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Tuesday, November 30, 2010

Statins: Indications and Uses, Safety and Modes of Action

Statins: Indications and Uses, Safety and Modes of Action.
By Gunnar N. Holmqvist

  • Publisher: Nova Science Publishers
  • Number Of Pages: 205
  • Publication Date: 2009-01
  • ISBN-10 / ASIN: 1606921037
  • ISBN-13 / EAN: 9781606921036


Product Description:

This book focuses on statins which are a relatively new group of drugs used to lower blood cholesterol levels. A high cholesterol level increases a person's risk of having a heart attack or stroke. The long-term use of statins reduces the risk of such an event and can increase the life expectancy of people with a history of heart disease. The statins work by blocking an enzyme in the body that is involved in the production of LDL cholesterol, especially in the liver. This enzyme is known as HMG coenzyme A reductase. The statins are the most effective group of drugs for lowering the levels of LDL cholesterol in the body. Potential side-effects include muscle cramps and gastrointestinal upsets. These are usually resolved on temporarily lowering the dose. Liver enzyme derangements may occur, which generally return to normal after briefly discontinuing the drug. Some report headaches. Other side-effects occur rarely.

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Modern Pharmaceutical Industry: A Primer

Modern Pharmaceutical Industry: A Primer.
By Thomas M. Jacobsen, Albert I. Wertheimer

  • Publisher: Jones & Bartlett Publishers
  • Number Of Pages: 320
  • Publication Date: 2009-06-05
  • ISBN-10 / ASIN: 0763766364
  • ISBN-13 / EAN: 9780763766368

Product Description:

Modern Pharmaceutical Industry: A Primer comprehensively explains the broad range of divisions in the complex pharmaceutical industry. Experts actively involved in each component discuss their own contribution to a pharmaceutical company's work and success. Divisions include regulatory affairs, research and development, intellectual property, pricing, marketing, generics, OTC, and more. The seventeen chapters included in this resource offer a wide range of topics, from discovery and formulation to post-approval and legal. Readers will be given a detailed look at the structure of a contemporary drug company and a thorough understanding of what goes on behind the scenes. Modern Pharmaceutical Industry: A Primer is a valuable resource for all pharmacy students, new hires at pharmaceutical companies, drug company management, and academic health center libraries. No other text provides a comprehensive look at one of the most dynamic industries related to the modern healthcare system.

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Perry's Chemical Engineers' Handbook 8/E Section 2:Physical and Chemical Data

Perry's Chemical Engineers' Handbook 8/E Section 2:Physical and Chemical Data.
By George H. Thomson, Daniel G. Friend, Richard L. Rowley, W. Vincent Wilding Bruce E. Poling

  • Publisher: McGraw-Hill Professional
  • Number Of Pages: 518
  • Publication Date: 2007-08-01
  • ISBN-10 / ASIN: 0071511253
  • ISBN-13 / EAN: 9780071511254

Product Description:

Now in its eighth edition, Perry's Chemical Engineers' Handbook offers unrivaled, up-to-date coverage of all aspects of chemical engineering. For the first time, individual sections are available for purchase. Now you can receive only the content you need for a fraction of the price of the entire volume. Streamline your research, pinpoint specialized information, and save money by ordering single sections of this definitive chemical engineering reference today.

First published in 1934, Perry's Chemical Engineers' Handbook has equipped generations of engineers and chemists with an expert source of chemical engineering information and data. Now updated to reflect the latest technology and processes of the new millennium, the Eighth Edition of this classic guide provides unsurpassed coverage of every aspect of chemical engineering-from fundamental principles to chemical processes and equipment to new computer applications.

Filled with over 700 detailed illustrations, the Eighth Edition of Perry's Chemical Engineers' Handbook features:

*Comprehensive tables and charts for unit conversion

*A greatly expanded section on physical and chemical data

*New to this edition: the latest advances in distillation, liquid-liquid extraction, reactor modeling, biological processes, biochemical and membrane separation processes, and chemical plant safety practices with accident case histories.

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Perry's Chemical Engineers' Handbook 8/E Section 18:Liquid-Solid Operations and Equipment

Perry's Chemical Engineers' Handbook 8/E Section 18:Liquid-Solid Operations and Equipment.
By David Dickey, Frank Baczek, Daniel Bedell, Kent Brown, Wu Chen, Daniel Ellis, Peter Harriott, Wenping Li, James McGillicuddy, Terence McNulty, James Oldshue, Fred Schoenbrunn, Julian Smith, Donald Taylor, Daniel Wells Wayne Genck

  • Publisher: McGraw-Hill Professional
  • Number Of Pages: 152
  • Publication Date: 2007-08-01
  • ISBN-10 / ASIN: 0071511415
  • ISBN-13 / EAN: 9780071511414



Product Description:

Now in its eighth edition, Perry's Chemical Engineers' Handbook offers unrivaled, up-to-date coverage of all aspects of chemical engineering. For the first time, individual sections are available for purchase. Now you can receive only the content you need for a fraction of the price of the entire volume. Streamline your research, pinpoint specialized information, and save money by ordering single sections of this definitive chemical engineering reference today.

First published in 1934, Perry's Chemical Engineers' Handbook has equipped generations of engineers and chemists with an expert source of chemical engineering information and data. Now updated to reflect the latest technology and processes of the new millennium, the Eighth Edition of this classic guide provides unsurpassed coverage of every aspect of chemical engineering-from fundamental principles to chemical processes and equipment to new computer applications.

Filled with over 700 detailed illustrations, the Eighth Edition of Perry's Chemical Engineers' Handbook features.

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Chromatography: A Science of Discovery

Chromatography: A Science of Discovery.
By Robert L. Wixom, Charles W. Gehrke

  • Publisher: Wiley
  • Number Of Pages: 410
  • Publication Date: 2010-09-22
  • ISBN-10 / ASIN: 0470283459
  • ISBN-13 / EAN: 9780470283455

Product Description:

Leading researchers discuss the past and present of chromatography

More than one hundred years after Mikhail Tswett pioneered adsorption chromatography, his separation technique has developed into an important branch of scientific study. Providing a full portrait of the discipline, Chromatography: A Science of Discovery bridges the gap between early, twentieth-century chromatography and the cutting edge of today's research.

Featuring contributions from more than fifty award-winning chromatographers, Chromatog-raphy offers a multifaceted look at the development and maturation of this field into its current state, as well as its importance across various scientific endeavors. The coverage includes:

  • Consideration of chromatography as a unified science rather than just a separation method

  • Key breakthroughs, revolutions, and paradigm shifts in chromatography

  • Profiles of Nobel laureates who used chromatography in their research, and the role it played

  • Recent advances in column technology

  • Chromatography's contributions to the agricultural, space, biological/medical sciences; pharmaceutical science; and environmental, natural products, and chemical analysis

  • Future trends in chromatography

With numerous references and an engaging series of voices, Chromatography: A Science of Discovery offers a diverse look at an essential area of science. It is a unique and invaluable resource for researchers, students, and other interested readers who seek a broader understanding of this field.

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High-Performance Thin-Layer Chromatography (HPTLC)

High-Performance Thin-Layer Chromatography (HPTLC).
By ManMohan Srivastava

  • Publisher: Springer
  • Number Of Pages: 360
  • Publication Date: 2011-01-29
  • ISBN-10 / ASIN: 3642140246
  • ISBN-13 / EAN: 9783642140242

Product Description:

The present edited book is the presentation of 18 in-depth national and international contributions from eminent professors, scientists and instrumental chemists from educational institutes, research organizations and industries providing their views on their experience, handling, observation and research outputs on HPTLC, a multi-dimensional instrumentation. The book describes the recent advancements made on TLC which have revolutionized and transformed it into a modern instrumental technique HPTLC. The book addresses different chapters on HPTLC fundamentals: principle, theory, understanding; instrumentation: implementation, optimization, validation, automation and qualitative and quantitative analysis; applications: phytochemical analysis, biomedical analysis, herbal drug quantification, analytical analysis, finger print analysis and potential for hyphenation: HPTLC future to combinatorial approach, HPTLC-MS, HPTLC-FTIR and HPTLC-Scanning Diode Laser. The chapters in the book have been designed in such away that the reader follows each step of the HPTLC in logical order.

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Instrumentation for High-performance Liquid Chromatography (Journal of Chromatography Library)

Instrumentation for High-performance Liquid Chromatography (Journal of Chromatography Library).
By J.F.K. Huber
  • Publisher: Elsevier Science Ltd
  • Number Of Pages: 216
  • Publication Date: 1978-08
  • ISBN-10 / ASIN: 044441648X
  • ISBN-13 / EAN: 9780444416483

Altex amperometry Anal analytical applied back-pressure capillary cell volume check valve Chem Chromatogr Column system column tube commercially available compounds compressibility constant counting precision depends described detection limits detector devices diaphragm reciprocating pump dual-head DuPont efficiency electrochemical electrode eluent flow flow-rate flow-through fluorimetry fraction glass columns gradient elution gradient system Hewlett-Packard high-pressure HPLC hydraulic increase injection port injectors inlet inner diameter Instrument ionization J.F.K. Huber Knauer linear liquid chromatography mass spectrometer measured metal columns Micromeritics mixing chamber ml/min mobile phase Model motor noise obtained operation Orlita peak broadening Perkin-Elmer piston pneumatic amplifier pumps pressure drop pressure resistance PTFE pulse pump head pumping system radiometric re-fill refractive index reservoir sample loop selected separation shown in Fig Siemens signal sinusoidal solenoid valve solvent solvent chamber Spectra-Physics speed Swagelok switching syringe syringe injection syringe-type pumps techniques theoretical plates Tracor tube materials Varian.

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Thursday, November 25, 2010

CATCH THE VIEWS TO CONTROL THE QUALITY OF API

Process and Control
Process should be validated against regulatory or “internal” process parameters and specification limits.
It is important that the proven-acceptable, regulatory, and operating ranges all be recognized and considered when writing validation protocols.
Many firms also use control ranges that lie between operating and regulatory ranges for added insurance against, and control over, minor plant deviations.
Regulatory range limits represent those that a firm includes in its registration.
Firm’s basic commitment is that product safety and efficacy will be ensured when regulatory limits are met.
Overheating a solution may cause predictable degradation reactions, while under heating could cause premature crystallization or failure to complete a desired reaction.
Firms employ more than one range of internal limits, such as control ranges for quality monitoring and approvals, as well as the usual, and somewhat tighter, operating ranges for shop-floor directions.
Each internal range must lie within the corresponding regulatory range found to be convenient, especially for in-process control test limits, but need not be regarded as essential.
Raw Materials
Quality and controls of raw materials coming into the process [Starting materials, Intermediates, Reagents, Catalysts, Solvents, Packing Materials should be address the TSE-safety of all materials coming into the process.
The premises should be designed for storing the raw material.
There should be no expired raw materials in the raw material stores.
Materials should be dispensed according to prescribed SOP meeting GMP requirements.
After release by quality control, raw materials and packaging materials should be released on First In First Out basis.
The store premises should be allow storage of raw materials at various temperatures.
In-process
Any material manufactured, blended, compacted or otherwise processed that is produced for and used in the preparation of a drug substance. (Corresponding materials used in the preparation of APIs are referred to as intermediates.)
In-process materials should be tested at appropriate phases for identity, strength, quality, purity and are they approved or rejected by Quality Control.
All necessary controls on starting materials, intermediate products and other in-process controls, calibrations and validation are carried out.
Critical Process
An operating variable that is assigned a required control range with acceptability limits, outside of which exists potential for product or process failure.
A critical process operating parameter is determined via process development and investigational work.
Critical Operating Conditions
A range of values for a critical process operating parameter that lie statistically at or below a specified maximum value and/or at or above a specified minimum operating value.

