Module 3 Presentations

Module 3: Regulatory Requirements for a New Active Substance: Quality

Date: 15 th – 17 th May 2024

Module: 3 of the TOPRA MSc Data Management and Digitalisation in Regulatory Affairs

Module Leader: Christian Maasch

©The Organisation for Professionals in Regulatory Affairs 2023 Presentations are supplied to delegates for their personal reference and are the copyright of the speaker and The Organisation for Professionals in Regulatory Affairs. The presentations must not be copied, stored in a retrieval system or transmitted in any form without prior permission from TOPRA. Agreement must be reached with TOPRA before any part of this material is reproduced, abstracted, stored in a retrieval system or transmitted in any form by any means – that is, electronic, mechanical, photocopying, recording or otherwise.

Module 3: Regulatory Requirements for a New Active Substance: Quality 15th May – 17th May 2024,

13TOPRA Office, 6 th Floor, 3 Harbour Exchange, London, E 14 9GE, UK

Module Leader(s) : Christian Maasch

Date: Wednesday 15 th May

Time

Activity

Speaker

13.00

Registration

13.15 – 13.30

Welcome & Introduction to Module 3

Christian Maasch Takeda

Management in Regulatory Affairs

Lecture 1: CMC in the Drug Development Programme

13.30 – 14.30

Mike James Cambridge Regulatory

Refreshment Break

14.30 - 15.00

15.00 – 16.00

Lecture 2: API Manufacture and In-Process Controls

Mike James Cambridge Regulatory

16.00 – 17.00

Lecture 3: Nomenclature and Characterisation of the Active Ingredient

Christian Maasch Takeda

17.00 – 18.00

Lecture 4: CMC Project Management

Christian Maasch Takeda

Module 3: Regulatory Requirements for a New Active Substance: Quality 15th May – 17th May 2024,

Date : Thursday 16 th May

Time

Activity

Speaker

09.00 – 10.00

Lecture 5: Analytical Methods and Validation

Jorge Colmenares Procter & Gamble UK

10.00 – 10.30

Refreshment Break

10.30 – 11.30

Lecture 6: Developing Specifications for the Active Ingredient

Christian Maasch Takeda

11.30 – 12.30

Lecture 7: Pharmaceutical Development and Manufacture of the Drug Product

Torsten Kneuss Bayer

12.30 – 13.30

LUNCH

13.30 – 15.30

Case Study 1 with discussions and presentations

Christian Maasch Takeda

Refreshment Break

15.30 – 16.00

16.00 – 17.00

Lecture 8: Stability of the Drug product

Torsten Kneuss Bayer

Module 3: Regulatory Requirements for a New Active Substance: Quality 15th May – 17th May 2024,

Date: Friday 17 th May

09.00 – 10.00

Lecture 9: Pharmaceutical Packaging

Torsten Kneuss Bayer

10.00 – 10.30

Refreshment break

10.30 – 12.00

Case Study 2 (Packaging) Torsten Kneuss Bayer

12.00 – 13.00

Lecture 10: Good Manufacturing Practice – Clinical Supply

Fiona Routley AstraZeneca

LUNCH

13.00 – 13.30

13.30 – 14.30

Lecture 11: Regulatory Agency Perspective

Anargyros Foivas MHRA

14.30 -15.00

Closing

14/05/2024

Importance of CMC in the Drug Development Process

Dr Mike James Cambridge Regulatory Services mikejames@cambreg.co.uk

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Learning Objectives

 To understand where the CMC development process fits into the overall development of a medicine  Briefly illustrate data needs and timelines  Highlight some problems encountered

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The Importance of CMC  Even if you have the best drug in the world it could (will?) fail from: o Market supply constrained by manufacturing problems (DS and/or DP) o Lack of stable RT formulation (>18 months shelf-life preferred by wholesalers) o Wrong dosage form (not liked by patients) o Competition from similar but cheaper products  CMC needs to look at the long-term not only getting product to market but keeping it there

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Reimbursement Issues  Drug budget under increasing pressure

o Formularies prohibit availability of all drugs in the same class o ‘Value for Money’ (NICE etc) assessments prevent or limit use of perceived expensive new drugs or ‘me too’ products  Orkambi (ivacaftor + lumacaftor) for F508del Cystic

