Module 3 2019

©TOPRA ( The Organisation for Professionals in Regulatory Affairs) 2019

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Module 3: Regulatory Requirements for a New Active Substance: Quality 4 th – 6 th December 2019

De Vere Latimer Estate, Church Lane, HP5 1UG Chesham, UK

Module Leader(s) : Per Niklasson

Date: Wednesday 4 th December

Time

Activity

Speaker

16.15

Registration

16.30 – 16.45

Welcome & Introduction to Module 3

Per Niklasson, AstraZeneca

Management in Regulatory Affairs

Lecture 1: CMC in the Drug Development Programme

16.45 – 17.45

Mike James Cambridge Regulatory C Mike James Cambridge Regulatory

17.45 – 18.45

Lecture 2: API Manufacture and In-Process Controls

18.45

New Student Tutorial

Dr Laura Brown Course Director

19.30

Dinner

Module 3: Regulatory Requirements for a New Active Substance: Quality 4 th – 6 th December 2019

Date : Thursday 5 th December

Time

Activity

Speaker

09.00 – 10.00

Lecture 3: Nomenclature and Characterisation of the Active Ingredient

Christian Maasch Takeda

10.00 – 10.30

Refreshment Break

10.30 – 11.30

Lecture 4: Analytical Methods and Validation

Craig Donnelly ICON Craig Donnelly ICON

11.30 – 12.30

Lecture 5: Developing Specifications for the Active Ingredient

12.30 – 13.30

LUNCH

13.30 – 14.30

Lecture 6: CMC Project Management

Christian Maasch Takeda

Case Study 1 with discussions and presentations with refreshment break Lecture 7: Pharmaceutical Development and Manufacture of the Drug Product

14.30 – 16.30

Per Niklasson

AstraZeneca

16.30 – 17.30

Tahir Nazir AstraZeneca

17.30 – 1815

Lecture 8: Stability of the Drug product

Tahir Nazir AstraZeneca

19.00

Dinner

Module 3: Regulatory Requirements for a New Active Substance: Quality 4 th – 6 th December 2019

Date: Friday 6 th December

09.00 – 10.00

Lecture 9: Good Manufacturing Practice – Clinical Supply

Anne Radmall AstraZeneca

10.00 – 10.30

Refreshment break

10.30 – 11.30

Lecture 10: Pharmaceutical Packaging

Torsten Kneuss Bayer Per Niklasson AstraZeneca

11.30 – 13.00

Case Study 2

LUNCH

13.00 – 13.30

13.30 – 14.30

Lecture 11: Regulatory Agency Perspective

Elspeth Gray MHRA Per Niklasson AstraZeneca

14.30 -15.00

Closing remarks and departure

Christian Maasch Head of Change Control Management/Support Regulatory Affairs CMC Takeda GmbH, Oranienburg, Germany Dec 4 th , 2019 Nomenclature and Characterisation of the Active Ingredient

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RA-CMC Team at Takeda Oranienburg (TOB)

Bridging Manufacturing and Market Supply by Regulatory Product and Dossier Compliance

 Support Filing and Maintaining the Marketing Authorizations of our Products (“The Process is the Product”) thru Changes and Improvements at TOB

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Learning Objectives

Characterization 1. The need for characterization studies 2. Different phases of drug development 3. Regulatory Dossier

Nomenclature 1. Regulatory Dossier 2. Guiding principles for naming 3. Sources

Nomenclature and Characterisationof the Active Ingredient

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Characterization

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Characterisation Studies ➢ Commence from early development through to clinical studies Investigate: − Evidence of structure − Physicochemical properties (solid & solution) − Explain/predict behavior under conditions not studied ➢

➢ Naturally divided into three areas: − Spectroscopic properties − Solid state properties − Solution properties

➢ Results are reflected in the control tests to ensure batch to batch uniformity

Nomenclature and Characterisationof the Active Ingredient

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Spectroscopic Properties

➢ Major objective to elucidate the structure of the chemical compound

➢ Typically methods - all highly specific:

NMR ( 1 H, 13 C plus others)

−

MS

−

IR

−

UV-Visible

−

➢ Used often during early development, only require small quantities of samples

Nomenclature and Characterisationof the Active Ingredient

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Solid State Properties

➢ Majority of candidates are solids at room temperature

➢

Typically properties include:

Surface area

−

Particle size distribution

−

Hygroscopicity

−

Polymorphism

−

Solid state stability

−

Intrinsic dissolution rate

−

➢ Used for the development of solid dosage forms

Nomenclature and Characterisationof the Active Ingredient

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Solution Properties

➢ Describe the solution properties of the compound

➢

Typical studies:

