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12.6 Inspections 285
Figure 12.2 (Continued)
1. Quality System.
This system assures overall compliance with cGMPs and internal procedures and
specications. The system includes the quality control unit and all of its review and
approval duties (e.g. change control, reprocessing, batch release, annual record review,
validation protocols, and reports, etc.). It includes all product defect evaluations and
evaluation of returned and salvaged drug products.
2. Facilities and Equipment System.
This system includes the measures and activities which provide an appropriate physi-
cal environment and resources used in the production of the drugs or drug products. It
includes:
(a) Buildings and facilities along with maintenance;
(b) Equipment qualications (installation and operation); equipment calibration and
preventative maintenance; and cleaning and validation of cleaning processes as
appropriate. Process performance qualication will be evaluated as part of the
inspection of the overall process validation which is done within the system where
the process is employed; and,
(c) Utilities that are not intended to be incorporated into the product such as HVAC,
compressed gases, steam and water systems.
3. Materials System.
This system includes measures and activities to control nished products, components,
including water or gases that are incorporated into the product, containers and closures.
It includes validation of computerised inventory control processes, drug storage, distri-
bution controls and records.
4. Production System.
This system includes measures and activities to control the manufacture of drugs and
drug products including batch compounding, dosage form production, in-process sam-
pling and testing and process validation. It also includes establishing, following, and
documenting performance of approved manufacturing procedures.
5. Packaging and Labelling System.
This system includes measures and activities that control the packaging and labelling of
drugs and drug products. It includes written procedures, label examination and usage,
label storage and issuance, packaging and labelling operations controls and validation
of these operations.
6. Laboratory Control System.
This system includes measures and activities related to laboratory procedures, test-
ing, analytical methods development and validation or verication and the stability
program.
Figure 12.3 FDA systems approach to GMP audits of pharmaceutical sites.
286 12 Oversight and Vigilance
as regards the level of compliance, will cover all six systems. Abbreviated audits
are normally employed for routine surveillance monitoring. These must include the
quality system, which is regarded as the core system that knits all the other systems
together, plus one other system. The choice of second system may be inuenced by
aspects such as the introduction of signicant changes or the desire to cover all sys-
tems over a series of audits. An abbreviated audit may also be used for issue-specic
compliance audits.
The FDA also use a systems approach when auditing device manufacturing sites.
This breaks down the GMP requirements for devices into seven primary subsystems
consisting of:
● Management Controls,
● Design Controls,
● Production and process Controls
● Records/Documents/Change Controls
● Material Controls
● Facility and equipment Controls
● Corrective and Preventative Actions
The relationship between the main subsystems and other minor systems is
illustrated in Figure 12.4. This places management at the core of the quality system
with the other systems arranged as major and minor satellites that revolve around
it. This perspective provides the basis for the Quality System Inspection Technique
(QSIT), which the FDA used for auditing medical device facilities. This is based on
a ‘top-down’ approach, which starts with management controls and then looks at
three other key subsystems of Design Controls, Corrective and Preventative Actions
(CAPA) and Production and Process Controls. The belief is that by focusing on
just these four subsystems, you will actually touch on all the other subsystems
and get a suciently satisfactory overview of the state of compliance of the
facility.
12.6.2 Audit Findings and Consequences
On completion of an audit and before leaving the premises, the management of
the site will be briefed as regards the main observations during the audit. Where
issues arise, FDA inspectors use Form 483 to present the manufacturer with a list of
items that may be deemed non-compliant with the regulations. A list of some spe-
cic non-compliances issued in recent 483 reportsis provided in Figure 12.5. Should
any non-conformances be highlighted at the audit close-out session, management
should state their commitment to correcting these, and if possible, indicate what
the corrective action strategy may be. Once the audit is over, it is prudent to start to
prepare a response to the auditing body outlining the proposed corrective without
waiting for an ocial report. Ocial reports are only written after leaving the site,
allowing inspectors the opportunity to consult with colleagues or obtain the results
of sample testing.
