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REGULATORY AND GMP CONCERNS ON QUALITY CONTROLS OF DRUG SUBSTANCES
Specification
The specifications should be in accordance with the current general and specific Pharmacopoeia monographs.
Where the monograph has been shown not suitable to control the quality of the substance, and in particular the related substances, the additional analytical methods should be identified.
Any additional specifications to those of the monograph shall be justified.
If any of these specifications vary during operation, this change should be investigated and appropriate action taken.
At the time of filing it is unlikely that sufficient data will be available to assess process consistency.
Therefore it is considered inappropriate to establish acceptance criteria that tightly encompass the batch data at the time of filing.
Justification of Specification
It should be stated if supplementary or improved tests are needed.
Any additional specifications or deviations should be justified.
The possible need for a revision of the Pharmacopoeia monograph should be discussed.
Omission of Tests
Where the monograph mentions a test for a named impurity (metal catalyst/reagent/solvent) but which is not used during manufacture, the manufacturer may omit the test in the specifications which should be made clear in the DMF.
However, the substance should comply with the monograph, if tested.
Out of Specifications
Any out-of-specification result obtained should be investigated and documented according to a procedure.
This procedure should require analysis of the data, assessment of whether a significant problem exists, allocation of the tasks for corrective actions, and conclusions.
Any re-sampling and/or retesting after OOS results should be performed according to a documented procedure.
Out-of-specification (OOS) investigations are not normally needed for in-process tests that are performed for the purpose of monitoring and/or adjusting the process.
Out-Of-Specification batches should not be blended with other batches for the purpose of meeting specifications.
Each batch incorporated into the blend should have been manufactured using an established process and should have been individually tested and found to meet appropriate specifications prior to blending.
Field Alert Reports
For those products that are the subject of approved full and abbreviated new drug applications, regulations require submitting within 3 working days a field alert report (FAR) of information concerning any failure of a distributed batch to meet any of the specifications established in an application (21 CFR 314.81(b)(1)(ii)).
OOS test results on these products are considered to be one kind of "information concerning any failure” described in this regulation.
Unless the OOS result on the distributed batch is found to be invalid within 3 days, an initial FAR should be submitted.
A follow-up FAR should be submitted when the OOS investigation is completed.
NEEDS OF QUALITY CONTROLS FOR DRUG SUBSTANCES
Description / Appearance
Description can normally embrace colour and physical form.
The term “white” is not used without qualification since, if viewed against a standard white material, very few pharmaceutical materials will appear truly white.
It is, of course, not intended that such a comparison be made but experience shows that certain users of the pharmacopoeia may insist on doing so as part of a purchasing contract.
The term “white or almost white” is used instead.
Where positive colours are to be described this is done in terms of primary colours or combinations of primary colours.
A qualitative statement about the state (e.g. solid, liquid) and colour of the drug substance.
Visible
White to off-white, white to pale yellow, “JP white”, colour descriptions are available, including recommendation of “white to almost white”
Qualitative test only
Genuine issues (e.g. impurities, contaminants) should be dealt with via quantitative tests; appearance doesn’t need to be quantitative.
Testing during stability may need to be a slightly different process to that for release where trends do not need to be monitored.
Solution Clarity
During development for APIs for solution formulation (internal test)
Clarity and Degree of Opalescence (DP test)
Silica: Acid + Silica Filtration, Recrystallizein API
Filter Housing : Acid + Filter
Turbidity
Quantitative (with weaknesses)
Ball-park figure of ~ 2NTU; EP test solution for clear = ~2.8NTU
Other tests
Odour
Generally no
Depending on route of delivery may need to limit solvents to <>
Degradation products e.g. Sulphates or Toluene degradation product
Mass balance
Useful scientific guide for evaluating data, but is not achievable in all circumstances
WHO guidelines discuss this with reference to Degree of Opalescence only
Address as part of development if notice significant discrepancies
No taste
Identification testing should optimally be able to discriminate between compounds of closely related structure, which are likely to be present.
Identification tests should be specific for the new drug substance, e.g., Infrared Spectroscopy.
Identification solely by a single chromatographic retention time, for example, is not regarded as being specific.