− Association and dissociation constants − Complexation constants − Solubility as function of pH − Solubility in selected solvents − Partition coefficients as a function of pH − Solution stability

➢ Used for development of solution dosage forms and understanding its pharmacological behaviour

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Compound Screening

➢ Limited number of characterisations

− Limited quantities of the compounds are available − Large number of compounds to test in a short period

e.g. chemical libraries in FBLD

−

➢ Typical studies performed during early development:

Enantiomeric composition

−

− Partition coefficients at selected pH − Estimated dissociation constant − Solubility at selected pH − Preliminary stability

Nomenclature and Characterisationof the Active Ingredient

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Nonclinical/Clinical Candidate

➢ Information required for the first clinical studies:

Solids

Hygroscopicity

− − − −

Preliminary polymorphism Dissolution rate constants

Solid state stability

Solutions

Partition coefficients as a function of pH

− − − − −

Solubility as a function of pH

Dissociation constant

Solubility in selected solvents Modified solution stability

➢

Also required for:

− Understanding behavior under physiological conditions − Development of the formulation − Development of analytical methods

Nomenclature and Characterisationof the Active Ingredient

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Late-stage Candidate

➢ Limited characterization data before initially filed with regulatory agencies for the first clinical studies

➢ Typical studies conducted whilst clinical trials are ongoing: Solids

Surface area

−

Particle size distribution

−

Polymorphism

−

Solutions

Complexation constants

−

Aggregation constants

−

Detailed solution stability

−

Nomenclature and Characterisationof the Active Ingredient

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Regulatory Dossier

➢ Where is this information contained: S.1 General Information S.1.1 Nomenclature S.1.2 Structure S.1.3 General Properties

S.3 Characterization S.3.1 Elucidation of Structure and other Characteristics S.3.2 Impurities

Nomenclature and Characterisationof the Active Ingredient

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S.1 General Information

➢ S.1.2 Structure − Structural formula including relative and absolute stereochemistry − Molecular formula − Relative molecular mass

➢

S.1.3 General Properties

Physicochemical properties

−

− Properties affecting pharmacological efficacy

Nomenclature and Characterisationof the Active Ingredient

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S.3.1 Elucidation of Structure and other Characteristics ➢ Full elucidation or with reference to a pharmacopoeial standard ➢ Evidence of Chemical Structure ➢ Physicochemical properties

Synthetic route Key intermediates

Solubility

− − − − −

− − − − −

Physical characteristics

Spectroscopic evidence

Polymorphism

Crystallography Elemental analysis

Partition coefficient

Hygroscopicity

➢ Potential Isomerism

Asymmetric carbons

− −

Other isomers

Nomenclature and Characterisationof the Active Ingredient

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Evidence of Chemical Structure (1)

➢

Synthetic route – Comprehensive, Unequivocal, Resolution of isomers

➢

Key intermediates – Contribution to stereochemistry – Retention of stereochemistry – Evidence of structure

➢ Spectroscopic evidence (with correct interpretation!) – UV-visible − IR – NMR: 1H, 13C, 15N, 31P − Mass – Other: Fluorescence, Raman

Nomenclature and Characterisationof the Active Ingredient

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Evidence of Chemical Structure (2)

➢ Diagnostic characteristic chemical reactions

➢ Optical rotation (for chiral molecules including racemates)

➢

Crystallography

Definitive, Polymorphism

−

➢ Elemental Analysis (with theoretical values)

… strengthened by orthogonal approaches

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Potential Isomerism: Asymmetric Carbons

➢ Chiral: Molecules containing a carbon atom attached to four different groups or atoms

➢ One chiral center: – Two enantiomers (enantiomorphs) – Non-superimposable mirror images – Optically active – Individual isomers: other properties the same ➢ Racemate: – Optically inactive – Some other properties differ (mp, solubility)

Nomenclature and Characterisationof the Active Ingredient

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Example: Thalidomide

➢ Administered as a racemate ➢ (R) isomer - effective sedative ➢ (S) isomer – teratogenic properties causing foetaldeformities ➢ Also undergoes racemisation in vivo

Nomenclature and Characterisationof the Active Ingredient

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Potential Isomerism: Asymmetric Carbons

➢ Two or more chiral centres

n centers - 2n isomers

−

Enantiomers as above

−

− Diastereoisomers - not mirror images: different properties − Epimer - change in configuration at one centre new diastereoisomer − Physical properties can be different

