Impurities Control Strategies In Pharmaceuticals: Why & How

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Introduction and outcome: Impurities Control Strategies

Impurities Control Strategies play a unique role in determining the quality, safety and efficacy of any pharmaceutical. The lesser the impurity in the pharmaceutical, the better it is. However, impurities control strategies have been a challenging task for any pharmaceutical company since most of the customer want pharmaceuticals with less number and less quantity of impurities. Some customers want active pharmaceuticals free from impurities. That is why I decided to share my skill-based knowledge on this topic. In this article, you will learn about impurities, their sources, types, challenges, guidelines, control strategies, and analytical techniques with case studies. You will also learn frequently asked questions.

Table of Content

• Introduction and outcome
• Impurities definition
• What is the Impurities Control Strategies ?
• Why is control of impurities required in pharmaceuticals?
• Sources of Impurities in pharmaceuticals
• ICH Impurities classifications
  • Case study: Types of impurities
• Guidelines on Impurities
• Terminology related to impurities
• Formation of Impurities in pharmaceutical
• Approaches to Identify the Unknown Impurities
• Formation of impurities in the formulations
• Approaches to Identify the Unknown Impurities
• Isolation and characterization of Known and Unknown Impurities
• Approaches to Control the Impurities
• How, Where and at What level should Impurities be controlled?
  • Control of SM/KSM and its related impurities
  • Control of purchasing materials and their impurities
  • Control of Isomeric impurities
  • Control of Residual solvents (OVI)
  • Control of Inorganic impurities
  • Control of Degradation impurities
  • ICH Classification of Elemental Impurities
• Advantages
• Case Studies on Control Strategies
• Conclusion
• FAQs on Impurities Control Strategies

Impurities definition

Any component of drug substance that is not the chemical entity defined as drug substance is called impurities. For a drug product, any component that is not the formulation ingredient is called impurities.

Impurities in APIs (active pharmaceutical ingredients) or drug products can form due to synthesis, manufacturing processes, degradation during storage, exposure to heat or light, due to packaging conditions and contamination.

What is the Impurities Control Strategies (ICS)?

The manufacturers of drug substances develop a vision-based strategy to ensure effective control over the level of impurities in the Active pharmaceutical ingredients (APIs). This is called Impurities Control Strategies (ICS). It includes the detailed procedure to control the impurities in the manufacturing process i.e. what is the source of impurities, what is the nature of the impurities, how impurities will be isolated and characterised, where impurities will be controlled and at what level impurities will be controlled.

Why is control of impurities required in pharmaceuticals?

If an impurity has therapeutic value then it is considered as a pharmaceutical. However, most of the impurities have no therapeutic value and hence reduce the quality, safety and efficacy of the medicine. That is why control over impurities in pharmaceuticals is necessary. For example, Cefuroxime Axetil is the mixture of Cefuroxime Axetil diastereomers A and B. Both A and B have therapeutic value.

Need of Control of Impurities

Due to the following reason control of impurities is required in pharmaceuticals:

• No one wants to purchase an API with impurities
• Impurity reduce the quality of the pharmaceuticals
• Impurities reduce safety and efficacy
• It reduces self life of pharmaceuticals
• Some of the impurities are highly toxic and presence of its residuals in the API can have major adverse effect.
• Impurities can change the physical and chemical nature of drug substances and drug products
• Can decrease therapeutic effect of drug substance
• May creates toxic effect or adverse effect
• It may change colour odour, and taste of the drug substances
• Impurities Control Strategies is the regulatory requirements

Case study-1 : Nitrosamines impurities

For example, Genotoxic impurities like N-nitrosodimethylamine NDMA, N-nitroso diethylamine (NDEA), N-nitroso-N-methyl-4-amino butanoic acid (NMBA), N-nitroso isopropyl ethyl amine (NIPEA), N-nitroso diisopropylamine (NDIPA), Nitrosodibutylamine (NDBA), and N-nitroso methyl phenylamine (NMPA) are highly toxic and the same should not be present in pharmaceutical products