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12.6 Inspections 287
MANAGEMENT
Corrective
and
preventative
actions
Records/
documents/
change
controls
Material
controls
Production
and
production
controls
Design
controls
Facilities
and
equipment
controls
Reports of
corrections
and
removals
Medical
device
reporting
Medical
device
tracking
Sterilisation
process
controls
Figure 12.4 Quality system regulation subsystems from the FDA guide to inspection of
quality systems.
The report template used for European GMP inspections has been included
earlier in this chapter (Figure 12.2). Deciencies may be ranked as critical, major, or
other, depending on the assessment scheme and the consequences for the product
(Figure 12.6). Auditors may also choose to make observations with the intention
of highlighting aspects that are not technically in breach of the requirements,
but which could be improved upon. Manufacturers should immediately respond
to the issues raised and outline how they will be addressed. In some instances
where a major overhaul of a system is required, it may be necessary to enter into
negotiations on an agreed plan and timeline. If the deciencies are viewed as
serious, a follow-up audit is likely to ensue to conrm the eectiveness of corrective
action. In most instances where the deciencies are minor, do not compromise
product safety and the manufacturer has committed to rectifying the problem,
no further action will be taken. However, if the regulatory authorities form the
288 12 Oversight and Vigilance
You used a non-pharmaceutical grade component in the formulation of a drug product.
You produced hazardous drugs without providing adequate cleaning of work surfaces and
cleaning of utensils to prevent cross-contamination.
Each batch of drug product purporting to be sterile is not laboratory tested to determine
conformance to such requirements.
Procedures designed to prevent microbiological contamination of drug products purport-
ing to be sterile did not include adequate validation of the aseptic and sterilization process.
Aseptic processing areas are decient regarding the system for monitoring environmental
conditions.
Equipment and utensils are not cleaned, maintained and sanitized at appropriate intervals
to prevent contamination that would alter the safety, identity, strength, quality or purity of
the drug product.
There is a failure to thoroughly review any unexplained discrepancy and the failure of a
batch or any of its components to meet any of its specications whether or not the batch
has been already distributed.
Results of stability testing are not used in determining appropriate storage conditions and
expiration dates.
Testing and release of drug product for distribution do not include appropriate labora-
tory determination of satisfactory conformance to the nal specications and identity and
strength of each active ingredient prior to release.
Clothing of personnel engaged in the manufacturing, processing, packing and holding of
drug products is not appropriate for the duties they perform.
You did not make adequate product evaluation and take remedial action where actionable
microbial contamination was found to be present in an area adjacent to the ISO 5 classied
aseptic processing area during aseptic production.
Your facility design allowed the inux of poor quality air into a higher classied area.
Your facility was designed and/or operated in a way that permits poor ow of personnel.
Personnel donned gowning apparel improperly,inawaythatmayhave caused the gowning
apparel to become contaminated.
Figure 12.5 Exemplar non-compliances (inspector ‘observations’) listed in recently issued
FDA form 483 reports. The actual reports will also provide more specific granular detail on
each observation listed.
opinion that the manufacturer has not provided an adequate response to the
issues raised, further action will follow. Under the US system, this could escalate
from an FDA warning letter to judicial action. If successful, this could result in
the courts issuing a ‘consent decree’, penalising the company for each day it is
not in compliance. Some large companies, to their cost, have ended up in this
situation when they decided to challenge the FDA on their interpretation of the
FDC Act. If GMP violations were to compromise public safety, product may be
seized or blocked from the market. In Europe, auditing bodies have the option of
withdrawing certicates of compliance and manufacturing authorisations, which
would in eect prevent the product from being placed on the market. A database
of pharmaceutical manufacturing authorisations and GMP certicates issued
by national Competent Authorities is maintained by the EMA on the EudraG-
MDP network, enabling the status of any manufacturer to be easily checked.
In general, punitive actions are not commonplace, as regulatory authorities
prefer to adopt a cooperative approach with manufacturers to get them back in
compliance.
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12.7 Market Vigilance and Oversight of Drugs 289
Critical Deciency:
A deciency which has produced, or leads to a signicant risk of producing either a prod-
uct, which is harmful to the human or veterinary patient or a product which could result
in a harmful residue in a food producing animal.