However, the use of two chromatographic procedures, where the separation is based on different principles or a combination of tests into a single procedure, such as HPLC/ UV diode array, HPLC/ MS, or GC/ MS is generally acceptable.
If the drug substance is a salt, identification testing should be specific for the individual ions.
An identification test that is specific for the salt itself should suffice.
Drug substances that are optically active may also need specific identification testing or performance of a chiral assay.
Specific spectroscopic technique
e.g. FTIR
Generally best strategy
Easy to do ‘Identification testing on receipt’ etc..
Chiral test if required
Optical Rotation
Or may get chromatographic ‘for free’ è see Chiral impurity control
Racemates if also developing Enantiomer or Chiral preference may occur
If more than two Chiral centres then control of Starting Materials/ Reagents may be more appropriate
The first tells you if you have the right species, the second confirms which enantiomer
Salt form identity
Release test
Not required to be measured on stability
An IR test for the API may be specific for the Salt form also
If not, a test for the counter ion may be required (may also double as an assay test for the counter ion if required)
Salt form assay
Assay determination of the counter ion may be omitted from the release specification if batch data shows good stoichiometry routinely achieved.
If the, generally organic, counter ion degrades may need to determine on stability or if the counter ion degradation products need to be controlled
Hemi-maleate / Hemi-hydrochloride can transform to Maleatetrihydrate + HCl at high humidity
Solid form identity
Polymorph, Solvate, De-solvated Solvates, Amorphous
From experience, mean is 3-4 per compound; record = 75 ?
If development work shows that no other forms are feasible/relevant then not required on specification
Similarly for stability, if other forms would not be formed at relevant temperatures/ humidities or timescales (hydrates, amorphous crystallisation), then shouldn’t be required on stability
PXRD in early development, once characterised, DSC more widely available
Form assay
Reactivity in the amorphous state is greater than that in the crystalline state
Possible release test if observing batch-to-batch variation in degradation rates
PXRD can measure amorphous content down to ~5%
Racemic drugs
Can be racemic compounds 90-95% of cases (racemic crystals)
- (RSRSRSRSRS)
or racemic conglomerate 5-10% of cases (enantiomorphous mixture of crystals)
- (SSSSS RRRRR)
rarely pseudoracemate
- (RSSRSRRSRS)
Release test
Crystal habit
Can affect solubility, dissolution rate, degradation and formulation processing
Determine using microscopy
Develop final step to ensure control
Release test
Assay
A specific, stability-indicating assay to determine strength (content) should be included for all drug products.
In many cases it is possible to employ the same procedure (e.g., HPLC) for both assay of the new drug substance and quantitation of impurities.
Results of content uniformity testing for drug products can be used for quantitation of drug product strength, if the methods used for content uniformity are also appropriate as assays.
In cases where use of a non-specific assay is justified, other supporting analytical procedures should be used to achieve overall specificity.
For example, where titration is adopted to assay the drug substance for release, the combination of the assay and a suitable test for impurities can be used.
A specific procedure should be used when there is evidence of excipient interference with the non-specific assay.
Main component assay
ICH Q6A
Stability indicating; If non-specific test, may need to subtract impurities from the result
For chiral drugs, an achiral assay with control of the enantiomeric impurity is acceptable
General limits
Upper limit 102.0% (on an anhydrous basis or dried i.e. anhydrous and solvent free)
Lower limit 98.0% depending on levels of impurities
Racemic drugs
Essentially equal efficacy/safety –then can control as a total of the two
Tend to be denser and thus stable than chiral counterparts
Organic Impurities
Organic impurities arising from degradation of the drug substance and impurities that arise during the manufacturing process for the drug product should be monitored in the new drug product.
Acceptance limits should be stated for individual specified degradation products, which may include both identified and unidentified degradation products as appropriate, and total degradation products.
Process impurities from the drug substance synthesis are normally controlled during drug substance testing, and therefore are not included in the total impurities limit.
However, when a synthesis impurity is also a degradation product, its level should be monitored and included in the total degradation product limit.
When it has been conclusively demonstrated via appropriate analytical methodology, that the drug substance does not degrade in the specific formulation, and under the specific storage conditions proposed in the drug application, degradation product testing may be reduced or eliminated upon approval by the regulatory authorities.
