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Writing a Convincing Dossier Writing a Convincing Dossier on Impurities and on Impurities and Method ValidationMethod Validation

Dr. Hans Ulrich GallySwissmedic – Swiss Agency for Therapeutic Products

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Writing a Convincing Dossier Writing a Convincing Dossier on Impurities and on Impurities and Method ValidationMethod Validation

Last edition: www.pharma.gally.ch„Aktuell“

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Requirements have changedRequirements have changed

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What will be presented?What will be presented?• Dossier and ethics: who is accountable• General principles for a winning dossier• Points to consider for impurities• Points to consider for method validations• Conclusions:

Quality dossiers and speed of marketing authorization

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Dossier and Ethics: who is accountableDossier and Ethics: who is accountable• Common goals of the applicant and the

agency• Rules to be observed

(Childress and Beauchamp):- principle of autonomy- principle of non-harm

• Who is responsible for the dossier and possible harms due to low quality medicines–MAH or agency?

• Who knows best – MAE or agency?• Who is the moral agent?

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Dossier, Risk Management and EthicsDossier, Risk Management and Ethics

QualityQualityRisk ManagementRisk Management

ICH Q9ICH Q9

Executive summary Executive summary for competent authorities and for competent authorities and

industryindustry

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Dossier, Risk Management and EthicsDossier, Risk Management and EthicsEmpowerment & Flexibility is needed

– Master complexity and streamline decision making– Proactive disclosure build trust and understanding– Improve communication through sharing best

practice and science based knowledge– Convert data into knowledge– Integrate corporate ethics into quality risk

management (Corporate Policy)

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Dossier, Risk Management and EthicsDossier, Risk Management and EthicsCorporate Responsibility and Risk Management

Risk

Likelihood

CorporatePolicies

Impact

Corporate Ethics

CorporateGoals

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Dossier, Risk Management and EthicsDossier, Risk Management and Ethics• Manage risk to patient, based on science and ethics:

– Product, process and facility– Robustness of Quality System– Relevant controls to assess & mitigate risk– Moral responsibility of corporation towards patient

• Level of oversight required commensurate with the level of risk to patient for:

– Marketing authorisation applications– Post-approval change review– GMP inspections

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Dossier, Risk M., Quality Systems, EthicsDossier, Risk M., Quality Systems, EthicsV. ConclusionsQuality professionals are aware that good intentions alone will not ensure good products.A robust quality system will promote process consistency by integrating effectiveknowledge-building mechanisms into daily operational decisions. Specifically, successfulquality systems share the following characteristics, each of which has been discusseddetail above:- Science-based approaches- Decisions based on an understanding of the intended use of a product - Proper identification and control of areas of potential process weakness - Responsive deviation and investigation systems that lead to timely remediation- Sound methods for assessing and reducing risk - Well-defined processes and products, starting from development and extending

throughout the product life cycle - Systems for careful analysis of product quality

- Supportive management (philosophically and financially)

FDA: Quality Systems Approach to Pharmaceutical cGMP Regulations, 9 / 2006

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Dossier, EthicsDossier, Ethics CheckCheckQuestions to answer before making a decision:

• Is it legal?Will I be violating either the law or the company policy?

• Is it risk balanced?Does it account for the risk for the patient and the production risks (is it achievable)?

• How will it make me fell about myself?Would I give this drug to my wife and my children?Would I feel good if my decision was published in the newspapers, in a journal?

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Ethical question or positive law?Ethical question or positive law?

Why shall we follow moral rules?(Kant, Bentham, Mill)

Philosophy – Ethical Question

Why shall we document all facts?It‘s a mustIt‘s the law

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Documentation Documentation –– Point to considerPoint to consider• The CTD should be clearly structured• All copies must be eligible• Pictures and diagrams must have a

reasonable size• Diagrams must be clearly labelled• Units must be included in each table• Calculations formulas must be unambiguous• Think as a reviewer, who sees this document

for the first time

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Night in the black forest?Night in the black forest?

