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.
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.
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