Environmental Conditions
Control of temperature and humidity required for processing areas.
Generally 65°F and 35-50% humidity are average.
Too high - Increases personnel shedding and too low - Increase static electricity.
Temperature should be controlled throughout all manufacturing areas.
Temperature and humidity should be monitored and controlled including warehouse areas where temperature / humidity sensitive raw materials are stored.
If not able to control humidity, need procedure to follow if humidity exceeds limit.
Emergency power supply should available to take care of entire energy demand or at least critical areas.
Intermediates
A material produced during steps in the synthesis of an API that must undergo further molecular change or processing before it becomes an API.
The degree to which a given intermediate should be rated “critical” must be determined by a firm’s experts based on such criteria as:
Potential toxicity or other physiological activity;
Degree to which equipment used is dedicated to the process, as opposed to having multiple uses; and
Ease or difficulty of removing process residuals when cleaning equipment (Note that the term “intermediate” is also occasionally used in relation to certain drug products in regulatory documents.)
Finished Product
A substance that is represented for use in a drug and, when used in the manufacturing, processing, or packaging of a drug, becomes an active ingredient or a finished drug product.
Such substances are intended to furnish pharmacological activity or other direct effects in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure and function of the body of humans or other animals.
Finished products should be correctly processed and checked according to the defined procedures.
Stability of finished products should be evaluated and documented prior to marketing.
Each batch prior to release confirms should be compliance of finished product specification.

Release and Specification Limits
API specification limits should be set such that the drug product made from that API batch would be within specification for its entire shelf life.
ICH Q6 “The concept of different acceptance criteria for release vs. shelf-life specifications applies to drug products only”
However, may need tighter internal limits for degradants to ensure that the API will remain within specification for its retest period, particularly if the drug product has the same degradation products

Release Vs Stability Tests
Parameters important to determining an API is suitable for use, including stability,
i.e. Release tests Vs those that need to be measured during stability, which may change and thus affect the quality, safety or efficacy of the dosage form either directly
e.g. through the existence of degradation products,
or
Indirectly such as manufacturability of the dosage form
e.g. water content
ICH Q1 : The testing should cover those features that are susceptible to change during storage and likely to influence quality, safety and/or efficacy.

Stages of Development
Most guidelines are for Registration
ICH criteria were not intended to be applied for investigational materials
US and EU regulations and guidelines do not specify that results from stability studies are required to be submitted.
While the expectation is that some measure of stability data is available at time of IND submission to demonstrate stability of drug substance and drug product through the retest period, the only true requirement is that stability studies on the clinical materials are conducted concurrent with the length of the clinical trial so that sponsors can assure regulators that the materials are stable through the investigational period.

Reprocessing of API
Introducing an intermediate or API, including one that does not conform to standards or specifications, back into the process and repeating a crystallization step or other appropriate chemical or physical manipulation steps that are part of the established manufacturing process.
Reprocessing of intermediates and APIs is generally acceptable.
If reprocessing is used for a majority of batches, it should be included as part of the standard manufacturing process.
Continuation of a process step after an in-process control test shows it is incomplete is considered part of the normal process, not reprocessing

Reworking of API
Subjecting an intermediate or API that does not conform to standards or specifications to one or more processing steps that are different from the established manufacturing process to obtain acceptable quality material.
Reason for non-conformance should be investigated before reworking batches.
Reworked batches should be subjected to appropriate evaluation, testing, stability testing, if warranted, and documentation to show that the reworked batches are of equivalent quality to that produced by the original process.
Impurity profile of each reworked batch should be compared against batches manufactured by the established process.
Additional analytical methods may be needed if routine methods are inadequate to characterize reworked batches :
Concurrent validation is appropriate
Protocol should define
Rework procedure
How performed and expected results
Interim results if only one batch

Review issues not resolved by ICH
Q7A addresses reprocessing and reworking as they relate to cGMP.
Review issues arise when a reprocessing or reworking process is—or should be—described in an application.
Original Application
Describing a reprocessing or reworking operation in an Application.
To include a reprocessing or reworking operation as part of the established process :
Drug Substance Guideline [1987] : If reprocessing is to be “routinely” employed
ICH Q7 : If reprocessing is used for a “majority” of batches
To obtain approval to release one or more reprocessed or reworked batches
Post Approval
Making a reprocessing or reworking operation part of the established process
Should be submitted in a supplement unless described in original application

After Approval
“Established” reprocessing or reworking operation
Batches can be released on basis of normal testing
Obtaining Approval to Release Batches
Reworked Drug Substance of High Concern
Reworked Intermediates of Less Concern
Delegate to CGMPs
Reprocessed Drug Substance and Intermediates of little concern if drug substance synthetic and well characterized, but not acceptable for biologic or poorly characterized Drug substances.

Usage of Recovered Solvents in Manufacturing Process of API
Usage of Recovered Solvents in manufacturing process is necessary.
But it is need to consider Environmental Load, Process Capabilities, Safety, Cost Effective Factor, etc.
Safety And Environmental Benefits Analysis
For safety and environmental reasons in national and international regulations, disposal of chemical waste has become increasingly difficult and costly.
It is a matter of sensible economics as well as good practice to generate as little waste as possible and, wherever practicable, substances should be recovered and recycled.
Introduction
Waste solvents are a contaminant and must be managed as a hazardous waste.
Solvents can dissolve other substances (solute) and form a uniformly dispersed mixture (solution).
The major uses include industrial cleaners, extractive processes, pharmaceuticals, etc.
Solvents are generally produced from petroleum or alcohol feedstock.
Many solvents are flammable, volatile and toxic; substances that can contribute to fire hazards and the contamination of air and water.
Explanation
Flash Point : Lowest temperature at which a flammable liquid produces a sufficient amount of vapor to ignite with a spark.
Fumes : Vapors of organic liquids.
Solvent : Alcohol or petroleum based liquids capable of dissolving another substance (solute) to form a uniformly dispersed mixture (solution) at the molecular level.
Vapor : An air dispersion of molecules of a substance that is liquid or solid in its normal state (at standard temperature and pressure).
Vapor Pressure : The pressure characteristic at any given temperature of a vapor in equilibrium with its liquid or solid form (Usually expressed in millimeters of mercury, mm Hg).
Characteristics
Solvents are flammable and toxic chemical liquids.
Some are more flammable than others because of differences in vapor pressure.
Solvents are toxic by ingestion, skin contact, and vapor inhalation.
Solvent vapors, if originate from flammable solvents, can explode.
If the vapor is present in air at concentrations higher than the lower explosive limit (LEL) and lower than the upper explosive limit (UEL), there is potential for an explosion if a spark or static charge is present.
Depending on type of solvent the vapor may be explosive in air at concentrations as low as one percent.
Potential Health and Safety Hazards Analysis
Exposure to solvents and other organic liquids is one of the most common health risks at work places.
Most of the organic solvents are combustible (having low flash point), often highly volatile and extremely flammable therefore they should always be handled with care.

Some solvents produce vapors that are heavier than air.
These may move down to the floor or ground to a distant ignition source, such as a spark from welding or caused by static electricity.
The vapors may also explode from smoking.
Vapors of solvents can also accumulate in confined places and stay there for a long time, presenting risks for health and property.
Amongst the most hazardous solvents are benzene, carbon disulphide and carbon tetrachloride.
Industrial Application
Pharma industries use solvents in their process and washing activities of process equipments and thus generate a substantial amount of spent solvent.
Pharmaceutical units use solvents for cleaning of their laboratory accessories and process equipment.
These industries purchase new solvents, use it and then either dispose for incineration or reuse for cleaning purpose in machines parts.
It is obvious that finally the solvent will end up in the environment.
Solvent will evaporate completely with the non-volatile pollutants left over or will be spilled on the ground contaminating soil and ground water.
It may find its way into any surface water stream also.
Some of the common solvents used in industries are Xylene, Toluene, Acetone, Methanol, Acetic acid etc.
Traditionally, hazardous solvents are being used in a variety of parts cleaning applications.
Use of hazardous solvents can have adverse environmental effects including hazardous waste generation and air emissions.
Therefore solvents which pose the most serious risk to health and environment should be substituted by less hazardous one.
Spent solvent is a saleable item.
It can also be recycled by proper treatment like filtration or distillation.
Recycled is usually not suitable for use, but can be used for cleaning purposes.
Solvent distillation, as a means of recycling, is a viable alternative to the single use and disposal of solvents.
It is environmentally benign and reduces the amount of solvent purchased and disposed.
Solvent distillation is well suited for processing waste solvents with excessive contamination.
The Solvent Distillation Unit allows solvents to be recycled instead of being used once and then disposed
What is Distillation?
Distillation is defined as separation according to molecular size, making use of the difference in their boiling points.
There are two major types of classical distillation i.e. continuous distillation and batch distillation.
Continuous distillation, as the name shows, continuously takes a feed and separates it into two or more products.
Batch distillation takes on a lot (or batch) at a time and splits it into two or more products by selectively removing the more volatile fractions over time.
Typical Distillation units are made up of several components, each of which is used either to transfer heat energy or enhance material transfer.
A typical distillation unit contains the following components:
A vertical shell where the separation of liquid components is carried out.
Column internals such as trays/plates and/or packings that are used to enhance component separations.
A re-boiler to provide necessary heat for vaporization during the distillation process.
A condenser to cool and condense the vapors which leave from the top of the column.
A reflux drum to hold the condensed vapor from the top of the column so that liquid (reflux) can be recycled back to the column.

Regeneration of waste solvent is also a good solution.
It can be done through atmospheric distillation.
The resultant solvent can be reused in industries for cleaning purpose.
Varieties of integrated distillation units are available in the local and international market.
However as the cost of the equipment is high and quantity of waste solvent involved is usually small, this arrangement at the level of an industrial unit may not be economically feasible.
However, simpler options for solvent recovery are also possible which can easily be fabricated locally according to the capacity and compositions of solvents.
Example : Following components involved in Distillation
A vertical shell where the separation of liquid components is carried out.
Column internals are used to enhance component separations.
A re-boiler to provide necessary heat for vaporization during the distillation process.
A condenser to cool and condense the vapors, which leave from the top of the column.
A reflux drum to hold the condensed vapor from the top of the column so that liquid (reflux) can be recycled back to the column.
Regeneration of waste solvent is also a good solution.
The resultant solvent can be reused.
The unit consists of a storage tank in which separation of suspended sludge will be done by settling.
Supernatant solvent is pumped to the still through filter, the still is water jacketed and equipped with control valves such as temperature recorder controller, pressure controller etc.
For economical reasons the heating media for the still is considered to be gas burners that connects with the control panel and will operate accordingly.
As temperature rises from ambient temperature the most volatile solvents start to evaporate and move up to the fractionating column having perforated plates which enhance the purity by increasing the detention time.
This process continues until approximately 85 to 90% of the waste solvent evaporates and condenses.
The mixture of condensed solvents thus collected can be used again in the respective section.
The sludge remaining at the bottom of the unit has a very high concentration of sludge.
Typically this only accounts for 10-15% of the original volume of the batch and is disposed off as hazardous solid waste.
Analysis of recovered solvents should match with specification.

Cost Benefit Analysis
By implementing this technique solvent purchase and disposal costs will be significantly reduced.
The cost to implement the above option varies depending on the size of the unit.
The costs associated with the purchase of new solvent and the disposal of waste solvent should be the primary driving force for purchasing the solvent recovery unit.
By installing the recovery equipment and minimizing the disposal of waste solvent, one can improve the profit margin and pay back its capital cost in a period of 1-2 year.

