The evaluation of the impact of the regulation of ...ª Apresentação_Florian Seidel_Impurities...ICH Q3A „Impurities in new Drug Substances⍈ ICH Q3B „Impurities in new Drug

The evaluation of the impact of the regulation of impurities of drugs and medicines on the pharmaceutical industry

Dr. Florian Seidel

[email protected]

• The impurities family – general considerations

• ICH Q3 Fishing for impurities – decomposition

• ICH M7 Hunting for impurities – potential mutagenic impurities

• ICH Q2 Analytical method validation – quantitation of impurities

Impurities, 18th June 2019, Dr. Florian Seidel 2

Content

The impurities family

General considerations

• An impurity is a substance that is present beside the desired compound(s) and might impact the quality of the final drug product.

• Impurities themselves might be uncritical or even critical to the patient.

• The criticality is related to the nature of the impurity (e.g. genotoxic compounds or heavy metals).

• “All compounds are toxic, and nothing is non-toxic; it is solely the dose, that makes a compound non-toxic”*

• Therefore, impurities should be controlled with appropriate methods at appropriate limits!


The impurities family - definition

* Paracelsus, Septem Defensiones 1538. Werke Bd. 2, Darmstadt 1965, S. 510


The impurities family – where they stem from

API DPManufacturing

SynthesisProcess EquipmentPackaging

Elemental impurities

Actual impurities

Decomposition

Leachables

Decomposition- Carry over

- Downstream

Excipients

Process EquipmentPackaging


The impurities family – where they stem from

API DPManufacturing

SynthesisProcess EquipmentPackaging

Elemental impurities

Actual impurities

Decomposition

Leachables

Decomposition- Carry over

- Downstream

Excipients

Process EquipmentPackaging

High risk of occurrence with direct imapact on DP quality

Control of impurities:

- Direct control: apply analytical methods

- Indirect control (on API): control strategy with scientific rationales based on analytic data and/or synthesis knowledge


The impurities family - general


The impurities family - Relevant ICH guidelines - the NCE world

ICH Q6A (valid for DS/DP, not for synthetic intermediates!)„Specifications: Test Procedures and acceptance criteria…“

ImpurityTesting


The impurities family – how to detect impurities

• LC-UV• LC-MS• GC-FID• GC-MS• IC• ICP-MS• ICP-OES• AAS• CE• TLC• NMR• KF Titration• Gravimetry (Sulphated Ash, Loss on drying, Residue on ignition)• Filter Test, Particulate impurities• Microbiological contamination

• Among others…


The impurities family - relevant ICH guidelines - the NCE world

ICH Q6A (valid for DS/DP, not for synthetic intermediates!)„Specifications: Test Procedures and acceptance criteria…“

ICH Q4„Pharmacopeia“

ICH Q3A„Impurities in new Drug Substances“

ICH Q3B„Impurities in new Drug Products“

ICH Q3C„Impurities: Guideline for residual solvents“

ICH Q3D„Guideline for elemental impurities“

ICH M7 „Mutagenic impurities“(guidance also for development!)

ICH Q1„Stability“

ICH Q2„Validation of analytical

procedures“

Fishing for impurities

Decomposition – forced degradation studies


ICH Q3 - Fishing for impurities

ICH Q3 Qualification Level (e.g. 0.15 %)

ICH Q3 Identification Level (e.g. 0.10 %)

ICH Q3 Reporting Level (e.g. 0.05 %)

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Presentation title, date, author 13

Potential degradation profile – regulatory perspective

RDC 53/2015 ICH Q1A (Stability) ICH Q2B (Validation)

Stress conditions: Art. 5:“heat, humidity, acid solution, basicsolution; oxidation; photolyses andmetallic ions.”

Stress conditions:DS: “..nature of stress testing will depend on the individual drug substance and the type of drug product involved.”“..include the effect of temperatures,.., humidity where appropriate, oxidation and photolysis on the drug substance. ...the susceptibility of the drug substance to hydrolysis..when in solution or suspension. Photostability testing should be an integral part...”

Stress conditions: Part II - Specificity; 2. When impurities are not available (1.2.2)“As appropriate, this should include samples stored under relevant stress conditions: Light, heat, humidity, acid/base hydrolysis and oxidation.”

Minimum 10% degradation or justification;

Not mentioned Not mentioned

Mass balance Not mentioned (ICH Q1E, stability data evaluation, for formal stability testing)

Not mentioned

API + Placebo + SamplesAll dose strengths (no bracketing)

Single API batch (for all parameters). Single DP batch (for photostability testing).