Organic
Contaminants –addressed as GMP issues
Process related impurities to be controlled at the API stage –release testing only
In early development phase impurity limits may be set at thresholds
As per ICH Q3A,
Specification should include:
Each specified identified impurity
Each specified unidentified impurity•
Total Impurities”
Any unspecified impurity with an acceptance criterion of not more than (≤) the identification threshold
If maximum Daily Dose is < 2 g / day - Unknown Impurity is 0.10%
Reporting Threshold is 0.05%
Identification Threshold is 0.10% or 1.0 mg per day intake (whichever is lower)
Qualification Threshold is 0.15% or 1.0 mg per day intake (whichever is lower)
If maximum Daily Dose is > 2 g / day - Unknown Impurity is 0.05%
Reporting Threshold is 0.03%
Identification Threshold is 0.05%
Qualification Threshold is 0.05%
When identification of an impurity is not feasible, a summary of the laboratory studies demonstrating the unsuccessful effort should be included in the application.
Could control to the qualification threshold as an unidentified specified impurity
Where there is no safety concern, impurity acceptance criteria should be based on data generated on batches of the new drug substance manufactured by the proposed commercial process, allowing sufficient latitude to deal with normal manufacturing and analytical variation and the stability characteristics of the new drug substance.
Thus limits for degradants should not be bounded within actual data available at time of filing, although thresholds in Q3A apply.
ICH Q6A “estimate maximum increase in impurity at retest date”
Estimate maximum by extrapolation:- 3 x Standard Deviation of predictions from the three batches or the upper one-sided 95% confidence limit out to retest period desired.
Chiral Impurities
Can significantly affect physicochemical properties of pure enantiomers.
Release test; if development work (scientific analysis, stress testing) shows that opposite enantiomer is not a degradation product, shouldn’t need to test on stability
A racemic degradant could be controlled as two separate enantiomers each to ICH Q3A threshold
Impurities -Analytical Methodology
Chromatographic methods in development stability may need to be more powerful than (or in addition to) those transferred to manufacturing : Stress in acid led to brown gum - Polymerisation
Noted disappearance of PRI dimers on stability, disappearance not seen during stress testing
Found that adsorbed onto certain vial types –changed to end-capped vials/altered pH
Total Impurities
Essentially a quality test only (assay and individual impurities controls ensure efficacy and safety)
By specifying impurities, rather than having unspecified impurities control only, may help to set more appropriate limits
TLC only for a specified impurity and only as last resort.
Veterinary Medicine
Different thresholds
Genotoxic impurity
According to current regulatory practice it is assumed that (in vivo) genotoxic compounds have the potential to damage DNA at any level of exposure and that such damage may lead/contribute to tumour development.
Thus for genotoxic carcinogens it is prudent to assume that there is no discernible threshold and that any level of exposure carries a risk.
However, the existence of mechanisms leading to biologically meaningful threshold effects is increasingly acknowledged also for genotoxic events.
This holds true in particular for compounds interacting with non-DNA targets and also for potential mutagens, which are rapidly detoxified before coming into contact with critical targets.
The regulatory approach to such chemicals can be based on the identification of a critical No-Observed-Effect Level (NOEL) and use of uncertainty factors.
Even for compounds which are able to react with the DNA molecule, extrapolation in a linear manner from effects in high-dose studies to very low level (human) exposure may not be justified due to several protective mechanisms operating effectively at low doses.
However, at present it is extremely difficult to experimentally prove the existence of threshold for the genotoxicity of a given mutagen.
Thus, in the absence of appropriate evidence supporting the existence of a threshold for a genotoxic compound making it difficult to define a safe dose it is necessary to adopt a concept of a level of exposure that carries an acceptable risk.
The toxicological assessment of genotoxic impurities and the determination of acceptable limits for such impurities in active substances is a difficult issue and not addressed in sufficient detail in the existing ICH Q3X guidances.
The data set usually available for genotoxic impurities is quite variable and is the main factor that dictates the process used for the assessment of acceptable limits.
In the absence of data usually needed for the application of one of the established risk assessment methods,
i.e. data from carcinogenicity long-term studies or data providing evidence for a threshold mechanism of genotoxicity, implementation of a generally applicable approach as defined by the Threshold of Toxicological Concern (TTC) is proposed.