Regulatory View to use Recovered Solvents in the Manufacturing Process
Recovery of solvents, reactants, intermediates or API from mother liquor or filtrate is acceptable.
Approved procedures should exist for recovery.
Recovered materials meet specifications and are suitable for their intended use.
Solvents can be recovered and reused in the same processes or different processes provided recovery procedures are controlled and monitored. Ensure solvents meet appropriate standards before reuse or co-mingling.
Fresh and recovered solvents can be combined if adequate testing shows suitability for use in manufacturing.
Use should be adequately documented.

Original filling is only with fresh solvents. If we wish to use recovered solvents in the manufacturing process. What would be the filing category for such variation
The proposal is coming under relaxation of specification of the solvents used in the manufacturing process.
Therefore this will fail the Type IB (Minor Variations à Assessment (short assessment as in current Type I)) criteria for minor changes to the manufacturing method for the active.
Hence, the active manufacturing method change, together with associated widening of solvent specifications, should be submitted as a single Type II (Major Variations à Assessment) standard application.

Information about Metal Residues in Drug Substances (API)
Residual metals used as process catalysts do not provide any therapeutic benefit and should therefore be evaluated and restricted on the foundation of safety- and quality-based criteria.
Metals will be classified in three categories based on their individual levels of safety concern and concentration limits will be set on the bases of the maximal daily dose, duration of treatment, route of administration and permitted daily exposure (PDE).
In the reviews the following assumptions and/or default values are used:
Body Weight (bw) of an adult: 50 Kg.
Breathing volume of an adult: 20 m3 per Day (24 Hr.).
Occupational (workplace) inhalation exposure: 8 Hr. per Day (24 Hr.).
Exposure limits were established using uncertainty factors as per ICH Q3.
For pragmatic reasons a number of uncertainty factors were adapted to arrive at a final safe and practical PDE setting - Q3 method for uncertainty factor (UF) calculation plus additional pragmatic factor for PDE calculation.
Acceptable Additional Lifetime Cancer Risk:
An increased cancer risk of 1 in 100,000 was identified as acceptable for genotoxic impurities in pharmaceuticals by the Committee for Human Medicinal Products (CHMP).
Limits set based on safety criteria may therefore be higher than limits set on the basis of GMP, process capabilities, or other suitable quality criteria.
Any interested party can make a request and submit relevant safety data.
Classification and limits may change as new safety data becomes available.
Metal catalysts and metal reagents are defined here as chemical substances that are used to change the rate of chemical reactions or which act on other chemical substances in chemical reactions.
Residues of metals can either be present as the original form of the metal or as a form of the metallic element altered by downstream chemical processing.
Excluded from this document are extraneous metal contaminants that should not occur in drug substances or excipients and are more appropriately addressed as Good Manufacturing Practice (GMP) issues.
Different limits are applied to oral and parenteral routes of administration due to limited oral bioavailability of many metals.
As different routes of exposure may have different toxicological properties, specific limits have been set for inhalation exposure to some metals.
When the exposure is short the PDE´s mentioned in this guideline may be adapted as indicated
Classification of Metals
Metals were evaluated for their potential risk to human health and placed into one of three classes as follows:
Class 1 Metals : Metals of significant safety concern
Metals of significant safety concern known or suspect human carcinogens, or possible causative agents of other significant toxicity.
Class 1 is subdivided into 3 subclasses.
Class 1A: Platinum (Pt) and Palladium (Pd)
Class 1B: Iridium (Ir), Rhodium (Rh), Ruthenium (Ru) and Osmium (Os)
Class 1C: Molybdenum (Mo), Nickel (Ni), Chromium (Cr), Vanadium (V)
Platinoids are in Class 1A and Class 1B.

For the Platinoids in subclass 1B a conservative approach has been adopted, because there are very limited toxicity data. Thus the indicated limit for Class 1B is the limit for the total amount of those platinoids that, based on the used synthesis procedures, are anticipated to be present.
Class 2 Metals : Metals with low safety concern
Copper (Cu) and Manganese (Mn)
Metals with low safety concern Metals with lower toxic potential to man.
They are generally well tolerated up to exposure.
They may be trace metals required for nutritional purposes or they are often present in food stuffs or readily available nutritional supplements.
Class 3 Metals : Metals with minimal safety concern
Zinc (Zn) and Iron (Fe)
Metals with minimal safety concern.
Metals with no significant toxicity.
Their safety profile is well established.
They are generally well tolerated up to doses.
Typically they are ubiquitous in the environment or the plant and animal kingdoms.

IMPURITIES IN DRUG IMPURITIES IN DRUG SUBSTANCE
According to US Federal Register Vol. 65, No. 251 and EMEA
Any component of the new drug substance that is not the chemical entity defined as the new drug substance is an impurity
Any component of the Drug Product that is not the chemical entity defined as drug substance or Excipients in the drug product is an impurity.
USP 30 <1086>
“Impurities in official articles “Concepts about impurities change with time are inseparable from developments in analytical chemistry.”
“If a material previously considered to be pure, can be resolved into more than one component, that material can be redefined into new terms of purity & impurity.”
“Inorganic, organic, biochemical, isomeric or polymeric component can all be considered impurities.”
“This is the continuous improvement.”
“Inorganic organic, biochemical, isomeric, or polymeric components can all be considered impurities.”
Classification of Impurities
Organic impurities (Process and Drug related)
Inorganic impurities
Residual solvents
Polymorphic forms
Enantiomeric impurities
Organic impurities can arise during the manufacturing process and/or storage of the API.
They can be identified or unidentified, volatile or non-volatile
e.g.: • Starting materials
• By-products
• Intermediates
• Degradation products
• Reagents, ligands and catalysts

Inorganic impurities can result from the manufacturing process, they are normally known and identified and include
e.g.: • Reagents, ligands, catalysts
• Heavy metals or other residual metals
• Inorganic salts
• Other materials, e.g. filter aids, charcoal….
Residual solvents can result from the manufacturing process, they are used solvents in process
e.g. • Class I : Solvents to be avoided
Benzene, carbon tetrachloride, 1,2-dichloroethane, 1,1-dichloroethene, 1,1,1- trichloroethane
It is critical to avoid the Class 1 residual solvents But it is need for control.
General cases as follows :
Starting Material : e.g. Benzene in early steps in synthesis.
By-products from chemical reaction: e.g. Benzene as a Grignard-by-product.
Impurity in another residual solvents: e.g. Benzene as an impurity in toluene.
• Class II : Solvents to be limited
Acetonitrile, Chloroform, Cyclohexane, Dioxane, Methanol, Methylbutylketone, Toluene, …...
• Class III : Solvents with low toxic potential
Acetone, Butanol, Butyl Acetate, DMSO, Ethanol, Ethyl Acetate, Ethyl Ether, …....
[Loss on drying should be less than 0.5%]
Unknown Impurity Limit in API
As per ICH Q3A è If maximum Daily Dose is < 2 g / day - Unknown Impurity is 0.10%
Reporting Threshold is 0.05%
Identification Threshold is 0.10% or 1.0 mg per day intake (whichever is lower)
Qualification Threshold is 0.15% or 1.0 mg per day intake (whichever is lower)
è If maximum Daily Dose is > 2 g / day - Unknown Impurity is 0.05%
Reporting Threshold is 0.03%
Identification Threshold is 0.05%
Qualification Threshold is 0.05%
Contaminants –Approach as per GMP
Organic Impurities
Process related impurities to be controlled at the API stage –release testing only
In early development phase impurity limits may be set at thresholds
As per Q3 specification should include:
Each specified identified impurity
Each specified unidentified impurity
Any unspecified impurity with acceptance criterion of not more than identification threshold
Total Impurities
“When identification of an impurity is not feasible, a summary of the laboratory studies demonstrating the unsuccessful effort should be included in the application”. Could control to the qualification threshold as an unidentified specified impurity.
Where there is no safety concern, impurity acceptance criteria should be based on data generated on batches of the new drug substance manufactured by the proposed commercial process, allowing sufficient latitude to deal with normal manufacturing and analytical variation and the stability characteristics of the new drug substance.
Thus limits for degradants should not be bounded within actual data available at time of filing, although thresholds in Q3 apply.
ICH Q6 “estimate maximum increase in impurity at retest date”

Estimate maximum by Extrapolation :- Three standard deviation of predictions from the three batches or the upper one-sided 95% confidence limit out to retest period desired.
Chiral Impurities can significantly affect physicochemical properties of pure enantiomers.
Release test; if development work (scientific analysis, stress testing) shows that opposite enantiomeris not a degradation product, shouldn’t need to test on stability
Chiral impurities excluded from ICH Q3 due to practical differences in qualifying at those levels; however apply if can…
A racemic degradantcould be controlled as two separate enantiomers each to ICH Q3 threshold…

Inorganic Impurities
Heavy Metals :
Shouldn’t need to test if no heavy metal used in Route and Starting Material. Criteria for inclusion of a heavy metals test :

Daily intake > 0.5 g/day, treatment < 30 days : Heavy metals test limit 20 ppm
Daily intake > 0.5 g/day, treatment > 30 days : Heavy metals test limit 10 ppm
Daily intake <> 30 days : Heavy metals test limit 10 ppm If the substance is used parenterally Heavy metals test limit 20 ppm Other wise
Daily intake < 0.5 g/day, treatment < 30 days : No heavy metals test
Specific Tests
Control of catalysts used during manufacturing process
Arsenic control for Japan may be required
Pharmacopoeial methodology or specific (but validated)
Residue on Ignition
Residue on Ignition is not more than 0.1% in reality a quality test only.
Iron
Iron oxide / hydroxide formation in alkaline solutions; ppm control.

Microbes and Endotoxins
Endotoxins Test
Release test only and only If intended for parenteral drug product.
Total Viable Aerobic Count
Generally test if for sterile product
May omit from specification based on ICH Q6 (process steps, capability of supporting growth) plus water activity considerations
If test on stability, may do at key checkpoints only, e.g. annually
Specific Organisms
May omit from specification based on ICH Q6 (process steps, capability of supporting growth) plus water activity considerations
Release test only as a quality/contamination test

Other Tests
Mass Balance
Useful scientific guide for evaluating data, but is not achievable in all conditions;
WHO guidelines discuss this with reference to DP only
Address as part of development if notice significant discrepancies

Odour
Generally no, EP Technical Guide 4th Edition (2005)
Depending on route of delivery may need to limit solvents to < ICH thresholds, e.g. pentane
Degradation products, e.g. sulphates or toluene degradation product…
Stability
Can scientifically justify removing tests from stability studies or change specification limits from those use for registration stability as still gathering knowledge during registration stability.
Genotoxic Impurities
According to current regulatory practice it is assumed that (in vivo) genotoxic compounds have the potential to damage DNA at any level of exposure and that such damage may lead/contribute to tumour development.
Thus for genotoxic carcinogens it is prudent to assume that there is no discernible threshold and that any level of exposure carries a risk.
However, the existence of mechanisms leading to biologically meaningful threshold effects is increasingly acknowledged also for genotoxic events.
This holds true in particular for compounds interacting with non-DNA targets and also for potential mutagens, which are rapidly detoxified before coming into contact with critical targets.
\The regulatory approach to such chemicals can be based on the identification of a critical No-Observed-Effect Level (NOEL) and use of uncertainty factors.
Even for compounds which are able to react with the DNA molecule, extrapolation in a linear manner from effects in high-dose studies to very low level (human) exposure may not be justified due to several protective mechanisms operating effectively at low doses.
However, at present it is extremely difficult to experimentally prove the existence of threshold for the genotoxicity of a given mutagen.
Thus, in the absence of appropriate evidence supporting the existence of a threshold for a genotoxic compound making it difficult to define a safe dose it is necessary to adopt a concept of a level of exposure that carries an acceptable risk.
The toxicological assessment of genotoxic impurities and the determination of acceptable limits for such impurities in active substances is a difficult issue and not addressed in sufficient detail in the existing ICH Q3X guidances.
The data set usually available for genotoxic impurities is quite variable and is the main factor that dictates the process used for the assessment of acceptable limits.
In the absence of data usually needed for the application of one of the established risk assessment methods, i.e. data from carcinogenicity long-term studies or data providing evidence for a threshold mechanism of genotoxicity, implementation of a generally applicable approach as defined by the Threshold of Toxicological Concern (TTC) is proposed.
A TTC value of 1.5 µg/day intake of a genotoxic impurity is considered to be associated with an acceptable risk (excess cancer risk of <1 in 100,000 over a lifetime) for most pharmaceuticals.
From this threshold value, a permitted level in the active substance can be calculated based on the expected daily dose.
Higher limits may be justified under certain conditions such as short-term exposure periods.
The concentration limits in ppm of genotoxic impurity in drug substance derived from TTC can be calculated based on the expected daily dose to the patient using equation
TTC [mg / day] è Threshold of Toxicological Concern
Concentration Limit (ppm) = --------------------------------
Dose [g / day]

