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2.3 Quality Assurance Systems 25
2.3 Quality Assurance Systems
The application of quality assurance systems and standards is a fundamental
element of the strategy to ensure that products are consistently safe, eective, and
of acceptable quality. Dierent quality systems are stipulated depending on the
activities involved, such as good manufacturing practices (GMP), good laboratory
practices (GLP), good clinical practices, or more general quality assurance systems
for design, development, production, installation, and servicing (e.g. ISO 9001). You
will look atspecic aspects of the dierent systems in later chapters, but atthis stage,
it is appropriate to examine some of common core principles on which the systems
are based.
2.3.1 Personnel
People are a key element in all quality systems. Every single individual in an organ-
isation must understand what their responsibilities are and how the task that they
perform can aect quality. Of course, they must also be capable of doing the job.
Job descriptions should be created to dene the duties, responsibilities, and author-
ity level of each position in an organisation. Job specications are used to identify
the qualications, skills, and experience that are required. Review of an individ-
ual’s qualications, skills, and experience in comparison to the job description will
identify the training needs of that individual. A qualied engineer may have all
the knowledge necessary for an engineering position, but will still have basic train-
ing requirements in terms of company policies, procedures, software systems, etc.
For many companies, a generic training plan is prepared in the form of an induc-
tion programme that can be tailored to an individual’s needs. Records of all training
delivered should be documented and maintained in a training record that can be
made available to auditors for examination during an inspection (see Figure 2.3).
The overall management structure must be clearly outlined in organisational
charts or other appropriate means. To demonstrate the organisation’s commitment
to quality, it is normal for the Quality Manager to report directly to the Chief
Executive Ocer. Regular management reviews of the quality system are also an
essential element and again it is common practice for all the senior management of
a facility to participate in such reviews.
2.3.2 Documentation
Documentation is another essential ingredient in all quality systems. It serves as
a mantra for auditors and inspectors that ‘if it is not documented it does not exist
Job description
Job specification
Training
requirements
Training
plan
Training
record
Figure 2.3 The training process.
26 2 Regulatory Strategy
or it never happened’. The documentation requirements can be split into two main
categories, procedures outlining what must be done and records showing what has
been done.
The performance of all tasks must be described in detailed written procedures.
Procedures describing recurring tasks are usually referred to as Standard Operating
Procedures (SOPs) or General Operating Procedures (GOPs) whereas procedures
describing non-repetitive tasks are called protocols (e.g. clinical trial protocol).
Specications complement procedures and are used to set the standards that apply
to any stage of a product or process.
A document control function is required to regulate the authorisation and circu-
lation of such documents. This involves sign-o on a master copy of the document
by authorized personnel, followed by a recorded circulation of ocial copies to rel-
evant departments. If a document needs to be updated, the revised version should
be reviewed and approved by the same functions that approved the original. The
revised version is then issued with a new version number and date and all copies of
the obsolete version should be destroyed other than the obsolete master, which may
be kept for historical traceability.
Records of all tasks performed and results obtained should be written down in
black or blue ink, if using paper records. Pencil is not acceptable. If you discover a
mistake, you should draw a single line through the error and write the correct infor-
mation above or beside it accompanied by the date and your initials (see Figure 2.4).
You should never obliterate the error with correcting uid. Your records could end
up as evidence in legal proceedings. Records in the form of various types of techni-
cal les serve to satisfy authorities that the products that you developed are safe and
eective and may be authorized for marketing. While such dossiers may just con-
tain condensed data summaries it is vital that the original raw data records can be
produced if necessary.
Traditionally, documentation has been maintained on hardcopy paper systems.
However, soft copy computer records are permitted provided it can be assured that
the records can be maintained without corruption. More sophisticated systems
that are used to create electronic records and electronic signatures must be capable
of identifying the time, date, and person responsible for creating or amending
the record. Specic regulations dealing with these requirements will be discussed
further in Chapter 11. Figure 2.5 provides an overview of the types of documents
associated with most quality systems.