Samples


Potential degradation profile – a view from scientific perspective

“Potential” degradation profile (forced degradation accelerating decomposition)

“Theoretical” degradation profile (forced degradation under harsh conditions)

“More realistic” degradation profile (accelerated stability profile)

“Real” degradation profile (long-term stability profile)



Conditions

Hydrogen peroxide, ironions, AIBN

105 °C (24 h), 70 °C(water saturated 3 d), light, basic and acidic

40 °C / 75 % R.H. (24 months)

25 °C / 65 % R.H. (36 months)

Change in reaction mechanism/kinetic leads to different reaction products than being expected as „potential“

and/or and/or

and/or



“Potential” degradation profile (forced degradation)- Depends on physical form (e.g. liquid/solid) and storage (e.g. PE bag/metal

container)- Stressing samples, considering environmental conditions, “super-accelerated

conditions” (e.g. Oxidation might by accelerated by dissolved compound)

“Theoretical” degradation profile (forced degradation)- Compounds are stressed under non-realistic conditions (e.g. H2O2 might be interesting to learn about the chemistry of the compound)

“More realistic” degradation profile (accelerated stability profile)- ICH Stability study at 40 °C / 75 % RH

“Real” degradation profile (long-term stability profile)- ICH Stability study at 25 °C / 60 % RH (or e.g. 30 °C / 75 % RH, climatic zone III/IV)

17


Intrinsic stabilityDS

Stability indicatinganalytical method

„Real“ X X

„More realistic“ X X

„Potential“ X X

„Theoretical“ X ---

- While the theoretical impurity profile might be important for development, the potential impurity profilehas to be covered by a stability indicating method

Conclusion

- It is very important to know the degradation profile in DS/DP!-> efficient development (e.g. formulation) is supported-> development of stability indicating methods is ensured

- Conditions to form the theoretical degradation profile contain conditions that might not occurr in reality(e.g. agents that change reaction mechanism/kinetics of oxidation)

- During forced degradation testing, a compound can be expected to be stable under the tested condition, even though not the desired decomposition is reached (e.g. no need to heat up to 200 °C!)

Impurities, 18th June 2019, Dr. Florian Seidel

Hunting for impurities

Potential mutagenic impurities


Potential mutagenic impurities

ICH Q3 Qualification Level (e.g. 0.15 %)

ICH Q3 Identification Level (e.g. 0.10 %)

ICH Q3 Reporting Level (e.g. 0.05 %)

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ICH M7TTC (1.5 µg)

30 % TTC


Mutagenic impurities

ICH M7: Hazard assessment - classificationClass Definition Proposed action for control

1 Known mutagenic carcinogens Control at or below compound-specific acceptable limit

2 Known mutagens with unknown carcinogenicpotential (bacterial mutagenicity positive*, norodent carcinogenicity data)

Control at or below acceptable limits (appropriate TTC)

3 Alerting structure, unrelated to the structure of the drug substance; no mutagenicity data

Control at or below acceptable limits (appropriate TTC) or conductbacterial mutagenicity assay; Ifnon-mutagenic = Class 5If mutagenic = Class 2

4 Alerting structure, same alert in drug substance or compounds related to the drug substance (e.g., process intermediates) which have been tested and are non-mutagenic

Treat as non-mutagenic impurity

5 No structural alerts, or alerting structure with sufficient data to demonstrate lack of mutagenicityor carcinogenicity

Treat as non-mutagenic impurity



ICH M7 requires the classification of the following impurities

Actual impurities

• Actual impurities include those observed in the drug substance above the ICH Q3A reporting thresholds.

• Identification of actual impurities is expected when the levels exceed the identification thresholds outlined by ICH Q3A.

• Actual degradation products in the drug product include those observed above the ICH Q3B reporting threshold during storage of the drug product in the proposed long-term storage conditions and primary and secondary packaging, and also include those impurities that arise during the manufacture of the drug product.

Potential impurities

• Potential impurities in the drug substance can include starting materials, reagents and intermediates in the route of synthesis from the starting material to the drug substance.

• The risk of carryover into the drug substance should be assessed for identified impurities…

• Potential degradation products in the drug substance and drug product are those that may be reasonably expected to form during long term storage conditions. Potential degradation products include those that form above the ICH Q3A/B identification threshold during accelerated stability studies (e.g., 40°C/75% relative humidity for 6 months) and confirmatory photo-stability studies as described in ICH Q1B…

-> there is no need to fish out all impurities at ppm levels for classification, it is a huntfor specific impurities



ICH M7: Control Options for process related impurities (DS)

Option 1:

Control at API stage (<= TTC)

Option 2:

Control at step before API (<= TTC)

Option 3:

Control at step before API (> TTC). This option can be justified when the level of the impurity in the drug substance will be less than 30% of the acceptable limit by review of

data from laboratory scale experiments.

Option 4:

Understand process parameters and impact on residual impurity levels (including fate and purge knowledge) with sufficient confidence that the level of the impurity in the drug substance will be below the acceptable limit such that no analytical testing is recommended for this impurity.

How to handle option 4?



ICH M7: Control Option 4

Potential approach: calculation of a purge factorRisk Assessment of Genotoxic Impurities in New Chemical Entities: Strategies To Demonstrate Control, Andrew Teasdale, David Elder, Sou-Jen Chang, Sophie Wang, Richard Thompson, Nancy Benz, and Ignacio H. Sanchez Flores, Organic Process Research & Development2013 17 (2), 221-230.