Major Deciency:
A non-critical deciency:
which has produced or may produce a product, which does not comply with its marketing
authorisation;
or
which indicates a major deviation from EU Good Manufacturing Practice;
or
(within EU) which indicatesa major deviation from the terms of the manufacturing autho-
risation;
or
which indicates a failure to carry out satisfactory procedures for release of batches or
(within EU) a failure of the Qualied Person to full his legal duties;
or
a combination of several “other” deciencies, none of which on their own may be major,
but which may together representa major deciency and should beexplained and reported
as such;
Other Deciency:
A deciency which cannot be classied as either critical or major but which indicates a
departure from good manufacturing practice.
(A deciency may be “other” either because it is judged as minor or because there is
insucient information to classify it as a major or critical).
Figure 12.6 Definition of the various categories of deficiencies used in EU GMP inspection
reports.
12.7 Market Vigilance and Oversight of Drugs
Pharmacovigilance is dened by the World Health Organization (WHO) as the
science and activities relating to the detection, assessment, understanding and
prevention of adverse eects or any other medicine-related problem.
Despite the extensive investigations that must be undertaken prior to placing a
drug on the market, it is not possible to guarantee that all safety issues have been
identied. Thus, market vigilance systems must be maintained after a drug has been
launched so as to detect safety issues that were not evident prior to commercialisa-
tion. For such systems to be eective, requires the participation and cooperation of
the medical and veterinary professions, patients, the pharmaceutical industry and
the regulators, inorder that critical safety information can be identied andacted on
in a timely manner. In some instances, this has resulted in the withdrawal or restric-
tion of drugs due to safety concerns that only emerged post-commercialisation.
12.7.1 Pharmacovigilance in the EU
The current requirements for pharmacovigilance systems in Europe are contained in
Directive 2010/84/EU and Directive 2012/26/EU which amend the text of Directive
2001/83/EC (Human medicines), Regulation No. (EU) 1235/2010 and Regulation
290 12 Oversight and Vigilance
No. (EU) 1027/2012 which amends Regulation (EC) No. 726/2004 and Regulation
(EU) 2019/6 (Veterinary medicines). Commission Implementing Regulation (EU)
No. 520/2012 (Human medicines) and Regulation (EU) 2021/1281 (Veterinary
medicines), provides practical detail on the implementation of the system.
Overall, the implementation of Europe’s pharmacovigilance regulatory system is
achieved via cooperation between the EMA, EU Member States (in particular their
Competent Authorities) and the European Commission. The EMA has developed
and published a good pharmacovigilance practice (GVP) guideline for human
medicines and a veterinary good pharmacovigilance practice (VGVP) guideline,
each containing a set of measures drawn up to facilitate the performance of
pharmacovigilance in the European Union (EU). The guidelines are split into a
number of modules as illustrated in Table 12.1. Targeted at marketing-authorisation
holders as well as the EMA itself and national Competent Authorities, the guide-
lines are applicable to both centrally authorised medicines and those authorised
at national level. The GVP guideline incorporates the international pharma-
covigilance principles published in ICH guidelines E2A – E2F (Table 12.2),
which have been adopted by the EU (and many other world regions, including
the USA).
EU pharmacovigilance activities are integrated into the full life cycle of medici-
nal products, embracing the planning of a pharmacovigilance framework while a
medicine is in development, as well as post-approval pharmacovigilance activities.
12.7.2 Pharmacovigilance Risk Assessment Committee (PRAC) and the
EudraVigilance System
The EMA is tasked with operating two key elements of the European pharmacovig-
ilance system, the Pharmacovigilance Risk Assessment Committee (PRAC) for
human medicines and the EudraVigilance IT system.
Composed predominantly of national experts drawn from EU member
states as well as European Commission nominees, PRAC is responsible for
assessing risk management aspects of human medicines, and it can provide
support/advice/recommendations on pharmacovigilance matters to the EMA itself
(mainly the Committee Human Medicinal Products, CHMP), National Competent
Authorities and the European commission. Its core responsibilities include:
● The detection, assessment, minimisation and communication of the risk of
adverse reactions
● Design and evaluation of post-authorisation safety studies;
● Pharmacovigilance audit.
The EudraVigilance system manages and analyses information on suspected
adverse reactions to human and veterinary medicines authorised or in clinical
trials in Europe. At its core is a large pharmacovigilance database with query and
tracking functionality.