2.3.3 Facilities and Equipment
Quality systems require that facilities and equipment should be appropriate to the
activities undertaken. Surfaces that are easy to clean and maintain in hygienic
condition are a requirement in many situations. For example, cloth-backed chairs
The average was calculated as 135. This is ….
Figure 2.4 Correction of an
error.
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2.4 Validation 27
Documentation
RecordsProcedures
Batch records
Log books
Experimental records
Technical files
SOPs
GOPs
Specifications
Protocols
Manufacturing formulae
Figure 2.5 Documentation summary.
would not be acceptable in a laboratory that handled potentially biohazardous
materials. Equipment should be checked at installation to demonstrate that it
can perform its desired function. This is frequently done using an installation
qualication, operational qualication, and performance qualication (IQ/OQ/PQ)
commissioning process. Routine maintenance and calibration programmes are then
required to ensure that equipment continues to deliver the specied performance.
2.3.4 Corrective and Preventative Action
Quality systems are intended to be self-correcting and self-improving. Triggers that
prompt corrective or preventative actions can come from a number of sources.
Regular internal auditing of a quality system is a fundamental requirement. These
audits should be conducted by personnel independent of the operational area being
audited e.g. a quality department should not audit their own activities. The results
of such audits, together with those from outside inspection bodies, will invariably
identify areas for improvement.
Feedback from the market is another key data source. This can come through cus-
tomer comments or complaints or through the vigilance systems that are mandatory
for drugs and devices.
Data collected on the day-to-day operation of a facility are a more immediate
source of information. This requires recording of all nonconformances, procedure
deviations, product failures or product recalls. A variety of statistical tools may be
used to analyse the data and identify underlying trends.
Thorough investigations should be conducted according to a predetermined SOP
to ensure that the root cause is identied, if not already obvious. Once this has been
done, a corrective action plan must be agreed and the process closed out by verifying
that the corrective or preventative action has been implemented eectively.
2.4 Validation
Validation is an activity that can be dened as providing conrmation by examina-
tion and objective evidence that the particular requirements for a specic intended
use can be consistently fullled.
28 2 Regulatory Strategy
It can be applied to either a product design or a process. It is important for you to
understand the dierence between verication and validation. Verication means
conrmation by examination or direct measurement that specied requirements
are met.
The following examples may serve to illustrate the dierences between both
activities;
If you were a box manufacturer producing boxes of specied dimensions, it could
be practically feasible to measure each box individually and verify that it meets the
specication. On this basis, you could have complete condence that each box will
be capable of holding objects of a certain size.
However, there are many situations where verication studies may be either
not practical or not possible so as to assure that a product or process functions as
required. Consider a process where you produce packaged sterile devices. You could
only verify that an individual device is sterile by breaking the seal and testing, after
which it is no longer sterile i.e. the verication testing is destructive. Validation
studies oer the only means of providing a high level of condence that all the
devices will be sterile. The validation studies in this case would involve challenging
the sterilisation process by exposing the devices to a signicant microbiological load
and then verifying that sterilization is achieved under the minimum sterilisation
condition. Once you can demonstrate that the process works under worst-case
conditions, you can then have condence that it will work consistently under
normal controlled operating conditions.
For product validation, the objective is to demonstrate that the product will meet
the users’ needs when operated under the intendeduse conditions. Consider thepre-
vious example of the box. The dimensional verication studies would have shown
that it was capable of holding objects of a certain dimension. However, this alone
would not guarantee that the box could perform its intended containment and pro-
tection functions. The weight of the object and consequent handling requirements
would have a signicant bearing on the required rigidity of the box. Similarly, if it
was intended for use in cold storage, uptake of moisture from the surrounding damp
conditions could have a negative impact on its rigidity. Field trials or testing under
simulated-use conditions are often the only way of demonstrating that a product
will function correctly under the totality of conditions that may be experienced in
normal use.
Validation also applies to software. In a simple example, you could create an excel
spreadsheet template with xed formulae to calculate the mean and standard devia-
tion of a range of data. To validate this template you would enter a set of sample data
and verify the template-calculated results against the manually calculated results. To
be condent that the template could be used for further data sets you would pass-
word protect the cell formulae and verify that they cannot be altered without it.
