Regulatory Affairs Overview

Biomedicine the Profession – 27 September 2016
REGULATORY AFFAIRS
Anna Rytter, PhD

Regulatory Affairs & Quality Assurance Manager
1 Regulatory Affairs, the role in pharma - BMC

Introduction
• Master program – molecular biology – Lund
• PhD – Experimental Brain Research, WNC -

Lund
• Post doc – Apoptosis Laboratory, KB-

Copenhagen
• LEO Pharma AB - originals, affiliate, national,

Malmö
• LEO Pharma A/S originals, Head Office global -

Ballerup
• EQL Pharma, - generics - Lund

Topics
• What is regulatory Affairs?
• Why regulate drug development
• Product Life Cycle - Regulatory Affairs Perspective
• Regulatory Affairs and its role in the Pharma company
• Regulatory documentation/tools
• A typical day in Regulatory Affairs

What is regulatory Affairs?
Definition according to Swedish Pharmaceutical Society:
Regulatory Affairs is the knowledge and application of strategic

and operational enforcement of the legal frame work concerning
pharmaceuticals and related products in a national and global
perspective.
Wiki:
Regulatory Affairs is a profession within regulated industries, such as pharmaceuticals, medical devices
(”…”).
Regulatory affairs (medical affairs) professionals (aka regulatory professionals) usually have responsibility
for the following general areas:
• Ensuring that their companies comply with all of the regulations and laws pertaining to their business.
• Working with federal, state, and local regulatory agencies and personnel on specific issues affecting
their business. i.e. working with such agencies as the Food and Drug Administrationor European
Medicines Agency
• Advising their companies on the regulatory aspects and climate that would affect proposed activities.
i.e. describing the "regulatory climate“…
Company perspective:
New medicinal products - and changes to marketed products – should be
approved asap and placed and kept on the market
Authority perspective:
To assess documentation submitted with the registration- or change
application and surveillance of the use of medicinal products
Why regulate?
• Drugs are not ordinary consumer products

– To ensure quality, safety and efficacy of drug products in order to
assure the continued protection of Public Health.
– Professional advice needed
– “Hidden quality”

Why regulate?
Benefit vs Risk
”All substances are poisons; there is none which is not a

poison. The right dose differentiates a poison and a remedy
(medicine)”
or
”The dose makes the poison”
Paracelsus (1493-1541)

Pharmaceutical regulation – A recent Development?
• Official books of drug quality standards – Italy 13th century
• First “modern” pharmacopoeias 16th century (e.g. Spanish

Pharmacopoeia)
• Pharmacopoeias define:
– the requirements for the qualitative and quantitative composition of medicines
– the tests to be carried out on medicines
– the tests to be carried out on substances and materials used in their
production
– But - no evaluation of safety or efficacy of medicines

Pharmaceutical regulation – driven by disasters
• Unfortunate events development of medicines regulation during
20th century
• 1937 – Sulfonamide - diethylene glycol poisoning, 100 people died

US Federal Food, Drug and Cosmetic Act and the birth of New
Drug application
• 1956 – thalidomide disaster, Neurosedyn. 10 000

newborn with deformities Major trigger for
development of the modern controls on the sale
and supply of pharmaceuticals
• EU Directive 65/65/EEC

0
The modern era of drug regulation
There is a wealth of Regulations, Directives and Guidelines controlling
the sale, supply and study of medicines.
Agencies such as
• FDA (Food and Drug Administration) in US
• EMA (European Medicines Agency) in EU
• LV/MPA (National agencies (Läkemedelsverket)
in SE
set up to administer these rules and to approve medicines before they can
be sold.

1
The modern era of drug regulation
ICH
• Need for a wider harmonization led to the establishment of
International Conference on Harmonisation of the technical
requirements of pharmaceuticals for human use (ICH) 1990
• A network of the authorities in EU, US, Japan and industry
organisations
• Provide guideline on Quality, Safety, Efficacy and CTD
• No authority – recommendations which will have to be
regionally implemented

2
Why is Regulatory Affairs Needed?
• Drug development and commercialization is highly regulated.
• The path to drug registration (Marketing Authorization) is paved with

good intention but can be complicated
• Things change....constantly!

