Module 3 2019

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

Please note that all printed material contained in the course handouts is, unless copyright is assigned elsewhere, the copyright of The Organisation for Professionals in Regulatory Affairs. Such materials are intended for the personal use of the registered students/delegates. Agreement must be reached with the Institute before any part of this material is reproduced, abstracted, stored in a retrieval system or transmitted in any form or by any means – that is, electronic, mechanical, photocopying, recording or otherwise.

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

Laura Brown Course Director

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

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

Tahir Nazir 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

11.30 – 13.00

Case Study 2

Tahir Nazir AstraZeneca

LUNCH

13.00 – 13.30

13.30 – 14.30

Lecture 11: Regulatory Agency Perspective

Elspeth Gray MHRA Tahir Nazir AstraZeneca

14.30 -15.00

Closing remarks and departure

Welcome and introduction to Module 3

Per Niklasson, Regulatory CMC Director, AstraZeneca

4 th December 2019

The Organisation for Professionals in Regulatory Affairs

Learning Outcomes

Regulatory Requirements for a New Active Substance: Quality

This Masterclass will help you understand and provide advice on quality data requirements in the pharmaceutical regulatory environment as well as addressing practical regulatory questions in this area.

This is also Module 3 of the TOPRA MSc Regulatory Affairs.

The Organisation for Professionals in Regulatory Affairs

The flow of the workshop

1. Lecture on CMC In the drug development programme

2. Lectures on drug substance development

3. Lecture on CMC Project management

4. Case study 1 on drug substance

5. Lectures on drug product development

6. Lecture on GMP for clinical supply

7. Case study 2 on drug product

8. Lecture on Regulatory Agency Perspective

The Organisation for Professionals in Regulatory Affairs

Terminology

ICH guidelines covers Quality , Safety , Efficacy and Multidisciplinary .

According to ICH, the Quality section of the application covers chemical and pharmaceutical data. According to ICH, The Quality section presents CMC (Chemistry, Manufacturing and Controls) information in a registration dossier.

Synonym for CMC: Chemistry and Pharmacy

Synonym for drug substance: API (Active Pharmaceutical Ingredient), active substance

The Organisation for Professionals in Regulatory Affairs

ICH

The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH).

10 Regulatory members:

Europe, USA and Japan

•

Canada and Switzerland

•

• Brazil, Republic of Korea, Singapore, China, Chinese Taipei

The Organisation for Professionals in Regulatory Affairs

ICH

Harmonisation achievements includes:

• content and structure of the Quality section of registration dossiers,

conduct of stability studies,

•

• defining relevant thresholds for impurities testing,

• and a more flexible approach to pharmaceutical quality based on Good Manufacturing Practice (GMP) risk management.

The Organisation for Professionals in Regulatory Affairs

ICH Quality Guidelines

ICH Guideline

Year

Q1A - Q1F Stability

1992 – 2006

Q2 Analytical Validation

1994 in revision, potentially combined with new Q14

Q3A - Q3D Impurities

1995 – 2019

Q4 - Q4B Pharmacopoeias

2006 – 2012

Q5A - Q5E Quality of Biotechnological Products

1999 - 2004

Q6A- Q6B Specifications

1997 - 1999

Q7 Good Manufacturing Practice

2000 – 2015

Q8 Pharmaceutical Development

2004 - 2010

Q9 Quality Risk Management

2005 – 2010

Q10 Pharmaceutical Quality System

2008 - 2010

Q11 Development and Manufacture of Drug Substances

2011 - 2012

Q12 Lifecycle Management

Step 4 in November 2019

Q13 Continuous Manufacturing of Drug Substances and Drug Products

Started in 2018

Q14 Analytical Procedure Development

Started in 2018

The Organisation for Professionals in Regulatory Affairs

ICH Multidisciplinary Guidelines

ICH Guideline

Year

M4Q The Common Technical Document: Quality

2002 - 2003

M7 Mutagenic Impurities

2013 - 2017

M9 Biopharmaceutics Classification System-based Biowaivers

Step 3 in June 2018

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Importance of CMC in the Drug Development Process