Looking at these examples, you can see that verication is very much a retrospec-
tive activity, where the objective is to conrm that what has happened is correct,
whereas validation takes a prospective view with the objective being to establish
condence that a product or process will work satisfactorily.
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2.5 Regulatory Bodies 29
2.5 Regulatory Bodies
Having looked at the strategies that are used to achieve regulatory goals we shall
now look at the principal bodies that are involved in implementing these strategies.
2.5.1 European Commission
The European Commission is organized into various departments, known as
Directorates General (DGs), which are the equivalent of civil service departments
at national level. DGs are responsible for dierent policy areas and DGs develop,
implement and manage EU policy and laws. Executive responsibility for drugs and
devices at European Commission level is located within the Directorate General
SANTE (Health and Food Safety).
In the context of pharmaceuticals and devices, the general policy aims are as
follows:
● ensure a high level of protection of public health,
● promote a single market for drugs and devices and
● foster a stable and predictable environment for innovation.
The activities can be broken down under four main headings: legislation, support
and guidance, external relations, and information technology.
In the legislative arena, the tasks are to:
● maintain, update and simplify EU legislation whenever feasible,
● draft new legislation,
● propose decisions for the authorisation and surveillance of medicinal products
under an EU centralised procedure and
● propose Commission regulations on maximum residue limits (MRLs) of veteri-
nary medicinal products in foodstus of animal origin.
In supporting consistent application of the regulations at national level the DG:
● draws up detailed guidance documents,
● provides guidance on legislation and ensures that it is properly implemented
within the EU and
● supports the mutual recognition of national marketing authorisation decisions for
drugs.
In external relations with non-EU countries the DG:
● participates in international assemblies that promote global harmonisation of
requirements,
● negotiates mutual recognition agreements with third countries,
● pursues cooperation with Central and Eastern European Countries and
● prepares for and veries the implementation of EC legislation in EU accession
candidate countries.
In the area of information technology and communication, the DG coordinates
the development of IT systems that permit greater visibility and interaction between
30 2 Regulatory Strategy
all concerned parties, whether they be regulators, manufacturers or consumers.
For the pharmaceuticals sector, it provides systems for secure transfer, sharing and
tracking of information between the regulatory bodies. It also hosts a number of
databases including the Union Register of medical products centrally approved
for human and veterinary use, and the EudraLex collection of the legislation and
guidance documents that constitute ‘The Rules Governing Medicinal Products in
the European Union’. This is a 10-volume compilation that is also available on CD.
Similarly for medical devices, an enhanced EUDAMED database is being developed
to support the implementation of the 2017medical device regulations. It is envisaged
as a multipurpose system that will function as a registration system, a collaborative
system, a notication system, and an information dissemination system open to
the public.
The commission is assisted by a number of consultative committees and expert
working groups (WGs). The legislation provides for committees with formal
consultative and regulatory functions. These contain representatives from each
Member State and the Commission and enable the states to express their opinion
at the stage when new legislative measures or decisions are being contemplated
or prepared. Through the use of IT, much of their business is conducted remotely
without the need for formal meetings. The relevant bodies involved in procedural
tasks are:
● The Standing Committee on Medicinal Products for Human Use,
● The Standing Committee on Veterinary Medicinal Products and
● The Medical Device Coordination Group (‘MDCG’).
In addition to the formal committees specied in legislation, the commission is
assisted by other expert committees and WGs. Depending on the subject matter,
these can be drawn from the regulatory bodies, the scientic community, or industry
and end-user associations.
