MEDICINE REGULATION
REGULATORY DEPARTMENTS
GOOD REGULATORY PRACTICE
SAAPRA
1 June 2012
OVERVIEW
Development of Legislation
 Medicines Regulation and Regulators
 Regulatory Affairs Department (RAD)
 Good Regulatory Practice (GRP)
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Development of Medicines Legislation
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Typically medicine regulations have been developed
‘after the fact’
Triggered by unwanted and sometimes disastrous
events
Information and knowledge on the use of medicines
increases exponentially
Result - Medicines legislation proliferates
Development of Legislation
USA
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1846 – 1848 Mexican-American War
American troops supplied with substandard
medicines
1848 – Import Drug Act passed
1901 – concern over unsanitary condition in meat
packing industry and also quality of medicines
Medicines legislation outgrowth of food legislation
Development of Legislation
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1902 – 12 children died from contaminated
diphtheria toxin in St Louis
Result - Biologics Act of 1902
Demanded licensing of biological products and
facilities
1902 – 1907 Study on safety of food additives with
human volunteers
Led to - 1906 Pure Food and Drugs Act
First federal drugs law
Development of Legislation
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Prohibited mislabelling and adulteration of medicinal products
and
Introduced USP and NF as official standards
Legal system still allowed for unacceptable bizarre practices false therapeutic claims
1912 - US vs Johnson case – promoters of “Dr. Johnson’s Mild
Combination Treatment for Cancer” challenged
1912 Act amended –prohibited labelling with false therapeutic
claims
Development of Legislation
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1937 – Massengill Company place throat lozenge on market
Sulfanilamide dissolved in diethylene glycol (common car
antifreeze agent)
107 people died (mostly children)
Legislators acted rigorously to prevent reoccurrence
1938 – Food, Drug and Cosmetic Act passed
Medicine could only be marketed after 60 days if no FDA
objections
Development of Legislation
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Required proof of safety and efficacy
1951 – another amendment to Act
Divided products into OTC and prescription requiring
professional supervision
1962 amendments made proof of efficacy mandatory
Introduced GMP
Development of Legislation
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Further amendments over 20 years such as
1983 Orphan Drugs Act – for marketing and
commercialisation of medicines to treat rare
diseases
1990 Nutrition and Labelling Act
1984 Drug Price Competition and Patent Term
Restoration Act
1996 Generic Drug Enforcement Act
Development of Legislation
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1988 Prescription Drug Marketing Act
To ensure that medicines purchased by consumers
are safe and effective, and
To avoid the unacceptable risk to American
consumers from counterfeit, adulterated,
misbranded, subpotent, or expired drugs.
Additionally Guidance documents to be taken into
account by industry
Other reform bills constantly under consideration
Development of Legislation
EUROPEAN UNION (EU)
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Germany and other countries originally focussed on
pharmacies only
No Marketing Authorisation required for industrially
produced medicines
1961 registration introduced to determine what was
on market – notification process only
In Germany 55 000 medicinal products on market at
time
Development of Legislation
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Beginning 1960s sleeping pill Contergan
(thalidomide) caused birth defects
Taken by mothers in early
stages of pregnancy
Children born without arms hands starting at the shoulders
Called ‘flipper babies’
Development of Legislation
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An estimated 10 000 children were affected in
Europe
1968 appetite suppressant Menocil (aminorex)
caused many deaths – withdrawn from market
Led to implementation of medicines legislation in UK
and other EU member states
Today legislation in EU member states mirrors EU
Directive
Development of Legislation
SOUTH AFRICA
 1965 Medicines and Related Substances Control Act
published and first medicines called up in 1968
 2002 Medicines and Related Substances Act
amended making provision for inter alia licensing of
manufacturers, wholesalers, distributors, etc.