Fibrosis treatment (~ 4,000 UK patients) o US price £207,000 ($272,000) per patient year

o Initial UK price £105,000 per patient year rejected by NHS o Confidential commercial deal struck to allow NHS use (could be as low as £20,000 per patient year to match generic from Argentina)

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Regulator’s and Company Interests

 Quality  Safety  Efficacy

Needed to apply for MA/NDA/BLA

 Regulators want safe and efficacious products on the market but not at any cost to patient health  Companies need to be realistic about new drugs and kill projects early

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Typical Timeline and Cost for Medicine Development

CMC Development

Post approval changes: • New formulation(s)

• Improved DS synthesis • New indications etc

From ABPI November 2019 6

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Product Development Needs

Desirable Characteristics  Simple DS synthesis from

Undesirable Characteristics  Complex synthesis using expensive reagents and/or difficult reactions (= costly)  Constrained manufacture reliant on sub-contractors or difficult to scale reactions (eg highly exothermic or explosive). GMP concerns?  Cold Chain (or worse frozen) storage and distribution unless critical (vaccines etc)

readily available compounds and ‘easy’ reactions; simple DP formulation and packaging

 Scalable with ease (both DS and DP) to cope with market demand (no out of stock situations)  Stable at ambient temperatures for oral dosage forms

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Aims of CMC Development

 Ultimately to develop a product that is: o Stable (shelf-life > 24 months for oral; > 12-18 months for injectable biologicals) o Reproducible batch to batch (DS and DP) o Easily scalable if market demands (DS and DP) o Made by well-understood and well-controlled processes (DS and DP) o Is economic to manufacture to control cost of goods and hence reimbursement price

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Plan for the Market Early

 CMC development takes time and planning: o DS synthesis and DP formulation for early trials unlikely to be market products  Involve all necessary disciplines as soon as a potential market candidate is identified: o Chemical development for feasible synthetic routes o Formulation development and marketing for desired commercial image that can be made at scale o Clinical for desired pharmacokinetics

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How to Achieve these Aims?  Learn from everything done in the past o Build on knowledge from Phase I, II, III etc and similar products from your company o No one person is the fount of all knowledge – take advice whenever needed (project team work and cross project team experience sharing) o Simplicity is always best – don’t add unneeded complexity such

as modified release tablets unless critical o Don’t be afraid to stop and start again • Problems will occur for unexpected/unknown reasons • Time and money spent on problem solving may not be a good investment • Projects die for more than safety/lack of efficacy reasons

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Know Your Target Market - 1

 Always look to the market for formulation needs: o Frozen liquid stored at ≤ -20 °C acceptable for Phase I trials • Not good for commercial distribution in the market o Administration by patient or health care provider? • Prefilled syringe (with auto-injector?) good for patients • Vial of liquid or powder + solvent may be preferred where HCP can claim preparation/administration fee

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Know Your Target Market - 2

 Oral dosage forms (eg for children or the elderly)

 Size 000: 26 x 13 mm Size 5: 11 x 6 mm

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Know Your Target Market - 3  Choice of materials and religious/cultural acceptability (e.g. pork products and Muslims)  Look at the competition! o May not be sensible to develop a lyophile in a vial if the competition is a liquid in a pre-filled syringe & autoinjector for patient administration o Large tablets/capsules and/or many per day for the correct dose are not patient friendly  Ignore specific dosage forms for children at your peril

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Data Development

 Candidate Selection  What do you need to know about the molecule besides pharmacology? o Can it be synthesised economically on a commercial scale? Choice of route for purity and yield. o Cell line and product yield? Scalable for market? o Purity and impurities (metals, genotoxic compounds especially) unchanged on scale up? o Stability o Physical Properties for formulation for humans

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Why Choice of Route is Important - 1

 Linear Route A  B  C  D  E  F  G  H  Convergent Route P  Q  R  G  H X  Y  Z   Best to investigate routes and decide on the desired industrial process early to maximise options for starting material choices (and need for GMP!)