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Potential Isomerism: Other

➢ Geometric isomer (alkenes)

− Both carbon atoms forming the double bond are attached to two different groups − E/Z isomers (cis/trans) ➢ Chirality associated with other elements − Sulphur, Nitrogen, Phosphorus

➢ Positional isomers − Ring substitution

Nomenclature and Characterisationof the Active Ingredient

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Potential Isomerism

➢ Effect on synthesis

Influence of reaction conditions

− −

Scale

− Resolved and unresolved center, mixtures of racemates

➢ Effect on other data

− Physical and chemical properties − Pharmacology and toxicology, Bioavailability, Biopharmaceutics

➢ Implications

What is theoretically possible? What is actually produced?

− −

− Is isomeric composition adequately demonstrated and controlled? − Has the composition changed?

Nomenclature and Characterisationof the Active Ingredient

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Physicochemical Characteristics

➢ Polymorphism

Evidence of structure

−

− Existence or absence of polymorphism: ▪ Amorphous, polymorph or pseudo-polymorph ▪ Techniques: DSC, XRD, IR (solid state), NMR (solid state) − Consequences of polymorphism ▪ Effect on physical properties ▪ Consistency of production ▪ Control on polymorphic form

➢ Partition coefficient – information for development pharmaceutics ➢ Hygroscopicity

Nomenclature and Characterisationof the Active Ingredient

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Nomenclature

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Regulatory Dossier

➢ Where is this information contained: S.1 General Information S.1.1 Nomenclature S.1.2 Structure S.1.3 General Properties

Nomenclature and Characterisationof the Active Ingredient

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S.1.1 Nomenclature

➢ International Nonproprietary Name

− Issued by WHO: Recommended, Proposed

➢ Compendial Name

European Pharmacopeia

−

➢ Chemical Name (systematic name)

− International Union for Pure and Applied Chemistry (IUPAC) − Chemical Abstracts Service (CAS) ➢ Other Name(s)

Acronym, Trivial name

− −

Laboratory Code

− British Approved Name ->Issued by the British Pharmacopoeia Commission − United States Adopted Name -> Issued by the US Adopted Names Council − Japanese Accepted Name

Nomenclature and Characterisationof the Active Ingredient

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Guiding Principles

➢ Distinctive in sound and spelling

➢

In addition:

Possibility of new stem for new group One-word name for acids; salts use name of acid or base e.g. “oxacillin”and “oxacillin sodium”

➢

Show group relationship to pharmacologically related

−

−

➢

substances (stems)

➢

Not too long

Avoid isolated letters or numbers

−

➢ Not confusing with common words

➢

No conflict with trade marks

Harmonised spelling

−

➢

Not misleading

➢

Not suggestive to patient

Nomenclature and Characterisationof the Active Ingredient

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Example of Stems

Stem Pharmacologically Related Group

Example INN

cef-

antibiotics derived from cephalosporanic acid systematic antifungals of the miconazole group

cefuroxime (Zinacef) fluconazole (Diflucan)

-conazole

-dronic acid -lukast

calcium metabolism regulators

alendronic acid (Fosamax)

antiasthmatics or antiallergics, not primarily antihistamines: leukotriene receptor antagonist

montelukast (Singulair)

-olol

ß-adrenoceptor antagonists

bisoprolol (Cardicor)

-pril, - prilat

angiotensin-converting enzyme inhibitors

ramipril (Tritace)

-racetam

amide type nootropic agents, piracetam derivatives

levetiracetam (Keppra) losartan (Cozaar) atorvastatin (Lipitor)

-sartan

angiotensin II receptor antagonists antihyperlipidaemic substances, HMG CoA reductase inhibitors

-vastatin

-tidine

histamine-H2-receptor antagonists of the cimetidine group

ranitidine (Zantac)

The use of common stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances’ WHO 2011 (with examples)

Nomenclature and Characterisationof the Active Ingredient

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Sources

➢ INN: International Nonproprietary Names (INN) for pharmaceutical substances

INN in four languages

−

Procedure for selection

−

General principles

−

− Subsequent lists of proposed and recommended INN: WHO Drug Information

➢ BAN: British Approved Names : incorporating International Nonproprietary Names.