Once on the market, monitoring risk as well as identifying and responding to
adverse drug events in Europe is achieved by a number of means. Central to this
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12.7 Market Vigilance and Oversight of Drugs 291
Table 12.1 Modules constituting the EU’s good pharmacovigilance practice guidelines (GVP and
VGVP). The GVP guideline contains modules covering major pharmacovigilance processes (modules
I–XVI) and modules covering product- or population-specific considerations. Some module
numbers, (e.g. XI–XIV) remain void, as their planned topics have been addressed by other EMA
guidance documents.
GVP module no. GVP module title Equivalent VGVP module
I Pharmacovigilance systems and
their quality systems
Pharmacovigilance systems, their
quality management systems and
pharmacovigilance system
master les
II Pharmacovigilance system master
le
III Pharmacovigilance inspections Controls and pharmacovigilance
Inspections
IV Pharmacovigilance audits
V Risk management systems
VI Collection, management and
submission of reports of suspected
adverse reactions to medicinal
products
Collection and recording of
suspected adverse events for
veterinary medicinal products
VI Addendum I Duplicate management of suspected
adverse reaction reports
VII Periodic safety update report
VIII Post-authorisation safety studies
VIII Addendum I Requirements and
recommendations for the
submission of information on
non-interventional
post-authorisation safety studies
IX Signal management Signal management
IX Addendum I Methodological aspects of signal
detection from spontaneous reports
of suspected adverse reactions
X Additional monitoring
XV Safety communication Veterinary pharmacovigilance
communication
XVI Risk minimisation measures:
selection of tools and eectiveness
indicators
XVI Addendum I Educational materials
Final GVP product- or population-specic considerations
I Vaccines for prophylaxis against
infectious diseases
II Biological medicinal products
IV Paediatric population
(Continued)
292 12 Oversight and Vigilance
Table 12.1 (Continued)
GVP module no. GVP module title Equivalent VGVP module
Associated CHMP
guideline
Safety and ecacy follow-up - risk
management
of advanced therapy medicinal
products
Denitions, templates and other guidelines
Annex I Denitions Glossary
Annex II Templates: Cover page of Periodic
Safety Update Report (PSUR)
Annex II Templates: Direct Healthcare
Professional Communication
(DHPC)
CHMP guideline The exposure to medicinal products
during pregnancy: need for
post-authorisation data
EMA note for
guidance
EudraVigilance Human – Processing
of safety messages and individual
case safety reports (ICSRs)
Table 12.2 ICH E2A – E2F (pharmacovigilance) guidelines.
Guideline no. Guideline title/topic
E2A Clinical safety data management: denitions and standards for
expedited reporting
E2B Clinical safety data management: Data elements for transmission of
Individual Case Safety Reports (ICSR)
E2C Periodic benet-risk evaluation report (PBRER)
E2D Post-approval safety data management: denitions and standards for
expedited reporting
E2E Pharmacovigilance planning
E2F Development safety update report
is the capture and consideration of ‘real world’ data (i.e. data collected in routine
clinical or veterinary practice). Both patients and human or animal healthcare
providers can report issues/suspected adverse events to their national Competent
Authority, or to the drug marketing authorisation holder, who will transmit the
report to the EudraVigilance database. Prominent among EudraVigilance submis-
sions are ICSRs, which describe suspected adverse reactions to a medicinal product
that occur in a single patient at a specic point in time. ICSRs reporting serious
adverse events must be submitted as soon as possible, but within a maximum of
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12.7 Market Vigilance and Oversight of Drugs 293
15 days after initial receipt of the information. The equivalent timeline for reporting
suspected adverse events in animals is 30 days.
Other sources of real-world data can also include health records generated in
healthcare settings, prescription databases and administrative claims records.
Moreover, the EMA is also tasked by European legislation to monitor published
medical literature for suspected adverse drug events. EudraVigilance also facilitates
the safety reporting of suspected unexpected serious adverse reactions (SUSARs) to
investigational medicinal products occurring during clinical trials.
Data submitted to the EudraVigilance database is monitored on an ongoing basis.