 2008 Amendment Act 72 introduced SAHPRA
 Latest draft amendment makes provision for the
structures required for the new juristic body
International Conference on
Harmonisation(ICH)
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ICH began to take place in 1989
Project of both Regulatory Bodies and
pharmaceutical industry from EU, Japan and United
States
Harmonisation the major factor
Goal - to expedite development and approval
processes for medicinal products
Does not compromise safeguards on Q/S/E
World Health Organisation (WHO)
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An intergovernmental organisation
166 member states within the Charter of the United Nations
Activities include support for ministries of health concerning
development of methods for assessing quality, effectiveness and
efficiency
Publications cover:
essential drugs
drug policies
quality control
ethical guidelines
safety assessment, drug research and development and
laboratories
Medicines Regulation and Regulators
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Medicine legislation makes provision for Regulatory
Authorities or Bodies
Have developed and continue to develop legislation
This had and continues to have a significant effect
on pharmaceutical industry
Medicines Regulation and Regulators
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Common misunderstanding – that Regulators
register our medicines
They keep medicines off the market unless the
applicant can prove quality, safety and efficacy
Ensure compliance with legislation
Control the use and minimise the abuse of
medicines
Re-evaluate the medicines on the market
Regulatory Affairs Departments (RAD)
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Why have companies established Regulatory Affairs
Departments ?
Simple answer – because there are regulations and
regulators
To understand and fulfil regulators’ needs as
environment has become more and more complex
Regulatory Affairs Departments (RAD)
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Mistakes cost a lot of money
Worst mistake – calling in RA after plans have been finalised
Pitfalls of product development:
Not involving RA in plans
Suppressing critics in the company – they are valuable in
identifying problems
Hiding critical issues chances good reviewer will spot
them
Telling all you know – leads to confusion
Regulatory Affairs Departments (RAD)
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Trying to make it perfect – a lot of time will be lost
Doing all the studies as early as possible e.g. marketing
studies
Using in-house methods to structure the documentation –
adapt to Regulator’s structure
Regulatory Affairs (RA)
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RA is usually recognised as having three basic functions:
The outlet of the company to Regulatory Bodies
The interpreter of regulations to companies
The influencer of new regulations
Makes RA the interface between companies and Regulatory
Bodies and
Key player in the product development and maintenance
process
Activities of the Regulatory Affairs
Department (RAD)
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Activities depend on each company’s structure and
organisation
Start at the initial development of medicinal products
Continue through until the launch of the product
Steer and maintain an application through the legislative
framework - allows a Regulatory Authority to reach a scientific
decision
Once launched, the RAD fully involved in Marketing
Authorisation (MA) maintenance and post-marketing activities
Activities of the RAD
Product Development
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RAD should be involved in the creation and evaluation of all
aspects of research and development plans
Advise departmental heads and project managers on the
requirements and any upcoming legal changes with potential
impact for registration
RAD should give advice for optimising development plans
By an accurate interpretation of the requirements of the existing
guidelines
Ideally should be done within the scope of a Regulatory Strategy
Document
Activities of the RAD
Product Development
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Ideally RAD should be able to liaise with Regulatory Authorities
on any scientific aspect of:
– future Marketing Authorisation (MA)
– dossier and co-ordinating with the other departments
– the briefing document including the questions and
company’s positions
On our wish list!
Activities of the RAD
New Registrations
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RAD responsiblities:
proposing the best registration strategy
taking into account the possible registration procedures
the impact of intellectual property rights
the peculiarities of the product
the scientific content of the different part of the dossier
RAD preparation of Regulatory Strategy Document (RSD)
containing all the essential global regulatory aspects of product
development
including scientific advice
meeting with the Regulatory Authority
Activities of the RAD
New Registrations
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RAD – ensure all activities related to obtaining registration comply with
existing legislation i.e.