− A dictionary of drug names for regulatory use in the UK

Names & guiding principles

−

Cross-index with proprietary names

−

− Guidelines for construction of pharmaceutical trademarks

➢ USAN: USP Dictionary of USAN and International Drug Names (US Pharmacopoeia)

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Contact Points

INN Dr R Balocco Mattavelli World Health Organization 1211 Geneva 27 Switzerland email: innprogramme@who.int BAN/INN British Pharmacopoeia Commission 151 Buckingham Palace Road London SW1W 9SZ UK email: bpcom@mhra.gov.uk Tel: +00 44 (0) 20 3080 6561

USAN The USAN Program American Medical Association 515 North State Street, Chicago,IL 60610 USA email: USAN@ama-assn.org Tel: 00 1 312 464 4045

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References

➢ EMA/454576/2016 Guideline on the chemistry of active substances

➢ Chemistry of Active Substances. 3AQ5A

➢ Investigation of Chiral Active Substances. 3CC29A

➢ ICH Harmonised Tripartite Guideline Q6A: Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances.CPMP/ICH/367/96

Nomenclature and Characterisationof the Active Ingredient

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Nomenclature and Characterisationof the Active Ingredient

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Analytical Procedures and Validation

Craig Donnelly, Director, Regulatory Affairs CMC and Regulatory Affairs, International, ICON Strategic Regulatory and Safety

05 December 2019

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Learning Outcomes – In this presentation we will cover

• Types of analytical procedures and validation • Method activities at various stages of development

The Validation Process

•

• Validation parameters for Drug Substance Assay

• Additional Parameters for Drug Substance Impurities

• Emerging Approaches: QbD for Analytical Procedures

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Analytical Procedures

Methods used to develop and control pharmaceutical products

Starting Materials (RSMs)

Raw Materials

DS Intermediate(s)

Drug Substance

Packaging

DP Intermediate(s)

Excipient(s)

Drug Product (Tablets, Capsules etc)

Packaging

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Analytical Procedures

Why do we test pharmaceutical products? • PATIENT SAFETY IS PARAMOUNT

• Identity • Quality • Safety • Efficacy • Support of regulatory filings • Analytical methods must be appropriately validated

• Validation – documented evidence that an analytical method will perform as expected to assure identity, quality, safety and efficacy of the material being tested

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Regulatory Environment

Much regulatory guidance exists

Vital

● ICH Q2(R1)*, Q3A(R2), Q3B(R2), Q3C(R6), Q3D, Q6A, Q6B

Important ● FDA Guidance for Industry -Analytical Procedures & Method Validation for Drugs and Biologics (July 2015) ● FDA Reviewer Guidance – Validation of Chromatographic Methods ● IUPAC –Harmonised Guidelines for Single-Laboratory Validation of Methods of Analysis

* R2 is coming – validation principles covering spectroscopic and spectrometric data * Q14 Analytical Procedure Development Guideline being discussed

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Attrition

•

New chemicals

8,000-10,000

•

Safety Testing

1000

•

Drugs enter development

12-18

•

Drugs enter clinical trials

6-9

•

Drugs marketed

1

Economic factors Determine necessity to

develop as much as possible off the high-attrition curve

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Validation / Procedure Types

• “The Objective of validation of an analytical procedure is to demonstrate that it is suitable for its intended purpose” 1

●

Validation proves the “ fitness for purpose ” of a method

• Therefore to determine the validation you need, first define the purpose of the method Examples: 1. Release of the first batches of API for toxicology 2. Release of the first materials (API & Product) for human use 3. Release and testing of batches (API & Product) for registration stability 4. Methods for tech transfer and Filing (same methods as (3) hopefully) • Each having a different purpose so differing validation may be appropriate

1 ICH Topic Q2 (R1) Validation of Analytical Procedures: Text and Methodology

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Phases of Validation and Method Utilization

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Early Development: Method Confidence

• Same attrition arguments apply to effort expended on method development as method validation

•

Material may be in extremely short supply.

• Only the compound itself may exist – no impurities

• Formal validation exercise is not possible (or desirable)

• “Generic methodology” can provide a starting point or be good enough to work on its own

• If necessary, utilise a rational method design to tailor the method to your needs

• Assuring selectivity is key at this point

• The generic starting point, coupled with a rational approach to method development builds confidence that the method is fit for purpose

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Early Method Development Approach - HPLC

• Inspect route and decide what intermediates/impurities need to be separated (and what’s available)

• Simple solution stress experiment (acid/base/photo/peroxide/thermal)

• Mix impurities/intermediates and stressed solutions together

• Development/Validation cocktail

• Choose starting point – could be a generic method with known column and mobile phase stability • Use predictive/optimisation approaches to get all components of the cocktail separated

• Re-inject to check cocktail chromatogram matches predictions

• The final method suitable for early use with proven selectivity and developed from a starting point of proven performance

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Generic Starting Points

Use of orthogonality increases confidence

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Phase of Validation and Method Utilization

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First Formal Validation Exercise

•

Timing – prior to first in human testing

• Needs documenting (validation protocol?) (pre-approved?)

