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 < ICH thresholds e.g. Pentane
Degradation products e.g. Sulphates or Toluene degradation product
Mass balance
Useful scientific guide for evaluating data, but is not achievable in all circumstances
WHO guidelines discuss this with reference to Degree of Opalescence only
Address as part of development if notice significant discrepancies
No taste
Identification
Identification testing should optimally be able to discriminate between compounds of closely related structure, which are likely to be present.
Identification tests should be specific for the new drug substance, e.g., Infrared Spectroscopy.
Identification solely by a single chromatographic retention time, for example, is not regarded as being specific.
However, the use of two chromatographic procedures, where the separation is based on different principles or a combination of tests into a single procedure, such as HPLC/ UV diode array, HPLC/ MS, or GC/ MS is generally acceptable.
If the drug substance is a salt, identification testing should be specific for the individual ions.
An identification test that is specific for the salt itself should suffice.
Drug substances that are optically active may also need specific identification testing or performance of a chiral assay.
Specific spectroscopic technique
e.g. FTIR
Generally best strategy
Easy to do ‘Identification testing on receipt’ etc..
Chiral test if required
Optical Rotation
Or may get chromatographic ‘for free’ è see Chiral impurity control
Racemates if also developing Enantiomer or Chiral preference may occur
If more than two Chiral centres then control of Starting Materials/ Reagents may be more appropriate
The first tells you if you have the right species, the second confirms which enantiomer
Salt form identity
Release test
Not required to be measured on stability
An IR test for the API may be specific for the Salt form also
If not, a test for the counter ion may be required (may also double as an assay test for the counter ion if required)
Salt form assay
Assay determination of the counter ion may be omitted from the release specification if batch data shows good stoichiometry routinely achieved.
If the, generally organic, counter ion degrades may need to determine on stability or if the counter ion degradation products need to be controlled
Hemi-maleate / Hemi-hydrochloride can transform to Maleatetrihydrate + HCl at high humidity
Solid form identity
Polymorph, Solvate, De-solvated Solvates, Amorphous
From experience, mean is 3-4 per compound; record = 75 ?
If development work shows that no other forms are feasible/relevant then not required on specification
Similarly for stability, if other forms would not be formed at relevant temperatures/ humidities or timescales (hydrates, amorphous crystallisation), then shouldn’t be required on stability
PXRD in early development, once characterised, DSC more widely available
Form assay
Reactivity in the amorphous state is greater than that in the crystalline state
Possible release test if observing batch-to-batch variation in degradation rates
PXRD can measure amorphous content down to ~5%
Racemic drugs
Can be racemic compounds 90-95% of cases (racemic crystals)
- (RSRSRSRSRS)
or racemic conglomerate 5-10% of cases (enantiomorphous mixture of crystals)
- (SSSSS RRRRR)
rarely pseudoracemate
- (RSSRSRRSRS)
Release test
Crystal habit
Can affect solubility, dissolution rate, degradation and formulation processing
Determine using microscopy
Develop final step to ensure control
Release test
Assay
A specific, stability-indicating assay to determine strength (content) should be included for all drug products.
In many cases it is possible to employ the same procedure (e.g., HPLC) for both assay of the new drug substance and quantitation of impurities.
Results of content uniformity testing for drug products can be used for quantitation of drug product strength, if the methods used for content uniformity are also appropriate as assays.
In cases where use of a non-specific assay is justified, other supporting analytical procedures should be used to achieve overall specificity.
For example, where titration is adopted to assay the drug substance for release, the combination of the assay and a suitable test for impurities can be used.
A specific procedure should be used when there is evidence of excipient interference with the non-specific assay.
Main component assay
ICH Q6A
Stability indicating; If non-specific test, may need to subtract impurities from the result
For chiral drugs, an achiral assay with control of the enantiomeric impurity is acceptable
General limits
Upper limit 102.0% (on an anhydrous basis or dried i.e. anhydrous and solvent free)
Lower limit 98.0% depending on levels of impurities
Racemic drugs
Essentially equal efficacy/safety –then can control as a total of the two
Tend to be denser and thus stable than chiral counterparts
Organic Impurities
Organic impurities arising from degradation of the drug substance and impurities that arise during the manufacturing process for the drug product should be monitored in the new drug product.
Acceptance limits should be stated for individual specified degradation products, which may include both identified and unidentified degradation products as appropriate, and total degradation products.
Process impurities from the drug substance synthesis are normally controlled during drug substance testing, and therefore are not included in the total impurities limit.
However, when a synthesis impurity is also a degradation product, its level should be monitored and included in the total degradation product limit.
When it has been conclusively demonstrated via appropriate analytical methodology, that the drug substance does not degrade in the specific formulation, and under the specific storage conditions proposed in the drug application, degradation product testing may be reduced or eliminated upon approval by the regulatory authorities.