LINE OF ATTACK TO MAKE SPECIFICATIONS FROM INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE
Guideline for Specifications :
ICH Q6A : Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances
ICH Q6B : Test Procedures and Acceptance Criteria for Biotechnological / Biological Products
Explanation of Specifications
A specification is defined as a list of tests, references to analytical procedures, and appropriate acceptance criteria which are numerical limits, ranges, or other criteria for the tests described.
It establishes the set of criteria to which a new drug substance or new drug product should conform to be considered acceptable for its intended use.
"Conformance to specifications" means that the drug substance and / or drug product, when tested according to the listed analytical procedures, will meet the listed acceptance criteria.
Specifications are critical quality standards that are proposed and justified by the manufacturer and approved by regulatory authorities as conditions of approval.
It is possible that, in addition to release tests, a specification may list in-process tests, periodic (skip) tests, and other tests which are not always conducted on a batch-by-batch basis.
In such cases the applicant should specify which tests are routinely conducted batch-by-batch, and which tests are not, with an indication and justification of the actual testing frequency. In this situation, the drug substance and / or drug product should meet the acceptance criteria if tested.
It should be noted that changes in the specification after approval of the application may need prior approval by the regulatory authority.
Perceptions to set Specifications for New Drug Substances
Chemical Substances
Periodic or Skip Testing
Release Vs. Shelf-life Acceptance Criteria
In-process Tests
Design and Development Considerations
Limited Data Available at Filing
Parametric Release
Alternative Procedures
Pharmacopoeial Tests and Acceptance Criteria
Evolving Technologies
Impact of Drug Substance on Drug Product Specifications
Reference Standard
Justification of Specifications
Former points of assessment to set Specifications for Biotechnological / Biological Products
Characterization
[Physicochemical Properties, Biological Activity, Immunochemical Properties, Purity, Impurities and Contaminants, Quantity]
Analytical Considerations
[Reference Standards and Reference Materials, Validation of Analytical Procedures]
Process Controls
[Process Related Considerations, In-process Acceptance Criteria and Action Limits, Raw Materials and Excipient Specifications]
Statistical Concepts

Periodic / Skip Testing
Periodic or Skip testing is the performance of specified tests at release on pre-selected batches and at predetermined intervals, rather than on a batch-to-batch basis with the understanding that those batches not being tested still must meet all acceptance criteria established for that product.
This represents a less than full schedule of testing and should therefore be justified and presented to and approved by the regulatory authority prior to implementation.
This concept may be applicable to, for example, residual solvents and microbiological testing, for solid oral dosage forms.
It is recognized that only limited data may be available at the time of submission of an application.
This concept should therefore generally be implemented post-approval.
When tested, any failure to meet acceptance criteria established for the periodic test should be handled by proper notification of the appropriate regulatory authority(ies).
If these data demonstrate a need to restore routine testing, then batch-by-batch release testing should be reinstated.
Release vs. Shelf-life Acceptance Criteria
The concept of release limits vs. shelf-life limits may be applied where justified.
This concept pertains to the establishment of limits, which are tighter for the release than for the shelf-life of the drug substance or drug product.
Examples where this may be applicable include potency and degradation products.
In some regions, the concept of release limits may only be applicable to in-house limits and not to the regulatory shelf-life limits.
The concept of different acceptance criteria for release vs. shelf-life specifications applies to drug products only; it pertains to the establishment of more restrictive criteria for the release of a drug product than are applied to the shelf-life.
Examples where this may be applicable include assay and impurity levels.
In Japan and United States, this concept may only be applicable to in-house criteria, and not to the regulatory release criteria.
Thus, in these regions, the regulatory acceptance criteria are the same from release throughout shelf-life; however, an applicant may choose to have tighter in-house limits at the time of release to provide increased assurance to the applicant that the product will remain within the regulatory acceptance criterion throughout its shelf-life.
In the European Union there is a regulatory requirement for distinct specifications for release and for shelf-life where different.
In-process Tests
In-process tests to be performed during the manufacture of either the drug substance or drug product, rather than as part of the formal series of tests which are conducted prior to release.
In-process tests are only used for the purpose of adjusting process parameters within an operating range.
Certain tests conducted during the manufacturing process, where the acceptance criterion is identical to or tighter than the release requirement, (e.g., pH of a Solution) may be sufficient to satisfy specification requirements when the test is included in the specification.
However, this approach should be validated to show that test results or product performance characteristics do not change from the in-process stage to finished product.
Design and Development Considerations
The experience and data accumulated during the development of a new drug substance or product should form the basis for the setting of specifications.
It may be possible to propose excluding or replacing certain tests on this basis.
Some examples are:
Microbiological testing for drug substances and solid dosage forms which have been shown during development not to support microbial viability or growth;
Extractables from product containers where it has been reproducibly shown that either no extractables are found in the drug product or the levels meet accepted standards for safety;
Particle size testing may fall into this category, may be performed as an in-process test, or may be performed as a release test, depending on its relevance to product performance;

Dissolution testing for immediate release solid oral drug products made from highly water soluble drug substances may be replaced by disintegration testing, if these products have been demonstrated during development to have consistently rapid drug release characteristics.
Limited Data Available at Filing
It is recognized that only a limited amount of data may be available at the time of filing, which can influence the process of setting acceptance criteria. .
As a result it may be necessary to propose revised acceptance criteria as additional experience is gained with the manufacture of a particular drug substance or drug product.
Example : Acceptance limits for a specific impurity.
The basis for the acceptance criteria at the time of filing should necessarily focus on safety and efficacy.
When only limited data are available, the initially approved tests and acceptance criteria should be reviewed as more information is collected, with a view towards possible modification.
This could involve loosening, as well as tightening, acceptance criteria as appropriate.
Parametric Release
Parametric release can be used as an operational alternative to routine release testing for the drug product in certain cases when approved by the regulatory authority.
Sterility testing for terminally sterilized drug products is one example.
In this case, the release of each batch is based on satisfactory results from monitoring specific parameters, e.g., temperature, pressure, and time during the terminal sterilization phase(s) of drug product manufacturing.
These parameters can generally be more accurately controlled and measured, so that they are more reliable in predicting sterility assurance than is end-product sterility testing.
Appropriate laboratory tests (e.g., chemical or physical indicator) may be included in the parametric release program.
It is important to note that the sterilization process should be adequately validated before parametric release is proposed and maintenance of a validated state should be demonstrated by revalidation at established intervals.
When parametric release is performed, the attribute which is indirectly controlled (e.g., sterility), together with a reference to the associated test procedure, still should be included in the specifications.
Alternative Procedures
Alternative procedures are those which may be used to measure an attribute when such procedures control the quality of the drug substance or drug product to an extent that is comparable or superior to the official procedure.
Example: for tablets that have been shown not to degrade during manufacture, it may be permissible to use a spectrophotometric procedure for release as opposed to the official procedure, which is chromatographic.
However, the chromatographic procedure should still be used to demonstrate compliance with the acceptance criteria during the shelf-life of the product.
Pharmacopoeial Tests and Acceptance Criteria
References to certain procedures are found in pharmacopoeias in each region.
Wherever they are appropriate, pharmacopoeial procedures should be utilized.
Whereas differences in pharmacopoeial procedures and acceptance criteria have existed among the regions, a harmonized specification is possible only if the procedures and acceptance criteria defined are acceptable to regulatory authorities in all regions.
The Pharmacopoeial Discussion Group (PDG) of EP, JP and USP has expressed a commitment to achieving harmonization of the procedures in a timely fashion.
Where harmonization has been achieved, an appropriate reference to the harmonized procedure and acceptance criteria is considered acceptable for a specification in all three regions.
For example, after harmonization sterility data generated using the JP procedure, as well as the JP procedure itself and its acceptance criteria, are considered acceptable for registration in all three regions.
To signify the harmonized status of these procedures, the pharmacopoeias have agreed to include a statement in their respective texts, which indicates that the procedures and acceptance criteria from all three pharmacopoeias are considered equivalent and are, therefore, interchangeable.

Evolving Technologies
New analytical technologies, and modifications to existing technology, are continually being developed.
Such technologies should be used when they are considered to offer additional assurance of quality, or are otherwise justified.
Impact of Drug Substance on Drug Product Specifications
In general, it should not be necessary to test the drug product for quality attributes uniquely associated with the drug substance.
Example : it is normally not considered necessary to test the drug product for synthesis impurities which are controlled in the drug substance and are not degradation products.
Reference Standard
A reference standard, or reference material, is a substance prepared for use as the standard in an assay, identification, or purity test.
It should have a quality appropriate to its use.
It is often characterized and evaluated for its intended purpose by additional procedures other than those used in routine testing.
For new drug substance reference standards intended for use in assays, the impurities should be adequately identified and / or controlled, and purity should be measured by a quantitative procedure.
Statistical Concepts
Appropriate statistical analysis should be applied, when necessary, to quantitative data reported.
The methods of analysis, including justification and rationale, should be described fully.
These descriptions should be sufficiently clear to permit independent calculation of the results presented.
Justification of Specifications
When a specification is first proposed, justification should be presented for each procedure and each acceptance criterion included.
The justification should refer to relevant development data, pharmacopoeial standards, test data for drug substances and drug products used in toxicology and clinical studies, and results from accelerated and long term stability studies, as appropriate.
Additionally, a reasonable range of expected analytical and manufacturing variability should be considered.
It is important to consider all of this information.
Approaches other than those set forth in ICH-Q3 may be applicable and acceptable.
The applicant should justify alternative approaches.
Such justification should be based on data derived from the new drug substance synthesis and/or the new drug product manufacturing process.
This justification may consider theoretical tolerances for a given procedure or acceptance criterion, but the actual results obtained should form the primary basis for whatever approach is taken.
Test results from stability and scale-up / validation batches, with emphasis on the primary stability batches, should be considered in setting and justifying specifications.
If multiple manufacturing sites are planned, it may be valuable to consider data from these sites in establishing the initial tests and acceptance criteria.
This is particularly true when there is limited initial experience with the manufacture of the drug substance or drug product at any particular site.
If data from a single representative manufacturing site are used in setting tests and acceptance criteria, product manufactured at all sites should still comply with these criteria.
Presentation of test results in graphic format may be helpful in justifying individual acceptance criteria, particularly for assay values and impurity levels.
Data from development work should be included in such a presentation, along with stability data available for new drug substance or new drug product batches manufactured by the proposed commercial processes.
Justification for proposing exclusion of a test from the specification should be based on development data and on process validation data (where appropriate).