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Why Choice of Route is Important - 2

Linear Route  Low yield of API (90% step yield over 7 steps is 48% overall)  Maximum manipulation of increasingly complex (and costly) molecules

Convergent Route  Higher yield of API (90% step yield over 6 steps is 65% overall)  Reduces manipulation of complex molecules since Q and Y could still be relatively simple  Q and Y could be

 Where is the RSM

(could be A with GMP cost implications)?

possible RSMs with reduced GMP costs

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Final Route Selection - 1  Synthetic route almost always changes during development, for example to o Improve step or overall yield o Increase purity of DS o Remove toxic reactants or reagents and limit genotoxic impurity formation o Control commercial cost: • EtOAc 99.5% = £79.65 for 2.5 L • EtOAc 99% = £68.60 for 2.5 L (more extensively tested) • EtOAC 99% = £46.40 for 2.5 L (lab reagent grade)

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Final Route Selection - 2  Usually multiple routes to the API

o Not all are industrially feasible (cost, difficulty, safety) o Prefer convergent synthesis for yield (cost) reasons o Patent infringement issues  Choice is dictated by inter alia o Starting materials (availability, cost, purity, GMP status) o Reagents (availability, cost, purity, safety) o Plant capabilities and availability – general or specialist (eg high pressure hydrogenation may be contracted out)  Cost of API affects cost of goods and hence profit margin and possibly reimbursement price

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Formulation Considerations  Excipient compatibility (chemical) o Change of polymorphic form on compression?  Dosage form: oral, parenteral, topical? o Simple tablet or sustained release? o Injection, infusion or concentrate?  Stability  Who will manufacture commercial batches? o In-house or contractor? o What do they need to know? o Location? 19

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Preclinical Studies  Need for drug substance (and a delivery system!)  ‘Relatively Dirty Batches’ needed to qualify impurity levels (ICH norms)  Can require lots of drug especially for long term studies so stability data needed  Long term studies (6m toxicity & carcinogenicity) ideally done on commercial route drug substance (should avoid surprise impurities late on)

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A Question on Drug Purity

 Batch A Potency 99.9 area % Individual related

 Batch B Potency 97.5 area % Individual related substances

substances < 0.05 area % each Total related substances < 0.05 area % 1 0.8 area % 2 1.5 area % 3 0.5 area % Others 0.1 – 0.3 area % Batch B gives better exposure to potential impurities - qualification

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Phase I Clinical Studies

 Limited quantities of drug needed  Synthesis cost (£ per gram) is a relatively minor consideration o More important to get supplies for clinic to make go/no-go decision o Probably will not use commercial synthesis  Simple formulation(s) and small batch sizes o Drug substance in capsule o Isotonic aqueous solution for injection

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Phase II and Phase III Studies

 Bigger quantities of drug needed  Phase II

o Begin to develop commercial route o Detailed characterisation of impurities o Consider reserve route (just in case) o Optimisation and scale up studies run concurrently

 Phase III studies best done with commercial route (and scale if possible) drug substance

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For the Market

 Larger quantities of drug substance and drug product needed so should have: o A product that will sell (not over priced!) o Established controlled and audited supply chain for all components and all markets o Well understood and well controlled processes o Reproducible product from batch to batch with known stability characteristics

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What could possibly go wrong?

The need to fully understand your DS and DP processes

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Changing DS Particle Size Distribution  Digoxin from the white foxglove digitalis lanata or purple foxglove digitalis purpurea – cardiac glycoside used to control atrial fibrillation, atrial flutter and heart failure  Narrow therapeutic index o Therapeutic plasma levels ~ 1 – 2 ng/ml o Toxic plasma levels > 2 ng/ml  In mid 1970s Lanoxin (UK brand leader) manufactured with reduced particle size drug sold – patients experienced toxicity due to more rapid dissolution and greater bioavailability compared to old formulation (pre 1972)

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14/05/2024

Impurities in APIs - Heparin  2008 Heparin Contamination lead to serious injuries (785) and deaths in USA (at least 81)  Chinese DS source sold by Scientific Protein Labs to Baxter USA intentionally contaminated with much cheaper over-sulphated chondroitin sulphate o Shortage of pigs for heparin production o Mimics heparin in vitro properties so was hard to see with monograph tests of the day o Only identified by chromatography after the event

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Heparin -2

 Illustrates need for MA holder to fully control API source (ICH Q7)  Manufacturers recalled many products containing heparin from China (gave anaphylactoid reactions)  Modified USP and Ph Eur monographs to add specific NMR and electrophoresis testing to control this impurity

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The Wrong Formulation - Osmosin  Osmosin was an osmotically driven sustained release formulation of indomethacin designed to reduce GI effects of the drug  Withdrawn within 9 months of marketing: o Indomethacin highly gastric irritant o Osmotic core contained KCl (known to induce gastric ulcers in high localised concentrations) o Semi-permeable membrane became ‘sticky’ in GI fluid o Tablet adhered to GI wall and drilled holes in wall when hole was in direct contact o Excess reports of GI perforation and death (>7 patients in UK)