Regulatory Affairs in drug development
• Strategic
• Company decisions on new projects or in licencing.
• How should this product be documented?
• Risk assessments, time plans
• How quick can the product be on the market? Which is the best way?
• Operational
• Applications to authorities, structure and format
• Time plan
• Compliance
• Responsive
• Respond to questions
• Problem solving

Product Life Cycle - Regulatory Affairs Perspective
Development Phase
• Advice on development
• Scientific Advice
• Clinical Trial Applications
• Project management / Strategy
• Product Information - Claims
Application and ApprovalPhase

• Application Procedure
• Authority meetings/hearings
• Electronic submission
• Readability Testing / Labeling Support
Post Approval Phase

• Life Cycle
Management/Compliance
• Post-approval Commitments
• Clinical Trial Applications
• New Indications
The role of regulatory affairs – development phase
– Ensuring that the legislative requirements are met
• Regulatory strategy
• Cross-functional project teams
• Ensure application of guidelines
• Advice on studies to demonstrate safety, quality and efficacy
• Preparation of submission of application for clinical trials

Managing the preparation of the regulatory submission
including labelling
• Labelling/Product information
• Readability Testing
• Quality audits
• GMP of manufacturers
• GCP
• QP statements
• RMP
Product Information - SmPC and package leaflet
SmPC – Summary for the prescribers
Package leaflet – Information for the patient
• Indication and dosing

• Precautions and warnings
• Interactions with other drugs
• Undesirable effects
The claims in the Product Information needs to be supported by scientific data

in the dossier.
Ensure input from different parties.
FASS
Prepare High-level documents
In all submission dossiers there will
overviews of the:
• non-clinical part
• quality part
• clinical part
– It is an introduction to the data
with a critical assessment of the
results.
– It justifies any deviations from
guidelines
– It justifies the development and
testing strategy.

The role of regulatory affairs – application and
approval phase
• Application Procedure
• Electronic submission
• Authority meetings/hearings
• Check progress of evaluation and anticipate questions (prepare

answers to expected questions)
• Clarify raised questions, plan response and strategies with

other departments
• Negotiate approval and Product Information with agencies

Approval!
Marketing authorisation (MA) granted
An agreement with the authorities
• Valid for a period of 5 years.
• After 5 years renewal required

The role of regulatory affairs – post approval phase
–Compliance - Submission of variations
–Renewals
–Pharmacovigilance
–Product information review LIFE CYCLE
–New indications / New formulations MANAGEMENT
• Regulatory input to development plans!
–Regulatory Intelligence
• What does the future hold?

The role of regulatory affairs - Summary
• GET THE PRODUCT ON THE MARKET QUICKLY
(Meet the legislative requirements and present the company position in the best
light to maximise competitiveness)
• KEEP THE PRODUCT ON THE MARKET FOR A LONG TIME

Regulatory documentation/tools
Regulatory documentation/tools
• In the past the regulatory documentation presented to the authorities
was printed on paper and organized in binders.
• Common Technical Document (CTD) is the standard format used for

Marketing Authorisation Applications (MAAs, EU) and New Drug
Applicatons (NDAs, US)
• Common agreed structure for the main sections (SAFETY, QUALITY, EFFICACY)
of a regulatory submission

The common technical document - CTD
• The Common Technical Document is divided into five modules:
– Module 1 Administrative and prescribing information
– Module 2 Overview and summary of modules 3 to 5
– Module 3 Quality (Pharmaceutical documentation)
– Module 4 Preclinical (Pharmacology/Toxicology)
– Module 5 Clinical - efficacy (Clinical Trials)

Tools - Electronic submission

26/Ut>/ U1t
Routes to registration
Routes To Registration
Centralised Mutual Decentralised National

Procedure Recognition Procedure Procedure
procedure
3
26-05-2016
Summary of MRP
• As soon as there is an existing MA, for same applicant and
same product, or pending application in Europe, MRP is
mandatory
• Submit national application in RMS
• National approval in RMS
• Applicant updates dossier in line with

assessment and re- submits to RMS
• Preparation of assessment report by RMS
• Submission of dossier to CMSs - validation

by CMSs
• MRP starts = 90 days
Example of an MRP • Local artwork in CMSs (post 90 days)