A TTC value of 1.5 µg/day intake of a genotoxic impurity is considered to be associated with an acceptable risk (excess cancer risk of <1>
From this threshold value, a permitted level in the active substance can be calculated based on the expected daily dose.
Higher limits may be justified under certain conditions such as short-term exposure periods.
The concentration limits in ppm of genotoxic impurity in drug substance derived from TTC can be calculated based on the expected daily dose to the patient using equation
TTC [mg / day]
Concentration Limit (ppm) = -------------------------------- è Threshold of Toxicological Concern
Dose [g / day]
Inorganic Impurities
Procedures and acceptance criteria for sulfated ash / residue on ignition should follow pharmacopoeial precedents; other inorganic impurities may be determined by other appropriate procedures, e.g., atomic absorption spectroscopy.
Inorganic Impurities (not on stability)
Heavy metals
Shouldn’t need to test if no Heavy metals used in route and RSMs/reagents are adequately understood/controlled.
Criteria and limits EP Technical Guide
Daily intake > 0.5 g/day, treatment <>
Daily intake > 0.5 g/day, treatment > 30 days : Heavy metals test limit 10 ppm
Daily intake <> 30 days: Heavy metals test limit 10 ppm If it is used parenterally
Heavy metals test limit 20 ppm Other wise
Daily intake <>
Global Specifications
Pharmacopoeias: Heavy metals for an API in Japan
JP Heavy metals test not adequate temperature
Used modified (validated) EP test accepted
For API usually set out with good intentions, however some tests may be region specific e.g. arsenic for Japan, or may end up with different agreed limits for impurities in different regions.
Depending what is easiest for one’s supply chain, may test API for specific markets or have a tighter internal control document put in place meeting all region requirements…
Similarly for API intended for >1 dosage form type…
Specific Tests
Control of catalysts used during manufacturing process
Arsenic control for Japan may be required
Pharmacopoeial methodology or specific (but validated)
Information about Metal Residues
Residual metals used as process catalysts do not provide any therapeutic benefit and should therefore be evaluated and restricted on the foundation of safety- and quality-based criteria.
Metals will be classified in three categories based on their individual levels of safety concern and concentration limits will be set on the bases of the maximal daily dose, duration of treatment, route of administration and permitted daily exposure (PDE).
In the reviews the following assumptions and/or default values are used:
Body Weight (bw) of an adult: 50 Kg.
Breathing volume of an adult: 20 m3 per Day (24 Hr.).
Occupational (workplace) inhalation exposure: 8 Hr. per Day (24 Hr.).
Exposure limits were established using uncertainty factors as per ICH Q3.
For pragmatic reasons a number of uncertainty factors were adapted to arrive at a final safe and practical PDE setting - Q3 method for uncertainty factor (UF) calculation plus additional pragmatic factor for PDE calculation.
Acceptable Additional Lifetime Cancer Risk:
An increased cancer risk of 1 in 100,000 was identified as acceptable for genotoxic impurities in pharmaceuticals by the Committee for Human Medicinal Products (CHMP).
Limits set based on safety criteria may therefore be higher than limits set on the basis of GMP, process capabilities, or other suitable quality criteria.
Any interested party can make a request and submit relevant safety data.
Classification and limits may change as new safety data becomes available.
Metal catalysts and metal reagents are defined here as chemical substances that are used to change the rate of chemical reactions or which act on other chemical substances in chemical reactions.
Residues of metals can either be present as the original form of the metal or as a form of the metallic element altered by downstream chemical processing.
Excluded from this document are extraneous metal contaminants that should not occur in drug substances or excipients and are more appropriately addressed as Good Manufacturing Practice (GMP) issues.
Different limits are applied to oral and parenteral routes of administration due to limited oral bioavailability of many metals.
As different routes of exposure may have different toxicological properties, specific limits have been set for inhalation exposure to some metals.
When the exposure is short the PDE´s mentioned in this guideline may be adapted as indicated
Classification of Metals
Metals were evaluated for their potential risk to human health and placed into one of three classes as follows:
Class 1 Metals : Metals of significant safety concern
Metals of significant safety concern known or suspect human carcinogens, or possible causative agents of other significant toxicity.