• Method Development has provided specificity & resolution

•

Additional parameters for an HPLC method

• Solution (analyte) stability (48hr)

• Linearity – 6 solutions/levels (consider automating this through volume variation)

• System Precision – repeated injections

• For Impurities method - Limit of Quantification • check that your 0.05% standard is detectable • System Suitability

• Should reflect method purpose, development & validation data

May be performed using an automated approach - “Autovalidation” utilising robotic capabilities of instrumentation

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Repeat validation Exercise

• During Development re-validation may occur for a variety of reasons ● New Route/synthetic process ● Polymorph ● Raw Material suppliers ● Changes in Formulation and/or packaging • Revalidation may only need to be partial and should be covered by a validation protocol which rationalises which tests need to be repeated

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Phase of Validation and Method Utilization

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Validation Prior to Registration Studies

• Validation of methodology should be essentially complete to ICH standards prior to registration (ICH/VICH) studies

• One exception may be intermediate precision if the studies are being done in- house

• These studies represent a high business cost for your company

• Both in terms of up-front cost and critical path timing

• Jeopardising these because of faulty methodology must be avoided at all costs

•

Expect to repeat tests to higher standards

• e.g. perform spiking experiments to assess accuracy

• Ensure that the validation actually supports what you will claim

• Ensure that your linearity range incorporates all quoted results (e.g. DL to 2 x specification level for impurities)

• Ensure that accuracy/precision support the specification limit and LOQ

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Method Validation Complete - File

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Method Validation Complete - File

• Final regulatory reports written • Documentation appropriate for pre-approval inspection ● All Validation protocols completed & signed off • If not completed earlier, consider final validation testing ● Intermediate precision ● Consider regional requirements

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The Validation Process

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Drug Substance Assay

Consider the following validation experiments

•

Specificity

•

Precision

•

Repeatability

•

Intermediate precision

•

Solution stability •

May be considered part of robustness testing but needs consideration earlier than the rest of the robustness test

•

Linearity

•

Accuracy, range

Robustness: May be considered part of method development

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Drug Substance Assay Specificity

• “Ability to assess unequivocally the analyte in the presence of components which may be expected to be present”

•

Dependant on method application

• May require a combination of two or more methods

• Retention time recording of structurally related impurities, degradation products etc recorded during method development • Peak homogeneity can be carried out during stress testing studies using either (simply) LC- DAD and/or LC-MS or multiple methods

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Drug Substance Assay Linearity

• “The linearity of the analytical method is its ability (within a given range) to obtain test results which are directly proportional to the concentration (amount) of analyte in the sample” • For a drug substance assay • ICH recommends 5 concentrations minimum over the range 80-120% • Pre approval protocol should carry requirements for correlation coefficient and y intercept • Can handle intercept statistically – or empirically • Analysis of residuals can prove helpful

Question: Is linearity important?

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Drug Substance Assay Linearity

r = 0.9999

Residuals Plot

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Drug Substance Assay Accuracy

•

“Expresses the closeness of agreement between the value which is accepted either as a conventional true value or an accepted reference

Accuracy normally needs to be inferred from other tests • There is normally no absolute method (titration may be the closest) • Infer from:

value and the value found… sometimes termed trueness”

• Recovery data, absence of bias as demonstrated by linearity and mass balance if possible

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Drug Substance Assay Precision

Repeatability

● “The precision under the same operating conditions over a short interval of time”

● Intra-assay precision – may be assessed with 9 determinations (3 concentrations/3 replicates each), or a minimum of 6 determinations at 100% test concentration

Intermediate Precision

● “Expresses within-laboratories variations: different days, different equipment, etc.”

Reproducibility

● “Expressed the precision between laboratories”

● Not needed for marketing authorization dossiers

● Elements of repeatability are covered during transfer of methods between research and manufacturing sites and also through transfer to Contract Research Organisations

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Drug Substance Assay Intermediate Precision

• “The applicant should establish the effects of random events on the precision….Typical variations….include days, analysts, equipment…” (Q2(R1) wording).

• Historically, a simple matrix of method

determination by two different analysts on three days using three different pieces of equipment has appeared globally acceptable.

But …Japan….?

