Module 3 - Strategic case studies in practice

TOPRA TRAINING COURSE MODULE 3

FEBRUARY 2021

MODULE 3 FOR REGULATORY AFFAIRS Online training / professional development for Regulatory Affairs staff

WHO IS THE COURSE FOR? This training course is intended for Regulatory Affairs and other professionals who want to refresh, explore and extend their knowledge on Module 3. Prior knowledge of Module 3 requirements is helpful, but if you are feeling a little rusty and are not sure, do not worry: the course includes some refresher sessions on the basics. WHAT AREAS WILL WE COVER? For this course we are going to concentrate on Module 3 requirements for OTC medicines: solid, liquid, and semi-solid formulations. We will look at: ? The challenges of managing old dossiers for new submissions, including ones that are: o licensed in from other companies o based on the old ‘Notice to Applicants’ format that have a baseline eCTD but have not been updated for some time o supported by ASMFs that need modernisation ? What to check when you are reviewing a Module 3 for a new application, including: o Gaps that are important and must be fixed o Gaps that you can live with and, if needed, can fix later ? Planning a new Module 3 for a submission ? Lifecycle management – tips and tricks for making sure your files stay up to date. HOW WILL WE LEARN? • Some tutorials • Some exercises - looking at real examples – internal and external • A case study, based on a real example • Your shared experiences of how to deal with old (and sometimes rather hairy) Module 3 files.

TOPRA TRAINING COURSE MODULE 3

FEBRUARY 2021

HOW DOES THE COURSE WORK? This is an online course involving collaboration between you, your colleagues and the tutor, Helen Erwood. For it to work effectively your active involvement is REALLY IMPORTANT: The course is designed to be interesting, informative and fun. We want you to explore, discover and share your current understanding of regulatory requirements for Module 3, in practical exercises and discussions with your colleagues. How will we do this? Your learning will include: • Short tutorials (typically 30 minutes long) • Interactive review of examples • Exercises and a case study • Individual tasks / activities for you to take away and complete Your commitment: To complete this course you will need to commit to:  Attend all day and positively contribute,  Feedback your case study findings  Return a tiny bit of post-course work back to Helen afterwards. WHO WILL YOU LEARN WITH? This is an online course, which has been developed and is led by Helen Erwood, who has more than 30 years’ experience in pharmaceuticals, devices and drug-device combinations. The tutor is a resource for you. Helen loves interaction, questions and requests for clarifications during the training. Do please get in touch afterwards to discuss the course material if you need help. COURSE FEEDBACK We welcome feedback on the course: we will ask you for your feedback on the course, once you have completed it, so that we can update and optimise how we work with you in the future. This is your course and we want you to feel that is has been worthwhile. CERTIFICATION This course contributes to your Continuing Professional Development (CPD) and when you complete it a certificate will be issued to you by TOPRA.

TOPRA TRAINING COURSE MODULE 3

FEBRUARY 2021

OUTLINE PROGRAMME

Approximate Timings

What we will cover

0900-0915 0915-0930 0945-1015

Introduction and aims of the course and our example

Your “wish list” for the course

Quick reminder session: • Module 3, the NTA and baseline eCTDs for OTC products.

1015-1045

Team exercise 1 (breakout groups): A first look at parts of an old dossier / the combination pack • CLUEDO – what is important and what might be missing?

1045-1100 1100-1115 1115-1130

… and feedback

Coffee break

Short tutorial – what the assessors say: • Where do most of the deficiencies occur with M3?

1130-1215

Interactive session 1 (slides and team discussion): Update of an established M3 file • Planning the submission / telling the story • Where do the data come from? • What remains and what is replaced? • What to do if it is unintelligible!

1215-1245

Team exercise 2 (breakout groups): the night / day pack • Key pointers for specific sections of 3.2.P – old and new

1245-1315 1315-1400 1400-1430

… and feedback

Lunch break

Short tutorial – Module 3.2.P.2 for established products • What is important / needed – ICH Q8 Interactive session 2 (slides and team discussion): • Filling the gaps • Additional aspects to think about with combination packs

1420-1500

1500-1515 1515-1530 1530-1615

… and feedback

Coffee break

Team CASE STUDY: • Planning your new M3 / thinking about lifecycle mgt • Where will the data come from?

1615-1630 1630-1640

… and feedback

Follow-up task / close

Module 3 Reminder…

Substance

3.2.S

QOS

Product

2.3

3.2.P

Quality data

Appendices

1.4.1

3.2.A

Expert sign-off

Regional information

3.2.R

3.2.S • 1.General Info • 2.Manufacture • 3.Raw materials • 4.DS Controls • 5.Ref Stds • 6.Container • 7.Stability

3.2.P • 1. General Info • 2. Pharm Devt • 3. Manufacture • 4. Excipients • 5. DP Controls • 6. Ref Stds • 7. Container • 8. Stability

P.1: What the product is P.2: How we developed the product The history behind the product P.3: How the product is made P.4: The other ingredients P.5: How we control the product P.6: What we measure the product against P.7: What we pack it into P.8: How we support the stated shelf-life 3.2.P….

QOS – 2.3.P • Same major headings as 3.2.P

• Summary of M3

• Critical commentary

• Justifying omissions

What went before?

NTA differences… • Part II of the MAA submission – QUALITY DATA

• IIA • IIB • IIC • IID • IIE • IIF • IIQ

NTA differences…

NTA differences…

NTA differences…

NTA differences… level of detail..

NTA differences… non-electronic • Hard copies • “Forests” of paper – hard to navigate • Later.. Poor quality scans… • Hand pagination • Poor consistency of data • Tabulated Expert report format

NTA differences… OTC products • Very little data in some sections… • Cross-referring to other products for some of it • Overall often poor quality of data

Legacy products still exist..