Class 1 is subdivided into 3 subclasses.
Class 1A: Platinum (Pt) and Palladium (Pd)
Class 1B: Iridium (Ir), Rhodium (Rh), Ruthenium (Ru) and Osmium (Os)
Class 1C: Molybdenum (Mo), Nickel (Ni), Chromium (Cr), Vanadium (V)
Platinoids are in Class 1A and Class 1B.
For the Platinoids in subclass 1B a conservative approach has been adopted, because there are very limited toxicity data. Thus the indicated limit for Class 1B is the limit for the total amount of those platinoids that, based on the used synthesis procedures, are anticipated to be present.
Class 2 Metals : Metals with low safety concern
Copper (Cu) and Manganese (Mn)
Metals with low safety concern Metals with lower toxic potential to man.
They are generally well tolerated up to exposure.
They may be trace metals required for nutritional purposes or they are often present in food stuffs or readily available nutritional supplements.
Class 3 Metals : Metals with minimal safety concern
Zinc (Zn) and Iron (Fe)
Metals with minimal safety concern.
Metals with no significant toxicity.
Their safety profile is well established.
They are generally well tolerated up to doses.
Typically they are ubiquitous in the environment or the plant and animal kingdoms.
Residue on Ignition
US & EP Guidelines : Residue on Ignition NMT 0.1%; Japan 0.10%; in reality a quality test only.
ICP-MS
Scans during development to gather information; specific tests may need to be developed depending on formulation/other considerations
Iron: iron oxide/hydroxide formation in alkaline solutions; ppm control.
Residual Solvents
The need for inclusion of tests and acceptance criteria for Residual Solvents should be studied during development and based on knowledge of the manufacturing process.
Acceptance criteria for Residual Solvents should follow Pharmacopoeial precedents and ICH; other Residual Solvents which are not covered in ICH and Pharmacopoeia can be determined by other appropriate standards (Like NIOSH : The National Institute for Occupational Safety and Health).
Class I : Solvents to be avoided
Benzene, carbon tetrachloride, 1,2-dichloroethane, 1,1-dichloroethene, 1,1,1- trichloroethane
Class II : Solvents to be limited
Acetonitrile, Chloroform, Cyclohexane, Dioxane, Methanol, Methylbutylketone, Tetrahydrofurane, Toluene, …...
Class III : Solvents with low toxic potential
Acetone, Butanol, Butyl acetate, DMSO, Ethanol, Ethyl acetate, Ethyl ether, Heptane, Isopropanol, Methylethyl Ketone, ….... [Loss on drying should be less than 0.5%]
Class I residual solvents to be avoided,
It is critical to avoid. General cases as follows :
1. Starting Material : e.g. Benzene in early steps in synthesis.
2. By-products from chemical reaction: e.g. Benzene as a Grignard-by-product.
3. Impurity in another residual solvents: e.g. Benzene as an impurity in toluene.
But it is need for control.
OVI : Organic Volatile Impurities are described in USP. This test is in effect until July 1, 2008.
There are many different solvents which are used in pharmaceutical manufacturing. USP mandates that at least six of these solvents be monitored in finished products : Benzene, Chloroform, 1,4-Dioxane, Ethylene Oxide, Methylene Chloride and Trichloroethylene.
Organic Volatile Impurities details are given in USP <467>.
Solvents are not required on stability; may do as part of an assay/ potency procedure if mass balance may be impacted by loss of solvent on stability.
Other information
Residues of residual toxic reagents should also be discussed and where applicable a suitable limit and test method proposed if the monograph does not provide a suitable test.
Residues of acids or bases that are not mentioned in the ICH guideline for residual solvents (e.g. HCl, organic acids) should also be discussed if the monograph does not provide a suitable test (pH, acidity or alkalinity).
Concerning residual triethylamine, a permitted daily exposure (PDE) of 3.2 mg/day giving a limit of 320 ppm (for a 10 g daily dose) was calculated from repeated Dose Toxicity and Reproductive Toxicity data. This limit of 320 ppm should therefore be used as a reference limit. (As per EDQM COS Content Dossier for Chemical Purity Microbiological Quality guide).
Higher limits should be justified by batch analysis data and the maximum daily dose of the concerned substance.