A consortium-driven framework to guide the implementation of ICH M7 Option 4 control strategies, Chris Barber, Vincent Antonucci, Jens-Christoph Baumann, Roland Brown, Elizabeth Covey-Crump, David Elder, Eric Elliott, Jared W. Fennell, Fabrice Gallou, Nathan D. Ide, Guido Jordine, Jeffrey M. Kallemeyn, Dirk Lauwers, Adam R. Looker, Lucie E. Lovelle, Mark McLaughlin, Robert Molzahn, Martin Ott, Didier Schils, Rolf Schulte Oestrich, Neil Stevenson, Pere Talavera, Andrew Teasdale,Michael W. Urquhart, David L. Varie, Dennie Welch, Regulatory Toxicology andPharmacology 2017 90, 22-28.

Quantitation of impurities

Analytical method validation

• Specificity

• Linearity

• Range

• Accuracy

• Precision

• Detection Limit

• Quantitation Limit

• Robustness


Quantitation of impurities – validation of analytical methods

General validation parameters according to ICH Q2 / RDC 166

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Concentration

It‘sprecise!

It‘sprecise!

Andaccurate

But not accurate



ICH Q7 ≠ RDC 166!

ICH Q7: “Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients”RDC 166: Validation of analytical methods

RDC 166, Art. 2: This Resolution is applicable to analytical methods employed in pharmaceutical inputs, medicines, and biological products throughout all their manufacturing steps.

ICH Q7, 12.81: The degree of analytical validation performed should reflect the purpose of the analysis and the stage of the API production process.

-> while RDC 166 requires all validation parameters independent from the manufacturing step, ICH Q7 gives more flexibility e.g. omission of a validation parameter.

• Specificity

-> Impurities are available (ICH Q2, 1.2.1)

Spiking of DS/DP with appropriate levels of impurities

-> Impurities are NOT available (ICH Q2, 1.2.2)

“As appropriate, this should include samples stored under relevant stress conditions: light, heat, humidity, acid/base hydrolysis and oxidation.”

How can you make sure that all impurities are available? If needed, choose stress conditions that might be relevant to generate potential impurities!

RDC 166, §1 “In order to demonstrate the absence of interference of degradation products, it is necessary to expose the sample to degradation conditions in a broad pH, oxidation, heat and light range.” -> in any case, even non-relevant conditions have to be employed!



ICH Q2 ≠ RDC 166!

• LinearityLinearity evaluation is needed to choose an adequate calibration model (e.g. linear vs quadratic)!

ICHQ2: “..test results should be evaluated by appropriate statistical methods..” ICH Q2: requires submission of correlation coefficient, y-intercept, slope of the regression line and residual sum of squares (including linearity plot).

What is linear? -> Define appropriate acceptance criterion for the correlation coefficient

(e.g. R ≥ 0.990).

How do you know, that your linear calibration model is adequate for the intended purpose? You could either do more statistical evaluations (however, with a very limited set of data points), or you evaluate the “accuracy” results which are obtained with the proposed calibration. If accuracy is within the pre-defined acceptance criteria, the calibration model is adequate!

RDC 166, “§ 1 The homoscedasticity of the data must be investigated for the use of a suitable model.” -> Evaluation of homoscedasticity does not lead to significant more accurate test results!



ICH Q2 ≠ RDC 166!


Questions

?


Backup

Degradation product is

greater than identification

threshold



Impurity qualification: ICH M7 and ICH Q3

Structure identifiedNo known human relevant risks

Greater thanqualificationthreshold

Consider patient population and duration of use and consider conducting: • Genotoxicity studies (point mutation, chromosomal aberration)• General toxicity studies (one species, usually 14 to 90 days)• Other specific toxicity endpoints, as appropriate

Partial ICH Q3 path from decision tree (attachment 3)

Is an AMES test required????

Degradation product is

greater than identification

threshold



Impurity qualification: ICH M7 and ICH Q3

Structure identifiedNo known human relevant risks

Greater thanqualificationthreshold

Partial ICH Q3 path from decision tree (attachment 3)

Is an AMES test required????

ICH M7 procedure

SAR negativeSAR positive In cases where the amount

of the impurity exceeds 1

mg daily dose for chronic

administration, evaluation of

genotoxic potential as

recommended in ICH

Q3A/B could be considered.

In cases where the amount

of the impurity is less than

1 mg, no further

genotoxicity testing is

required regardless of

other qualification

thresholds.

YES NO

• RangeICH Q2B: “It is established by confirming that the analytical procedure provides an acceptable degree of linearity, accuracy and precision when applied to samples containing amounts of analyte within or at the extremes of the specified range of the analytical procedure.”



RL AC

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Accuracy resultsFrom spiked sample

Repeatability resultsfrom real sample

Linearity resultfrom diluted solutions

RL AC

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Concentration

RL: reporting limit, AC: acceptance criterion

-> tightening the AC does not exhibit negative impact on the range!-> having shown linearity wider than the range is appropriate, however the range is the intersection with accuracy experiments!

Documents

The evaluation of the impact of the regulation of ...ª Apresentação_Florian Seidel_Impurities...ICH Q3A „Impurities in new Drug Substances⍈ ICH Q3B „Impurities in new Drug