FOLLOWING TESTS AND ACCEPTANCE CRITERIA ARE USUALLY RELATED TO APIS
Description : A qualitative statement about the state (e.g. solid, liquid) and color of the new drug substance.
If any of these characteristics change during storage, this change should be investigated and appropriate action taken.
Identification : Identification testing should optimally be able to discriminate between compounds of closely related structure which are likely to be present.
Identification tests should be specific for the new drug substance, e.g., Infrared Spectroscopy.
Identification solely by a single chromatographic retention time, for example, is not regarded as being specific.
However, the use of two chromatographic procedures, where the separation is based on different principles or a combination of tests into a single procedure, such as HPLC/UV diode array, HPLC/MS, or GC/MS is generally acceptable.
If the new drug substance is a salt, identification testing should be specific for the individual ions.
An identification test that is specific for the salt itself should suffice.
New drug substances which are optically active may also need specific identification testing or performance of a chiral assay.
Assay : A specific, stability-indicating procedure should be included to determine the content of the new drug substance.
In many cases it is possible to employ the same procedure (e.g., HPLC) for both assay of the new drug substance and quantitation of impurities.
In cases where use of a non-specific assay is justified, other supporting analytical procedures should be used to achieve overall specificity.
For example, where titration is adopted to assay the drug substance, the combination of the assay and a suitable test for impurities should be used.
Impurities : Organic and inorganic impurities and residual solvents are included in this category.
At the time of filing it is unlikely that sufficient data will be available to assess process consistency.
Therefore it is considered inappropriate to establish acceptance criteria which tightly encompass the batch data at the time of filing.
Specific Tests / Criteria
In addition to the universal tests listed above, the following tests may be considered on a case by case basis for drug substances.
Individual tests/criteria should be included in the specification when the tests have an impact on the quality of the drug substance for batch control.
Tests other than those listed below may be needed in particular situations or as new information becomes available.
Physicochemical Properties : These are properties such as pH of an aqueous solution, melting point / range, and refractive index.
The procedures used for the measurement of these properties are usually unique and do not need much elaboration.
E.g., Capillary Melting Point
The tests performed in this category should be determined by the physical nature of the new drug substance and by its intended use.
Particle Size : For some new drug substances intended for use in solid or suspension drug products, particle size can have a significant effect on dissolution rates, bioavailability, and / or stability.
In such instances, testing for particle size distribution should be carried out using an appropriate procedure, and acceptance criteria should be provided.

Polymorphic Forms : Some new drug substances exist in different crystalline forms which differ in their physical properties.
Polymorphism may also include solvation or hydration products (also known as pseudopolymorphs) and amorphous forms.
Differences in these forms could, in some cases, affect the quality or performance of the new drug products.
In cases where differences exist which have been shown to affect drug product performance, bioavailability or stability, then the appropriate solid state should be specified.
Physicochemical measurements and techniques are commonly used to determine whether multiple forms exist.
Examples of these procedures are : Melting Point (including hot-stage microscopy), Solid State IR, X-ray powder diffraction, Thermal analysis procedures (like DSC, TGA and DTA), Raman spectroscopy, optical microscopy, and solid state NMR.
It is generally technically very difficult to measure polymorphic changes in drug products.
A surrogate test (e.g., dissolution) can generally be used to monitor product performance, and polymorph content should only be used as a test and acceptance criterion of last resort.
Tests for Chiral APIs : Where a new drug substance is predominantly one enantiomer, the opposite enantiomer is excluded from the qualification and identification thresholds given in the ICH–Q3 because of practical difficulties in quantifying it at those levels.
However, that impurity in the chiral new drug substance and the resulting new drug product(s) should otherwise be treated according to the principles established in those Guidelines.
If chiral identity tests, impurity tests, and assays to be needed for new drug substances according to the following concepts:
Impurities : For chiral drug substances which are developed as a single enantiomer, control of the other enantiomer should be considered in the same manner as for other impurities.
However, technical limitations may preclude the same limits of quantification or qualification from being applied.
Assurance of control also could be given by appropriate testing of a starting material or intermediate, with suitable justification.
Assay : An enantioselective determination of the drug substance should be part of the specification.
It is considered acceptable for this to be achieved either through use of a chiral assay procedure or by the combination of an achiral assay together with appropriate methods of controlling the enantiomeric impurity.
Identity : For a drug substance developed as a single enantiomer, the identity test(s) should be capable of distinguishing both enantiomers and the racemic mixture.
For a racemic drug substance, there are generally two situations where a stereospecific identity test is appropriate for release/acceptance testing:
Where there is a significant possibility that the enantiomer might be substituted for the racemate, or
When there is evidence that preferential crystallization may lead to unintentional production of a non-racemic mixture.

THE FOLLOWINGS ARE MINIMUM INSTRUCTION TO CONTROL THE QUALITY OF API As per ICH Q7A
The system for managing quality should encompass the organisational structure, procedures, processes and resources, as well as activities necessary to ensure confidence that the API will meet its intended specifications for quality and purity.
All quality related activities should be defined and documented.
Specifications should be established and documented for raw materials, intermediates where necessary, APIs, and labelling and packaging materials.
In addition, specifications may be appropriate for certain other materials, such as process aids, gaskets, or other materials used during the production of intermediates or APIs that could critically impact on quality.
Acceptance criteria should be established and documented for in-process controls.
If time limits are specified in the master production instruction, these time limits should be met to ensure the quality of intermediates and APIs.

Deviations should be documented and evaluated.
Time limits may be inappropriate when processing to a target value (e.g., pH adjustment, hydrogenation, drying to predetermined specification) because completion of reactions or processing steps are determined by in-process sampling and testing.
Packaging and labelling materials should conform to established specifications.
Those that do not comply with such specifications should be rejected to prevent their use in operations for which they are unsuitable.
All specifications, sampling plans, and test procedures should be scientifically sound and appropriate to ensure that raw materials, intermediates, APIs, and labels and packaging materials conform to established standards of quality and/or purity.
Specifications and test procedures should be consistent with those included in the registration/filing.
There can be specifications in addition to those in the registration/filing.
Specifications, sampling plans, and test procedures, including changes to them, should be drafted by the appropriate organizational unit and reviewed and approved by the quality unit(s).
An impurity profile describing the identified and unidentified impurities present in a typical batch produced by a specific controlled production process should normally be established for each API.
The impurity profile should include the identity or some qualitative analytical designation (e.g. retention time), the range of each impurity observed, and classification of each identified impurity (e.g. inorganic, organic, solvent).
The impurity profile is normally dependent upon the production process and origin of the API.
Impurity profiles are normally not necessary for APIs from herbal or animal tissue origin.
Biotechnology considerations are covered in ICH Guideline Q6B.
Intermediates and APIs failing to meet established specifications should be identified as such and quarantined.
These intermediates or APIs can be reprocessed or reworked as described below.
The final disposition of rejected materials should be recorded.
Introducing an intermediate or API, including one that does not conform to standards or specifications, back into the process and reprocessing by repeating a crystallization step or other appropriate chemical or physical manipulation steps (e.g., distillation, filtration, chromatography, milling) that are part of the established manufacturing process is generally considered acceptable.
However, if such reprocessing is used for a majority of batches, such reprocessing should be included as part of the standard manufacturing process.

FORMER INFORMATION
Acceptance Criteria
Numerical limits, ranges, or other suitable measures for acceptance of the results of analytical procedures.
Chiral
Not super-imposable with its mirror image, as applied to molecules, conformations, and macroscopic objects, such as crystals.
The term has been extended to samples of substances whose molecules are chiral, even if the macroscopic assembly of such molecules is racemic.
Combination Product
A drug product which contains more than one drug substance.
Degradation Product
A molecule resulting from a chemical change in the drug molecule brought about over time and/or by the action of e.g., light, temperature, pH, water, or by reaction with an excipient and/or the immediate container/closure system.
Also called decomposition product.
Enantiomers
Compounds with the same molecular formula as the drug substance, which differ in the spatial arrangement of atoms within the molecule and are non-super-imposable mirror images.

New Drug Substance
The designated therapeutic moiety, which has not previously been registered in a region or Member State (also referred to as a new molecular entity or new chemical entity).
It may be a complex, simple ester, or salt of a previously approved drug substance.
Polymorphism
The occurrence of different crystalline forms of the same drug substance.
This may include solvation or hydration products (also known as pseudopolymorphs) and amorphous forms.
Quality
The suitability of either a drug substance or drug product for its intended use.
This term includes such attributes as the identity, strength, and purity.
Reagent
A substance, other than a starting material or solvent, which is used in the manufacture of a new drug substance.
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 or the manufacture of a new drug product.
Impurity
Any component present in the drug substance or drug product which is not the desired product, a product-related substance, or excipient including buffer components. It may be either process- or product-related.
Specified Impurity
An identified or unidentified impurity that is selected for inclusion in the new drug substance or new drug product specification and is individually listed and limited in order to assure the quality of the new drug substance or new drug product.
Unidentified Impurity
An impurity which is defined solely by qualitative analytical properties, (e.g.,chromatographic retention time).
Universal Test
A test which is considered to be potentially applicable to all new drug substances, or all new drug products; e.g., appearance, identification, assay, and impurity tests.
Action Limit
An internal (in-house) value used to assess the consistency of the process at less critical steps.
Biological Activity
The specific ability or capacity of the product to achieve a defined biological effect. Potency is the quantitative measure of the biological activity.
Contaminants
Any adventitiously introduced materials (e.g., chemical, biochemical, or microbial species) not intended to be part of the manufacturing process of the drug substance or drug product.
Degradation Products
Molecular variants resulting from changes in the desired product or product-related substances brought about over time and/or by the action of, e.g., light, temperature, pH, water, or by reaction with an excipient and/or the immediate container/closure system.
Such changes may occur as a result of manufacture and/or storage (e.g., deamidation, oxidation, aggregation, proteolysis). Degradation products may be either product-related substances, or product-related impurities.
Drug Product (Dosage Form; Finished Product)
A pharmaceutical product type that contains a drug substance, generally, in association with excipients.
Excipient
An ingredient added intentionally to the drug substance which should not have pharmacological properties in the quantity used.

Drug Substance (Bulk Material)
The material which is subsequently formulated with excipients to produce the drug product. It can be composed of the desired product, product-related substances, and product- and process-related impurities. It may also contain excipients including other components such as buffers.
In-house Primary Reference Material
An appropriately characterized material prepared by the manufacturer from a representative lot(s) for the purpose of biological assay and physicochemical testing of subsequent lots, and against which in-house working reference material is calibrated.
In-house Working Reference Material
A material prepared similarly to the primary reference material that is established solely to assess and control subsequent lots for the individual attribute in question. It is always calibrated against the in-house primary reference material.
Potency
The measure of the biological activity using a suitably quantitative biological assay (also called potency assay or bioassay), based on the attribute of the product which is linked to the relevant biological properties.
Process-Related Impurities
Impurities that are derived from the manufacturing process. They may be derived from cell substrates (e.g., host cell proteins, host cell DNA), cell culture (e.g., inducers, antibiotics, or media components), or downstream processing (e.g., processing reagents or column leachables).
Product-Related Impurities
Molecular variants of the desired product (e.g., precursors, certain degradation products arising during manufacture and/or storage) which do not have properties comparable to those of the desired product with respect to activity, efficacy, and safety.
Product-Related Substances
Molecular variants of the desired product formed during manufacture and/or storage which are active and have no deleterious effect on the safety and efficacy of the drug product.
These variants possess properties comparable to the desired product and are not considered impurities.
Dosage Form
A dosage form is the physical form of a dose of medication, such as a capsule or injection.
The route of administration is dependent on the dosage form of a given drug.
Various dosage forms may exist for the same compound, since different medical conditions may warrant different routes of administration.
For example, persistent vomiting may make it difficult to use an oral dosage form; in this case, it may be advisable to use either an injection or a suppository .
Also, specific dosage forms may be warranted for certain medications, since there may be problems with stability, e.g. insulin cannot be given orally since it is digested by the gut.
Examples :
Inhaled Dosage Forms Aerosol, Gas, Inhaler & Metered dose inhaler, Solution for nebulizer
Ophthalmic Dosage Forms Eye drop (solution or suspension), Ophthalmic gel, Ophthalmic ointment
Oral Dosage Forms Capsule, Powder, Solution, Suspension, Tablet, Buccal or sublingual tablet
Otic Dosage Forms Ear drop (solution or suspension)
Parenteral Dosage Forms Solution or suspension for injection
Rectal Dosage Forms Enema, Suppository
Topical Dosage Forms Cream, Gel, Liniment, Lotion, Ointment, Paste, Transdermal patch
Vaginal Dosage Forms Douche, Intrauterine device, Pessary (vaginal suppository), Vaginal ring, Vaginal tablet