• The Old NTA format is still prevalent in old products • Need for BASELINE eCTDs • Then AFTERWARDS update the approved details, as needed.

Exercise 1

Exercise 1 – Strategy for an old dossier

OBJECTIVE(s) The aim of this exercise is to make you think about how to manage construction of a Module 3 in support of a new application for a combination pack, based on two existing products that are supported by a Notice to Applicants dossier.

TEAM TASK This is a team task – please allocate one of the team to provide feedback.

TIMINGS Hopefully, you will have had some time to read this exercise before the course. You have 30 minutes to undertake the task and we will spend 15 minutes afterwards on feedback. In that time you need to allocate: • 5 minutes to review the questions and the information provided. • 15 minutes to review and decide on your answers • 5 minutes to agree your feedback. You have been asked to plan construction of a Module 3 for a COMBINATION PACK over the counter (OTC) product. The aim of the pack will be to provide “Day” and “Night” versions of a formulation indicated for the alleviation of cold and ‘flu’ symptoms. The “Day” formulation contains Paracetamol Ph Eur, Phenylephrine Hydrochloride Ph Eur and Caffeine Ph Eur. The “Night formulation contains Paracetamol Ph Eur, and Phenylephrine Hydrochloride Ph Eur. The presence of caffeine in the “Day” formulation alters the pharmacokinetic profile of paracetamol in vivo resulting in a faster time to peak concentration of paracetamol and a longer half-life. However, as a stimulant, caffeine needs to be avoided for the “Night” formulation. Each of the “Day” and “Night” formulations are conventional immediate-release gelatin capsules. The current approved dossiers for each of the “Day” and “Night” products have until recently, been based on the NTA format. A baseline dossier in eCTD format now exists. THE TASKS Background

Exercise 1

Your task 1. Map out the structure of Module 3.2.P for the COMBINATION PACK. a. Which parts of 3.2.P would you duplicate?

b. Which would you combine? Explain your reasons for this.

2. Review Module 3.2.P.3.3 for Case study 1 and Case study 2 and comment on any obvious differences. What approach should you take to generate a new version for submission?

What the Assessors say.. .. Regulatory data integrity..

World Health Organisation 2019 DATA INTEGRITY IS IMPORTANT

...the degree to which data are complete, consistent, accurate, trustworthy and reliable

“ALCOA” principles

ALCOA Principles

Data Specification

A L C O A

• Attributable • WHO

Data Collection

Destruction

• Legible • Readable, Sensible & Permanent

Data Life Cycle

• Contemporaneous • .. also, Complete, Consistent

Data Processing

Data Storage

• Original • Source / Raw Data (includes Metadata)

Data Reporting

Data Use

• Accurate • Error-free, Truthful

The submission…

Who is involved?

Multiple functions Varying competencies Different aims Not enough awareness of the regulatory customer

Areas of greatest changes

Not enough time is devoted to making life easier for the Assessor • … by assuring data integrity • … complete, consistent, accurate, trustworthy and reliable data

Assessor concerns Consistent deficiencies… EMA surveys • Borg et al., 2009 − Where is Industry Getting it Wrong? • Cilia et al., 2018 − Quality Issues Identified During the Evaluation of Biosimilars

Borg 2009

Where is Industry Getting it Wrong? A Review of Quality Concerns Raised at Day 120 by the Committee for Medicinal Products for Human Use during European Centralised Marketing Authorisation Submissions for Chemical Entity Medicinal Products. J J Borg,et al J Pharm Pharmaceut Sci (www.cspsCanada.org) 12(2):181-198, 2009

Borg 2009

Where is Industry Getting it Wrong? A Review of Quality Concerns Raised at Day 120 by the Committee for Medicinal Products for Human Use during European Centralised Marketing Authorisation Submissions for Chemical Entity Medicinal Products. J J Borg,et al J Pharm Pharmaceut Sci (www.cspsCanada.org) 12(2):181-198, 2009

Manufacture

Manufacture

Borg 2009

Where is Industry Getting it Wrong? A Review of Quality Concerns Raised at Day 120 by the Committee for Medicinal Products for Human Use during European Centralised Marketing Authorisation Submissions for Chemical Entity Medicinal Products. J J Borg,et al J Pharm Pharmaceut Sci (www.cspsCanada.org) 12(2):181-198, 2009

Manufacture

Manufacture

Control of DS

Control of DP

Borg 2009

Where is Industry Getting it Wrong? A Review of Quality Concerns Raised at Day 120 by the Committee for Medicinal Products for Human Use during European Centralised Marketing Authorisation Submissions for Chemical Entity Medicinal Products. J J Borg,et al J Pharm Pharmaceut Sci (www.cspsCanada.org) 12(2):181-198, 2009

Stability

Stability

Manufacture

Manufacture

Control of DS

Control of DP

Borg 2009

Where is Industry Getting it Wrong? A Review of Quality Concerns Raised at Day 120 by the Committee for Medicinal Products for Human Use during European Centralised Marketing Authorisation Submissions for Chemical Entity Medicinal Products. J J Borg,et al J Pharm Pharmaceut Sci (www.cspsCanada.org) 12(2):181-198, 2009

Stability

Pharmaceutical development

Stability

Manufacture

Manufacture

Control of DS

Control of DP

Borg 2009 During evaluation of 52 MAAs, 1,991 concerns were raused at Day 120 on M3:

• 32 of these were major objections from 13 MAAs DRUG SUBSTANCE MAJOR OBJECTIONS:

• Mostly relating to various aspects of impurities, and specifications

DRUG PRODUCT MAJOR OBJECTIONS:

• Mostly relating to Pharmaceutical Development, control of drug product, and stability

Specific issues..