Related topic: Genotoxic Chemicals in Pharmaceuticals: How to Identify

Case study-2: Teratogenic nature chiral impurities (Thalidomide tragedy)

The Thalidomide tragedy was one of the darkest episodes of the Pharmaceutical history. Thalidomide is a chiral molecules and it contains two isomers, R-Thalidomide and S-Thalidomide. R-Thalidomide is biologically active whereas S-Thalidomide is Teratogenic in nature. Initially, it was not prepared as a pure form (R-Thalidomide and it was prepared as a racemic mixture due to various limitations (like Analytical and synthetic technique limitations). The S-Thalidomide present in the Thalidomide drug was the source of the Thalidomide tragedy.

Related topic: Nitrosamine Impurities in Pharmaceuticals: Challenges …

Sources of Impurities in pharmaceuticals

The following are the main sources of impurities in the pharmaceuticals:

• Key starting material or starting material
• Purchasing materials
• Intermediates
• Process related impurities
• Final product
• Contamination
• Storage condition
• Packaging material

ICH Impurities classifications

ICH has classified impurities into three categories, Organic impurities, Inorganic impurities and Residual solvents. The following is the details of the impurities classification

1. Organic impurities: The organic impurities have been classified into Process related impurities (PRIs) and Degradation related impurities (DRIs)
   • Classification of Process related impurities (PRIs):
     • Starting material
     • By-products
     • Intermediates
     • Reagents, ligands and catalysts
     • Excipients interaction
   • Classification of Degradation related impurities (DRI):
     • API (active pharmaceutical ingredient) degradation
     • API- residue(s) interaction
     • API- container interaction
     • API- excipient (s) interaction
     • Excipients interactions
2. Classification of Inorganic impurities:
   • Inorganic salt
   • Reagents, ligands and catalysts
   • Heavy metals or metals
   • Other materials like filter aids, charcoal
3. Classification of Residual solvents:
   • Organic solvent
   • Inorganic solvent

Case study: Types of impurities

The following are the route of synthesis of paracetamol and its different impurities

The following are the different types of impurities and their sources of above paracetamol process;

Related topic: Chemistry Behind Genotoxicity and Mutagenicity

Guidelines on Impurities

The following guidelines are very helpful while controlling the impurities:

• ICHQ1A/B (Stability/Photostability)
• ICHQ3A/B [Impurities in new drug substances (DS) and nre drug products (DP)]
• USP<1086> – impurities in drug substances and in drug products
• USP<476> – Organic impurities in drug substances and in drug products
• ANVISA RDC 318/2019, RDC166/2017 and RDC53/2015 – ANVISA FDS requirements for API and drug products
• MAPP 5017.2 (Establishing impurities acceptance criteria as part of the specifications for NDAs, ANDAs, and BLAs based on clinical relevance)

Terminology related to impurities

The following terminology relates to impurities and is widely used in pharmaceutical industries :

Pharmaceuticals

Molecules used in the diagnosis, treatment or prevention of disease or in the manufacture of drug substances or drug products are called pharmaceuticals. It may be API, dosage form, starting material or key starting material

API (Active pharmaceutical ingredient)

Active pharmaceutical ingredient (API) is the biologically active component of a pharmaceutical product (tablet, capsule, cream, injection) that produces the desired effect.The is the main ingredient in medicine. Medicines may contain one or more than one APIs. Each API acts in different ways in the body

DS (drug substances)

DS (drug substances) and Active pharmaceutical ingredient (API) are the same

Intermediates

There are several steps involved in the manufacturing of desired pharmaceuticals. The steps which are isolated and some testing like impurity profiles, assay etc are performed are called intermediates.

Penultimate Intermediates

The (n-1) isolated step is called Penultimate Intermediates, where n is the desired pharmaceutical.

By-products

In addition to the desired pharmaceutical/intermediate unwanted side product may form during the reaction. That side product is called by-product. By-product also acts as an impurity and it is purified in the process. Some time it is also called Transformation products. In the paracetamol process By-product is formed by the following mechanism:

Degradation products or Degradants (DP)

The impurities formed due to degradation of pharmaceutical is called degradation products or degradants. Generally degradation products are formed due to heat, light, storage etc.