ANTHOLOGY OF INFORMATION :

ICH Q2 : Validation of Analytical Procedures : Text and Methodology
ICH Q3A : Impurities in New Drug Substances
ICH Q3C : Impurities : Guideline for Residual Solvents
ICH Q6A : Test Procedures & Acceptance Criteria for New Drug Substances and New Drug Products:Chemical Substances
ICH Q6B : Test Procedures and Acceptance Criteria for Biotechnological / Biological Products
ICH Q7 : Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients
USP : United States Pharmacopoeia
EP : European Pharmacopoeia
BP : British Pharmacopoeia
JP : Japan Pharmacopoeia
IP : Indian Pharmacopoeia
Technical Guide for the Elaboration of Monographs : European Pharmacopoeia (EDQM) 4th Edition 2005., etc.
CPMP/SWP/QWP/4446/00 Corr. : Draft Guideline on the Specification Limits for Residues of Metal Catalysts / Committee …………………………………………for Human Medicinal Products (CHMP)



NOTE: Please consider that this transcript is only for updating and sharing the Knowledge. ……… …If any inaccuracy is there in above preparation. Please update me to precise myself.


Wednesday, November 17, 2010

REGULATORY AND GMP CONCERNS ON QUALITY CONTROLS OF DRUG SUBSTANCES-II

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REGULATORY AND GMP CONCERNS ON QUALITY CONTROLS OF DRUG SUBSTANCES

Specification

The specifications should be in accordance with the current general and specific Pharmacopoeia monographs.

Where the monograph has been shown not suitable to control the quality of the substance, and in particular the related substances, the additional analytical methods should be identified.

Any additional specifications to those of the monograph shall be justified.

If any of these specifications vary during operation, this change should be investigated and appropriate action taken.

At the time of filing it is unlikely that sufficient data will be available to assess process consistency.

Therefore it is considered inappropriate to establish acceptance criteria that tightly encompass the batch data at the time of filing.

Justification of Specification

It should be stated if supplementary or improved tests are needed.

Any additional specifications or deviations should be justified.

The possible need for a revision of the Pharmacopoeia monograph should be discussed.

Omission of Tests

Where the monograph mentions a test for a named impurity (metal catalyst/reagent/solvent) but which is not used during manufacture, the manufacturer may omit the test in the specifications which should be made clear in the DMF.

However, the substance should comply with the monograph, if tested.

Out of Specifications

Any out-of-specification result obtained should be investigated and documented according to a procedure.

This procedure should require analysis of the data, assessment of whether a significant problem exists, allocation of the tasks for corrective actions, and conclusions.

Any re-sampling and/or retesting after OOS results should be performed according to a documented procedure.

Out-of-specification (OOS) investigations are not normally needed for in-process tests that are performed for the purpose of monitoring and/or adjusting the process.

Out-Of-Specification batches should not be blended with other batches for the purpose of meeting specifications.

Each batch incorporated into the blend should have been manufactured using an established process and should have been individually tested and found to meet appropriate specifications prior to blending.

Field Alert Reports

For those products that are the subject of approved full and abbreviated new drug applications, regulations require submitting within 3 working days a field alert report (FAR) of information concerning any failure of a distributed batch to meet any of the specifications established in an application (21 CFR 314.81(b)(1)(ii)).

OOS test results on these products are considered to be one kind of "information concerning any failure” described in this regulation.

Unless the OOS result on the distributed batch is found to be invalid within 3 days, an initial FAR should be submitted.

A follow-up FAR should be submitted when the OOS investigation is completed.


NEEDS OF QUALITY CONTROLS FOR DRUG SUBSTANCES

Description / Appearance

Description can normally embrace colour and physical form.

The term “white” is not used without qualification since, if viewed against a standard white material, very few pharmaceutical materials will appear truly white.

It is, of course, not intended that such a comparison be made but experience shows that certain users of the pharmacopoeia may insist on doing so as part of a purchasing contract.

The term “white or almost white” is used instead.

Where positive colours are to be described this is done in terms of primary colours or combinations of primary colours.

A qualitative statement about the state (e.g. solid, liquid) and colour of the drug substance.

Visible

White to off-white, white to pale yellow, “JP white”, colour descriptions are available, including recommendation of “white to almost white”

Qualitative test only

Genuine issues (e.g. impurities, contaminants) should be dealt with via quantitative tests; appearance doesn’t need to be quantitative.

Testing during stability may need to be a slightly different process to that for release where trends do not need to be monitored.

Solution Clarity

During development for APIs for solution formulation (internal test)

Clarity and Degree of Opalescence (DP test)

Silica: Acid + Silica Filtration, Recrystallizein API

Filter Housing : Acid + Filter

Turbidity

Quantitative (with weaknesses)

Ball-park figure of ~ 2NTU; EP test solution for clear = ~2.8NTU

Other tests

Odour

Generally no

Depending on route of delivery may need to limit solvents to <>

Degradation products e.g. Sulphates or Toluene degradation product

Mass balance

Useful scientific guide for evaluating data, but is not achievable in all circumstances

WHO guidelines discuss this with reference to Degree of Opalescence only

Address as part of development if notice significant discrepancies

No taste


Identification

Identification testing should optimally be able to discriminate between compounds of closely related structure, which are likely to be present.

Identification tests should be specific for the new drug substance, e.g., Infrared Spectroscopy.

Identification solely by a single chromatographic retention time, for example, is not regarded as being specific.

However, the use of two chromatographic procedures, where the separation is based on different principles or a combination of tests into a single procedure, such as HPLC/ UV diode array, HPLC/ MS, or GC/ MS is generally acceptable.

If the drug substance is a salt, identification testing should be specific for the individual ions.

An identification test that is specific for the salt itself should suffice.

Drug substances that are optically active may also need specific identification testing or performance of a chiral assay.

Specific spectroscopic technique

e.g. FTIR

Generally best strategy

Easy to do ‘Identification testing on receipt’ etc..

Chiral test if required

Optical Rotation

Or may get chromatographic ‘for free’ è see Chiral impurity control

Racemates if also developing Enantiomer or Chiral preference may occur

If more than two Chiral centres then control of Starting Materials/ Reagents may be more appropriate

The first tells you if you have the right species, the second confirms which enantiomer

Salt form identity

Release test

Not required to be measured on stability

An IR test for the API may be specific for the Salt form also

If not, a test for the counter ion may be required (may also double as an assay test for the counter ion if required)

Salt form assay

Assay determination of the counter ion may be omitted from the release specification if batch data shows good stoichiometry routinely achieved.

If the, generally organic, counter ion degrades may need to determine on stability or if the counter ion degradation products need to be controlled

Hemi-maleate / Hemi-hydrochloride can transform to Maleatetrihydrate + HCl at high humidity

Solid form identity

Polymorph, Solvate, De-solvated Solvates, Amorphous

From experience, mean is 3-4 per compound; record = 75 ?

If development work shows that no other forms are feasible/relevant then not required on specification

Similarly for stability, if other forms would not be formed at relevant temperatures/ humidities or timescales (hydrates, amorphous crystallisation), then shouldn’t be required on stability

PXRD in early development, once characterised, DSC more widely available


Form assay

Reactivity in the amorphous state is greater than that in the crystalline state

Possible release test if observing batch-to-batch variation in degradation rates

PXRD can measure amorphous content down to ~5%

Racemic drugs

Can be racemic compounds 90-95% of cases (racemic crystals)

- (RSRSRSRSRS)

or racemic conglomerate 5-10% of cases (enantiomorphous mixture of crystals)

- (SSSSS RRRRR)

rarely pseudoracemate

- (RSSRSRRSRS)

Release test

Crystal habit

Can affect solubility, dissolution rate, degradation and formulation processing

Determine using microscopy

Develop final step to ensure control

Release test

Assay

A specific, stability-indicating assay to determine strength (content) should be included for all drug products.

In many cases it is possible to employ the same procedure (e.g., HPLC) for both assay of the new drug substance and quantitation of impurities.

Results of content uniformity testing for drug products can be used for quantitation of drug product strength, if the methods used for content uniformity are also appropriate as assays.

In cases where use of a non-specific assay is justified, other supporting analytical procedures should be used to achieve overall specificity.

For example, where titration is adopted to assay the drug substance for release, the combination of the assay and a suitable test for impurities can be used.

A specific procedure should be used when there is evidence of excipient interference with the non-specific assay.

Main component assay

ICH Q6A

Stability indicating; If non-specific test, may need to subtract impurities from the result

For chiral drugs, an achiral assay with control of the enantiomeric impurity is acceptable

General limits

Upper limit 102.0% (on an anhydrous basis or dried i.e. anhydrous and solvent free)

Lower limit 98.0% depending on levels of impurities

Racemic drugs

Essentially equal efficacy/safety –then can control as a total of the two

Tend to be denser and thus stable than chiral counterparts


Organic Impurities

Organic impurities arising from degradation of the drug substance and impurities that arise during the manufacturing process for the drug product should be monitored in the new drug product.

Acceptance limits should be stated for individual specified degradation products, which may include both identified and unidentified degradation products as appropriate, and total degradation products.

Process impurities from the drug substance synthesis are normally controlled during drug substance testing, and therefore are not included in the total impurities limit.

However, when a synthesis impurity is also a degradation product, its level should be monitored and included in the total degradation product limit.

When it has been conclusively demonstrated via appropriate analytical methodology, that the drug substance does not degrade in the specific formulation, and under the specific storage conditions proposed in the drug application, degradation product testing may be reduced or eliminated upon approval by the regulatory authorities.

Organic

Contaminants –addressed as GMP issues

Process related impurities to be controlled at the API stage –release testing only

In early development phase impurity limits may be set at thresholds

As per ICH Q3A,

Specification should include:

Each specified identified impurity

Each specified unidentified impurity•

Total Impurities”

Any unspecified impurity with an acceptance criterion of not more than (≤) the identification threshold

If maximum Daily Dose is < 2 g / day - Unknown Impurity is 0.10%

Reporting Threshold is 0.05%

Identification Threshold is 0.10% or 1.0 mg per day intake (whichever is lower)

Qualification Threshold is 0.15% or 1.0 mg per day intake (whichever is lower)

If maximum Daily Dose is > 2 g / day - Unknown Impurity is 0.05%

Reporting Threshold is 0.03%

Identification Threshold is 0.05%

Qualification Threshold is 0.05%

When identification of an impurity is not feasible, a summary of the laboratory studies demonstrating the unsuccessful effort should be included in the application.

Could control to the qualification threshold as an unidentified specified impurity

Where there is no safety concern, impurity acceptance criteria should be based on data generated on batches of the new drug substance manufactured by the proposed commercial process, allowing sufficient latitude to deal with normal manufacturing and analytical variation and the stability characteristics of the new drug substance.

Thus limits for degradants should not be bounded within actual data available at time of filing, although thresholds in Q3A apply.

ICH Q6A “estimate maximum increase in impurity at retest date”

Estimate maximum by extrapolation:- 3 x Standard Deviation of predictions from the three batches or the upper one-sided 95% confidence limit out to retest period desired.