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Ignore Polymorphism at Your Peril - 1!  An example from the literature – Ritonavir (Norvir, Abbott, HIV protease inhibitor)  Initially sold as hard capsule with semi-solid solution of drug, approved in August 1996  >240 lots made before May – June 1998  Then DISASTER a second (Form II, thermodynamically more stable) polymorph suddenly appeared: o Form II 50 % lower intrinsic solubility than Form I o Failed dissolution release testing o Reduced bioavailability o Product withdrawn from market (>$ 250 M lost sales)

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Ignore Polymorphism at Your Peril - 2!  The solution: o Much work and money spent o New interim soft gel formulation (refrigerated storage for bulks, not patients) to keep Form II in solution o New filings made January 1999 o Approved in US June 1999 and EU November 1999  Tablets (room temperature storage) not approved until 2009 (EU) or 2010 (USA)

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Conclusions  CMC is not the poor relation in medicines development and cannot be left to last  CMC data needs change constantly throughout development and during product life cycle  In the long term well understood and reproducible quality is the best protection against product quality failure or supply issues in the market But it is not infallible

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A Closing Thought

“ There are many mysteries of nature that we have not solved. Hurricanes, for example, continue to occur and often cause massive devastation. Meteorologists can not predict months in advance when and with what velocity a hurricane will strike a specific community. Polymorphism is a parallel phenomenon. We know that it will probably happen. But not why or when. Unfortunately, there is nothing that we can do today to prevent a hurricane from striking any community or polymorphism from striking any drug. ”

Dr. Eugene Sun MD, Antivirals Ventures Head, Abbott Laboratories, 1998

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API MANUFACTURE AND IN-PROCESS CONTROLS: Section 3.2.S.2 Dr Mike James Cambridge Regulatory Services mikejames@cambreg.co.uk

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Learning Objectives

 What to put in the subsections of 3.2.S.2 Manufacture of Drug Substance  Considerations for choice of Regulatory Starting Materials  Critical Quality Attributes and Control of Process Description  Changes to synthetic route and need to relate them to commercial route in 3.2.S.2.2

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Section 3.2.S.2 Parts

 2.1 Manufacturers  2.2 Description of Manufacturing Process and Process Controls  2.3 Control of Materials  2.4 Control of Critical Steps and Intermediates  2.5 Process Validation and/or Evaluation Studies  2.6 Manufacturing Process Development

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Section 3.2.S.2.2  This is where the commercial GMP route using the chosen RSM(s) is described including: o Synthetic route as diagram (overall and steps as necessary) with text description of conditions etc o Scale of each step (quantities of reactants, reagents catalysts etc) as ratios or absolute amounts o Typical step yields (ranges) o In process controls and acceptance criteria (Table with full details in 3.2.S.2.4) o Reprocessing criteria and methods

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Why are you asked for lots of details in 3.2.S.2.2?

 Regulators need to know that you understand your route and its limitations (Proven Acceptable Ranges, PAR):

 At ~ 80°C α-form predominates (kinetic)  At ~ 160°C β-form is major product (thermodynamic)  As temperature rises β predominates but how much above80 ° C is acceptable for α of acceptable purity?

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3.2.S.2.3 Control of Materials: Specification Setting

 Considerations apply equally to RSM and isolated intermediates (intermediate specification in 3.2.S.2.4)  Only key criteria are controlled for early use compounds: o Assay (‘potency’) o Purity (organic, inorganic, catalysts)  More testing and/or tighter limits usually apply to key intermediates or nearer to the final API  RSM and key intermediates need validated assay methods  Aim is for impurities from RSM to be ≤ 0.1% in API by control of key impurities in RSM and intermediates

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Starting Materials

 Need to robust scientific argument to define regulatory starting materials (RSM) to know where GMP controls begin o Scientific advice is critical to avoid nasty surprises  No clear definition from authorities but ICH provides some help (next slide) and choice is a balance of perceived added quality against certain increased costs (staff, plant, testing, GMP)  Note that EU and US views on same synthesis may define different RSM compounds

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Starting Material: ICH Q11 Definition  An “Active Substance Starting Material” is a raw material, intermediate, or an active substance that is used in the production of an active substance and that is incorporated as a significant structural fragment into the structure of the active substance. An Active Substance Starting Material can be an article of commerce, a material purchased from one or more suppliers under contract or commercial agreement, or produced in-house . Active Substance Starting Materials normally have defined chemical properties and structure .