Chiral Impurities or Enantiomeric impurities

The unwanted optical isomer is considered as a chiral impurities

Related substances or Related Impurities

The impurities that are formed during synthesis due to raw materials, solvents, intermediates and by-products are called Related impurities or related substances.

Inorganic impurities

Generally, Inorganic impurities form during manufacturing processes and the source of these impurities is the equipment used in the manufacturing process. for example Heavy metals, ligands, and catalysts

Organic Volatile Impurities (OVI)

The source of Organic Volatile Impurities (OVI) is the residual solvents used in the manufacturing process

Key Starting materials (KSM)

A raw material, intermediate or an API that is used in the production of an API and that is incorporated as a significant structural fragment into the structure of the API is called a key starting material

Carryover Study

The study in which the impurities of the previous stage are examined in the present stage and their absence or control is proved is called carry-over study. This is a one-time test or in some cases a skip test is done. Secondly, in carryover testing, only mini-validation/Verification is performed.

Formation of Impurities in pharmaceutical

Impurities can form in a variety of ways during pharmaceutical synthesis. The following are some common mechanisms of formation of impurities in pharmaceuticals:

1. Hydrolysis
2. Decarboxylation
3. Removal of water or dehydration
4. Racemization
5. Tautomerization
6. Photocleavage
7. Oxidation

Hydrolysis

Hydrolysis is a common phenomenon for the ester type of drugs. During hydrolysis, ester is converted into alcoholic impurity by the following mechanism:

Decarboxylation

In decarboxylation, the -CO₂ functional group of the drug is removed and impurity is formed. This impurity is formed in those pharmaceuticals which contain a carboxylic group by the following mechanism:

Removal of water or dehydration

In dehydration, the water of the drug substance is removed and impurity is formed. Pregabalin lactam impurity is formed by the removal of water from the Pregabalin by the following mechanism:

Pregabalin has therapeutic value whereas Pregabalin lactam impurity is toxic.

Racemization

Racemization impurity form in chiral drug substances. It depends upon the following factors:

• Type of process (e.g. chemical or enzymatic): The chemical process is favourable for racemization compared to the Enzymatic process. The Enzymatic process is highly stereoselective.
• Type of molecule (e.g. alanine type molecule being racemized in this process)
• Basic condition is more favorable for racemization than acidic and neutral condition
• Elevated temperatures as well as basic conditions are more favorable for racemization

For example, when Ezetimibe is prepared by a chemical process, the RRS isomer is formed in greater quantities than when it is prepared by an enzymatic process.

Typical drug substances in which racemisation impurities form in the process: Edoxaban, Atorvastatin and Anacetrapib

Formation of impurities in the formulations

Formulation-related impurities may form due to the following reasons:

• Environmental conditions such as exposures to temperature, light-especially UV light and humidity
• Mutual interaction amongst ingredients (API-Excipients or between the excipients)
• Hydrolysis
• Oxidative degradation
• Decarboxylation
• Photolytic cleavage

Approaches to Identify the Unknown Impurities

The following approaches should be applied to identify the unknown impurities:

• Review of ROS(Route of synthesis) with reagents and chemicals of
  • APIs
  • SM/KSM
  • Purchasing material
• Literature or Reported impurities (from published literature)
• Spike study
• Forced degradation study
• Photostability study
• Isolation and characterisation

Isolation and characterization of Known and Unknown Impurities

Impurity synthesis is a challenging task and acts as an individual project. If an impurity is known then it can be synthesized or purchased from the market. But if an impurity is unknown then it needs skill-based expertise as well as a lot of work for isolation, characterization and control.