Unwillingness to present the FULL PICTURE of what didn’t work… as well as what worked • Lack of understanding of why this is so important. • Leads to MORE regulatory questions..

• Missing narrative of steps in analytical procedures • Wrong HPLC columns specified • Insufficient information on how solutions are prepared • and if the solutions need to be stored under particular conditions

Not following the guidelines… When dissolution goes wrong..

Immediate release tablet: Ph Eur paddle method 2 hours 45 minutes pH 1.2 [This is REFERENCE product]

Immediate release tablet: Ph Eur paddle method 45 minutes pH 1.2

Not following the guidelines… When dissolution goes wrong..

NO Challenge testing of the Dissolution method

Other reported findings

• Deletion or manipulation of data • Aborted sample analysis without justification • Invalidated OOS results without justification • Destruction or loss of data • Failure to document work contemporaneously • Uncontrolled documentation

Making sure what you put in the file is correct

Maintaining the link to source data

“Supplier” review

Maintaining RA data Integrity

Anticipating concerns BEFORE submission

RA Peer review

Regulatory data risks…

Too much data in the submission

Too little data in the submission

Commitments not communicated properly

Commitments not UNDERSTOOD

Impossible to back-track to find the source data for a question

Think about the Assessor as you build your M3

Exercise 2

Exercise 2 – Night and Day pack sections

OBJECTIVE(s) The aim of this exercise is to explore how to manage updating various sections of the “Night” and “Day” combination Module 3, as a means of thinking about how best to do this. TEAM TASK This is a team task – please allocate one of the team to provide feedback. There are two teams ( A and B ) – one for each breakout – and each team is being given a different task. TIMINGS Hopefully, you will have had some time to read this exercise before the course. You have 30 minutes to undertake the task and we will spend 15 minutes afterwards on feedback. In that time you need to allocate: • 5 minutes to review the questions and the information provided. • 15 minutes to review and decide on your answers • 5 minutes to agree your feedback. THE TASKS Team A Review the information in case study 1 for Module 3.2.P.7 ( container closure system ). Identify any information that you could: • Summarise, or • Leave out .. in your update of this Module. • And explain why.. Team B Review the information in case study 2 for Module 3.2.P.7 ( container closure system ). Identify any information that you could: • Summarise, or • Leave out .. in your update of this Module. • And explain why..

Updating an established M3 file Established drug products

Established product M3: …things to think about..

• Planning your actions • Being clear about what you’re aiming for • Identifying the gaps / issues • What remains and what is replaced? • Too much / too little detail? • Where are the new data coming from? • Is the supplying function clear on what is needed?

Where does your M3 fit within the submission?

Quality

Safety

Efficacy

WHO IS THE CUSTOMER FOR YOUR SUBMISSIONS? The tired and over-worked regulator • The quality of what you provide is really important!

Quality data modules The regulators concerns:

 CONSISTENCY - data and processes

 COMPLIANCE - standards and guidelines

 SAFETY - (impurities!)

 SUITABILITY - for use by the patient

Module 3 is NOT… A technology transfer document

A GMP compliance tool

An internal reference manual • For the manufacturing site • For the RA team

Planning the submission

Very important to PLAN THE CONTENT OF YOUR MODULE 3 • Including − The minimum data requirements − What you propose to include and WHERE − The FLOW of the document − How you present the data – to improve readability • Can you use graphics? • Can you use tables • Can you use bulleted text − Signposting / hyperlinking between sections

Establish some sort of plan / tracker document

Very important to

IDENTIFY the relevant regulatory guidances for your M3 • Have any of them changed recently?

Effective 01.02.2021

Identifying the guidelines that apply ICH: https://www.ich.org/page/quality-guidelines EMA: https://www.ema.europa.eu/en/human-regulatory/research- development/scientific-guidelines/quality-guidelines Medical devices MDCG https://ec.europa.eu/health/md_sector/new_regulations/guidance_en

FDA:

• https://www.fda.gov/drugs/pharmaceutical-quality-resources/guidances-and- manuals-pharmaceutical-quality

3.2.P.2 – very important section!

ICH Q8 – Pharmaceutical Development

• Guideline • Q&A • TRAINING MATERIALS – if you are not sure

Very important to

If you can… REVIEW questions raised by regulators for previous submissions • Are there any key points that you need to clearly deal with in your file

− To avoid the same question again − To help “future-proof” your file.

Remember the comments from Borg et al

Very important to

ESTABLISH A TEMPLATE STRUCTURE FOR YOUR M3 MODULES • But don’t repeat errors / problems from other submissions − Lots of people pick up the previous Module and just copy the same structure and level of detail..

• Use templates with guidance – if you have them

Very important to CONSIDER your regulatory agency target • Including − The time that the Reviewer has allocated to review the document (if you know this)

− Do they have English as their first language? − What is likely to be the FOCUS of their review?

Does the agency concerned have a reputation for concerns about a particular aspect of CMC?

− ALWAYS expect concerns about the potential for impurities!

Very important to

AGREE WHO WILL PERFORM THE INTERNAL REVIEW • Always peer review − You may get so close to the page that you can’t see a problem • Always (if you can).. − Have the person who will be formally releasing the product as the Quality Signatory This MAKES them review the file properly

Check the baseline files..

Let’s look at what we have…

Case study set 1

Let’s look at what we have…

Case study set 2

Use your tracking document to record your review?

Remedial actions..

Using 3.2.P.3 as an example…

• 3.2.P.3.1:

• Any issues?