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Unsuitable Starting Materials  Mixtures  Non-isolated intermediates  Compounds that undergo few changes to make final DS: o ‘Base’ + HCl ‘Base.HCl’ (drug substance) o ‘Base’ is not a suitable starting material because of lack of GMP controls on manufacture of ‘Base’  Rule of thumb for EU is to have at least 3 isolated intermediates before DS in section 3.2.S.2.2 9

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Justification for RSM Choice

 Ability of analytical procedures to detect impurities in the starting material.  Fate and purge of those impurities and their derivatives in subsequent processing steps.  How the proposed specification for each starting material will contribute to the control strategy.  Generally need not justify the use of a commercially available chemical. A commercially available chemical is usually one that is sold as a commodity in a pre-existing, non pharmaceutical market in addition to its proposed use as an RSM.  Chemicals produced by custom syntheses are not considered to be commercially available . If a chemical from a custom synthesis is proposed as a starting material, it should be justified in accordance with the general principles for the selection of starting materials.  If additional purification steps by the drug substance manufacturer are needed to ensure the consistent quality of a commercially available starting material the additional purification steps should be included as part of the description of the drug substance manufacturing process. Specifications should normally be provided for both incoming and purified starting material (in section 3.2.S.2.3).

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Desirable Properties of an RSM

 Simple structure:

o Fewer isomers or analogues o Easier to characterise o Discriminating methods easier to develop for routine use  Stable with characterised purity profile that can

be easily defined and understood: o Purity per se may not be important o Knowing fate of impurities is critical

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Where to choose the RSM?

 Consider the early steps of this hypothetical synthesis:

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1,3-Dichlorobenzene – Simple RSM

• Simple materials are often cheap and can be readily purified • Specification limits are relatively easy to set

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A More Complex RSM - 1

 If all

isomers/impurities from simple RSM react

 Complexity = HPLC assay  More controls on

impurity limits needed

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A More Complex RSM - 2

 Possible process related impurities

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Impurities in the RSM  Reactions can be specific (single product from pure starting material) A  B  However if A contains impurities A' and A'' that also react then A + A' + A''  B + B' + B''  C + C' + C'' etc  For impurities in RSM that do not react A+ X + Y  B + (X + Y) [X+Y removed by purification here or later step]  Need ways of controlling unwanted products

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A Disaster in the Making?  Is it highly desirable to have pure starting materials and specific transformations? Maybe but help is at hand to increase or control purity: o Solid intermediates can be recrystallised o Liquids can be distilled o A detailed knowledge and understanding of the synthesis can identify early-stage impurities that will not participate in the downstream process and can thus be discounted (removed by some means)

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3.2.S.2.4 Control of Critical Steps and Intermediates - 1  What are ‘critical steps’ in the synthesis?  Critical Quality Attributes (CQAs) are DS and DP properties that could affect clinical safety and efficacy: o A physical, chemical, biological or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality (ICH Q8(R2) ANNEX)  Critical steps are those steps that can affect the DS/DP CQAs  Need to have CQAs identified and justified in dossier comes from ICH Q7: Validation: Defining the API in terms of its critical product attributes  ICHQ8(R2): At a minimum, those aspects of drug substances [...] that are critical to product quality should be determined and control strategies justified  ICH Q11: Manufacturing process development should include, at a minimum, the following elements: Identifying potential CQAs associated with the drug substance [...]  FDA MaPP Applying ICH Q8, Q9, Q10 Principles to CMC Review: Applications should include the following minimal element [...]: - Critical Quality Attributes (CQAs) of the drug product - CQAs of the drug substance and excipients 18

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3.2.S.2.4 Control of Critical Steps and Intermediates - 2  Risk based approach to identifying CQAs and hence critical steps, for example: o Reaction conditions on impurity formation o Crystallisation conditions on solid state form  Criticality Score = Impact x Uncertainty o Impact (safety/efficacy effects): Very High (20), High (16), Moderate (12), Low (4), Very Low (2) o Uncertainty (occurrence likelihood): Very High (7), High (5), Moderate (3), Low (2), Very Low (1) o Range 2 – 140; define threshold for CQA eg ≥100