Isolation Unknown Impurities

Isolation of impurities depends on various factors such as polarity, structure, physicochemical properties and availability of the Analytical tool. Generally, Preparative HPLC, Flash chromatography, Thin layer chromatography (TLC), Column chromatography, and Extraction (Liquid – Liquid extraction or Liquid-Solid extraction) are widely used for the isolation of impurities:

Preparative HPLC

Preparative HPLC is one of the widely used tools for impurity isolation. The goal of preparative-high-performance liquid chromatography (prep-HPLC) is to separate trace amounts of a pure compound as easily as possible in the most economical manner. Its principle is similar to that of HPLC. Columns with larger particle sizes are used in preparative HPLC.

Flash chromatography¹

Flash chromatography is a purification technique that uses glass columns filled with silica as the stationary phase and a solvent – ​​either polar, non-polar or a mixture of the two depending on the polarity of the compounds to be separated.

Thin layer chromatography

Investigation is often done by UV light or iodine vapour to detect most organic substances. To extract material from plates, the simplest method is to scrape off the sorbent containing the material of interest and extract it with a suitable solvent, followed by filtration or centrifugation. The solvent is removed to collect the desired substance. If aluminum plates are used, cut and discard the sample.

Supercritical fluid extraction (SFE)

Supercritical fluid extraction provides an ideal means of isolating impurities, due to high solute diffusivity, low viscosity and excellent solvent properties, they provide an excellent means of separating impurities and other compounds of interest in a short time. Carbon dioxide is most commonly used for SFE due to its availability, ease of use, and disposal. Ammonia and n-heptane can also be used.

Column chromatography

Column chromatography is a traditional technique used to purify compounds based on their polarity or hydrophobicity. In column chromatography, a mixture of molecules is separated based on their differential partitioning between a mobile phase and a stationary phase. Column chromatography in normal phase mode widely used for isolation of impurities.

Characterisation of unknown impurities

Once an impurity is isolated then work starts for characterisation of the same. Characterisation of an unknown impurity is a challenging task and it needs a lot of work and expertise. The selection of the instrument depends upon the cost, limit of the impurity and the sensitivity of the impurity. The analytical instruments like FTIR, UV, HPLC, LC-MS, GC-MS, NMR, Elemental analyser, ICP-optical emission spectrometry (OES), ICP-mass spectrometry (MS), TGA and XRD are to identify and characterize the unknown impurity.

FTIR

It gives the functional and structural information group information of the impurity/molecule

GC-MS

It gives mass and structural information of the volatile molecules. GC gives both qualitative purity and quantitative purity of the compound.

HPLC-MS

It gives mass and structural information of the non-volatile molecules. HPLC gives both qualitative purity and quantitative purity of the compound.

NMR

It gives complete structural information about an unknown impurity like the number of protons, number of carbons and their nature.

Elemental analyser

An elemental analyzer is an instrument that can determine the elemental composition of a sample. The analyst may simply determine which elements are present, or it may perform quantitative analysis to identify how much of each element is present. In some cases, the isotopic composition can also be determined.

UV Spectrophotometer

It gives UV spectral information and wavelength maxima of the molecule.

Taking the help of all the above instruments an unknown impurity is characterised and potency of the impurity standard is calculated. The following formula is used to calculate the potency:

Potency = Purity – (Sulphated ash/residue of ignition + Loss on drying/water content/residual solvent + counter ion) etc..)

Approaches to Control the Impurities

The following approaches are used in the industries to control the impurities:

• Scientific justification using the chemistry of impurities
• QBD
• Purge factor
• Purification of impurities in the process
• Impurities monitoring strategy in the process
• Control of impurities with specification at the API stage
• Interactions between applicants and authorities during development are highly valuable

How, Where and at What level should Impurities be controlled?

