug substance:

- Each specified identified or unidentified impurity

- Any unspecified impurity

- Total impurity

Specified unidentified impurities are referred to by an appropriate qualitative analytical description (e.g. relative retention time) [3, 4, 13, 14 and 20].

Control of Organic Impurities:

Control of the organic impurities in new drug substances is based on the Maximum Daily Dose and total daily intake (TDI) of the impurities. Table 3.1 provides the ICH threshold for control of the organic impurities in new drug substances. Depending on whether the Maximum Daily Dose is higher or lower than 2g, organic impurities in a new drug substance at (or greater than) 0.05% or 0.1% requires identification. Control of organic impurities in new drug products are outlined in Table 3.2. Based on the Maximum Daily Dose, the identification thresholds for organic impurities in new drug products are divided into 4 groups to give more consideration to low dose drug products. For most new drug products, the Maximum Daily Dose is between 10 mg–2 g/day, therefore, any impurities at 0.2% or greater would have to be identified [5, 8 and 13].

Table 3.1 Organic impurity Threshold in new drug substances based on ICHQ3A [4, 5 and 20]

Maximum daily dose1



Identification Threshold2,3

Qualification Threshold2,3






0.1 or 1.0mg/day intake (whichever is lower)



0.15% or 1.0mg/day (whichever is lower)


> 2g/day








Note: 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

Table 3.2 Organic impurity Threshold in new drug products based on ICH Q3B [4, 13 and 20]

Reporting Thresholds

Maximum Daily Dose 1


≤1 g


> 1 g



Identification Thresholds

Maximum Daily Dose1


< 1 mg

1.0% or 5 µg TDI, whichever is lower

1mg – 10mg

0.5% or 20 µg TDI, whichever is lower

>10 mg - 2 g

0.2% or 2 mg TDI, whichever is lower

> 2 g



Qualification Thresholds

Maximum Daily Dose 1


< 10 mg

1.0% or 50 µg 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


Note: TDI – total daily intake
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.

Identification of impurities is an analytical activity aiming to elucidate the chemical structures and the possible mechanisms of formation of unknown impurities observed during various phases of the drug development process [8, 9]. A description of the identified and unidentified existing impurities in a chemical drug substance is referred to as the impurity profile (IP). Impurity profiling includes the procedure aimed at the detection, structure elucidation/identification and the quantitative determination of impurities [3, 14].

According to current requirements, the concentration of detectable and identifiable organic impurities in new pharmaceutical preparation must be no higher than 0.05 – 0.1% depending on the preparation the determination of impurities at lower level ( 10-3% and below) is necessary only in rare cases; however, on the accumulation of the data on the detrimental effect of impurities that occurs in pharmaceutical preparations even at a level of 10-4% - 10-3%, the decrease in the detection limits of different methods for the determination of impurities become more important [2].

Impurity profiling of drug substances and drug formulation begin with the detection of the impurities. The most frequently used method for this are thin layer chromatography (TLC), high performance liquid chromatography (HPLC), but in case of volatile, thermally stable materials, Gas chromatography (GC) also plays an important role [21]. Other chromatographic and electrophoretic techniques such as supercritical fluid chromatography, capillary electrophoresis and capillary electrochromatography can also be used. Mass spectroscopy (MS) and high resolution nuclear magnetic resonance (NMR) can also contribute to the detection of the impurities [7]. The next step is the attempted identification of impurities by retention matching with potential impurities using 2-3 separation methods with different retention mechanisms. If the retention matching is not successful, the identification/ structure elucidation is carried out by means of the joint application of chromatographic and spectroscopic techniques. The final proof of the structure proposed on the basis of the integrated information obtained from the evaluation of various spectra of the impurity is retention and spectral matching with the synthesized impurity sample. The synthesized sample can also be used for toxicological studies [2, 3, 7 and 14].

Organic Impurities present in Food Products:

A recent interest of the food chemistry devoted to the safeguard of human health concerns synthetic dyes which are commonly added to a great number of foodstuffs and largely preferred to natural colors, essentially because of their greater stability along the production industrial process [22].

The use of artificial color in food has a long history. In the 18th and 19th centuries, both “unnatural” color and vegetable extracts were used in food and drink. Sweets, for example, were colored with lead chromate, mercuric sulfide, lead oxide and copper arsenite. Legislation and the newly developed chemically synthesized dyes eliminated the use of these metallic compounds. The synthetic dyes were much brighter, cheaper, more uniform, more stable (in their reactions to high processing temperatures, acids, carbon dioxide, storage and light) and more potent (i.e., less could be used to gain the same effect) than anything seen before, and offered a wider range of shades, so they had great advantages over natural dyes as well. As the use of new dyes became more popular, their toxic properties also became apparent. Since that time, there has been an increase in synthetic dye use, but we have also become even more aware of toxicity [23].