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Identify CQAs by Risk Assessment

Criticality Score

Impact

Uncertainty

Quantitative measure for an attribute‘s impact on safety and efficacy. Using best possible surrogates for clinical safety and efficacy

Known or potential consequences on safety and efficacy, considering: •Biological activity •PK/PD

Relevance of information e.g. •literature •prior knowledge •in vitro •preclinical •clinical •or combination of information

•Immunogenicity •Safety (Toxicity)

Manufacturer‘s accumulated experience, relevant information, data e.g. literature, prior & platform knowledge, preclinical and clinical batches, in vitro studies, structure-function relationships

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3.2.S.2.4 Control of Critical Steps and Intermediates  Critical quality attributes (CQAs) of DS could be: o Purity/potency o Impurity profile (including potentially genotoxic compounds, nitrosamines and metals residues) o Solvation or hydration o Residual solvents and/or water o Solid state form (polymorphism/desired polymorph/solvate)

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Ranges and Controls for Critical Steps

 Normal Operating Range (NOR): o Natural variations that occur without any change being made in set points o NOR is within the PAR but cannot be controlled  Control Range (CR): o Set point ± limits for target setting e.g. desired temperature ± X⁰C  Proven Acceptable Range (PAR): o Upper and lower limits of a parameter (e.g temperature, reaction time etc) that have been shown to have no detrimental effects on quality o State mid-point of PAR as fixed point in dossier

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In-Process Control Tests

 Why?  Where?  What?

An in-process control is a test done whilst the batch is in progress and the start of the next operation is often reliant on a satisfactory result

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Why Test?

 Process control is important for Patient Safety and o Avoidance of failure o Supply security o Plant utilisation – if you reprocess you cannot make new materials in the same plant o Control of costs

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Where to Test?  In the non-CQA world all steps could be tested since the important ones may not be known  Need to balance ‘perceived increased quality from testing’ against cost of: o Plant and laboratory resources o Increased cost of goods (API and product)  By concentrating on CQAs and hence Critical Steps resources are focussed on those aspects known (or suspected) to have the biggest potential impact on safety and efficacy

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What to Test  Range of tests and acceptance criteria must be justified  Typical tests could include o End of reaction (disappearance of reactants, appearance of product, purity of product) o pH, water by KF  End of reaction could be off-line HPLC with all the problems of method development  All tests should do something positive to improve control of the process and not be testing for testing’s sake (to try to look good!)

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Can IPC Testing be Avoided?

 On the whole ‘no’ but Process Analytical Technology (PAT) may replace some traditional IPC testing if technology is available (eg spectroscopy for reaction end point monitoring)  PAT offers the potential to increase quality by o Improved process control by real time monitoring o Reduced testing of intermediates and maybe API  Debate by no means finalised so IPC testing will be with us for years to come

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3.2.S.2.5 Process Validation  In-process testing is not the answer to all control strategies  CHMP/QWP/130/96, 3.2.S.2.5 states

Steps that are identified in 3.2.S.2.4 as critical for the quality of the active substance should be validated, eg o Mixing of multiple components o Control of temperature and pH are critical o Addition of significant structural elements o Final purification step  PV data for chemical DS not normally included in dossier according to ICH Q11(7.1)

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3.2.S.2.6 Manufacturing Process Development  Manufacturing process history and changes linked to purity/impurity profiles for nonclinical/clinical batches (safety)  Choice of RSM (why and why not) from proposed synthetic route o Labelled flow diagrams of synthesis of each RSM  Identification of CQAs and Critical Steps and control strategies  Impurity control strategies

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Summary

 A well understood and well controlled API process saves money and time in the long run  API specifications are easier to develop from a well controlled synthesis  Batch to batch reproducibility (chemical and physical) is enhanced  Should avoid the unexpected happening in late stage development or marketing!

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07/05/2024

Christian Maasch Head of Quality Regulatory Compliance, Change Control Mgmt & Deputy Quality Systems Lecture 3: Nomenclature and Characterisation of the Active Ingredient

Takeda GmbH, Oranienburg, Germany May 15 th ,2024

Disclaimer: Confidential. For internal use only. The opinions expressed in this presentation and on the following slides are solely those of the presenter and not necessarily those of Takeda. Takeda does not guarantee the accuracy or reliability of the information provided herein.”