Organic
Contaminants –addressed as GMP issues
Process related impurities to be controlled at the API stage –release testing only
In early development phase impurity limits may be set at thresholds
As per ICH Q3A,
Specification should include:
Each specified identified impurity
Each specified unidentified impurity•
Total Impurities”
Any unspecified impurity with an acceptance criterion of not more than (≤) the identification threshold
If maximum Daily Dose is < 2 g / day - Unknown Impurity is 0.10%
Reporting Threshold is 0.05%
Identification Threshold is 0.10% or 1.0 mg per day intake (whichever is lower)
Qualification Threshold is 0.15% or 1.0 mg per day intake (whichever is lower)
If maximum Daily Dose is > 2 g / day - Unknown Impurity is 0.05%
Reporting Threshold is 0.03%
Identification Threshold is 0.05%
Qualification Threshold is 0.05%
When identification of an impurity is not feasible, a summary of the laboratory studies demonstrating the unsuccessful effort should be included in the application.
Could control to the qualification threshold as an unidentified specified impurity
Where there is no safety concern, impurity acceptance criteria should be based on data generated on batches of the new drug substance manufactured by the proposed commercial process, allowing sufficient latitude to deal with normal manufacturing and analytical variation and the stability characteristics of the new drug substance.
Thus limits for degradants should not be bounded within actual data available at time of filing, although thresholds in Q3A apply.
ICH Q6A “estimate maximum increase in impurity at retest date”
Estimate maximum by extrapolation:- 3 x Standard Deviation of predictions from the three batches or the upper one-sided 95% confidence limit out to retest period desired.
Chiral Impurities
Can significantly affect physicochemical properties of pure enantiomers.
Release test; if development work (scientific analysis, stress testing) shows that opposite enantiomer is not a degradation product, shouldn’t need to test on stability
A racemic degradant could be controlled as two separate enantiomers each to ICH Q3A threshold
Impurities -Analytical Methodology
Chromatographic methods in development stability may need to be more powerful than (or in addition to) those transferred to manufacturing : Stress in acid led to brown gum - Polymerisation
Noted disappearance of PRI dimers on stability, disappearance not seen during stress testing
Found that adsorbed onto certain vial types –changed to end-capped vials/altered pH
Total Impurities
Essentially a quality test only (assay and individual impurities controls ensure efficacy and safety)
By specifying impurities, rather than having unspecified impurities control only, may help to set more appropriate limits
TLC only for a specified impurity and only as last resort.
Veterinary Medicine
Different thresholds
Genotoxic impurity
According to current regulatory practice it is assumed that (in vivo) genotoxic compounds have the potential to damage DNA at any level of exposure and that such damage may lead/contribute to tumour development.
Thus for genotoxic carcinogens it is prudent to assume that there is no discernible threshold and that any level of exposure carries a risk.
However, the existence of mechanisms leading to biologically meaningful threshold effects is increasingly acknowledged also for genotoxic events.
This holds true in particular for compounds interacting with non-DNA targets and also for potential mutagens, which are rapidly detoxified before coming into contact with critical targets.
The regulatory approach to such chemicals can be based on the identification of a critical No-Observed-Effect Level (NOEL) and use of uncertainty factors.
Even for compounds which are able to react with the DNA molecule, extrapolation in a linear manner from effects in high-dose studies to very low level (human) exposure may not be justified due to several protective mechanisms operating effectively at low doses.
However, at present it is extremely difficult to experimentally prove the existence of threshold for the genotoxicity of a given mutagen.
Thus, in the absence of appropriate evidence supporting the existence of a threshold for a genotoxic compound making it difficult to define a safe dose it is necessary to adopt a concept of a level of exposure that carries an acceptable risk.
The toxicological assessment of genotoxic impurities and the determination of acceptable limits for such impurities in active substances is a difficult issue and not addressed in sufficient detail in the existing ICH Q3X guidances.
The data set usually available for genotoxic impurities is quite variable and is the main factor that dictates the process used for the assessment of acceptable limits.
In the absence of data usually needed for the application of one of the established risk assessment methods,
i.e. data from carcinogenicity long-term studies or data providing evidence for a threshold mechanism of genotoxicity, implementation of a generally applicable approach as defined by the Threshold of Toxicological Concern (TTC) is proposed.
A TTC value of 1.5 µg/day intake of a genotoxic impurity is considered to be associated with an acceptable risk (excess cancer risk of <1 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]
Concentration Limit (ppm) = -------------------------------- Threshold of Toxicological Concern
Dose [g / day]
Inorganic Impurities
The need for inclusion of tests and acceptance criteria for inorganic impurities (e.g., catalysts) should be studied during development and based on knowledge of the manufacturing process.
Procedures and acceptance criteria for sulfated ash / residue on ignition should follow pharmacopoeial precedents; other inorganic impurities may be determined by other appropriate procedures, e.g., atomic absorption spectroscopy.
Inorganic Impurities (not on stability)
Heavy metals
Shouldn’t need to test if no Heavy metals used in route and RSMs/reagents are adequately understood/controlled.
Criteria and limits EP Technical Guide
Daily intake > 0.5 g/day, treatment < 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 < 0.5 g/day, treatment > 30 days: Heavy metals test limit 10 ppm If it is used parenterally
Heavy metals test limit 20 ppm Other wise
Daily intake < 0.5 g/day, treatment < 30 days : No heavy metals test
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