Chiral Impurities

Can significantly affect physicochemical properties of pure enantiomers.

Release test; if development work (scientific analysis, stress testing) shows that opposite enantiomer is not a degradation product, shouldn’t need to test on stability

A racemic degradant could be controlled as two separate enantiomers each to ICH Q3A threshold

Impurities -Analytical Methodology

Chromatographic methods in development stability may need to be more powerful than (or in addition to) those transferred to manufacturing : Stress in acid led to brown gum - Polymerisation

Noted disappearance of PRI dimers on stability, disappearance not seen during stress testing

Found that adsorbed onto certain vial types –changed to end-capped vials/altered pH

Total Impurities

Essentially a quality test only (assay and individual impurities controls ensure efficacy and safety)

By specifying impurities, rather than having unspecified impurities control only, may help to set more appropriate limits

TLC only for a specified impurity and only as last resort.

Veterinary Medicine

Different thresholds

Genotoxic impurity

According to current regulatory practice it is assumed that (in vivo) genotoxic compounds have the potential to damage DNA at any level of exposure and that such damage may lead/contribute to tumour development.

Thus for genotoxic carcinogens it is prudent to assume that there is no discernible threshold and that any level of exposure carries a risk.

However, the existence of mechanisms leading to biologically meaningful threshold effects is increasingly acknowledged also for genotoxic events.

This holds true in particular for compounds interacting with non-DNA targets and also for potential mutagens, which are rapidly detoxified before coming into contact with critical targets.

The regulatory approach to such chemicals can be based on the identification of a critical No-Observed-Effect Level (NOEL) and use of uncertainty factors.

Even for compounds which are able to react with the DNA molecule, extrapolation in a linear manner from effects in high-dose studies to very low level (human) exposure may not be justified due to several protective mechanisms operating effectively at low doses.

However, at present it is extremely difficult to experimentally prove the existence of threshold for the genotoxicity of a given mutagen.

Thus, in the absence of appropriate evidence supporting the existence of a threshold for a genotoxic compound making it difficult to define a safe dose it is necessary to adopt a concept of a level of exposure that carries an acceptable risk.

The toxicological assessment of genotoxic impurities and the determination of acceptable limits for such impurities in active substances is a difficult issue and not addressed in sufficient detail in the existing ICH Q3X guidances.

The data set usually available for genotoxic impurities is quite variable and is the main factor that dictates the process used for the assessment of acceptable limits.


In the absence of data usually needed for the application of one of the established risk assessment methods,

i.e. data from carcinogenicity long-term studies or data providing evidence for a threshold mechanism of genotoxicity, implementation of a generally applicable approach as defined by the Threshold of Toxicological Concern (TTC) is proposed.

A TTC value of 1.5 µg/day intake of a genotoxic impurity is considered to be associated with an acceptable risk (excess cancer risk of <1>

From this threshold value, a permitted level in the active substance can be calculated based on the expected daily dose.

Higher limits may be justified under certain conditions such as short-term exposure periods.

The concentration limits in ppm of genotoxic impurity in drug substance derived from TTC can be calculated based on the expected daily dose to the patient using equation

TTC [mg / day]

Concentration Limit (ppm) = -------------------------------- è Threshold of Toxicological Concern

Dose [g / day]

Inorganic Impurities

The need for inclusion of tests and acceptance criteria for inorganic impurities (e.g., catalysts) should be studied during development and based on knowledge of the manufacturing process.

Procedures and acceptance criteria for sulfated ash / residue on ignition should follow pharmacopoeial precedents; other inorganic impurities may be determined by other appropriate procedures, e.g., atomic absorption spectroscopy.

Inorganic Impurities (not on stability)

Heavy metals

Shouldn’t need to test if no Heavy metals used in route and RSMs/reagents are adequately understood/controlled.

Criteria and limits EP Technical Guide

Daily intake > 0.5 g/day, treatment <>

Daily intake > 0.5 g/day, treatment > 30 days : Heavy metals test limit 10 ppm

Daily intake <> 30 days: Heavy metals test limit 10 ppm If it is used parenterally

Heavy metals test limit 20 ppm Other wise

Daily intake <>

Global Specifications

Pharmacopoeias: Heavy metals for an API in Japan

JP Heavy metals test not adequate temperature

Used modified (validated) EP test accepted

For API usually set out with good intentions, however some tests may be region specific e.g. arsenic for Japan, or may end up with different agreed limits for impurities in different regions.

Depending what is easiest for one’s supply chain, may test API for specific markets or have a tighter internal control document put in place meeting all region requirements…

Similarly for API intended for >1 dosage form type…


Specific Tests

Control of catalysts used during manufacturing process

Arsenic control for Japan may be required

Pharmacopoeial methodology or specific (but validated)

Information about Metal Residues

Residual metals used as process catalysts do not provide any therapeutic benefit and should therefore be evaluated and restricted on the foundation of safety- and quality-based criteria.

Metals will be classified in three categories based on their individual levels of safety concern and concentration limits will be set on the bases of the maximal daily dose, duration of treatment, route of administration and permitted daily exposure (PDE).

In the reviews the following assumptions and/or default values are used:

Body Weight (bw) of an adult: 50 Kg.

Breathing volume of an adult: 20 m3 per Day (24 Hr.).

Occupational (workplace) inhalation exposure: 8 Hr. per Day (24 Hr.).

Exposure limits were established using uncertainty factors as per ICH Q3.

For pragmatic reasons a number of uncertainty factors were adapted to arrive at a final safe and practical PDE setting - Q3 method for uncertainty factor (UF) calculation plus additional pragmatic factor for PDE calculation.

Acceptable Additional Lifetime Cancer Risk:

An increased cancer risk of 1 in 100,000 was identified as acceptable for genotoxic impurities in pharmaceuticals by the Committee for Human Medicinal Products (CHMP).

Limits set based on safety criteria may therefore be higher than limits set on the basis of GMP, process capabilities, or other suitable quality criteria.

Any interested party can make a request and submit relevant safety data.

Classification and limits may change as new safety data becomes available.

Metal catalysts and metal reagents are defined here as chemical substances that are used to change the rate of chemical reactions or which act on other chemical substances in chemical reactions.

Residues of metals can either be present as the original form of the metal or as a form of the metallic element altered by downstream chemical processing.

Excluded from this document are extraneous metal contaminants that should not occur in drug substances or excipients and are more appropriately addressed as Good Manufacturing Practice (GMP) issues.

Different limits are applied to oral and parenteral routes of administration due to limited oral bioavailability of many metals.

As different routes of exposure may have different toxicological properties, specific limits have been set for inhalation exposure to some metals.

When the exposure is short the PDE´s mentioned in this guideline may be adapted as indicated


Classification of Metals

Metals were evaluated for their potential risk to human health and placed into one of three classes as follows:

Class 1 Metals : Metals of significant safety concern

Metals of significant safety concern known or suspect human carcinogens, or possible causative agents of other significant toxicity.

Class 1 is subdivided into 3 subclasses.

Class 1A: Platinum (Pt) and Palladium (Pd)

Class 1B: Iridium (Ir), Rhodium (Rh), Ruthenium (Ru) and Osmium (Os)

Class 1C: Molybdenum (Mo), Nickel (Ni), Chromium (Cr), Vanadium (V)

Platinoids are in Class 1A and Class 1B.

For the Platinoids in subclass 1B a conservative approach has been adopted, because there are very limited toxicity data. Thus the indicated limit for Class 1B is the limit for the total amount of those platinoids that, based on the used synthesis procedures, are anticipated to be present.

Class 2 Metals : Metals with low safety concern

Copper (Cu) and Manganese (Mn)

Metals with low safety concern Metals with lower toxic potential to man.

They are generally well tolerated up to exposure.

They may be trace metals required for nutritional purposes or they are often present in food stuffs or readily available nutritional supplements.

Class 3 Metals : Metals with minimal safety concern

Zinc (Zn) and Iron (Fe)

Metals with minimal safety concern.

Metals with no significant toxicity.

Their safety profile is well established.

They are generally well tolerated up to doses.

Typically they are ubiquitous in the environment or the plant and animal kingdoms.

Residue on Ignition

US & EP Guidelines : Residue on Ignition NMT 0.1%; Japan 0.10%; in reality a quality test only.

ICP-MS

Scans during development to gather information; specific tests may need to be developed depending on formulation/other considerations

Iron: iron oxide/hydroxide formation in alkaline solutions; ppm control.

Residual Solvents

The need for inclusion of tests and acceptance criteria for Residual Solvents should be studied during development and based on knowledge of the manufacturing process.

Acceptance criteria for Residual Solvents should follow Pharmacopoeial precedents and ICH; other Residual Solvents which are not covered in ICH and Pharmacopoeia can be determined by other appropriate standards (Like NIOSH : The National Institute for Occupational Safety and Health).


Class I : Solvents to be avoided

Benzene, carbon tetrachloride, 1,2-dichloroethane, 1,1-dichloroethene, 1,1,1- trichloroethane

Class II : Solvents to be limited

Acetonitrile, Chloroform, Cyclohexane, Dioxane, Methanol, Methylbutylketone, Tetrahydrofurane, Toluene, …...

Class III : Solvents with low toxic potential

Acetone, Butanol, Butyl acetate, DMSO, Ethanol, Ethyl acetate, Ethyl ether, Heptane, Isopropanol, Methylethyl Ketone, ….... [Loss on drying should be less than 0.5%]

Class I residual solvents to be avoided,

It is critical to avoid. General cases as follows :

1. Starting Material : e.g. Benzene in early steps in synthesis.

2. By-products from chemical reaction: e.g. Benzene as a Grignard-by-product.

3. Impurity in another residual solvents: e.g. Benzene as an impurity in toluene.

But it is need for control.

OVI : Organic Volatile Impurities are described in USP. This test is in effect until July 1, 2008.

There are many different solvents which are used in pharmaceutical manufacturing. USP mandates that at least six of these solvents be monitored in finished products : Benzene, Chloroform, 1,4-Dioxane, Ethylene Oxide, Methylene Chloride and Trichloroethylene.

Organic Volatile Impurities details are given in USP <467>.

Solvents are not required on stability; may do as part of an assay/ potency procedure if mass balance may be impacted by loss of solvent on stability.

Other information

Residues of residual toxic reagents should also be discussed and where applicable a suitable limit and test method proposed if the monograph does not provide a suitable test.

Residues of acids or bases that are not mentioned in the ICH guideline for residual solvents (e.g. HCl, organic acids) should also be discussed if the monograph does not provide a suitable test (pH, acidity or alkalinity).

Concerning residual triethylamine, a permitted daily exposure (PDE) of 3.2 mg/day giving a limit of 320 ppm (for a 10 g daily dose) was calculated from repeated Dose Toxicity and Reproductive Toxicity data. This limit of 320 ppm should therefore be used as a reference limit. (As per EDQM COS Content Dossier for Chemical Purity Microbiological Quality guide).

Higher limits should be justified by batch analysis data and the maximum daily dose of the concerned substance.

It should be noted that this limit is not immediately applicable to other organic bases for which limits should be calculated on available toxicological data.

Particle Size

For some drug substances intended for use in solid or suspension drug products, particle size can have a significant effect on dissolution rates, bio-availability, and / or stability.

In such instances, testing for particle size distribution should be carried out using an appropriate procedure, and acceptance criteria should be provided.

Particle size

May affect formulation and stability

Methodology and acceptance criteria: “May be performed as an in-process test or…release test.”


Agglomeration: for API for suspensions, or if note powder processing issues during formulation manufacture or other formulation issues, may need to investigate agglomeration on API stability via microscopy.