An integrated approach encompassing all steps of the entire synthetic process and the types of impurities at each step should be taken into account when deciding on impurities control strategies:

1. Control of SM/KSM and its related impurities
2. Control of purchasing materials and their impurities
3. Control of Process related impurities
4. Control of Isomeric impurities
5. Control of Residual solvents
6. Control of Inorganic impurities
7. Control of Degradation impurities
8. Control of DNA reactive (Mutagenic) Impurities

Control of SM/KSM and its Related Impurities

Follow the following steps to control impurities related to SM/KSM:

• Control of known impurities
  • Based on the trend data limit should be kept
  • Purification power must be established (≥ threshold value impurities)
• Control of unknown impurities
  • First priority should be given to control at ICH threshold
  • Impurities ≥ 0.10% must be identified/characterised(if possible)
  • Purification power must be established for impurities ≥ 0.10% (if characterisation not possible)
• Control of Residual solvents and Inorganic impurities:
  • Control at 1/10th of ICH limit to avoid testing at next stage or up to (n-1) stage(if possible)
  • Control at ICH limit at API stage (if not possible at previous stages)
• Control of SM and KSM
  • Must be controlled at any stage of the process
  • Purification power must be established

Control of purchasing materials and their impurities

Follow the following steps to control impurities related to purchasing materials:

• Control of reagents, chemicals, solvents, catalysts etc
• Control of known impurities
  • Based on trend data limit should be kept
  • Purification power must be established (≥ threshold value impurities)
• Control of unknown impurities
  • First priority should be given to control the impurity at ICH threshold
  • Impurities ≥ 0.10% must be identified/characterised(if possible)
  • Purification power must be established for impurities ≥ 0.10% (if characterisation not possible)
• Control of Residual solvents and Inorganic impurities
  • Control at 1/10th of ICH limit to avoid testing at next stage or up to (n-1) stage(if possible)
  • Control at ICH limit at API stage (if not possible)
• Control of purchasing materials
  • Must be controlled at any stage in the process
  • Purification power must be established

Control of Process related impurities

Follow the following steps to control impurities related to Process related impurities:

• Rational monitoring program to control the reaction
• Purification and control of unreacted material
• Impurities related to intermediates should be controlled at intermediate stage and its purification should be established
• Each intermediate must be controlled somewhere in the process
• Transformation product, Dimer, Degradants
• Control of chemicals and reagents used in the process
• Purification power should be established

Control of Isomeric impurities

Follow the following steps to control impurities related to Isomeric impurities:

• Chiral isomer related to KSM/SM
  • Should be controlled at the same stage (if possible) and racemization not take place in the process
  • Skip testing should be kept at the next stage ( based on the level of isomeric impurities)
  • Should be controlled at next stage/API stage if racemization takes place
• Chiral isomer generated at intermediate stage (in the process)
  • Should be controlled at the same stage (if possible) and racemization not take place in the process
  • Should be controlled at next stage/API stage if racemization takes place
• Chiral isomer generated at API stage
  • Should be controlled at API stage
• Rotamers, Tautomer and structural isomers (positional and geometrical)
  • Should be controlled or justified ( at appropriate step)

Control of Residual solvents (OVI)

Follow the following steps to control impurities related to Residual solvents (OVI):

• Source of residual solvents
  • Purchasing materials (SM, KSM/Chemicals, reagents) used in the process
  • Solvents used in the process
• Write down all solvents related to purchasing material and process
• Each solvent must be controlled somewhere in the process
• Controlling specification purchasing material:
  • Control at 1/10th of ICH limit to avoid/minimize testing at API stage
  • Control at ICH limit at API stage (if not possible)
• Controlling specification solvents used in the process:
  • Control at 1/10th of ICH limit at intermediate stage to avoid/minimize testing at API stage
  • Initially control at ICH limit at API stage (if not possible)
  • Once data of several lots are available then tighten the specification to avoid any DLs

ICH Classification of Elemental Impurities

The following are the ICH classification of the Elemental Impurities:

Note:

• Class-1 and Class-2A metals need to be included in the evaluation due to their toxicity
• The presence of all 24 elements should be evaluated in three or more than three lots and based on result release specification should be decided
• The limit of other elements should be evaluated as per process requirement

Control of Inorganic impurities

Follow the following steps to control the Inorganic impurities:

• Control of the elemental impurity content of a drug substance can be ensured through a thorough understanding of the manufacturing process, including equipment selection, equipment qualification, GMP procedures, packaging components, and selection and application of appropriate control strategies.
• Control of the elemental impurity content of a drug substance can be ensured through a thorough understanding of the manufacturing process, including equipment selection, equipment qualification, GMP procedures, packaging components, and selection and application of appropriate control strategies.
• Elemental impurities of less than 30% of the PDE to support the need for no further testing.
• A major responsibility of any drug substance manufacturer is to develop a strategy to ensure effective control over the levels of elemental impurities in the finished drug substance.
• An approach based on assessment and control of potential sources of elemental impurities, with focused, limited testing, is preferable to thorough testing on the finished drug substance.
• A scientific, risk-based approach, combined with knowledge and control of major sources of elemental impurities, such as catalysts, in the drug-substance manufacturing process provides an efficient and comprehensive elemental impurity control strategy for finished drug substances.
• Manufacturing equipment
  • Hastelloy, stainless steel, and glass are the most commonly used materials of construction for drug substance manufacturing equipment, due to their superior chemical resistance.
  • Nickel, cobalt, vanadium, molybdenum, chromium, and copper are key elements in some Hastelloy and stainless-steel alloys.
  • Under extreme/corrosive reaction conditions, such as high temperature and low/high pH, these elements would have the potential to leach from manufacturing equipment
• Processing aids/inorganic reagents
  • Charcoal, silica, celite, and darco, and inorganic reagents such as sodium chloride, magnesium sulfate, and sodium sulfate, are often used in drug-substance manufacturing processes
• Packaging or container-closure system (CCS) is one of the potential sources of elemental impurities

Control of Degradation impurities

To identify, characterise and control the Degradation impurities (DIs) is complex time time-consuming process. DIs should be identified, characterised and controlled using the following approaches:

• ROS review
• Literature review
• A stability study [Long term stability study and Accelerated stability study
• Forced degradation study
• Photostability study and spiked study

Control of DNA reactive (Mutagenic) Impurities

Control of DNA reactive (mutagenic) impurities should be done based on classification

Advantages of Impurities control strategies

Impurities control strategies is have several advantages such as

• To maintain the quality, safety and efficiency of the medicine
• Very helpful in making impurity control report during DMF filing
• Very helpful for answering deficiency letter queries
• Very Helpful in getting approval during regulatory audit

Case Studies: DLs on Impurities Control Strategies

DL: Non-adequate or poorly justified specifications proposed to control the quality of isolated intermediates (11% of all questions) and starting materials (7% of all questions).

The specificity should be maintained based on purification power and trend data. In this case, data was available up to 7% but the starting material limit NMT was kept at 11% without any justification. For this reason DL was given during review.

DL: Failure to adequately address the origin, fate, and carryover of related substances into the final substance. (4% of all questions)

Purification power or carry-over study must be performed then only a higher limit of any impurity can be kept. In this case without purification power or carry-over study higher limit (4%) was kept. That is the reason this DL was given.

Conclusion

Impurities control strategies are a challenging task for any pharmaceutical company. This article provides valuable information about types of impurities, their classification, and their control strategies using different analytical techniques. I hope this article has helped you understand Impurities control strategies in pharmaceuticals and its importance. Now you can independently design and implement impurities control strategies in pharmaceutical development.

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FAQs on Impurities Control Strategies

What are the different types of impurities?

ICH has classified impurities into three categories, Organic impurities, Inorganic impurities and Residual solvents.

What are the residual solvents?

Organic volatile substances like methanol. Ethanol, toluene, acetonitrile etc. used in the manufacturing of pharmaceutical substances are called residual solvents.

What are the sources of impurities in pharmaceuticals?

Common sources of impurities in drug substances are key starting material or starting material, purchasing materials, intermediates, process related impurities, contamination, storage condition and packaging material

How do you calculate percentage of impurities of drugs in pharmaceutical analysis?

Area % method and external standard method are widely used in the industries to calculate the impurities. In few cases internal standard method is also used to calculate the impurities.