•

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Drug Substance Assay Intermediate Precision

•

PMDEC presentation • annual meeting of the Pharmaceutical Society of Japan March 28/30 2001 • “An evaluation based on the result obtained under two test conditions, where none of the variation factors are identical in both conditions, is not appropriate. The number of test conditions should be set as at least 6”

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Drug Substance Assay Intermediate Precision

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Accuracy versus Precision

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Drug Substance Assay Range

• “The interval between the upper and lower concentration (amounts) of analyte in the sample (including these concentrations) for which it has been demonstrated that the method has a suitable level of precision, accuracy and linearity • Normally derived from linearity study and application of the method • Minimum 80 – 120% of nominal theoretical value • Should cover the range of expected results e.g. for impurities DL to 2 x specification level

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Drug Substance Assay Robustness •

“measure of its capacity to remain unaffected by small, but deliberate variations in method parameters and provides an indication of reliability during normal usage” e.g (ICH) • e.g. for chromatographic methods: pH, temperature, columns and supplier, mobile phase composition • Univariate or multivariate approach. • Univariate approach is conceptually simple and often quicker – has been acceptable by regulators historically. • Multivariate – should provide more information. Perception that this may be slower but correct design can lead to understanding of interactions between parameters. Commercial software readily available to help guide design. • Both methods useful for estimating reliability (and transferability) and also for assessing system suitability parameters (in conjunction with data through routine use).

Questions:

• Is an understanding of Robustness more important than an understanding of Ruggedness?

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• Implications of QbD for Analytical Methods?

Examples Outputs from Robustness Testing

Increasing Flow Rate

Increasing Buffer Concentration

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System Suitability

Tests employed in the routine use a method that assures that the method is performing, or will perform, as expected and within its validated parameters HPLC example ● Reproducibility – 6 injections of a standard, RSD < 1% ● Resolution between closest eluting components ● Tailing factor

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Drug Substance Impurities Organic Impurities by HPLC

• Validation suite very similar to main band assay • Limit of detection, limit of quantitation need consideration • The range of the linearity experiment needs careful consideration. • How do main band and impurities linearities interact (method design)? • RRFs for individual impurities?

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• Various experimental methods • Two common methods 1. Drug Substance Impurities Organic Impurities by HPLC

LOQ is level where replicate injections of analyte have an RSD of less than 10%. 2. LOQ level where S/N ratio = 10:1 But need to consider regional requirements / interpretation • The LOQ needs to be below the reporting threshold for the impurity as given by ICH Q3A(R2) (0.05% for  2g/day drug) • For LOD – follow method 2 above but with 3:1 being a suitable S/N ratio

Question: Is LOD relevant if routinely measuring LOQ?

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LOD / LOQ for Impurities

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Drug Substance Impurities Consideration of Linear Range

A suitable Linear Range should be validated which will be suitable throughout the development and (at least some of) the commercial lifecycle of the drug substance

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Drug Substance Impurities Other Impurities

Some separative techniques for impurities can be treated with very similar validation approaches (e.g. GC, IC, CE) ● Limit tests require less validation parameters to be validated (see ICH Q2 (R1)) ● Trace Analysis may need validation or verification ‘in use’ ● Others (e.g. Water ) need some adaptation

– To show lack of side reactions/interference – Optimise extraction and titration conditions

Currently under discussion: ICH Q2(R2)/Q12 – to include spectroscopic and spectrometric data/techniques

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Pharmacopoeial Methods and Validation

• Assumed to be validated • Official reference methods • Additional validation potentially required to demonstrate applicability to your product • Alternative methods allowable if equivalence (or superiority) shown

• Better sensitivity, selectivity • How is equivalence shown?

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The Future

• Regulatory Guidelines do change/evolve. • Experimental Design becoming more important / Reporting Criteria changing and using more statistics • Focus on genotoxic impurities • Process Assessment Technology (PAT) • Automation / robotics will play an increasing role in experimentation • Intelligent validation software is beginning to appear • Reporting standards and information gained from the validation exercise should continue to be enhanced • QbD for Analytical Methods (AQbD) gaining increasing traction

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The Future AQbD?