– laws, regulations, directives and guidelines
– need to be proactive
RAD - should establish ethical, practical, technical and regulatory
standards:
laid down in policies and SOPs
specify the responsibility of each staff member involved
describe the process
ensure content of dossiers in compliance with existing
legislation and standard needed to obtain registration of the
product
Activities of the RAD
New Registrations
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RAD responsiblities:
– writing, co-writing, editing and/or authorising all documentsfor use
in registration dossiers or communication with the Authority e.g.
manuscripts, expert reports, method of use, standard advice for
patients and labels
– should strive for world-wide implementation of harmonised
prescribing information
– should be responsible for the accurate planning and co-ordination
of compiling the dossiers
– Take into account the possibilities for electronic submission of the
dossier or parts of it especially in terms of submission of eCTDs
Activities of the RAD
New Registrations
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Ensuring administrative validation
Chasing up the dossier throughout the assessment and
Anticipating the possible questions from the Regulatory Authority
in order to optimise the timing, quality of the answer and Marketing
Authorisation (MA) approval and package insert (PI) wording
Queries from the RA should be answered in a consistent manner and
within the time limits set by the agency when indicated, according to
internal guidelines
Status reports should be issued regularly in order to provide
information on the world-wide registration situation
Activities of the RAD
Registrations
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submission strategies (timing, responsibilities, free sale certificates
and answers to the Authority, questions, intellectual property
dossier updates (variations and safety)
dossier renewals
Periodic Safety Update Reports (PSURs) planning and a
contingency plan
must address the proposed labelling with Marketing and Sales
the impact on discussion with pricing and reimbursement
authorities
Activities of the RAD
Maintenance of Existing Registrations
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All existing registrations should be carefully maintained and regularly
updated to reflect the current standards and knowledge
Variations and change control:
– Management of change control forms are an important element of
GRP - Such changes include:
o Product data or specifications
o Manufacturing of analytic methods
o Facilities or suppliers as well as line extensions
o Additional indications, etc.
All such changes have to be communicated to the RA in accordance
with the respective legal requirements affected
Activities of the RAD
Maintenance of Existing Registrations
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Queries raised by the RA to ensure regulatory compliance
RAD and quality assurance department should liaise closely on all
aspects affecting variations and change control
Responsibility of RAD, Responsible Pharmacist and QA (Quality
Assurance) to ensure manufacturing and QC (Quality Control) comply at
all times with the registration dossier
RAD should assure regulatory compliance by the manufacturer,
packager and marketing department
Activities of the RAD
Maintenance of Existing Registrations
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Changes to PI and/or PIL
Changes might be initiated by marketing or medical department
Can also be requested for new safety data
RAD and medical / pharmacovigilance c liaise closely for the
preparation and timely implementation once the revised wording is
approved
RAD in close collaboration with the Drug Safety department and a
Qualified Person for Pharmacovigilance
Do PSURs planning on a yearly basis for each product
Collect all the information needed for their submission, taking into
consideration post-approval commitment or follow-up measures
Activities of the RAD
Maintenance of Existing Registrations
It is the duty of RAD
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to ensure activities related to post marketing studies are carried out in
compliance with and reported according to, existing legislation.
to inform the Regulatory Authorities of any pharmacovigilance issue and
to implement and file the necessary data into the official documents
this will be done in close co-operation with the medical department and
Qualified Person for Pharmacovigilance
Activities of the RAD
Regulatory intelligence – Objective 1
RAD should –
 have a system in place to ensure the tracking of all the versions, either
approved or a draft for comment, of regulations guidelines and concepts
papers
 on an on-going basis review relevant world-wide legislation, guidelines,
discussion papers, codes of conduct, etc.
 interpret the scope and possible consequences arising from such
legislation and codes and inform the company accordingly(may affect the
activities of the company)
 ensure and co-ordinate the necessary activities arising from changes to
ensure that compliance with regulations will be met.
Activities of the RAD
REGULATORY INTELLIGENCE - Objective 2
RAD should –
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comment on new draft guidelines / draft legislation and take an active role in
participating in the outcome of final regulatory comments.
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for this purpose preferably join pharmaceutical associations to represent the needs
of pharmaceutical industry on a higher level.
Good Regulatory Practice (GRP)
Problem today:
 Insufficient quality submissions to the Regulatory Authority
 Industry and Regulator perceive each other as opponents
rather than partners
 We are like opposite sides of the
same coin -neither side detracts from the
value of the coin but rather together give it
its character and identity.