Using 3.2.P.3 as an example…

• 3.2.P.3.1 • 3.2.P.3.2: • Compare the Case studies

Using 3.2.P.3 as an example…

• 3.2.P.3.1 • 3.2.P.3.2 • 3.2.P.3.3

• Case study 1…

Using 3.2.P.3 as an example…

• 3.2.P.3.1 • 3.2.P.3.2 • 3.2.P.3.3 • 3.2.P.3.4 • What are the critical steps?

Using 3.2.P.3 as an example…

• 3.2.P.3.1 • 3.2.P.3.2 • 3.2.P.3.3 • 3.2.P.3.4 • 3.2.P.3.5

• Case study 2… • What additional questions do you need to ask?

Pharmaceutical Development (3.2.P.2)

for established products

3.2.P.2

3.2.S • 1.General Info • 2.Manufacture • 3.Raw materials • 4.DS Controls • 5.Ref Stds • 6.Container • 7.Stability

3.2.P • 1. General Info • 2 . Pharm Devt • 3. Manufacture • 4. Excipients • 5. DP Controls • 6. Ref Stds • 7. Container • 8. Stability

Drug Product Design

New drug products • ….are not invented in a single step Like every other manufacturing process • ….trial and error takes place

3

Drug Product Design

Understanding the learnings from the trial and error process • ….helps the regulatory reviewer to understand the remaining information provided within the file.

4

Drug Product Design

This is why the Pharmaceutical Development section comes BEFORE all of the other information on manufacture and control of the product

5

Purpose of pharmaceutical development… “To demonstrate that the:

• Dosage form proposed • Manufacturing process • Container closure system • Microbiological attributes • Usage instructions ….are appropriate for the purpose specified in the application”

Why is this needed?

“To identify and describe the formulation and process attributes (critical parameters) that can influence batch reproducibi l i ty, product performance and drug product qual i ty,

… and which must therefore be rout inely control led.”

There are lots of guidelines relevant to 3.2.P.2…

ICH Guidelines

• Q8 – Pharmaceutical Development (R2) • Q9 – Quality Risk Management • Q10 – Pharmaceutical Quality System • Related ICH Guidelines • Q11 – Development and manufacture of drug substances • Q12 –Technical and Regulatory Considerations for Pharmaceutical Product Life Cycle Management • Q13 –Continuous manufacturing of drug substances and drug products (concept paper) • Q14 –Analytical procedure development (concept paper)

Other EU / ICH guidelines

• Section-specific:

Other specific EU guidelines…

• Excipients, antioxidants and antimicrobial preservatives

• Modified release products (oral and transdermal)

• Inhalation and nasal products

• Medicinal gases

Q&A documents

We have to prepare a 3.2.P.2. using Q8

Underlying principles

In order to develop any DP • QUALITY has to be built into the design

The aim of Pharmaceutical Development… • To DESIGN a quality product and process • Assess the RISKS associated with the process − And to mitigate them • To DELIVER DP in a REPRODUCIBLE way

What is the reviewer looking for?

Perspective for the submission

What worked? • What didn’t work? … this can be very revealing

How you eventually arrived at the product

REMINDER - Pharmaceutical Development

A CRUCIAL part of the submission

Provides HISTORICAL information • Does not usually give you a regulatory commitment QUESTION: what should we include for a combination of two established products?

So what about our combination pack product?

What is currently registered…? [One page]

What is currently registered…? THE CHALLENGE… • Prepare what is normally a development history file, for something that already exists!

Drug Substance important aspects

• Compatibility with excipients

• Compatibility between drug substances in a combination • Key physicochemical characteristics • And how these impact the drug product • Overages

Drug Substance Physical Characteristics • Factors most likely to play an important role EXAMPLES:  Particle size: Affects bioavailability/solubility/ stability  Crystal form and moisture content  You need appropriate limits in raw material specifications

EXCIPIENTS

Excipients

• WHY were these chosen? • You probably don’t know, but you know what their role is…

26

Excipients

• WHY were these chosen? • You probably don’t know, but you know what their role is…

27

Excipients

• WHY were these chosen? • And the capsule shell… [what are the implications of all of these colours?]

28

Excipients

• WHY were these chosen?

• What characteristics do they have that might affect drug product PERFORMANCE?

29

Excipients

• ALL excipients must be considered • Including those that are not present in the final formulation

− Is there a granulation process where water is used?

30

Notes for Guidance - excipients

DRUG PRODUCT

Drug Product

• The EVOLUTION of the formulation design and the CHOICE of components • You probably don’t have any information on this either…

− QUESTION: how might you deal with this?

Drug Product • ALL formulations − Clinical trial – you won’t have this − Safety, efficacy, bioequivalence, bioavailability − If it’s a generic or WEU do you have comparative BE data? − Was it performed using the proposed formulation?

Solid Dosage Forms: - Performance Testing

• Dissolution testing • Immediate release • Modified release

• Disintegration

• Homogeneity

Any Additives - Antioxidants and Preservatives?

Note for Guidance (Excipients, antioxidants and preservatives)…  The reason for inclusion  Proof of efficacy  Method of control in the DP  Details of the labelling  …and the physical and chemical compatibility of the antioxidant and preservative with other constituents of the drug product, container and closure

36

Overages – and Justifying Them

Manufacturing loss

Stability loss

Administration losses

Manufacturing Process Development…

– what type of process have you got? • Have you got any data to justify the process you are using? − Recent validation data?

43

Container-Closure Systems

Container closure factors

• What type of container have you got?

• QUESTION: for our combination pack, what have we got?

• Is there any likelihood of an interaction between the product(s) and the pack?

Container closure factors • QUESTION: for our combination pack, what have we got?

Container-Closure Systems The SUITABILITY of the container-closure for the intended use

• Choice of materials • Protection from moisture and light • Compatibility with the dosage form • Safety of materials of construction • PERFORMANCE − Reproducibility of dosage delivery

Microbiological attributes • The rationale for not performing microbial limits testing for non-sterile DPs.