• Science and risk based approach • Development of analytical methodologies in a systematic manner against pre-defined criteria • Gain deeper understanding of measurement systems • More robust and efficient process and product control strategies. • Improve reliability of the method by understanding, reducing and controlling sources of variability • Provide greater assurance that quality attributes of the drug substance, drug product or in-process materials can be reliably and reproducibly assessed. • Facilitates continuous improvement of methods throughout product lifecycle. • Provide opportunities for regulatory flexibility

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Analytical QbD Elements

Definition of ATP Define characteristics of measurement system which will ensure accurate assessment of quality attributes over product lifecycle

Method Design Measurement technique selection and initial method development experiments to define knowledge space

Risk Assessment Identification of method parameters and assessment of their impact on method performance

Method Evaluation Assessment of experimental results and impact of method parameters on method performance. Define and verify Method Operable Design Region. Define and validate Normal Operating Conditions.

Definition of Method Control Strategy Establish critical method parameters. Define system suitability test to evaluate critical method attributes

Lifecycle Management Plan Define post approval management plan

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Elements

QbD for Analytical Methods

QbD

Operational Excellence

Product profile

Define

Definition of ATP

CQAs

Measure

Method Design

Risk assessment

Analyse

Risk Assessment

Method Evaluation

Design space

Improve / Implement

Control strategy

Definition of Method Control Strategy

Control

Continual Improvement

Lifecycle Management Plan

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Method Operable Design Region

Method Operable Design Region (MODR) can be described in a number of ways e.g

Table of Ranges

Picture/Plot

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In this presentation we covered

● Method Types and Stages of Development and Validation ● The Validation Process ● Validation Parameters – Drug Substance Assay – Drug Substance Impurities – Other Impurities – Pharmacopeial Methods ● The Future – AQbD

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QUESTION?

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Recommended references

ICH Q2(R1)

https://database.ich.org/sites/default/files/Q2_R1__Guideline.pdf

ICH Q3A (R2)

https://database.ich.org/sites/default/files/Q3A_R2__Guideline.pdf

ICH Q3B (R2)

https://database.ich.org/sites/default/files/Q3B_R2__Guideline.pdf

ICH Q3C (R6)

https://database.ich.org/sites/default/files/Q3C- R6_Guideline_ErrorCorrection_2019_0410_0.pdf

ICH Q3D (R1)

https://database.ich.org/sites/default/files/Q3D- R1EWG_Document_Step4_Guideline_2019_0322.pdf

ICH Q6A

https://database.ich.org/sites/default/files/Q6A_Guideline.pdf

ICH Q6B

https://database.ich.org/sites/default/files/Q6B_Guideline.pdf

FDA Analytical Procedures and Methods Validation for Drugs and Biologics GfI

https://www.fda.gov/regulatory-information/search-fda-guidance- documents/analytical-procedures-and-methods-validation-drugs-and- biologics https://www.fda.gov/regulatory-information/search-fda-guidance- documents/reviewer-guidance-validation-chromatographic-methods

FDA Reviewers Guidance – Validation of Chromatographic Methods

Harmonized guidelines for single-laboratory validation of methods of analysis (IUPAC Technical Report)

http://publications.iupac.org/pac/2002/pdf/7405x0835.pdf

ICH Q8 (R2)

https://database.ich.org/sites/default/files/Q8_R2_Guideline.pdf

Implications and Opportunities of Applying QbD Principles to Analytical Measurements

https://www.researchgate.net/publication/282481497_Implications_and_ opportunities_of_applying_QbD_principles_to_analytical_measurements

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Setting Specifications

Craig Donnelly, Director, Regulatory Affairs, CMC and Regulatory Affairs, International, ICON Strategic Regulatory and Safety

05 December 2019

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In this presentation we will cover

Dossier requirements and specification definitions

● ICH Q6A

Adjusting Specifications during development

● Staged Risk

Justification of Specifications

● How do we do this?

How does Real Time Release affect the control strategy

Comparison of RTRt with Traditional Specification / Control Strategy

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What is a specification?

• A list of tests, references to analytical procedures, and appropriate acceptance criteria, which are numerical limits, ranges, or other criteria for the tests described • It establishes the set of criteria to which a drug substance or drug product should conform to be considered acceptable for its intended use. • "Conformance to specifications" means that the drug substance and / or drug product, when tested according to the listed analytical procedures, will meet the listed acceptance criteria.

ICH Topic Q6A – Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances

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What is a specification? For Example :

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What is a specification

Quality standards that are proposed and justified by the manufacturer and approved by regulatory authorities as conditions of approval. Specifications are one part of a total control strategy for the drug substance and drug product designed to ensure product quality and consistency. Other parts of the control strategy, importantly are: ● Critical controls on in-going materials ● Critical process parameters (CPP) ● Critical starting material / intermediate attributes

ICH Topic Q6A – Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances

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When are specifications set or updated?