Good Regulatory Practice (GRP)
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Present system based on mutual mistrust
Involves high cost i.t.o. time, manpower, rejects on both sides
Quality cannot be added by regulations, guidelines, etc.
Without any real dossier quality improvement timelines cannot
improve
Good Regulatory Practice (GRP)
Could GRP be the solution to the problem?
Good Regulatory Practice (GRP)
What is GRP?
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Establishment of a quality system
Involves both industry and Regulator
About trying to achieve quality by less rather than more control
About producing quality in the first place
Based on sound science, coupled with organisational ability
Good Regulatory Practice (GRP)
What are the goals of GRP?
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Efficiency: quick and qualified decisions on Q/S/E of products
Effectiveness/productivity: effective use of resources, costeffectiveness
Results: achieve and preserve an image of high standing
Good Regulatory Practice
What are the advantages of GRP?
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Quality medicines available to patients in timely fashion
Because global picture is seen and
Entire process is designed to produce quality
Good Regulatory Practice
How?
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Decide on goals
What must be done by whom and how
Write it down
Adhere to it
Watch the results and if necessary modify the system
Good Regulatory Practice(GRP)
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A pre-requisite to GRP - the communication of all relevant
information, including its evaluation and relevance for the
existing product, to ALL interested parties within the
organisation
Pivotal to GRP is the need to keep abreast of world-wide
legislation including potential changes and
The interpretation of possible consequences in the event of
failure to meet requirements
Good Regulatory Practice(GRP)
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The involvement of GRP in the concept of Total Quality
Management (TQM) is essential from initial development
phase of the product and continues for its entire life
Efficient RAD organisation and working methods are
mandatory
RAD skills for communication and communicating
information to other departments - a key parameter to
ensure compliance with regulatory requirements
Good Regulatory Practice (GRP)
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Implementation of GRP essentially contributes towards
continuous Total Quality Assessment of all aspects of
regulatory affairs and is
The essential link between each discipline in Total Quality
Management
Increasing complexity of regulatory requirements especially
as RADs operate numerous interfaces within a
pharmaceutical company
Good Regulatory Practice (GRP)
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GRP Guidelines define the role and position of the RAD within
the organisation
Appropriate and effective management of the regulatory
process is mandatory for:
– Bringing a medicinal product to the market and keeping it
there
– In compliance with legal, scientific, ethical and
administrative requirements
– To ensure the compliance of the relevant company’s
activities to the local and global regulations in terms of
official and company regulations
PERSONNEL
There should be sufficient personnel at all levels within the
organisation with the:
 Ability
 Education
 Training
 Experience and
 Appropriate professional skills to perform the tasks assigned to them
 All personnel should be trained regularly in their skills to ensure they
possess sufficient skill and knowledge of the procedures and policies
of the organisation
 Ideally, all graduate personnel should have a multidisciplinary
background
PERSONNEL
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Ideally, all graduate personnel should have:
– multidisciplinary background
– scientific expertise
– communication and negotiation skills
– regulatory knowledge
– planning capacity
– be able to work in teams
– to organize multidimensional projects
– to work in a multidimensional manner
Standard operating procedures should be designed to deal with
communication and flow of information
PERSONNEL
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The responsibilities of the Responsible Pharmacist (RP) and the
Qualified Person for Pharmacovigilance (QPPV) in relation to the RAD
should be clearly defined
These responsibilities should be explained and written into the job
description for each person together with any training and education
required on product registration
Key personnel in responsible positions should be accountable for:
– authorizing procedures and tasks and
– having adequate supporting staff
– persons should be designated to deputise for them in their
absence
PREMISES
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Premises should be designed and maintained in good order
To provide sufficient space to suit the activities being carried out
Should allow efficient work flow
Should permit effective communication and supervision
Physical and non-physical working conditions:
– Ergonomics
– Environmental factors
– Stress
All necessary equipment for the activities to be performed efficiently should
be provided – personnel should be instructed in the proper use of equipment:
– Computer hardware and software
– Printers and copiers
– Archives and means of communication
QUALITY ASSURANCE (QA)
A good quality management system (QMS) should be
set-up by RAD for all the activities under its
responsibility
QUALITY ASSURANCE
Procedures
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Procedures should be laid down in writing in standard operating
procedures
Authorised by appropriate staff and communicated to the relevant
personnel
This should be readily available and be checked and updated regularly
SOPs should be adapted / renewed in the case of new or amended
standards
SOPs should be established on how to implement relevant legislation
and codes and the consequences for the organisation’s policy
RAD should develop policies for situations in which changing
legislation and codes make it necessary to adapt to it
QUALITY ASSURANCE
Procedures
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Procedures should cover the different areas in RA to:
– Specify responsibilities and organisation
o regulatory development plan
o development of PI and PIL
o preparation of CTD
o compilation of dossier
o change control
o preparation of response documents
o maintenance of registration
o preparation of renewals, etc.