Stability of the API: “Results should be included for physical as well as chemical tests e.g. particle size…”

Generally no need to measure on stability.

Physicochemical Properties

These are properties such as pH of an aqueous solution, melting point / range, and refractive index.

The procedures used for the measurement of these properties are usually unique and do not need much elaboration, e.g., capillary melting point.

Tests performed in this category should be determined by the physical nature of the drug substance and by its intended use.

What are the physicochemical properties including physical description, pKa, polymorphism, aqueous solubility (as function of pH), hygroscopicity, melting points, and partition coefficient ?

List all physicochemical properties listed in the question even if they are not critical;

If a property is left out, explain why

Example, No pKa because there are no ionizable groups in the chemical structure

Include other applicable properties of the drug substance if they are critical

Pay special attention to these critical properties such as solubility, polymorphism, etc.

Why do we ask you to provide these physicochemical properties?

Physical properties of the drug substance may affect drug product development, manufacture, or performance; e.g. particle size, polymorphism etc.

Chemical properties of the drug substance may also affect the drug product development, manufacture, or performance, e.g., compatibility between excipients and drug substance, etc.

Polymorphic Forms

Some drug substances exist in different crystalline forms which differ in their physical properties.

Polymorphism may also include solvation or hydration products (also known as pseudopolymorphs) and amorphous forms.

Differences in these forms could, in some cases, affect the quality or performance of the new drug products.

In cases where differences exist which have been shown to affect drug product performance, bioavailability or stability, then the appropriate solid state should be specified.

Whether multiple forms exist. examples of these procedures are:

Melting point (including hot-stage microscopy)

Solid State IR

X-ray Powder Diffraction

Thermal Analysis Procedures (like DSC, TGA and DTA)

Raman Spectroscopy

Optical Microscopy

Solid State NMR.


Polymorphism

List all polymorphic forms reported in literature and provide brief discussion (i.e., which one is the most stable form).

Example

It is reported in the literature that there are two anhydrous polymorphic forms for the drug substance, form I and II; and no known hydrate forms; Form I is the most stable form. The references are made to….

For example, if there are known different polymorphic forms

Specify which polymorphic form is used

Supporting evidence for the claim (X-ray, DSC, and Literatures)

Information should be provided in PD report for polymorphic form selection, if it is critical

Tests for Chiral

Where a new drug substance is predominantly one enantiomer, the opposite enantiomer is excluded from the qualification and identification thresholds given in the ICH Guidelines on Impurities in New Drug Substances and Impurities in New Drug Products because of practical difficulties in quantifying it at those levels.

However, that impurity in the chiral new drug substance and the resulting new drug product(s) should otherwise be treated according to the principles established in Guidelines.

Impurities

For chiral drug substances which are developed as a single enantiomer, control of the other enantiomer should be considered in the same manner as for other impurities.

However, technical limitations may preclude the same limits of quantification or qualification from being applied.

Assurance of control also could be given by appropriate testing of a starting material or intermediate, with suitable justification.

Assay

An enantioselective determination of the drug substance should be part of the specification.

It is considered acceptable for this to be achieved either through use of a chiral assay procedure or by the combination of an achiral assay together with appropriate methods of controlling the enantiomeric impurity.

Identity

For a drug substance developed as a single enantiomer, the identity test(s) should be capable of distinguishing both enantiomers and the racemic mixture.

For a racemic drug substance, there are generally two situations where a stereospecific identity test is appropriate for release/acceptance testing:

- where there is a significant possibility that the enantiomer might be substituted for the racemate, or

- when there is evidence that preferential crystallization may lead to unintentional production of a non-racemic mixture

Enantiomers:

Distinguished by biological systems

Same or different pharmacologic / pharmacokinetic / toxicologic activity

Same physico-chemical properties except optical activity

Specific techniques necessary to identify them, separate, assay and synthesis


(e.g. it is easier and less expensive to manufacture the racemic mixture)

(+) and (-) Ibuprofene: both anti-inflammatory agents

(+) Sotalol: antiarrhythmic but (-) sotalol : b-blocker ® Critical

(-) Levocetirizine active as 5 mg dosage but (±) racemic cetirizine marketed as 10 mg ® Critical

(-) Lamivudune: selected and registered

(+) Lamivudine and racemic mixture (±) more cytotoxic (EMEA/CPMP/375/96 EPAR) ® Critical

Batch-to-batch consistency and reproducibility of the manufacture with preclinical and clinical batches (innovator) or with the bio-batch used in the bioequivalence study (Generic products) should be guaranteed

Either by suitable controls included in specifications for identity, control of the opposite enantiomer as an impurity or chiral assay of the API

Lamivudine monograph in USP and draft in Ph. Eur.: opposite enantiomer limited to NMT 0.3%

Tenofovir EPAR CPMP/3510/01: enantiomeric purity NLT 98% for the R-isomer claimed

Either by control of stereochemistry (control of chirality) through the route of synthesis i.e. appropriate controls on starting materials and intermediates + demonstration that there is no racemiation up to the end

Case of Efavirenz, indinavir, nelfinavir, ritonavir…(tricky as the information is not publicly available for comparison)

Non pharmacopoeial Chiral APIs claimed as a single enantiomer

See the ICH Q6A decision tree, # 5: establishing identity, assay and enantiomeric impurity procedures for chiral NCEs

1. If the substance is chiral and one enantiomer claimed.

Consider need for Chiral identity, chiral assay, enantiomeric impurity

Chiral assay or an enantiomeric impurity procedure may be acceptable in lieu of chiral identification

An achiral assay + a method for control of the opposite enantiomer is acceptable in lieu of a chiral assay

The level of the opposite enantiomer may be derived from chiral assay

Stereospecific testing of the drug product is not necessary if racemisation is shown to be insignificatif during manufacture and storage of FPP

Possible to justify not carrying either chiral assay or control of the opposite enantiomer when 3 or more chiral centres present

Water Content

This test is important in cases where the new drug substance is known to be hygroscopic or degraded by moisture or when the drug substance is known to be a stoichiometric hydrate.

The acceptance criteria may be justified with data on the effects of hydration or moisture absorption.

In some cases, a Loss on Drying procedure may be considered adequate; however, a detection procedure that is specific for water (e.g., Karl Fischer titration) is preferred.

Water Content

Determine limits for release based on degradation mechanisms and stability knowledge; this will actually inform drying of API and packaging decisions

Determining water on stability largely irrelevant other than to inform packaging decisions –it is other factors that are actually important i.e. degradation product levels


Microbial Limits

There may be a need to specify the total count of aerobic micro organisms, the total count of yeasts and molds, and the absence of specific objectionable bacteria.

e.g., Staphylococcus aureus

Escherichia coli

Salmonella

Pseudomonas aeruginosa

These should be suitably determined using pharmacopoeial procedures.

The type of microbial test(s) and acceptance criteria should be based on the nature of the drug substance, method of manufacture, and the intended use of the drug product.

For example, sterility testing may be appropriate for drug substances manufactured as sterile and endotoxin testing may be appropriate for drug substances used to formulate an injectable drug product.

Endotoxins

Release test only and only If intended for parenteral drug product

Total viable aerobic count

Generally test if for sterile product

May omit from specification based on ICH Q6A Decision Tree #6 (process steps, capability of supporting growth) plus water activity considerations

If test on stability, may do at key checkpoints only, e.g. annually

Specific organisms

May omit from specification based on ICH Q6A Decision Tree #6 (process steps, capability of supporting growth) plus water activity considerations

Release test only as a quality/contamination test


QUALITY CONTROL TIPS TO DURING MANUFACTURING OF DRUG SUBSTANCES

Precipitation or Crystallization

During this step critical process parameters may be pH or seeding at appropriate stage.

One should be very careful during this stage.

There should be clear-cut instruction when seeding to be done, may be on certain pH or based on physical observation when haziness appears.

A good crystallization can be a control parameter.

Centrifuging or Washing of Cake

During these steps knowledge of the process is very must to the operators.

Centrifuging is not only the separation technique between solid and liquids.

It also controls impurities of the products by effective means.

Following points can help for better Centrifuging:

Centrifuge bag arrangement in the basket

Before centrifuging the product, it is always advisable which is ignored sometimes; there should not be any fold of the centrifuge bag in the basket.

Bag should be properly intact with the basket.

In any case if this not followed product get deposited at one place where the bag is folded which could be resulted in unbalancing of centrifuge and product will not separate out impurities as well as properly.

Rate of feeding the product slurry

The feeding rate of slurry should be comparable with respect to the expelling out mother liquor.

Once the cake is formed in the basket, feeding rate and speed of centrifuge can be increased.

Washing with Solvents

Knowledge on the process is important thing before washing the product.

Why washing is being given to control OVI or to Reduce Water Content ?

In both cases the washing pattern should be standardized.

Before washing ensure mother liquor is completely removed and there should not be any crack in the cake wall of the product otherwise the washing being given will pass through the cracks and cake will not be washed properly.

Washing rate is also important in most of the time washing is given with (1”) hosepipe at full speed, which do not serve any purpose.

The washing rate should be very slow and if required use (¼“) or (½”) pipe and give washing manually in such a way that the cake is washed completely by up and down solvent spray on the cake.

Spinning should be node for appropriate time.

As a physical observation hardening of the cake should be the control parameter before unloading the cake from centrifuge.

During the centrifuging operation, execution should be done by the skilled operators only who know the operation and master in this operation.

Most of the time shortcuts are used in this operation, which led inconstancy in the final product quality.

Drying of the Wet Cake

As every body knows, drying process have very critical role to reduce residual solvents by effective drying.

Following man be the tips for effective drying


Temperature distribution and Heat penetration

The dryer should be actually validated for the temperature distribution and heat penetration during qualification studies.

Cooling spots must be identified during the study and rectified by clearing / cleaning of the hot water circulation loops.

In hot air dryers air velocity and airflow to the chamber must be checked and studies.

Loading of Tray Dryers

Incase, if the cake is of hard or big lumps.

The cake should be milled before loading it to dryer otherwise heat penetration will not take place and after drying there may be chances of increasing moisture content.

There should be clear-cut instruction how to load uniform the trays and how much quantity should be filled ? In terms of number of scoops.

Material should not be over filled or pressed.

Heap of the product should not touch any portion of the upper trey.

Touching of upper tray can disturb airflow temperature distribution, Heat perpetration etc, if required written instruction can be displayed near dryer.

In-process control

Sampling should be done from all trays and especially from the coolest point identified during qualification.

After achieving desired water content, If require dried material should be re-shuffled, or disturbed and dryer should be run without heating for at least 2 hours or appropriate time for reducing residual solvent.

Instruction to Operator

In all step from crystallization onwards, whatever the critical parameters, cut off points off points should be mentioned in batch records and displayed near to the equipment and supervisory staff should be responsible for the monitoring / following those instruction during the operation.

Operation should be dedicated to perform the specific operations wherever possible.

Practices / procedures should be uniform and standardized.

No short cuts / time saving on the process for achieving targets should be allowed or deviated the written down procedures / displayed instructions.

ANTHOLOGY OF INFORMATION :

ICH : International Conference on Harmonisation

Presentation of PFIZER on “Setting Specifications for Drug Substances” [AAPS Stability Workshop: Strategies for Setting Global Stability Specifications, Track B1 - Bethesda, Sep. 2007 - Dr. Jon Beaman]

Technical Guide for the Elaboration of Monographs : European Pharmacopoeia (EDQM) 4th Edition 2005., etc.

CPMP/SWP/QWP/4446/00 : Draft Guideline on the Specification Limits for Residues of Metal Catalysts / Committee …………………………… ……for Human Medicinal Products (CHMP)

NOTE: Please consider that this transcript is only for updating and sharing the Knowledge. ……… …If any inaccuracy is there in above preparation. Please update me to precise myself.