What are the different types of isomeric impurities present in pharmaceutical products?

Isomeric impurities such as chiral isomers, rotamers, tautomers and structural isomers (positional and geometric) present in pharmaceutical products.

How do storage conditions contribute to impurities in pharmaceutical products?

Pharmaceutical products decompose on storing due to the presence of heat, air, light and oxygen

What are the common methods and techniques used for identification and quantification of impurities in pharmaceutical products?

HPLC, GC, GC-MS,LC-MS Preparative HPLC, FTIR, UV spectrophotometer and NMR are the common methods and techniques used for the identification and quantification of impurities in pharmaceutical products.

How to set impurities in drug products?

Several factors like trend analysis data, purification power, nature/toxicity and type of impurities are considered while setting the impurities limit

What is the ICH limit of the impurities?

The ICH limit of unknown impurity is not more than 0.10%. If the structure is known in that case limit of the impurity will be 0.15%.

What is the ICH total impurities limit?

The total limit should be kept based on the trend data. ICH does not say anything about total impurities

Are related substances and impurities the same?

No. Related substances deal with only process-related impurities whereas impurities contain all types of impurities.

What are the organic impurities in drug substances and drug products?

Starting materials, byproducts, intermediates, reagents, ligands, catalysts and degradation products come under the organic impurities in drug substances and drug products

What is the acceptance criteria of total impurities?

The total acceptance criteria are decided based on the trend data, impurities present in the innovator’s samples and pharmacopoeia monograph

What is the qualification of the impurities?

The process of acquiring and evaluating data that establishes the biological safety of an individual impurity or a given impurity profile at the level(s) specified is called the qualification of the impurities.

What are the common factors affecting impurities in pharmaceuticals?

The common factors affecting impurities in pharmaceuticals are temperature, light, air, moisture, storage condition and packaging condition

Which ICH guidelines refer to impurities?

ICH guidelines Q3A(R),Q and 3 B (R2) ICH Q3C refer to impurities

What do you mean by pharmaceuticals?

Molecules used in the diagnosis, treatment or prevention of disease or in the manufacture of drug substances or drug products are called pharmaceuticals.

What is the control strategy of impurities?

The manufacturers of drug substance develop a vision based strategy to ensure effective control over the level of impurities in the Active pharmaceutical ingredients (APIs) and this is called Impurities control Strategies (ICS)

What are the impurity isolation techniques?

Preparative HPLC, Flash chromatography, Thin layer chromatography (TLC), Column chromatography, and Extraction (Liquid – Liquid extraction or Liquid-Solid extraction) are widely used for the isolation of impurities

What are Class 1 and Class 2A elemental impurities?

Class-1 contains Arsenic (As), Lead (Pb), Cadmium (Cd), and Mercury (Hg). Class-2A contains Cobalt (Co), Nickel (Ni), and Vanadium (V) elements

Abbreviations

• ROS: Route of synthesis
• API: Active pharmaceutical ingredient
• SM: Starting material
• KSM: Kaey starting material
• OVI: Organic volatile impurities
• DP: Degradation product
• DS: Drug substance
• DLs: Deficiency letters

References

• Top 10 DLs – edqm-eu
• ICHQ1A(R2
• Q3A(R2),
• Q3B(R2)
• M3(R2)
• https://www.linkedin.com/pulse/brazilian-new-resolution-rdc-3182019-stability-studies-lozano
• https://fda.report/media/124859/5017+2+Rev+1+Establishing+Impurity+Acceptance+Criteria+Admin+5+1+2020.pdf
• https://database.ich.org/sites/default/files/Q1B%20Guideline.pdf
• https://www.ema.europa.eu/en/ich-q3a-r2-impurities-new-drug-substances-scientific-guideline
• https://www.uspnf.com/sites/default/files/usp_pdf/EN/USPNF/usp-nf-notices/c1086_m99805_PF436.pdf
• https://www.usp.org/sites/default/files/usp/document/get-involved/monograph-modernization/chapter-476.pdf

1. Flash chromatography ↩︎