• National Marketing Authorisation (MA) in lreland (IE) for a one strength cream.
Want to extend cover to the UK, PT, FR and NL.
• License grant in CMSs
• RMS (Reference Member State): IE

• CMS (Concerned Member State): UK, PT, FR and NL
• MRP Timeline
• 90-day procedure
• Followed by 30 day National Phase, Submit national translations of
PIL, SPC and Labelling
5
26-05-2016
Summary of CP
• Submit once to EMA plus Rapporteur/Co-

Rapporteur
• Full assessment done by two countries
• Majority decision
• 210 days to positive opinion, 250 days to

"decision".
• Only possible if originator was CP
• Only one MAH
• Only one product name
5
•National
Only possible if no existing MA in EU for same
applicant and same product, and only one
country targeted
•DCP
As soon as application is made, by same
applicant for same product, in more than one
Member State and no CP is chosen, DCP is
mandatory.
The various roles within Regulatory Affairs
• Project management
• Submission management
• Maintenance management - LCM
• CMC specialist (quality)
• Pre-clinical/Clinical specialist
• Labelling expert
• Regulatory intelligence
• Product responsible

Regulatory Intelligence
• Is a systematic process initiated by a defined need
• It is a collection of data and analysis of the data linked to a strategy
• It is legal and ethical (not espionage/hacking)
• So much information available on websites/databases
• Typical question – what other modified release

products with indications x and y exist in Europe? What clinical trials
supported the approval?

Global versus local Regulatory Affairs
• Global/Head office
– Strategies
– Specialized
– Contact with experts
– Compile common documents and variations and send to affiliates
– Contact with manufactre, sales and logistics
• Affiliate/local/market
– Specialist in local requirements – adapt the common documents
– Translations
– Contact with market, sales and logistics
– Customer complaints and questions

Original versus Generics
-
Generics Originator
Production Often contract Own facilities

manufacturing
Products High number of Few high volume products
different products
and different types of
products
3
30-05-2016
An average day at work
EQL Pharma AB:

• Small generic company in Lund
• Nordic market
• All manufacturing activities are outsourced to suppliers
• Final batch release in EU for a few products

,
3
– planning, coordinating, summarizing
• Read, review, write
– Interpret legislations and, guidelines etc.
• Communication/collaboration – meetings/e-mails/TC
– Business Partners, CROs, manufacturers,
consultants and other experts
– Medicines Agencies
– Colleagues
• Small details versus bigger picture
• Fast but still precise…

Generics
• What is a Generic?
• Data Exclusivity
• Reference Product
• Differences in
Challenges

Generic Product - Definition
The term ‘generic medicinal product’ is described in article 10, paragraph 2 under b) of
Directive 2001/83/EG:
‘“generic medicinal product” shall mean a medicinal product that has the
same qualitative and quantitative composition in active substances and
the same pharmaceutical form as the reference medicinal product, and
whose bioequivalence with the reference medicinal product has been
demonstrated by appropriate bioavailability studies.’
• API has the same qualitative and quantitative composition

• Product has the same pharmaceutical form
• bioequivalence has been demonstrated

Reference Product - Definition
The ‘reference medicinal product’ is a medicinal product authorised

under Article 6, in accordance with the provisions of Article 8 of Directive
2001/83/EG’ (full dossier)
Article 10 of Directive 2001/83/EG not only governs the contents of the

generic medicinal product’s file, but also lays out rules for the
protection of data in the reference medicinal product’s dossier (data
exclusivity).

Lb/U! J/LU It
Patents, Data Exclusivity

• Patents
• Drug substance patents
• Product patents
• Process patents
• Drug Product patents
• Formulation
• Process What is a Patent?
• Application (usage)
A patent is a grant made by a government that confers upon the
creator of an invention the sole right to make, use, and sell that
-
invention for a set period of time.
New
Have an inventive step Be sufficiently
described First to file
1t
Data exclusivity