2.5.2 The EMA
The second body with a pan-European regulatory remit is the European Medicines
Agency (EMA; formerly known as the European Medicines Evaluation Agency or
EMEA). Whereas the Commission is concerned mainly with legislative and admin-
istrative tasks, the Agency focuses on providing supporting scientic expertise,
advice, and evaluation services. TheAgency was established in1995 as the European
Medicines Evaluation Agency on foot of EU regulation No. 2309/93. This regulation
created the rst centralised Community procedures for authorization of medicines
(Chapter 6). The name of the agency was shortened by a subsequent regulation
to its current title of the European Medicines Agency. The function of the EMA is
not to duplicate the activities of national competent authorities (see next section),
but to co-ordinate the scientic resource base found in these competent authorities
with a view to the evaluation, supervision and pharmacovigilance of medicinal
products. It directly employs a relatively modest number of sta (approximately
900) and reported an annual revenue of just over €400 million in 2020.
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2.5 Regulatory Bodies 31
The agency has a number of goals as outlined in its mission statement, which is
to foster scientic excellence in the evaluation and supervision of medicines, for the
benet of public and animal health in the European Union. At its core, the EMA
serves to protect human and animal health by:
● Facilitating the development of and access to medicines.
● Evaluating applications for marketing authorization of medicines.
● Monitoring the safety of medicines across their life cycle.
● Providing independent and reliable information on medicines.
It is also important to note regulatory-related activities thatfall outside of theremit
of the EMA. The EMA does not:
● Evaluate marketing authorizations for all medicines – as we will see later, many
medicines available in individual EU states are authorized at national state level.
● Evaluate medical devices, which occur via Notied Bodies.
● Evaluate applications to carry out clinical trials within the EU – such applications
are currently authorized at individual member state level.
● Evaluate food supplements and cosmetics, which again are evaluated at member
state level.
● Issue marketing authorizations or develop laws concerning medicines (a role
which is reserved for the European Commission itself).
● Regulate the price of medicines.
The agency is a decentralised body located in Amsterdam, The Netherlands and
consists of:
● A management board,
● An executive director,
● Agency sta and
● Scientic Committees.
The management board is responsible for general supervision of the agency and
among other dutiesadopts the annual work programmes and budgets forthe agency.
The board is comprised one representative of each Member State, as well as repre-
sentatives from the Commission, the European Parliament, patient groups, doctors’
associations and veterinarians’ associations. Each board serves a term of three years
and is led by a chairperson elected from among its members.
The executive director is appointed by the board for a term of ve years, and is,
together with approximately 900 sta, responsible for the day-to-day operation of
the agency. A prominent function of the sta is to provide scientic, technical and
administrative support to the Scientic Committees. The EMA organisational struc-
ture is shown in Figure 2.6.
The scientic committees are key to the functioningof the agency. They are the sci-
entic decision-making component responsible for delivering opinions and advice
on any issue relating to medicines. There are seven committees focused on dierent
areas:
● The Committee for Medicinal Products for Human Use (CHMP),
● The Committee for Medicinal Products for Veterinary Use (CVMP),
32 2 Regulatory Strategy
Executive director
Human
medicines
division
Veterinary
medicines division
Scientific
evidence
generation
department
Quality and
safety of
medicines
department
Committees
and quality
assurance
department
Evaluation and
innovation
support
department
Surveillance and
regulatory
support
department
Figure 2.6 Partial organizational structure of the EMA, focusing upon its scientific and
regulatory functions.
● The Committee on Orphan Medicinal Products (COMP),
● The Committee on Herbal Medicinal Products (HMPC),
● The Paediatric Committee (PDCO),
● The Committee for Advanced Therapies (CAT) and
● The Pharmacovigilance Risk Assessment Committee.
Member states can nominate one expert andan alternate to each committee. These
in eect come from the national regulatory bodies, which they also represent. The
committees may additionally co-opt up to ve other members. The committees can
draw on the expertise of several thousand scientists using a network that extends
through the national regulatory bodies and form further advisory committees and
WGs as appropriate.
2.5.3 National Competent Authorities
Executive responsibility for administration of regulations at national level is
divested in dedicated agencies. Although distinct from government departments,
the Ministers of Health are the usual political masters of these national Competent
Authorities. For example, the authority in Ireland is known as the Health Products
Regulatory Authority (HPRA) and it covers both drugs and devices. Other countries
have split healthcare regulatory responsibilities amongst 2 or more dierent
national authorities. The various national competent authorities which regulate
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2.5 Regulatory Bodies 33
Table 2.1 National Competent Authorities for human medicines in EU and EEA member
states.