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Discussion of Results and ConclusionsDiscussion of Results and Conclusions• Concise summary of the results• Overview tables• Final, sound conclusions • It is the duty of the MAH to draw the right

conclusions and to suggest limits and eventually improvements (commitments)

• The Agency must look critically at the results and check the logic of the conclusion,but it is not her duty to do the work the MAH has forgotten to do

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CTD Structure:CTD Structure:Documents and GranularityDocuments and Granularity• A document is defined for a paper

submission as a set of pages, numbered sequentially and divided by a tab. A document can be equated to a file for an electronic submission.

• “Granularity”:how many CTD sections a document should cover

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Document pagination and segregationDocument pagination and segregation

• If a section contains more than one document, a specific Table of Contents for that section can be included to identify the chronology and titles of the documents contained therein, for example:

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Document pagination and segregationDocument pagination and segregationTab with “3.2.S.4.2 Analytical Procedures”

•Table of Contents, listing the title of Procedure A, Procedure B, Procedure C

Tab with “3.2.S.4.2 “Procedure A”;

Tab with “3.2.S.4.2 “Procedure B”;

Tab with “3.2.S.4.2 “Procedure C”;

•Procedure A (i.e. document, page 1-n)

•Procedure B (i.e. document, page 1-n)

•Procedure C (i.e. document, page 1-n)

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CTD Module 3CTD Module 33.1

3.2.S.1.13.2.S.1.23.2.S.1.33.2.S.2.13.2.S.2.23.2.S.2.33.2.S.2.43.2.S.2.53.2.S.2.63.2.S.3.13.2.S.3.23.2.S.4.13.2.S.4.23.2.S.4.33.2.S.4.43.2.S.4.5

3.2.S.53.2.S.6

3.2.S.7.13.2.S.7.23.2.S.7.3

Module 3 Note 1

The TOC is only needed in the paper version of theCTD; there is no entry needed for the eCTD

3.2 3.2.S Note 2 3.2.S.1

3.2.S.2

3.2.S.3

3.2.S.4

3.2.S.7

N t 3

3.2.S.7.33.2.P.1

3.2.P.2.33.2.P.2.43.2.P.2.53.2.P.2.63.2.P.3.13.2.P.3.23.2.P.3.33.2.P.3.43.2.P.3.53.2.P.4.13.2.P.4.23.2.P.4.33.2.P.4.43.2.P.4.53.2.P.4.63.2.P.5.13.2.P.5.23.2.P.5.33.2.P.5.43.2.P.5.53.2.P.5.6

3.2.P.63.2.P.7

3.2.P.8.13.2.P.8.23.2.P.8.3

3.2.A.13.2.A.23.2.A.3

3.2.R3.3 One file per

reference Note 5

3.2.P Note 3

3.2.P.2 3.2.P.2.1 Note 4

3.2.P.2.2 Note 4

3.2.P.3

3.2.P.4

3.2.P.5

3.2.P.8

3.2.A

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CTD Module 3CTD Module 3

3.1

3.2.S.1.13.2.S.1.23.2.S.1.33.2.S.2.13.2.S.2.23.2.S.2.33.2.S.2.43.2.S.2.53.2.S.2.63.2.S.3.13.2.S.3.23.2.S.4.13.2.S.4.23.2.S.4.33.2.S.4.43.2.S.4.5

3.2.S.53.2.S.6

3.2.S.7.13.2.S.7.23.2.S.7.3

3.2.P.1

3.2.P.2.33.2.P.2.43.2.P.2.53.2.P.2.63.2.P.3.13.2.P.3.23.2.P.3.33.2.P.3.43.2.P.3.53.2.P.4.13.2.P.4.23.2.P.4.33.2.P.4.43.2.P.4.53.2.P.4.63.2.P.5.13.2.P.5.23.2.P.5.33.2.P.5.43.2.P.5.53.2.P.5.6