• Selection and effectiveness of preservative systems

• The integrity of the container closure (sterile products) • preventing contamination

Compatibility IMPORTANT FOR PARENTERAL PRODUCTS – Not usually relevant for oral tablets / capsules With…

• Reconstitution diluents • Dosage devices

Over the recommended in-use shelf-life • At the recommended storage temperature • At the likely extremes of concentration

49

Pharmaceutical Development… - for a new product

• HISTORY OF THE DEVELOPMENT • HOW YOU ARRIVED AT THE FINAL PRODUCT • WHAT HAPPENED ON THE WAY • WHY CERTAIN CHANGES HAD TO BE MADE

• HOW YOU HAVE ESTABLISHED THE “DESIGN SPACE”

50

Pharmaceutical Development… - for an established product • HISTORY OF THE MANUFACTURE OF THE PRODUCT • Similarity to other products sold / supplied • SUITABILITY OF THE MATERIALS USED

• Standards / consistency applied • Compatibility of the formulation • LONG TERM QUALITY OF THE PRODUCT • Dissolution profiles • Stability characteristics etc

51

Pharmaceutical Development

For an existing product… • You are reassuring the Assessor that you understand the science behind it.

Updating an established M3 file Filling the gaps.. … and additional things to think about

What’s the target?

Combination pack Similar to a Competitor product? • Target population? • Dosing? • Issues with the formulations? • Special requirements for the pack?

Combination pack • Target population? • 16+ including the elderly • Dosing? • Issues with the formulations? • Special requirements for the pack?

Combination pack • Target population? • 16+ including the elderly • Dosing? • Daytime: 2 caps every 4 hours up to a maximum of 3 doses during the day • Issues with the formulations? • Special requirements for the pack?

Combination pack • Target population? • 16+ including the elderly • Dosing? • Daytime: 2 caps every 4 hours up to a maximum of 3 doses during the day • Issues with the formulations? • Contains paracetamol! • Special requirements for the pack?

• Target population? • 16+ including the elderly • Dosing? • Daytime: 2 caps every 4 hours up to a maximum of 3 doses during the day • Issues with the formulations? • Contains paracetamol! • Special requirements for the pack? • Child-resistance / making sure the consumer doses properly

What special features should the product have?

Special features? • The formulations

• The pack

• The manufacturing process

Special features? • The formulations • Particle size of DS? • Does comparative dissolution matter? • Different appearance for each formulation • The pack • The manufacturing process

Special features? • The formulations • Particle size of DS? • Does comparative dissolution matter? • Different appearance for each formulation • The pack • Child resistance • CLEAR instructions for all consumers • The manufacturing process

Special features? • The formulations • Particle size of DS? • Does comparative dissolution matter? • Different appearance for each formulation • The pack • Child resistance • CLEAR instructions for all consumers • The manufacturing process • Segregation to avoid incorrect assembly – GMP!

Capsule appearance

• COLOUR is linked to compliance !

• TWO DIFFERENT CAPSULES • They need to look different − Consider colour blindness

The pack

• Braille • How to differentiate products in a pack? • Other ways to discourage children

The pack

• What’s the dose in the pack? • Per day

− Daytime 6 capsules − Night-time 2 capsules • Per pack (3 days?) − 6 + 2 in a daily tray?

Filling the gaps…

Other hints and tips

THERE ARE ALSO GRANULARITY RULES

} Options for granularity ◦ ICH M4 General guidance

} Choice of level for 3.2.P.2 ◦ 3.2.P.2 or 3.2.P.2.1 etc….

} Sections may contain one or multiple documents ◦ e.g. analytical methods

Common issues with Module 3 Confusing layout of modules • Hard to find information • Hard to work out what section you’re in (wrong headers) Abbreviations not clear Too much detail • Differences between EU and US • Specifying standard items of equipment • Showing container spec diagrams for simple common containers • Too little flexibility introduced

Managing flexibility

USING “WEASEL WORDS” (WHERE ITEMS ARE NOT CRITICAL) • Up to

• Approximately • or equivalent • about • a minimum of / a maximum of Versioning SOPs / method documents • Avoid it if you can!

The 4 Cs…

• CLEAR • COMPLIANT WITH GUIDELINES • CONCISE • CONCLUSIONS!

USE OF GRAPHICS!

USE OF GRAPHICS!

3.2.S.2.6. Manufacturing process Development • Follow ICH Q11 principles:

Define an appropriate manufacturing process addressing CQAs

Define a control strategy to ensure process performance and DS quality

Identify potential CQAs of the Drug substance

Telling a consistent story…

Identify critical process parameters. Deliver quality attributes

Manufacturing Process Development

Confirm that CPPs and CQAs are consistently achieved by the process

Manufacturing Process Validation

Manufacturing Process Description

Define how the future commercial process will be controlled to deliver consistent DP

Stability – follow the ICH guidelines

ICH Q1A ICH Q1B ICH Q1C ICH Q1D ICH Q1E ICH Q1F

Stability Testing of New Drug Substances and Products Photostability Testing of New Drug Substances and Products

Stability Testing for New Dosage Forms

Bracketing and Matrixing Designs for stability testing of New Drug Substances and Products

Evaluation of Stability Data

Stability data package for Climatic Zones III and IV

ICH Q5E

Stability testing of Biotechnology Products

Sometimes… 3-dimensional chess!