26/05/201 f
Data Exclusivity Data Exclusivity
• 6/10 year rule states that the reference medicinal • Data Exclusivity
drug products must be marketed in the community • Directive 2004/27/EC amending Directive
for a period of at least 6/10 years before an 2001/83/EC introduced 8 + 2 + 1 years
application for a generic drug product can be made. = 8 years approved before submission of
• Example: abridged application
• 10 year countries: Belgium, Germany, ltaly. The = 10 years approved before marketing of
Netherlands, Sweden, UK, and Luxembourg. approved abridged application
= 11 years for extra innovative therapeutic
indication
• 6 year countries: Austria, Denmark, Finland,
lreland, Portugal, Spain, Greece, Norway and
lceland.
Drug Product - Dissolution
Comparing dissolution profiles
• 12 units
• F2 factor
• If F2 >50, profiles considered similar
• If dissolution i 85% in 15 minutes, profiles considered similar
without mathematical justifications
Immediate release product

• Discriminatory power – not always required
• Specification: single point (80% in 15 minutes) – or
replaced by integration test
Prolonged release product

• Specification example:
• Discriminatory power required- Critical
1. 20-40% at 1 hr
manufacturing variables that may affect
2. 46-65% at 4 hrs
bioavailability
3. >85% at 10 hrs

Quality
&
GMP
(Good Manufacturing Practice)
1
GMP - Generics vs. Originator
•The GMP requirements are identical for manufacturing of
Generics and Originator products
•However the typical business structure is in general different

-
Generics Originator
Production Often contract Own facilities

manufacturing
Products High number of Few high volume products
different products
and different types of
products
3
Challenges
Variations to the manufacturer of the product after

approval
Changes in the product or manufacturing process is often initiated by CMO due to

their needs or in some cases needs of other costumers. We must prepare and
submit the variations to implement the change.
Since we are one step away from the production it can be difficult to evaluate if
a changes is needed or just convenient for the CM
Challenges with this can be that we as contract giver is notified with short
deadline to prepare and submit the variation to the authorities The variation
documentation may be in-complete long timeline for approval at the
Authorities challenges in relation to the coordination of timing of the
implementation in relation to new orders
Challenges
Addition of a new API manufacturer :
The variation should include a QP Declaration
An audit of the API manufacturer and intermediate site if relevant is required.

Has often been performed by the CM since they use the same API for
several customers
QP must approve the quality of the audit and audit report and agree with
the auditor about the conclusion .
- Sometimes there are different interpretation of the audit requirement
within EU (regarding frequency and content).
30-05-2016
Release of products
- Transport conditions
- Control af the product and artwork
- CoA (Certificate af Analysis)
- CoC (Certificate af Conformance)
- Audit status
- Deviations (from manufacturing)
- Change controls (variations)
- Batch record review
- CoA from EU testing (for products manufactured outside EU/EEA/MRA}
Life Cycle management
•Audit of API and contract manufacturer (at least every 3rd year)
•Variations and implement approvals

•Product Quality Review (PQR)
•The objective is to verify the consistency of the existing process, the appropriateness of current
specificat ions for both starting materials and finished product to highlight any trends and to
identify product and process improvements.
•PQR also includes a review of
- All batch related data and test results including stability test results
- Starting materials
- Commitments and variations related to module 3
- Changes to equipment, process and analytical methods
- Technical agreement
- Deviations, Complaints and Recalls
Pharmacovigilance
30-05-2016
Pharmacovigilance for Generic Products
(Almost) Same obligations for generics and originator

medicinal products.
However there are differences:
9
Pharmacovigilance
Pharmacovigilance is an important part ot the lite cycle management for generic

products together with RA and QA
Generic companies have the same obligations as originator companies to secure

that the products is sate to use for the patients.
The authorities, originator and generic companies must cooperate to secure that the
benetit ot the product outweighs the risks and that the satety profile is up-to-date
with the latest knowledge and publicly available.
The implementation ot pharmacovigilance legislation will be on-going for several

years to find the appropriate leve! ot surveillance for originator and generic
products.
30-05-2016
Originator Medicinal Product

• For a new product on the market, the:
• surveillance must be intense,
• the safety profile for type of adverse reactions and frequency,
contraindications, interactions etc. must be updated frequently.
• One single serious adverse reaction can require immediate action:

• Urgent changes in the SPC;
• Withdrawal of the product from the market
• temporary or permanent.
• Each report for adverse reactions must be evaluated throughout by specialists

(doctors, pharmacists etc.)
• Several departments involved in safety and pharmacovigilance:

- Clinical Research Operations - Medical Information
- Drug Safety Department - Medical Advisors
Pharmacovigilance tasks
Risk Management Plans (RMP)
A risk management plan should describe the activities of a MAH to minimise the risks
associated with a product after it is marketed.
Extra monitoring of specific issues, PASS, educational material.
Originator product - more unknowns at first launch Generic products - well-known risk
The risk management plan for the generic product can/should be based on the risk
management plan for the reference product. However, when there is no RMP for
originator a new RMP should be prepared from scratch for the generic product!
Surveillance of adverse events

Receipt and evaluation of reports from the market
Literature surveillance
Implementation of EU initiatives
For example recommendations on labelling
– planning, coordinating, summarizing
• Read, review, write
– Interpret legislations and, guidelines etc.
• Communication/collaboration – meetings/e-mails/TC
– Business Partners, CROs, manufacturers,
consultants and other experts
– Medicines Agencies
– Colleagues
• Small details versus bigger picture
• Fast but still precise…

Regulatory Affairs – what I like
• Collaborations and contacts
• Diversity of tasks and challenges
• Finding solutions
• Learn new things
• Defining needs, planning

Thank you!

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Biomedicine the Profession – 27 September 2016

Anna Rytter, PhD

1 Regulatory Affairs, the role in pharma - BMC

• PhD – Experimental Brain Research, WNC -

• Post doc – Apoptosis Laboratory, KB-

• LEO Pharma AB - originals, affiliate, national,

• LEO Pharma A/S originals, Head Office global -

• EQL Pharma, - generics - Lund

2 Regulatory Affairs, the role in pharma - BMC

• Why regulate drug development

• Product Life Cycle - Regulatory Affairs Perspective

• Regulatory Affairs and its role in the Pharma company

• A typical day in Regulatory Affairs

3 Regulatory Affairs, the role in pharma - BMC

Regulatory Affairs is the knowledge and application of strategic

• Drugs are not ordinary consumer products

7 Regulatory Affairs, the role in pharma - BMC

”All substances are poisons; there is none which is not a

”The dose makes the poison”

8 Regulatory Affairs, the role in pharma - BMC

• First “modern” pharmacopoeias 16th century (e.g. Spanish

9 Regulatory Affairs, the role in pharma - BMC

• 1937 – Sulfonamide - diethylene glycol poisoning, 100 people died

• 1956 – thalidomide disaster, Neurosedyn. 10 000

1 Regulatory Affairs, the role in pharma - BMC

1 Regulatory Affairs, the role in pharma - BMC

1 Regulatory Affairs, the role in pharma - BMC

• Drug development and commercialization is highly regulated.

• The path to drug registration (Marketing Authorization) is paved with

10 Regulatory Affairs, the role in pharma - BMC

10 Regulatory Affairs, the role in pharma - BMC

Application and ApprovalPhase

Post Approval Phase

• Ensure application of guidelines

• Advice on studies to demonstrate safety, quality and efficacy

• Preparation of submission of application for clinical trials

16 Regulatory Affairs, the role in pharma - BMC

• Indication and dosing

The claims in the Product Information needs to be supported by scientific data

Ensure input from different parties.

19 Regulatory Affairs, the role in pharma - BMC

• Check progress of evaluation and anticipate questions (prepare

• Clarify raised questions, plan response and strategies with

• Negotiate approval and Product Information with agencies

20 Regulatory Affairs, the role in pharma - BMC

An agreement with the authorities

• Valid for a period of 5 years.

• After 5 years renewal required

21 Regulatory Affairs, the role in pharma - BMC

22 Regulatory Affairs, the role in pharma - BMC

• KEEP THE PRODUCT ON THE MARKET FOR A LONG TIME

23 Regulatory Affairs, the role in pharma - BMC

• Common Technical Document (CTD) is the standard format used for

20 Regulatory Affairs, the role in pharma - BMC

– Module 1 Administrative and prescribing information

– Module 2 Overview and summary of modules 3 to 5

– Module 3 Quality (Pharmaceutical documentation)

– Module 4 Preclinical (Pharmacology/Toxicology)

– Module 5 Clinical - efficacy (Clinical Trials)

27 Regulatory Affairs, the role in pharma - BMC

28 Regulatory Affairs, the role in pharma - BMC

Centralised Mutual Decentralised National

• Submit national application in RMS