It should be noted that this limit is not immediately applicable to other organic bases for which limits should be calculated on available toxicological data.
Particle Size
For some drug substances intended for use in solid or suspension drug products, particle size can have a significant effect on dissolution rates, bio-availability, and / or stability.
In such instances, testing for particle size distribution should be carried out using an appropriate procedure, and acceptance criteria should be provided.
Particle size
May affect formulation and stability
Methodology and acceptance criteria: “May be performed as an in-process test or…release test.”
Agglomeration: for API for suspensions, or if note powder processing issues during formulation manufacture or other formulation issues, may need to investigate agglomeration on API stability via microscopy.
Stability of the API: “Results should be included for physical as well as chemical tests e.g. particle size…”
Generally no need to measure on stability.
These are properties such as pH of an aqueous solution, melting point / range, and refractive index.
The procedures used for the measurement of these properties are usually unique and do not need much elaboration, e.g., capillary melting point.
Tests performed in this category should be determined by the physical nature of the drug substance and by its intended use.
What are the physicochemical properties including physical description, pKa, polymorphism, aqueous solubility (as function of pH), hygroscopicity, melting points, and partition coefficient ?
List all physicochemical properties listed in the question even if they are not critical;
If a property is left out, explain why
Example, No pKa because there are no ionizable groups in the chemical structure
Include other applicable properties of the drug substance if they are critical
Pay special attention to these critical properties such as solubility, polymorphism, etc.
Why do we ask you to provide these physicochemical properties?
Physical properties of the drug substance may affect drug product development, manufacture, or performance; e.g. particle size, polymorphism etc.
Chemical properties of the drug substance may also affect the drug product development, manufacture, or performance, e.g., compatibility between excipients and drug substance, etc.
Some drug substances exist in different crystalline forms which differ in their physical properties.
Polymorphism may also include solvation or hydration products (also known as pseudopolymorphs) and amorphous forms.
Differences in these forms could, in some cases, affect the quality or performance of the new drug products.
In cases where differences exist which have been shown to affect drug product performance, bioavailability or stability, then the appropriate solid state should be specified.
Whether multiple forms exist. examples of these procedures are:
Melting point (including hot-stage microscopy)
Solid State IR
X-ray Powder Diffraction
Thermal Analysis Procedures (like DSC, TGA and DTA)
Raman Spectroscopy
Optical Microscopy
Solid State NMR.
Polymorphism
List all polymorphic forms reported in literature and provide brief discussion (i.e., which one is the most stable form).
Example
It is reported in the literature that there are two anhydrous polymorphic forms for the drug substance, form I and II; and no known hydrate forms; Form I is the most stable form. The references are made to….
For example, if there are known different polymorphic forms
Specify which polymorphic form is used
Supporting evidence for the claim (X-ray, DSC, and Literatures)
Information should be provided in PD report for polymorphic form selection, if it is critical
Tests for Chiral
Where a new drug substance is predominantly one enantiomer, the opposite enantiomer is excluded from the qualification and identification thresholds given in the ICH Guidelines on Impurities in New Drug Substances and Impurities in New Drug Products because of practical difficulties in quantifying it at those levels.
However, that impurity in the chiral new drug substance and the resulting new drug product(s) should otherwise be treated according to the principles established in Guidelines.
Impurities
For chiral drug substances which are developed as a single enantiomer, control of the other enantiomer should be considered in the same manner as for other impurities.
However, technical limitations may preclude the same limits of quantification or qualification from being applied.
Assurance of control also could be given by appropriate testing of a starting material or intermediate, with suitable justification.
Assay
An enantioselective determination of the drug substance should be part of the specification.
It is considered acceptable for this to be achieved either through use of a chiral assay procedure or by the combination of an achiral assay together with appropriate methods of controlling the enantiomeric impurity.
Identity
For a drug substance developed as a single enantiomer, the identity test(s) should be capable of distinguishing both enantiomers and the racemic mixture.