Correlation Table :

EU-CTD (NTA, Vol. 2B, edition May 2006 ) vs. NTA, Vol. 2B (edition 1998)

MODULE 1 - ADMINISTRATIVE INFORMATION AND PRESCRIBING INFORMATION

CTD

EU CTD (NTA, Vol. 2B, Edition 2006)

NTA, Vol. 2B (Edition 1998)

NTA

1.0 1.1 1.2

Cover Letter

Comprehensive table of content

---

Application Form

Administrative Data

I A

1.3

Product Information

Summary of Product Characteristics, Labelling and Package Leaflet

I B

1.3.1

Summary of Product Characteristics, Labelling and Package Leaflet

Summary of Product Characteristics

I B 1

Proposal for packaging, labelling & package leaflet

I B 2

1.3.2 1.3.3 1.3.4 1.3.5

Mock-up Specimen

I B 2

Consultation with Target Patient Groups

Product Information already approved in the Member States

SPCs already approved in the Member States

I B 3

1.3.6

Braille

1.4

Information about the Experts

Expert Reports: Signature of Experts

I C

1.4.1 1.4.2 1.4.3

Quality

Non-clinical

Clinical

1.5

Specific Requirements for different types of applications Information for bibliographical applications Information for Generic, “Hybrid” or Bio-similar Applications

--- --- ---

1.5.1 1.5.2

1.5.3 1.5.4 1.5.5

(Extended) Data/Market Exclusivity

Exceptional Circumstances

Conditional Marketing Authorisation

1.6

Environmental risk assessment

Environmental risk assessment

Environmental risk assessment / ecotoxicity (for non- GMOs) Data related to the environmental risk assessment for products containing, or consisting of genetically modified organisms (GMOs)

1.6.1

Non-GMO

III R

1.6.2

GMO

II H

1.7

Information relating to Orphan Market Exclusivity

1.7.1 1.7.2

Similarity

Market Exclusivity

1.8

Information relating to Pharmacovigilance

1.8.1 1.8.2

Pharmacovigilance System Risk-management System

1.9

Information relating to Clinical Trials Responses to Questions

Responses to Questions

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MODULE 1 - ADMINISTRATIVE INFORMATION AND PRESCRIBING INFORMATION

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NTA, Vol. 2B (Edition 1998)

NTA

Additional Data

Additional Data

MODULE 2 - COMMON TECHNICAL DOCUMENT SUMMARIES

CTD

EU CTD (NTA, Vol. 2B, Edition 2001)

NTA, Vol. 2B (Edition 1998)

NTA

2.1 2.2 2.3

Overall CTD Table of Contents of Modules 2, 3, 4, and 5 Table of Contents for remainder of the dossier

I.A I.C

Introduction

Product profile

Quality Overall Summary

Expert report on the chemical, pharmaceutical and biological documentation Expert Report on the toxico-pharmacological documentation Expert Report on the Clinical Documentation Appendices to the toxico-pharmacological Expert Report

I C 1

2.4

Non-clinical Overview

I C 2

2.5 2.6

Clinical Overview

I C 3 I C 2

Non-clinical Summary

2.6.1 2.6.2 2.6.3 2.6.4 2.6.5 2.6.6

Pharmacology Written Summary Pharmacology Tabulated Summary Pharmacokinetics Written Summary Pharmacokinetics Tabulated Summary Toxicology Written Summary Toxicology Tabulated Summary

Written Summary Tabular Formats Written Summary Tabular Formats

I C 2 I C 2 I C 2 I C 2 I C 2 I C 3 I C 3 I C 3 I C 3 I C 3 I C 3 ---

---

Tabular Formats

2.7

Clinical Summary

Appendices to the clinical Expert Report

2.7.1

Summary of biopharmaceutics and associated analytical methods Summary of clinical pharmacology studies

Written Summary

2.7.2 2.7.3 2.7.4 2.7.5

Written Summary Written Summary Written Summary Tabular Formats

Summary of clinical efficacy Summary of clinical safety Synopses of Individual Studies

MODULE 3 – QUALITY

CTD

EU CTD (NTA, Vol. 2B, Edition 2001)

NTA, Vol. 2B (Edition 1998)

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3.1 3.2

MODULE 3 TABLE OF CONTENTS

---

---

BODY OF DATA

Chemical, Pharmaceutical, Biological Documentation II

3.2.S DRUG SUBSTANCE 3.2.S.1 General Information

Scientific Data

II C 1.2

3.2.S.1.1 3.2.S.1.2 3.2.S.1.3

Nomenclature

Nomenclature

II C 1.2.1 II C 1.2.2 II C 1.2.5 II C 1.2.3

Structure

Description: Structural formula Physico-chemical characterization

General Properties

3.2.S.2

Manufacture

Manufacture

3.2.S.2.1 3.2.S.2.2

Manufacturer(s)

Name(s) address(es) of the manufacturing source(s) II C 1.2.3

Description of manufacturing process and process controls

Synthetic or manufacturing route Description of process Quality control during manufacture Quality control during manufacture

II C 1.2.3

3.2.S.2.3 3.2.S.2.4 3.2.S.2.5 3.2.S.2.6

Control of materials

II C 1.2.4 II C 1.2.4

Controls of critical steps and intermediates

Process validation and/or evaluation Manufacturing process development

--- ---

---

3.2.S.3

Characterisation

3.2.S.3.1 3.2.S.3.2

Elucidation of structure and other characteristics

Development chemistry

II C 1.2.5 II C 1.2.6

Impurities

Impurities

3.2.S.4

Control of drug substance

Specifications and routine tests

II C 1.1 II C 1.1 II C 1.1

3.2.S.4.1 3.2.S.4.2

Specification

Specifications and routine tests Specifications and routine tests

Analytical Procedures

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MODULE 3 – QUALITY

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NTA, Vol. 2B (Edition 1998)

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3.2.S.4.3 3.2.S.4.4 3.2.S.4.5