Country Name (in English) Web address
Austria Austrian Agency for Health and
Food Safety
www.ages.at
Belgium Federal Agency for Medicines
and Health Products
www.fagg-afmps.be/
Bulgaria Bulgarian Drug Agency www.bda.bg
Croatia Agency for medicinal products
and medical devices of Croatia
www.almp.hr
Cyprus Ministry of Health –
Pharmaceutical Services
www.moh.gov.cy/phs
Czechia State Institute for Drug Control www.sukl.cz
Denmark Danish Medicines Agency www.laegemiddelstyrelsen.dk
Estonia State Agency of Medicines www.ravimiamet.ee
Finland Finnish Medicines Agency www.mea.
France National Agency for the Safety of
Medicine and Health Products
www.ansm.sante.fr
Germany Federal Institute for Drugs and
Medical Devices
www.bfarm.de
Germany Paul Ehrlich Institute www.pei.de/
Greece National Organization for
Medicines
www.eof.gr
Hungary National Institute of Pharmacy
and Nutrition
www.ogyei.gov.hu
Iceland Icelandic Medicines Agency www.ima.is
Ireland Health Products Regulatory
Authority (HPRA)
www.hpra.ie
Italy Italian Medicines Agency www.agenziafarmaco.it
Latvia State Agency of Medicines www.zva.gov.lv
Liechtenstein Oce of Health/Department of
Pharmaceuticals
www.llv.li
Lithuania State Medicines Control Agency www.vvkt.lt
Luxembourg Ministry of Health www.ms.etat.lu
Malta Medicines Authority www.medicinesauthority.gov.mt
Netherlands Medicines Evaluation Board www.cbg-meb.nl
Netherlands Healthcare Inspectorate www.igz.nl
Norway Norwegian Medicines Agency https://legemiddelverket.no
Poland Oce for Registration of
Medicinal Products, Medical
Devices, and Biocidal Products
www.urpl.gov.pl
(Continued)
34 2 Regulatory Strategy
Table 2.1 (Continued)
Country Name (in English) Web address
Poland Chief Pharmaceutical
Inspectorate
www.gif.gov.pl
Portugal National Authority of Medicines
and Health Products
www.infarmed.pt
Romania National Medicines Agency www.anm.ro
Slovakia State Institute for Drug Control www.sukl.sk
Slovenia Agency for Medicinal Products
and Medical Devices of the
Republic of Slovenia
www.jazmp.si
Spain Spanish Agency for Medicines
and Health Products
www.aemps.gob.es
Sweden Medical Products Agency www.lakemedelsverket.se
human medicines are listed in Table 2.1. Similar to the EMA, the authorities are
scientic and technical in orientation and are guided by various advisory panels.
Their main tasks typically include:
● Evaluation of applications for drug marketing authorisations made either directly
to the national authority or indirectly via the centralised procedure to the EMA,
● Monitoring and approval of information provided on leaets, and promotional
material,
● National licensing of drugs,
● Inspection and licensing of facilities,
● Approval and licensing of clinical trials,
● Operation of market vigilance systems at national level and
● Performance of tasks mandated under the medical device regulations.
2.5.4 Notified Bodies
Notied bodies play aspecial role in theregulation of medical devices.They are com-
mercial inspection and auditing organisations rather than statutory bodies. They
must be able to demonstrate that they have the technical competence and indepen-
dence to deliver objective assessments. They,rather than the Competent Authorities,
provide the main regulatory interface with medical device manufacturers and are
required to conduct conformity assessments on high-risk devices to ensure that they
meet the essential requirements set out in the regulations. By using Notied Bodies
the Competent Authorities do not have to maintain the variety of specialist sta that
would be required to assess the dierent types of technology platforms that are used
for medical devices. Individual Notied Bodies do not have to be able to cover all
specialist areas, but can just be designated as competent for specic types of devices.
Their services are not restricted to national boundaries.
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