For a racemic drug substance, there are generally two situations where a stereospecific identity test is appropriate for release/acceptance testing:
- where there is a significant possibility that the enantiomer might be substituted for the racemate, or
- when there is evidence that preferential crystallization may lead to unintentional production of a non-racemic mixture
Enantiomers:
Distinguished by biological systems
Same or different pharmacologic / pharmacokinetic / toxicologic activity
Same physico-chemical properties except optical activity
Specific techniques necessary to identify them, separate, assay and synthesis
(e.g. it is easier and less expensive to manufacture the racemic mixture)
(+) and (-) Ibuprofene: both anti-inflammatory agents
(+) Sotalol: antiarrhythmic but (-) sotalol : b-blocker ® Critical
(-) Levocetirizine active as 5 mg dosage but (±) racemic cetirizine marketed as 10 mg ® Critical
(-) Lamivudune: selected and registered
(+) Lamivudine and racemic mixture (±) more cytotoxic (EMEA/CPMP/375/96 EPAR) ® Critical
Batch-to-batch consistency and reproducibility of the manufacture with preclinical and clinical batches (innovator) or with the bio-batch used in the bioequivalence study (Generic products) should be guaranteed
Either by suitable controls included in specifications for identity, control of the opposite enantiomer as an impurity or chiral assay of the API
Lamivudine monograph in USP and draft in Ph. Eur.: opposite enantiomer limited to NMT 0.3%
Tenofovir EPAR CPMP/3510/01: enantiomeric purity NLT 98% for the R-isomer claimed
Either by control of stereochemistry (control of chirality) through the route of synthesis i.e. appropriate controls on starting materials and intermediates + demonstration that there is no racemiation up to the end
Case of Efavirenz, indinavir, nelfinavir, ritonavir…(tricky as the information is not publicly available for comparison)
Non pharmacopoeial Chiral APIs claimed as a single enantiomer
See the ICH Q6A decision tree, # 5: establishing identity, assay and enantiomeric impurity procedures for chiral NCEs
1. If the substance is chiral and one enantiomer claimed.
Consider need for Chiral identity, chiral assay, enantiomeric impurity
Chiral assay or an enantiomeric impurity procedure may be acceptable in lieu of chiral identification
An achiral assay + a method for control of the opposite enantiomer is acceptable in lieu of a chiral assay
The level of the opposite enantiomer may be derived from chiral assay
Stereospecific testing of the drug product is not necessary if racemisation is shown to be insignificatif during manufacture and storage of FPP
Possible to justify not carrying either chiral assay or control of the opposite enantiomer when 3 or more chiral centres present
Water Content
This test is important in cases where the new drug substance is known to be hygroscopic or degraded by moisture or when the drug substance is known to be a stoichiometric hydrate.
The acceptance criteria may be justified with data on the effects of hydration or moisture absorption.
In some cases, a Loss on Drying procedure may be considered adequate; however, a detection procedure that is specific for water (e.g., Karl Fischer titration) is preferred.
Water Content
Determine limits for release based on degradation mechanisms and stability knowledge; this will actually inform drying of API and packaging decisions
Determining water on stability largely irrelevant other than to inform packaging decisions –it is other factors that are actually important i.e. degradation product levels
Microbial Limits
There may be a need to specify the total count of aerobic micro organisms, the total count of yeasts and molds, and the absence of specific objectionable bacteria.
e.g., Staphylococcus aureus
Escherichia coli
Salmonella
Pseudomonas aeruginosa
These should be suitably determined using pharmacopoeial procedures.
The type of microbial test(s) and acceptance criteria should be based on the nature of the drug substance, method of manufacture, and the intended use of the drug product.
For example, sterility testing may be appropriate for drug substances manufactured as sterile and endotoxin testing may be appropriate for drug substances used to formulate an injectable drug product.
Endotoxins
Release test only and only If intended for parenteral drug product
Total viable aerobic count
Generally test if for sterile product
May omit from specification based on ICH Q6A Decision Tree #6 (process steps, capability of supporting growth) plus water activity considerations
If test on stability, may do at key checkpoints only, e.g. annually
Specific organisms
May omit from specification based on ICH Q6A Decision Tree #6 (process steps, capability of supporting growth) plus water activity considerations
Release test only as a quality/contamination test
QUALITY CONTROL TIPS TO DURING MANUFACTURING OF DRUG SUBSTANCES
Precipitation or Crystallization
During this step critical process parameters may be pH or seeding at appropriate stage.
One should be very careful during this stage.