The PRAC plays a prominent role in this regard, although European legislation
also requires national Competent Authorities and market authorisation holders
to monitor and analyze this data. The information on a new (or indeed already
known) adverse event is known as a ‘safety signal’, and analysis primarily focuses
on investigating if there is a true causal relationship between the medicine and the
reported adverse event.
Following its evaluation of safety signals, PRAC may instigate additional regula-
tory investigations or actions.
Post-authorisation safety studies (PASS) represent another element of the EUs
pharmacovigilance landscape. The conduct of any such PASS can be imposed on
the MAH by the EMA or a national Competent Authority, as applicable during the
evaluation of the initial marketing authorisation application or post-product autho-
risation phase when/if a risk concern is identied. The MAH themselves may also
voluntarily initiate a PASS.
12.7.3 Pharmacovigilance and Marketing Authorisation Holders
Marketing authorisation holders play a key, lead role in pharmacovigilance
activities.
To support/undertake these activities marketing authorisation, holders must
have permanently and continuously at their disposal in the EU a nominated
Qualied Person, with responsibility for pharmacovigilance. This person should
have experience in all aspects of pharmacovigilance and if not the holder of a
medical or veterinary qualication, should have access to such a person. The duties
of the Qualied Person include the following:
● Establish and maintain a pharmacovigilance system
● Prepare relevant reports on such matters for the regulatory authorities
● Respond to requests for further information from regulatory authorities
● Provide the regulatory authorities with other information relevant to maintaining
an up-to-date picture of the risk-benet prole of the product.
● Be involved in the review and sign-o of protocols of PASS.
A legal requirement exists for marketing authorisation holders to devise and
maintain a pharmacovigilance system master le (PSMF). The PSMF describes the
pharmacovigilance system for one (or more) medicinal products of the marketing
authorisation holder and contains information including:
294 12 Oversight and Vigilance
● The role remit and details of the Qualied Person responsible for pharmacovigi-
lance
● A description of the organisational structure of the marketing authorisation
holder relevant to the pharmacovigilance system
● A description of the sources of safety data collected
● Information detailing the computerised systems and databases used to receive,
collate, record and report safety information
● A description of the documented processes used to operationalise pharmacovigi-
lance activities (e.g. collection, analysis and actioning of safety information)
● Details of the ongoing monitoring of performance of the pharmacovigilance activ-
ities and systems
● A description of the quality management system, in terms of the structure of the
organisation and the application of the quality to pharmacovigilance
As previously mentioned, marketing authorisation holders also perform signal
detection and analysis for their product(s), and in the case of human medicines are
legally obliged to produce periodic safety update reports (PSURs), which eectively
represent updated risk: benet evaluations of their product(s) as pharmacovigilance
data accrues. In the case of nationally authorised products in a single EU mem-
ber state, PSURs are evaluated by the national Competent Authority. For centrally
authorised products, PSURs are considered by the PRAC, which reports any rec-
ommendations to the CHMP. This, in turn, can lead to the variation, suspension or
revoking of the product’s marketing authorisation if warranted. The frequency of
PSUR submission is based upon risk and can vary from six months to several years.
Marketing authorisation holders for veterinary medicines are not required to submit
PSURs as the signal management process is deemed sucient to identify changes to
the risk-benet prole that may warrant changes to the marketing authorisation.
12.7.4 Pharmacovigilance Inspections and Audits
Pharmacovigilance inspections of marketing authorisation holders are undertaken
in order to determine if the MAH complies with pharmacovigilance obligations
established within the EU. In cooperation with the EMA (whose primary role is
one of coordination and monitoring), the actual inspections are carried out by the
national Competent Authorities in each Member State. The frequency of routine
inspections is determined by a risk-based approach. ‘For cause’ inspections are
triggered to examine suspected non-compliance or potential risk, usually with
impact on a specic product or products.
Inspections can incorporate inspections of premises, records, documents and the
PSMF. Non-compliance will be communicated to the other EU Member States, the
EMA and the European Commission. Follow-up actions will be proportionate to
the non-compliance(s) identied (Figure 12.7)
EU pharmacovigilance law also requires marketing authorisation holders,
Competent Authorities in the Member States and the EMA itself to perform audits
of their respective pharmacovigilance systems, including risk-based audits of their
quality systems.
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