3.2.P.63.2.P.7

3.2.P.8.13.2.P.8.23.2.P.8.3

3.2.A.13.2.A.23.2.A.3

3.2.R Note 53.3 One f ile per

reference Note 6

Module 3 Note 1

The TOC is only needed in the paper version of theCTD; there is no entry needed for the eCTD

3.2 3.2.S Note 2 3.2.S.1

3.2.S.2

3.2.S.3

3.2.S.4

3.2.S.7

3.2.P Note 3

3.2.P.2 3.2.P.2.1 Note 4

3.2.P.2.2 Note 4

3.2.P.3

3.2.P.4

3.2.P.5

3.2.P.8

3.2.A

Documents rolled up to this level are not allowed

One or multiple documents may be submitted at this level

Note 1 : In choosing the level of granularity for this Module the applicant should consider that it will be expected that replacements of complete documents /files are provided in the CTD and eCTDwhen the information is changed at any point in the product's lifecycle.

Note 2 : For a drug product containing more than one drug substance, the information requested for part “S” should be provided in its entirety for each drug substance

Note 3 : For a drug product supplied with reconstitution diluent(s), the information on the diluent(s) should be provided in a separate part “P”, as appropriate

Note 4 : The lower level of headings included in CTD-Q at this point are unlikely to be individual documents or files

Note 6 : Literature References should be listed in the tables of contents.

Module 3

Note 5 : Refer to regional guidance

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ImpuritiesImpurities-- Limits Limits ((PhPh. Forum Vol 32(5)). Forum Vol 32(5))• Pharmaceutical manufacturer interact with

regulatory agencies in developing new drug substances and new drug products, ...

• Establishment of impurity limits in drug substances and drug products should proceed in a rational basis so that everyone involved ... can carry on their work in a predictable manner

• Manufacturer share with regulatory agencies and with the compendia the goal of making available to the public high-quality products that are both safe and efficacious

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ImpuritiesImpurities-- Limits Limits ((PhPh. Forum Vol 32(5)). Forum Vol 32(5))• The ultimate goal is to produce a final drug

product of high quality that is safe and efficacious and remains so throughout shelf live.

• Setting of limits should consider:toxicology of a drug substance containing typical levels of impurities and/or the toxicology of impurities, the route of administration, the daily dose, the target population, the pharmacology of impurities, the source of a drug substance, the duration of therapy, the capability of a manufacturer to produce consistently high-quality material

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ImpuritiesImpurities-- Limits Limits ((PhPh. Forum Vol 32(5)). Forum Vol 32(5))• For drug substances and drug products, limits

are appropriately set no higher than the level that can be justified and no lower than the level achievable by the manufacturing process and analytical capabilities

• Where there are no safety concerns, limits should be based on (a) data generated on actual batches of the drug substance or drug product, allowing sufficient latitude to deal with the normal process and analytical variations, and (b) stability characteristics.

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ImpuritiesImpurities-- Limits Limits ((PhPh. Forum Vol 32(5)). Forum Vol 32(5))

Limits for impurities/3-sigma-rule

Level ofImpurities

Batch No

Validation/Production

Validation-/production-batches for setting the limits!

Development

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Impurities and limitsImpurities and limits• ICH Q3A/B:

mean value + 3 Sigma is acceptable• Limits should be calculated from

typical/validation batches, not from very early batches before optimisation of the process

• Recommendation: commitment to check the limits eg after the first ten production batches

• Limits should guarantee, that the process runs always in the validated range

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ImpuritiesImpurities-- QualificationQualification• All impurities above a limit must be qualified:

ICH Q3A and Q3B• Clear overview over all batches used for

preclinical and clinical studies and production/validation batches

• Eventually syntheses of impurities and special toxicological tests necessary

• Safe by use – what does this mean?

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ImpuritiesImpurities-- are all detectable?are all detectable?• Impurities covered by the substance peak• Impurities with high molecular weight: can

they possibly exist or can they be excluded ?• Is there a reasonable mass balance?• Heavy metals/catalysts: must there be a

specification/test or can they be excluded (validation)

• Residual solvents: can solvents of early stages be excluded or must there be a test?