First Specification set prior to use for first administration to humans Relevance of specification is checked regularly throughout development ● May revise an acceptance criterion or add an attribute to an existing specification when required – By new information – By Regulatory feedback – When compound transitions from one phase (clinical or development) into another – e.g. from Phase 2 to Phase 3 – e.g. from R&D to registration New specification may be set when significant change made to synthetic process or drug product

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How are specifications set

Considering the safety of volunteers and patients

Tests and Acceptance Criteria set considering: ● Pre-clinical safety (Tox) data [Impurities] ● Bioavailability data [Pharmacokinetics, Dissolution, Particle Size] ● Stability data ● Other information (e.g. clinical info, process understanding, design space, statistics) Considering the principles in guidance: ● ICH (Q6A [Q6B], Q3A, Q3B, Q3C, Q3D) [Q5A, Q5B, Q5C, Q5D, Q5E] ● Internal guidances ● Guidance for Industry (e.g. Biowaiver guidance)

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How are acceptance criteria set?

Considering Staged Risk

Threshold

Exploratory Dev

Full Dev

Reporting

0.05%

ICH

Identification

0.10%

ICH

Phases 1 and 2

Phase 3

Qualification

DS 0.5%

DP 0.5%

ICH

Identified*

Unidentified

0.2% 0.2%

* Provided no structural alert (e.g. for GenTox)

Impurities acceptance criteria >0.5% only if agreed qualified by Safety Sciences

In early Phases: if study duration is sufficiently long, default to Full Development controls

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ICH Threshold

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Tests and Acceptance Criteria - Principles

Safety of volunteers and patients is paramount

Tests based on general Regulatory Requirements and Expectations (ICH) and Scientific Rationale Impurities ● Follow ICH Q3 principles for qualification / identification / reporting ● Appropriately tailored (thresholds) for phase of development / duration of study – Acceptance criteria ≤ qualified level

– Level of analytical rigour will increase with time – Reporting thresholds aim at ICH in all phases

ICH (Q6A/B and pharmacopoeias provide guidance on expected attributes

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How do we set acceptance criteria? For Example: Specified Impurities

• The presence of impurities in compound x capsules can be attributed to three potential sources:

1. Drug substance impurities introduced with the ingoing drug substance,

2. Degradation products produced during manufacture of the drug product and

3. Degradation products formed during storage of the drug product.

•

(1) Controlled by API specification

• (2) and (3) Controlled by use of a specific HPLC method and the DP Specification

•

Consistent with ICH

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How do we set acceptance criteria? For Example: Specified Impurities

The acceptance criterion for UK-123,456 has been established as 0.7% maximum . This acceptance criterion was based on the following considerations: ● UK-123,456 is a potential process related impurity in drug substance. It is controlled by the drug substance specification to 0.4%. ● UK-123,456 does not form during manufacture of the drug product. ● UK-123,456 is qualified to 1.0% ● UK-123,456 is also a potential degradation product of the drug product and has been observed in stress testing studies on the drug substance. Minor changes in the level of UK-123,456 have been observed during drug product stability studies to date. – Accelerated stability studies using high temperature and humidity and quantified using a modified Arrhenius equation (ASAP) show acceptable shelf life at the acceptance criterion of 0.7%

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How do we set acceptance criteria? For Example: Drug Product Performance

Compound x is a BCS Class 1 compound ● High solubility a across physiological pH range ● Immediate Release Hard Gelatin Capsule (wet granulation) ● Rapidly Dissolving (>85% Dissolution in 15 minutes) – pH independent release

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How do we set acceptance criteria?

For Example: Drug Product Performance

Dissolution performed in pH 6.8 Phosphate Buffer on stability – no changes on storage

Disintegration performed on stability – rapid disintegration with no change on storage

Specification set to control Disintegration time in lieu of dissolution

● Possible when certain prerequisites are met – high solubility, high permeability and rapid dissolution – link between dissolution and disintegration

Even when these prerequisites are not met it may still be possible to not perform dissolution routinely …

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• Clinical formulation dry granules in capsules • Commercial formulation wet granulated in capsule • T max 6 hours, T ½ 14 – 16 hours • Proposed approach to Performance BA/BE Strategy • Understand the effect of storage on dissolution performance • Understand effect of DP release (In-vitro dissolution) on In-vivo performance • Leads to demonstration of satisfactory In-vivo performance of a wide range of dissolution profiles • These effects can be modelled using commercially available software • In the scenario above it was predicted that dissolution curves with 80% release in 6 hours would have no effect on BE Performance Testing: Scenario

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