The Organisation for Professionals in Regulatory Affairs

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Takeda: A Global Biopharmaceutical Company

Nomenclature and Characterisation of the Active Ingredient

The Organisation for Professionals in Regulatory Affairs

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07/05/2024

Takeda – A Research and Development driven Company

At Takeda, we exist to create better health for people and a brighter future for the world. While the science and technology we advance are constantly evolving, our ambition remains. We move science forward, so we can transform more lives.

Nomenclature and Characterisation of the Active Ingredient

The Organisation for Professionals in Regulatory Affairs

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TAKEDA Manufacturing Site in Oranienburg; GER

E2E Commercial Product Market Supply and Clinical Trial Manufacturing

860.5 FTEs

5.6 Bill.

Nomenclature and Characterisation of the Active Ingredient

The Organisation for Professionals in Regulatory Affairs

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07/05/2024

BASICS OF (c)GMP – The 5Ps (+1P)

Nomenclature and Characterisation of the Active Ingredient

The Organisation for Professionals in Regulatory Affairs

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GMP and REGULATORY COMPLIANCE … are indispensably connected

Local site manufacturing and quality operations and Supply Chain

Market and Patient

Regulatory

GMP

Nomenclature and Characterisation of the Active Ingredient

The Organisation for Professionals in Regulatory Affairs

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07/05/2024

RA-CMC Team: An Integrated Approach And Interface Function

 Bridges local Operations/Quality with global Functions and Market Supply  Is the Quality Liaison between Global Regulatory Affairs (GRA), and local GMP Operations to ensure Regulatory Compliance  Enables efficient Communication and Decision-making related to the Quality of our Products (Product Q Oversight)  Addresses market-specific Requirements/Procedures at the local Manufacturing Site  Reduces Risks for Market Supply and Quality Incidents  Supports new Business Cases for new Transfers, Supply chain, and Planning FY23 M1 & 3 Updates Variations 69 302

Dossier Checks

GMP Site renewals 8

MAT and TTs 32

>260

Nomenclature and Characterisation of the Active Ingredient

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Nomenclature and Characterisation of the Active Ingredient

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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  Synthetic route  Key intermediates  Spectroscopic evidence  Crystallography  Elemental analysis  Potential Isomerism  Asymmetric carbons  Other isomers  Physicochemical properties  Solubility  Physical characteristics  Polymorphism  Partition coefficient  Hygroscopicity

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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

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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)

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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

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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

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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?

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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

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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

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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

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Guiding Principles

 Distinctive in sound and spelling  Show group relationship to pharmacologically related  substances (stems)  Not too long  Not confusing with common words  No conflict with trade marks  Not misleading  Not suggestive to patient

 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”





Avoid isolated letters or numbers Harmonised spelling



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Example of Stems

Stem Pharmacologically

Related Group

Example INN cefuroxime (Zinacef) fluconazole (Diflucan)

cef

antibiotics derived from cephalosporanic acid systematic antifungals of the miconazole group

-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) ramipril (Tritace)

-pril, - prilat

angiotensin-converting enzyme inhibitors

-racetam -sartan -vastatin

amide type nootropic agents, piracetam derivatives

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

angiotensin II receptor antagonists antihyperlipidaemic substances, HMG CoA reductase inhibitors

-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)

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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

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Lecture 4: CMC Project Management

Christian Maasch Head of Quality Regulatory Compliance, Change Control Mgmt & Deputy Quality Systems

Takeda GmbH, Oranienburg, Germany May 15 th ,2024

Disclaimer: Confidential. For internal use only. The opinions expressed in this presentation and on the following slides are solely those of the presenter and not necessarily those of Takeda. Takeda does not guarantee the accuracy or reliability of the information provided herein.”

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Learning Outcomes

1. The “y2024 Framework” for Project Managers 2. Definition and Challenges of CMC Project Management 3. Project Management Approaches and Tools 4. Bridging PM and RA - Putting Dossier Development in Context

CMC Project Management

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PM Framework – the VUCA World

CMC Project Management

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(R)Evolution in the Era of Pharmaceuticals

2 nd wave of gold rush for (bio)therapeutics, but with three major differences …

Past

New Challenges and Opportunities to the Field are:

New manufacturing techniques used to produce products.

Technological advances to characterize products.

Today

Rapidly evolving scientific and regulatory landscape and related development strategies and procedures.

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