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ImpuritiesImpurities-- are all detectable?are all detectable?

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ImpuritiesImpurities

Ermer/Miller:

Method Validation in Pharmaceutical Analysis

Wiley-VCH2005

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Impurities and analytical methodsImpurities and analytical methodsPeak purity investigations should be integrated into method development/robustness.Only the absence of evidence, not the evidence of absence can be shown.

Variation in chromatographic conditions and /or re-chromatography is a simple, sensitive approach

Peak shape investigations and DAD must be discussed for small co-eluting substances

MS is very sensitive and highly selective, but is also dependent on substance properties

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Impurities and analytical methodsImpurities and analytical methods• Unknown impurities: can they be detected?

eg UV-detection/measuring wavelength • Are reference substances for all impurities

available. How are the response factors?• How can unknown impurities be separated

into classes like „by-products from synthesis“, „decomposition products“

• Changes of method: comparative impurity profiles of least three batches, new detectable impurities?

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GenotoxicGenotoxic ImpuritiesImpurities• This is new for the MAH and the agency• You are the experts and you must explain• There should be a statement, that genotoxic

impurities can/can‘t be present• Discussion, why a synthesis without us of

genotoxic intermediates/starting materials is not practicable

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Validation of AM: System SuitabilityValidation of AM: System SuitabilitySystem suitability tests are an integral part of gas and liquid chromatographic methods. They are used to verify that the detection sensitivity, resolution, and reproducibility of the chromatographic system are adequate for the analysis to be done. ...

The detection sensitivity is a measure used to ensure the suitability of a given chromatographic procedure for the complete detection of the impurities in the Chromatographic purity or Related compounds tests by injecting a volume of a quantitation limit solution equal to that of the Test solution. ... at a 0.05% concentration level relative to the amount of drug substance in the Test solution for drug substances, and a 0.1% level relative to the amount of drug substance in the Test solution for drug products. The signal-to-noise ratio for the drug substance peak obtained with the quantitation limit solution should be not less than 10

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Validation of AM: System SuitabilityValidation of AM: System Suitability• Must probe, that all impurities above the

disregard limit can be detected: limit of quantification

• Must make shure, that all impurities are separated: Resolution between the peaks that are closest must be shown

• SST not only for chromatographic methods: particle size, UV-spectra

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Validation of AM: Intermediate PrecisionValidation of AM: Intermediate Precision• Intermediate precision must be done for all

analytical methods• Intermediate Precision is not robustness• For the validation of the intermediate

precision of impurities sound limits must be defined before the validation is done (validation protocol is often not include!)

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Validation of AM: Stability Indicating MethodValidation of AM: Stability Indicating Method• A list of all known impurities and

decomposition products should be include• It should be shown, that all these substances

are separated• HPLC Peak purity is not sufficient to show

that there is no impurity covered by the substance peak. Substance with similar chromophoric groups may have LOD above 0.1%

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Validation of AM: all methods?Validation of AM: all methods?• As a rule all analytical methods must be

validated• Methods from Ph. Eur. or USP have been

validated for monographs of the Ph. only• Methods for the following determinations are

often not validated:- Water according to Karl Fischer- Particle Size Measurement- Optical Rotation

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Validation of AM: further considerationsValidation of AM: further considerations• A summary of the validation results is

welcomed, but all results of the validation test must be supplied

• Eligible, clearly labelled chromatograms must be supplied

• There must be sound assessment and a final conclusion: usually „requirements fulfilled“or corrective measurements

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SummarySummary• It is the duty of the marketing authorization

holder to make sure, that the dossier conforms to the law and the regulations.The agency is not a consulting company!

• All data should be evaluated by the marketing authorization holder. It is not the duty of the agency to do the work you should do: to analyze the data, to come to the conclusions and make decision

• Make sure that the dossier does not only conform to the law and the regulations, but do also the ethic check

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