Validation of analytical procedures

Development Chemistry: Analytical Validation

II C 1.2.5 II C 1.2.7 II C 1.2.5

Batch analyses

Batch analysis

Justification of Specification

Development Chemistry: Comments on the choice of routine tests and standards Development chemistry: Full characterization of the primary reference material Batch analysis: Reference material

3.2.S.5

Reference Standards or Materials

II C 1.2.5 II C 1.2.7

Container Closure System

---

3.2.S.6

3.2.S.7 Stability

Stability Tests on Active Substance(s)

II F 1

3.2.P

DRUG PRODUCT

3.2.P.1

Description and composition of the drug product

Composition and container (brief description) Development Pharmaceutics and clinical trial formulae

II A1 II A2 II A 4 II A3 II B3

3.2.P.2

Pharmaceutical Development

3.2.P.2.4 Controls and critical steps and intermediates

Manufacturing process (including in-process control and phamraceutical assembly process) Control tests on intermediate products

II D II B

3.2.P.3

Manufacture

Method of Preparation

3.2.P.3.1 3.2.P.3.2 3.2.P.3.3

Manufacturer(s) Batch formula

Administrative Data Manufacturing Formula

I A

II B 1 II B 2

Description of Manufacturing Process and Process Controls Controls of critical steps and intermediates

Manufacturing Process (including In-process Control and Pharmaceutical Assembly Process) Manufacturing Process (including In-process Control and Pharmaceutical Assembly Process)

3.2.P.3.4

II B 2

3.2.P.3.5

Process validation and / or evaluation

Validation of the Process

II B 3 II C 2

3.2.P.4

Control of excipients

Excipients(s)

3.2.P.4.1 3.2.P.4.2 3.2.P.4.3 3.2.P.4.4 3.2.P.4.5 3.2.P.4.6

Specifications

Specifications and routine tests Specifications and routine tests

II C 2.1 II C 2.1 II C 2.2 II C 2.2

Analytical procedures

Validation of analytical procedures

Scientific data Scientific data

Justification of specifications

Excipients of human or animal origin

---

Novel Excipients (ref to A 3)

Excipient(s) not described in a pharmacopoeia Scientific data

II C 2.2.1 II C 2.2

3.2.P.5 Control of drug product

Control Tests on the Finished Product

II E

3.2.P.5.1

Specification(s)

Product specifications Quality specifications for the proposed shelf life

II E 1.1 II F 2 II E 1.2 II E 2.1 II E 2.2

3.2.P.5.2 3.2.P.5.3 3.2.P.5.4 3.2.P.5.5 3.2.P.5.6

Analytical Procedures

Control Methods

Validation of Analytical Procedures

Analytical validation of methods

Batch analyses

Batch analysis

Characterisation of Impurities Justification of specification(s)

---

Comments on the choice of routine tests and standards

II E 2.1

3.2.P.6 3.2.P.7 3.2.P.8

Reference Standards or Materials

Batch analysis: Reference material

II E 2.2

Packaging Material (Immediate Packaging)

Container Closure System

II C 3 II F 2

Stability

Stability Tests on the Finished Product

3.2.A

APPENDICES

3.2.A.1 3.2.A.2 3.2.A.3

Facilities and Equipment

--- --- ---

Adventitious Agents Safety Evaluation

Excipients

3.2.R

REGIONAL INFORMATION LITERATURE REFERENCES

Validation of the process OTHER INFORMATION

-II B3--

3.3

II Q

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MODULE 4 - NONCLINICAL STUDY REPORTS

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4.1 4.2

MODULE 4 TABLE OF CONTENTS

---

--- III

STUDY REPORTS

TOXICO-PHARMACOLOGICAL DOCUMENTATION

4.2.1

PHARMACOLOGY

PHARMACODYNAMICS

III F

4.2.1.1

Primary pharmacodynamics

Pharmacodynamics effects relating to the proposed indications

III F 1

4.2.1.2 4.2.1.3 4.2.1.4

Secondary pharmacodynamics

General pharmacodynamics General pharmacodynamics

III F 2 III F 2 III F 3

Safety pharmacology

Pharmacodynamic drug interactions

Drug interactions

4.2.2

PHARMACOKINETICS

PHARMACOKINETICS

III G III Q

4.2.2.1 4.2.2.2

Analytical Methods and Validation Reports

Other Information

Absorption

Pharmacokinetics after a single dose Pharmacokinetics after repeated administration Distribution in normal and pregnant animals

III G 1 III G 2 III G 3 III G 4

4.2.2.3 4.2.2.4 4.2.2.5 4.2.2.6 4.2.2.7 4.2.3.1 4.2.3.2 4.2.3.3 4.2.3.4 4.2.3.5 4.2.3

Distribution Metabolism

Biotransformation Pharmacokinetics

Excretion

III G 1, 2

Pharmacokinetic Drug Interactions (nonclinical)

--- ---

Other Pharmacokinetic Studies

TOXICOLOGY

TOXICITY

III A

Single-dose toxicity Repeat-dose toxicity

Single dose toxicity studies Repeated dose toxicity studies

III A 1 III A 2

Genotoxicity

Mutagenic Potential Carcinogenic Potential

III D III E III B III C III H III Q III Q

Carcinogenicity

Reproductive Function Embryo-foetal and Perinatal Toxicity

Reproductive and developmental toxicity

4.2.3.6 4.2.3.7

Local tolerance

Local Tolerance Other Information

Other toxicity studies

4.3

LITERATURE REFERENCES

OTHER INFORMATION

MODULE 5- CLINICAL STUDY REPORTS

CTD

EU CTD (NTA, Vol. 2B, Edition 2001)

NTA, Vol. 2B (Edition 1998)