The toxicity risk generally is not due to the dye itself, whose use is regulated by EEC directives, but it might derive from impurities present in compounds used in the synthesis or from side-products formed in the synthesis process itself Recently, very alarming sources of such an undesired product have been envisaged in the degradation reactions that can naturally occur in the commercial products, due to unsuitable conservation conditions. This is the case of soft drinks that, in summer, are often exposed to strong conditions of temperature and sun light [24]. The dye dose in human consumption is evaluated at as large as about 10 g/year. As concerns the use of dyes in food and drinks, only in 1995 did the European legislation standardized the normative admitting, for example, in Europe, the use of Amaranth (E123) before being forbidden in Italy , as well as in USA , by the FDA. A number of directives report a “positive” list of the permitted colorants and of their maximum allowed concentration. The 78/25/EEC directive also considers the presence of organic impurities in food dyes and allows 0.5% as their maximum content. The dyes that are the most commonly used in mixtures, and in commercial soft drinks, namely: Tartrazine (E102), Quinoline Yellow (E104), Sunset Yellow (E110), Carmoisine (E122), Amaranth (E123), New Coccine (E124), Patent Blue Violet (E131), and Brillant Blue FCF (E133) [22].

Overseas agencies have recently reported the presence of benzene in some beverages. In the past, testing by the United States Food and Drug Administration also confirmed the presence of benzene in some soft drinks [25]. Reformulation of some soft drinks was said to have resolved the issue in some cases, but not all manufacturers have reformulated. . In early 2006 independent testing in the United States found levels of benzene 2-5 times the World Health Organization (WHO) water quality guideline levels of 10 parts per billion (ppb) (or 0.01 milligrams per litre). The news created international interest, with the United Kingdom , Germany and South Korea all conducting tests. Following this international interest and findings of low levels of benzene in soft drinks and other beverages, FSANZ (Food safety Australia New Zealand) investigated a range of Australian beverages [27]. Benzene is classified as a Group 1 carcinogen by the International line with international standards [26].

Many beverages contain ascorbic acid (vitamin C) and sodium benzoate. When benzoate salts and Vitamin C come in contact with high levels of light and/or heat, there is a strong chance that a chemical reaction will occur. Benzene is the product of this process [25]. Benzene formation may occur at part per billion (micrograms per kilo) levels in some beverage formulations [24]. Sodium benzoate is a permitted food preservative that may be added to many food products to ensure the microbiological safety of the food. Ascorbic acid is also an approved food additive (antioxidant) which may be added to drinks. It also occurs naturally in fruit and fruit juices. Ascorbic acid reacts with metals (copper, iron) found in water to form hydroxyl radicals, which react with benzoic acid to form low levels of benzene.

Worldwide there is no specific benzene limit for soft drinks and drinking water, limits vary from country to country. The WHO drinking water guideline is 10 ppb which is used in the UK and New Zealand, other water guidelines are 5 ppb in the US and 1 ppb in Europe and Australia. The National Health and Medical Research Centre (NHMRC) Water Quality Guidelines are not mandatory standards; however they provide a guide for determining the safety and quality of drinking water. Benzene levels are likely to be higher in beverages where benzoic acid and ascorbic acid are deliberately added to ensure microbial safety [27].


Identification and regulatory consideration of organic impurities is a highly complex problem owing to numerous sources ranging from microbial contamination to degradation products of APIs apart from traces of intermediates. Though, ICH has outlighted procedure with regard to impurities but much more need to be done. There is a strong need to have unified specifications/standards with regard to impurities. These specifications/standards can be made applicable in all the countries under the supervision of WHO. Such an approach will lead desired harmonization.


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About Authors:

Poonam Kushwaha

Poonam Kushwaha
Faculty of Pharmacy, Integral University, Lucknow - 226026 (India)
Phonenumber: +91-9451144299 ; E-mail:

Volumes and Issues: 


Lakshya's picture

A very good write up. I can see no Organic Impurities present in this article at least. But the problem is that we get lot many impurities in the solvents which may pass on to the drugs, despite very good brand & all care there are impurities in the solvents which need to be controlled to control impurities in drugs.
It would have been still more interesting if you could have mentioned some details on how to overcome these impurities.
But overall a good effort & deserves credit for the work.

Murugan Veerapandian's picture

Nice information.This representation gave an immense information regard the different ranges of organic impurities exist in food and pharmaceutical products.Thanks.


A.R.Khan's picture

Its not only limited to the organic impurities, but to the quality of the products.


Mehnaz Kamal's picture

nice article

Palalokesh's picture

Provided information is very useful& many thanks.

If any body provide the guidelines for related to quality control department in pharma industry, why the instruments out put results not to be rounded. example pH instrument out put.

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