QUALITY ASSURANCE
Self-Inspection
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Regular self-inspections should be performed by RAD in cooperation with QA to –
check and ensure compliance with the relevant regulations
by staff at all levels
check the compliance with the procedures and
adapt the procedure according to current practices
QUALITY ASSURANCE
Training
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An initial training program should be in place for new employees to
ensure a good understanding and therefore compliance
All RAD staff should be regularly trained in procedures to ensure good
understanding and therefore compliance
Each new procedure or update of existing procedure should also lead
to a specific training on the changes implemented
Understanding of all these aspect of the procedure should preferably
be assessed by knowledge control
A tracking system of the annual training should be organized
DOCUMENTATION
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Good documentation is essential for the
whole organisation and especially the RAD
All documentation should be prepared with
great care and clearly written to prevent
errors that can arise from oral
communication
DOCUMENTATION
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Documents should contain all the information necessary for
proper use:
– Title, type and objectives should be unambiguous and
clearly stated in SOPs
– All documentation should be reviewed regularly and kept up
to date
– Amendments should be dated, authorized and signed by
the appropriate personnel
DOCUMENTATION
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An appropriate system should be in place to:
o ensure traceability of documents and their different
versions
o answers to the Regulatory Authorities
o changes in PI
o variations etc.
All documentation should be securely stored but readily
accessible to RA personnel
When prepared or stored electronically validation processing
programmes should be used
DOCUMENTATION
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Data should be protected against loss or damage e.g.
– Use of backup procedures
– Only authorised personnel should be allowed to enter or
change data
ARCHIVING
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A good archiving system is mandatory:
– It should be described in a procedure
– Describe, both the documentation and electronic
documents,
– The archiving plan,
– The management of the different versions,
– The answer to questions from Regulatory Authorities,
– The traceability and the measures taken to ensure regular
backup.
COMMUNICATION
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Due to the multidisciplinary activities under the responsibility of
RAD close relationship with almost all the departments is
needed:
– Pre-clinical
– Medical
– Pharmacovigilance
– Production
– Quality Control
– Quality Assurance
– Marketing and sales etc
COMMUNICATION
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RAD skills for communication and communicating information
to other departments, Regulatory Authorities, Professional
Associations
Communication - Key parameter to GRP in terms of compliance
with regulatory requirements, lobbying, negotiation, effective
relationship with external bodies
Checklist for Performance of RADs
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Perceives disciplines and Regulators as partners, not enemies
Establishes/maintains efficient contact with Regulator
Works proactively
Proactive in product development/maintenance teams
Market orientated and customer focussed
Submits dossiers of sufficiently high quality in a timely fashion
to obtain and maintain registrations
Maintains a quality system
Advice
Make your mission in the organisation clear.
Make your voice heard.
You are one of the most valuable team
members if allowed to live up to full capacity.
Suggested Reading
Good Drug Regulatory Practices
A Regulatory Affairs Quality Manual
Helene I. Dumitri
Over to you!
MRA Regulatory Consultants
381 Rossouw Street
Murrayfield
Pretoria
Tel: +27 (0)12 803-6223
allison@mra-regulatory.com
henriette@mra-regulatory.com
robyn@mra-regulatory.com