Regulation of Clinical Products
Production Manager, EnteroBiotix
• Regulatory affairs is a profession developed from the desire
of governments to protect public health by controlling the
safety and efficacy of products in areas including
pharmaceuticals, veterinary medicines, medical devices,
pesticides, agrochemicals, cosmetics and complementary
• Professional Body – TOPRA (The Organisation for
Professionals in Regulatory Affairs)
• Described by one as science in a suit
• Less laboratory based
Substances and Medicines
• Paracelsus (1493-1541)
• All substances are
poisons; there is none
which is not a poison.
The right dose
differentiates a poison
and a remedy (medicine)
• On June 15, 1667, Dr. Jean-Baptiste
Denys, personal physician to King
Louis XIV, performed the first human
blood transfusion. The patient was a
15 year old boy who had been treated
by using leeches to suck out “the bad
• His experiments with animal blood
provoked controversy and in 1670 the
procedure was banned in France.
• Regulation by king, pope and
parliament - Stopped progress for
nearly 150 years
Landsteiner – Blood Groups
• 1900 Landsteiner describes blood groups
Transfusion comes good
• Blood transfusion is often cited as the major
medical advancement of the First World War
• 1919 Aberdeen surgeon Henry Gray gives talk to
Rotary club describing his war experience
• 1928 Staff of infirmary set up transfusion service
and 6 years later 34 on donor panel and 32
transfusions that year.
• 1988 European Blood Directive
• Thalidomide was first manufactured for the purpose of treating
respiratory infections but was also used for morning sickness.
• During clinical trial everything went well and as it was impossible
to die from an overdose of the medicine, it was deemed safe, and
it hit the shelves in 1956
• In 1961 the link between Thalidomide, offspring and the occurring
limb deformities was discovered.
• Over 10,000 people paid the price
• 2001 – Medicines Directive
• Development of Biologics
• After initial rejection problems there were successful
Bone Marrow transplants from 1968
• Many centres started peripheral blood stem cell
transplants and cord transplants in the 1990s.
• Quality of some of this work varied leading to the
requirement for regulatory controls
• 2004 – European Tissue and Cells Directive (EUTCD).
• Mainly regulated by Human Tissue Authority
• An Advanced Therapeutic Medicinal Product is defined as either:
(a) a gene therapy ‘medicinal product’
(b) a somatic cell therapy ‘medicinal product’
(c) a tissue engineered product – a product that:
• contains cells or tissues that have either been subject to ‘substantial
• is presented as having properties for treating or preventing disease in human
• MHRA is the competent authority
• Specials Scheme - interpreted to mean the absence of a pharmaceutically
equivalent and available licensed product
• 1964 - The Declaration of Helsinki establishes Ethical principles for
• 1965 - EU decides that Medicinal Products need to be authorised
before being placed on the market and developed structured
medicinal regulations. (UK Medicines Act, 1968)
• 1989 – First Guidelines on GMP
• 2001 – Medicines Directive
• 2004 – EUTCD (UK – Human Tissue Quality and Safety Regs 2007)
• 2007 – Regulation on ATMP
• To ensure quality, safety and efficacy of drug products in
order to assure the continued protection of Public Health.
• No drug product is completely safe or efficacious in all
• There is a moral and legal expectation that appropriate
steps are taken to assure optimal quality, safety and efficacy
by the producers.
• Benefit versus Risk.
• Regulation provides standards
• Standards give specification and develop guidelines
• Audit or inspection based around standards
• Compliance means conforming to a rule, such as a
specification, policy, standard or law.
• Regulatory compliance describes the goal that
organisations aspire to achieve in their efforts to
ensure that they are aware of and take steps to
comply with relevant laws, policies, and regulations
• Regulatory affairs officers ensure that products
such as cosmetics, pharmaceuticals, and veterinary
medicines meet legislative requirements and
• Key duties of the job include: studying scientific
and legal documents
• Ensuring compliance with regulations
• Development – advice, dossier preparation – quality
and clinical, product claims, clinical trial.
• Licence approval – application / submission,
compliance, ‘go-between’- business, quality,
production, support functions.
• Post licence – life cycle(drug) management, compliance
with limitations, clinical trials, new angles of
• Quality control – checking against defined set
of quality criteria
• Quality Assurance - determining whether a product
or service meets specified requirements. Ensures
• Regulatory Affairs - handle regulatory matters for
• Get the product to market
• Keep it safely there as long as possible
• Balance business with regulatory and quality
• Keep investors happy
• Achieve best Manufactures Licence (MIA)
Clinical trial error
• France clinical trial: One person brain-dead
and five in hospital after drug testing
'accident' in Rennes
• Dose should have been
1.25mg, but used up to 100mg.
• Insufficient pre clinical data.
• The requirements and procedures for marketing
authorisation, as well as the rules for monitoring
• Additionally, EU legislation provides for common
rules for the conduct of clinical trials (to test the
safety and efficacy of medicines under controlled
conditions) in the EU.
Hierarchy of risk
1 A licensed UK medicine
2 An off-label use of a UK licensed medicine
3 An imported product licensed in the country of
4 A UK manufactured special made in MHRA-
5 An extemporaneously dispensed medicine
6 An imported product not licensed in the
country of origin
7 A non-UK-made unlicensed medicine or food
Regulated manufacturing centres
• Moving technique from essentially research to
• Requires a Quality Management System(QMS).
• Must work to GMP.
• Inspection body checks compliance against current
• Generally a risk based approach.
Summary of trial regulations - linking the stages
Phase I, II, III
National licence – CTA
Unlicensed (hospital exemption, Specials)
Grafts / transplants
Processing, preservation, storage, distribution
Cert of Quality &
MHRA view of GMP
– Required for all medicinal product manufacture
• Risk-based inspections – across all GxPs (GMP, GLP, GCP, GSP,
GDP) – lab, clinical, storage, distribution.
• GPvP - Pharmacovigilence
– Quality Risk Management (QRM), ICH Q9, principles in Chapter 1
• evaluation of risk to quality based on scientific knowledge and
link to the protection of the patient
• EudraLex - Volume 4 - Good Manufacturing Practice
• Contains guidance for the interpretation of the
principles and guidelines.
• Basis for MHRA standards.
• Guidance on clinical trial – Investigational medicinal
General GMP issues
• Tends to be focus of attention due to capital and running costs
– Quality Systems:
• Main elements: documentation, change control, validation, training,
production, QC, batch release, self-inspection, quality incidents
(deviations, complaints, recall)
• may not be given full attention, focus is on facilities / equipment
• ‘simple as you can, complex as you must’
– Annex 13 requirements for IMPs:
• Product Specification File
• Validation is required for facilities and equipment
• Process validation relaxation – focus on safety