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

1

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

2

Regulator’s and Company Interests

➢ Quality ➢ Safety Needed to apply for MA/NDA/BLA ➢ Efficacy But what is missing from this list for the real world? Money – can you sell the product? Reimbursement Price can make or break a product in today’s market

3

Reimbursement Issues ➢ Drug budget under increasing pressure o Formularies to 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 ➢ 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)

4

Typical Timeline and Cost for Medicine Development

CMC Development

From ABPI November 2019 5

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

6

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

7

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

8

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

9

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

10

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

11

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

12

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) o Stability o Physical Properties for formulation for humans

13

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

14

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

15

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)

16

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

17

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?

18

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)

19

A Question on Drug Purity

➢ Batch A Potency 99.9 area % Individual related

➢ Batch B Potency 97.5 area % Individual related substances 1 0.8 area % 2 1.5 area % 3 0.5 area % Others 0.1 – 0.3 area %

substances < 0.05 area % each Total related substances < 0.05 area %

Batch B gives better exposure to potential impurities - qualification

20

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

21

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

22

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

23

What could possibly go wrong?

The need to fully understand your DS and DP processes

24

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)

25

Impurities in APIs - Heparin

➢ 2008 Heparin Contamination lead to serious injuries and deaths in USA (at least 81) ➢ Chinese DS source sold by Scientific Protein Labs ➢ Manufacturers recalled many products containing heparin from China contaminated with over-sulphated chondriotin sulphate ➢ Modified USP and Ph Eur monographs to add specific NMR and electrophoresis testing

26

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)

27

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)

28

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

29

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

30

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

1

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

2

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

3

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

4

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 above 80 ° C is acceptable for α of acceptable purity?

5

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

6

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

7

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 .

8

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

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).

10

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

11

Where to choose the RSM?

The Process:

O

O Cl

N

N

Cl

Cl

Cl

Cl

Cl

Cl

OH

N

N

Cl

Cl

12

1,3-Dichlorobenzene – Simple RSM

Characteristics: Commodity like molecule. Relatively high boiling, analysis by gc Manufacture - chlorination of benzene by chlorine.

Cl

Cl

Possible impurities:

Cl

Cl

Cl

Cl

Cl

Cl

Cl

13

A More Complex RSM - 1

OH

N

More complicated molecule. Analysis has to be via hplc Numerous closely related analogues. Several process related impurities (previous step and a dimer)

N

Cl

Cl

OH

OH

N

OH

N

N

N

N

N

Cl

Cl

Cl

3 Isomers

2 other isomers

OH

N

OH

N

N

N

Cl

Cl

Cl

Cl

2 isomers

1 isomer

14

A More Complex RSM - 2

Process Related impurities

Cl

O

N

N

OH

Cl

N

Cl

N

Cl

OH

Cl

Cl

15

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) ➢ Need ways of controlling unwanted products

16

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

17

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

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

19

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

20

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 and metals residues) o Solvation or hydration o Residual solvents and/or water o Solid state form

21

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

22

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

23

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

24

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

25

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!)

26

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

27

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)

28

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

29

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!

30

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

The Organisation for Professionals in Regulatory Affairs

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

Nomenclature and Characterisationof the Active Ingredient

The Organisation for Professionals in Regulatory Affairs

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

The Organisation for Professionals in Regulatory Affairs

Characterization

The Organisation for Professionals in Regulatory Affairs

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

The Organisation for Professionals in Regulatory Affairs

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

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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

−

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

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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

Nomenclature and Characterisationof the Active Ingredient

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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

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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

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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)

Nomenclature and Characterisationof the Active Ingredient

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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

Nomenclature and Characterisationof the Active Ingredient

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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

The Organisation for Professionals in Regulatory Affairs

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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