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5.1 5.2

MODULE 5 TABLE OF CONTENTS

---

---

TABULAR LISTINGS OF ALL CLINICAL STUDIES

EXPERT REPORT ON THE CLINICAL DOCUMENTATION, APPENDIX 2: WRITTEN SUMMARY – TABULAR OVERVIEW

I C 3

5.3

CLINICAL STUDY REPORTS

CLINICAL DOCUMENTATION

IV

5.3.1 5.3.2

Reports of Biopharmaceutic Studies

Pharmacokinetics Pharmacokinetics

IV A 2 IV A 2

Reports of Studies Pertinent to Pharmacokinetics using Human Biomaterials Reports of human pharmacokinetic (PK) studies Reports of human pharmacodynamic (PD) studies

5.3.3 5.3.4 5.3.5 5.3.6 5.3.7

Pharmacokinetics Pharmacodynamics

IV A 2 IV A 1 IV B 1 IV B 2 IV B 1

Reports of efficacy and safety studies Reports of post-marketing experience

Clinical Trials

Post-marketing experience (if available) Appendix to each clinical study report, when submitted (Appendix 16.3) PUBLISHED AND UNPUBLISHED EXPERIENCE (OTHER THAN 1) OTHER INFORMATION

Case report forms and individual patient listings, when submitted

5.4

LITERATURE REFERENCES

IV B 3

IV Q

NTA, Vol. 2B-CTD, foreword & introduction, edition June 2006

Page 29

PL 12063/0073

CONFIDENTIAL

Batch Formula

3.2.P.3.2

Day Capsules The following table gives the batch formula for a 150 kg pilot batch of bulk Day capsule product.

3.2.P.3.2.1

Formula Quantity/kg

Quality Standard

Raw Material

Paracetamol, fine crystal Phenylephrine Hydrochloride

128.00

Ph.Eur Ph.Eur Ph.Eur Ph.Eur Ph.Eur Ph.Eur Ph.Eur Ph.Eur

1.57 6.42 7.50 1.52 0.77 2.31 1.54

Caffeine

Croscarmellose Sodium Sodium Laurilsulfate Magnesium Stearate

Maize Starch Purified Talc

TOTAL 150 kg A 150 kg batch size yields approximately 257,000 capsules.

The proposed maximum full-scale production batch size of Day capsules is 1000 kg bulk product. The following table gives the proposed batch formula for a maximum full-scale production batch of Day capsules.

Formula Quantity/kg

Quality Standard

Raw Material

Paracetamol, fine crystal Phenylephrine Hydrochloride

856.00 10.40 42.80 50.00 10.10 5.14 15.40 10.30

Ph.Eur Ph.Eur Ph.Eur Ph.Eur Ph.Eur Ph.Eur Ph.Eur Ph.Eur

Caffeine

Croscarmellose Sodium Sodium Laurilsulfate Magnesium Stearate

Maize Starch Purified Talc

TOTAL 1000 kg A 1000 kg batch size yields approximately 1,711,000 Day capsules. It is proposed that other suitably validated smaller batch sizes will be used up to the proposed maximum batch size of 1000 kg.

PL 12063/0073

CONFIDENTIAL

Night Capsules The following table gives the batch formula for a 143.6 kg pilot batch of bulk Night Capsule product.

3.2.P.3.2.2

Formula Quantity/kg

Quality Standard

Raw Material

Paracetamol, fine crystal Phenylephrine Hydrochloride Croscarmellose Sodium

128.4.00

Ph.Eur Ph.Eur Ph.Eur Ph.Eur Ph.Eur Ph.Eur Ph.Eur

1.57 7.50 1.52 0.77 2.31 1.54

Sodium Laurilsulfate Magnesium Stearate

Maize Starch

Talc

TOTAL 143.6 kg A 143.6 kg batch size yields approximately 257,000 capsules.

The proposed maximum full-scale production batch size of Night capsules is 1000 kg bulk product. The following table gives the proposed batch formula for a maximum full-scale production batch of Night capsules.

Formula Quantity/kg

Quality Standard

Raw Material

Paracetamol, fine crystal Phenylephrine Hydrochloride Croscarmellose Sodium

894.00 10.90 52.2 10.60 5.37 16.1 10.7

Ph.Eur Ph.Eur Ph.Eur Ph.Eur Ph.Eur Ph.Eur Ph.Eur

Sodium Laurilsulfate Magnesium Stearate

Maize Starch

Talc

TOTAL 1000 kg A 1000 kg batch size yields approximately 1,780,000 Night capsules. It is proposed that other suitably validated smaller batch sizes will be used up to the proposed maximum batch size of 1000 kg.

3.2.P

Drug Product: Max Strength Cold & Flu Day & Night Capsules

3.2.P.7

Container Closure System

3.2.P.7

Container Closure System Primary Packaging

The container closure system comprises opaque, white, 250 micron PVC blisters lidded with 30 micron hard-temper pyramidal Aluminium foil. Each blister contains eight capsules in a 4 × 2 format, comprising 6 Day capsules and 2 Night capsules. The specifications for the PVC laminate and the 30 micron CRC Aluminium foil are provided overleaf. This pack combination has been approved as BS 8408 compliant in line with current Child Resistant Closure (CRC) regulations. A declaration of conformity and CRC testing report (Burford Report) are provided in 3.2.P.7. along with a blueprint of an example blister pack (approximately 80 mm × 57 mm). The results of the Burford Report indicated that 99 out of 100 adults tested could open the blister and remove a tablet. Certificates of Conformance from the foil supplier, Ethiprint Limited, Sandown Road, Derby DE24 8SR and from the PVC supplier, Alfatherm Industriale S.p.A, 21040 Venegono Superiore, Varese, Italy – Via Marconi, 25 are also provided in overleaf.