There should be clear-cut instruction when seeding to be done, may be on certain pH or based on physical observation when haziness appears.
A good crystallization can be a control parameter.
Centrifuging or Washing of Cake
During these steps knowledge of the process is very must to the operators.
Centrifuging is not only the separation technique between solid and liquids.
It also controls impurities of the products by effective means.
Following points can help for better Centrifuging:
Centrifuge bag arrangement in the basket
Before centrifuging the product, it is always advisable which is ignored sometimes; there should not be any fold of the centrifuge bag in the basket.
Bag should be properly intact with the basket.
In any case if this not followed product get deposited at one place where the bag is folded which could be resulted in unbalancing of centrifuge and product will not separate out impurities as well as properly.
Rate of feeding the product slurry
The feeding rate of slurry should be comparable with respect to the expelling out mother liquor.
Once the cake is formed in the basket, feeding rate and speed of centrifuge can be increased.
Washing with Solvents
Knowledge on the process is important thing before washing the product.
Why washing is being given to control OVI or to Reduce Water Content ?
In both cases the washing pattern should be standardized.
Before washing ensure mother liquor is completely removed and there should not be any crack in the cake wall of the product otherwise the washing being given will pass through the cracks and cake will not be washed properly.
Washing rate is also important in most of the time washing is given with (1”) hosepipe at full speed, which do not serve any purpose.
The washing rate should be very slow and if required use (¼“) or (½”) pipe and give washing manually in such a way that the cake is washed completely by up and down solvent spray on the cake.
Spinning should be node for appropriate time.
As a physical observation hardening of the cake should be the control parameter before unloading the cake from centrifuge.
During the centrifuging operation, execution should be done by the skilled operators only who know the operation and master in this operation.
Most of the time shortcuts are used in this operation, which led inconstancy in the final product quality.
Drying of the Wet Cake
As every body knows, drying process have very critical role to reduce residual solvents by effective drying.
Following man be the tips for effective drying
Temperature distribution and Heat penetration
The dryer should be actually validated for the temperature distribution and heat penetration during qualification studies.
Cooling spots must be identified during the study and rectified by clearing / cleaning of the hot water circulation loops.
In hot air dryers air velocity and airflow to the chamber must be checked and studies.
Loading of Tray Dryers
Incase, if the cake is of hard or big lumps.
The cake should be milled before loading it to dryer otherwise heat penetration will not take place and after drying there may be chances of increasing moisture content.
There should be clear-cut instruction how to load uniform the trays and how much quantity should be filled ? In terms of number of scoops.
Material should not be over filled or pressed.
Heap of the product should not touch any portion of the upper trey.
Touching of upper tray can disturb airflow temperature distribution, Heat perpetration etc, if required written instruction can be displayed near dryer.
In-process control
Sampling should be done from all trays and especially from the coolest point identified during qualification.
After achieving desired water content, If require dried material should be re-shuffled, or disturbed and dryer should be run without heating for at least 2 hours or appropriate time for reducing residual solvent.
Instruction to Operator
In all step from crystallization onwards, whatever the critical parameters, cut off points off points should be mentioned in batch records and displayed near to the equipment and supervisory staff should be responsible for the monitoring / following those instruction during the operation.
Operation should be dedicated to perform the specific operations wherever possible.
Practices / procedures should be uniform and standardized.
No short cuts / time saving on the process for achieving targets should be allowed or deviated the written down procedures / displayed instructions.
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ANTHOLOGY OF INFORMATION :
ICH : International Conference on Harmonisation Presentation of PFIZER on “Setting Specifications for Drug Substances” [AAPS Stability Workshop: Strategies for Setting Global Stability Specifications, Track B1 - Bethesda, Sep. 2007 - Dr. Jon Beaman] Technical Guide for the Elaboration of Monographs : European Pharmacopoeia (EDQM) 4th Edition 2005., etc. CPMP/SWP/QWP/4446/00 : Draft Guideline on the Specification Limits for Residues of Metal Catalysts / Committee …………………………… ……for Human Medicinal Products (CHMP)
NOTE: Please consider that this transcript is only for updating and sharing the Knowledge. ……… …If any inaccuracy is there in above preparation. Please update me to precise myself.
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