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Articles
GMP and GDP: a review of regulatory
inspection findings and defective
medicines reports for 2004–05
The purpose of this article is to indicate to manufacturers and distributors areas on which they may wish to focus their training programmes, internal audit and quality improvement, in order to increase their compliance with Good Manufacturing Practice and Good Distribution Practice
his article reports the nature and frequency of serious deficiencies in compliance with Good Manufacturing Practice
(GMP) and Good Distribution Practice
(GDP) found on regulatory inspections by
the Medicines and Healthcare products
Regulatory Agency (MHRA) during the year
2004–05. It covers industrial manufacturing
and distribution sites in the UK, manufacturing sites in third countries and sites where the
NHS is the licence holder. Data for the years
1996–97,1 1998–992 and 2001–023 were published previously. The paper also reviews reports of defective medicines received by the
MHRA’s Defective Medicines Report
Centre (DMRC) and drug alerts issued in
2005 to support recalls issued by the relevant
importers, manufacturers and marketing authorisation holders.
T
Method
The authors
Deficiencies reported in this article are those
categorised as “critical” or “major” in the report to the licence holder; other deficiencies,
often minor, are not considered here. Critical
deficiencies are those that indicate a significant risk that a product could or would be
harmful to a patient, or a deficiency that has
produced a harmful product. A combination
of major deficiencies that indicates a critical
systems failure may also be classed as critical.
Major deficiencies are those non-critical deficiencies that could or would produce a
product not in compliance with its marketing
authorisation, those that contravene the provisions of a manufacturing authorisation or
wholesale dealer’s licence to a significant exJohn Taylor, FRSC, is the quality and
standards manager of the MHRA’s
inspection and standards division and
enforcement and intelligence group,
Gerald Heddell, MIBiol, is director of the
inspection and standards division,
Ian Holloway, MRPharmS, is the head of
the Defective Medicines Report Centre,
Graham Matthews, MRPharmS, is a
pharmaceutical assessor in the DMRC and
Ian Rees, MRCVS, is a senior GMP inspector
Correspondence to: John Taylor, Medicines
and Healthcare Products Regulatory Agency,
Market Towers, 1 Nine Elms Lane, London
SW8 5NQ
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Table 1: Deficiencies per inspection for UK and third country sites in successive years
Year
UK manufacturers (including NHS)
Third country manufacturers
99–00
00–01
01–02
02–03
03–04
04–05
2.2
3.4
1.8
3.2
1.4
4.8
1.6
2.8
1.3
2.2
1.5
2.2
tent and those that relate to a Qualified
Person or Responsible Person failing to carry
out his or her obligations. A major deficiency
is also indicated if relevant changes in premises, production, processes or controls have
not been notified to, or agreed by the licensing authority, or if there is a significant departure from GMP or GDP not covered by the
above categories.
Data concerning critical and major deficiencies (reported collectively as “serious” deficiencies) reported below are derived from
inspection reports issued in 2004–05. To inform the analysis each deficiency is assigned to
one of 40 categories. Comparisons are made
between findings in different sectors, ie, UK
industrial manufacturers, UK NHS manufacturers and third country industrial manufacturing sites. Serious GDP deficiencies recorded
at wholesale distributors are also considered.
Findings
Analysis of GMP deficiencies for
2004–05 Data from inspections in 2004–05
of UK manufacturers (including NHS sites)
and third country (ie, non-EU or non-EEA)
manufacturers were analysed.The numbers of
serious (ie, critical and major) deficiencies
recorded per inspection in each sector were
1.50 for UK sites, 1.57 for NHS sites and
2.23 for third country sites. As for the previous years since analysis began in 1994, more
deficiencies were recorded per inspection of
third country sites than UK sites.
Comparative figures for the past five years are
shown in Table 1.The number of deficiencies
per inspection for UK industrial sites and
NHS sites has remained relatively constant for
the past four years, and the number of deficiencies per inspection for third country
manufacturing sites has also fallen.
Table 2 shows the categories and the number of GMP deficiencies most frequently reported in 2004–05 for all sectors. These
represent 79 per cent of the total number.
Table 2: Most frequently reported GMP
deficiencies in 2004–05 in all sectors
Category of GMP deficiency
Quality management
Batch release and duties of the QP
Quality system documentation
Potential for microbial contamination
Evidence of compliance with TSE guidelines
Design and maintenance of premises
Environmental monitoring
Process validation
Potential for non-microbial contamination
Cleaning validation
In-process control and monitoring of
production operations
Validation documentation
Line clearance, segregation and potential
for mix-up
Handling and control of packaging
components
Starting material and packaging component
testing
Warehousing and distribution activities
Complaints and product recall
Design and maintenance of equipment
Manufacturing documentation
Training
Incidence (%)
8.0
5.9
5.9
5.0
4.6
4.6
4.6
4.6
3.8
3.8
3.8
3.8
3.4
3.4
2.5
2.5
2.1
2.1
2.1
2.1
In the previous two years, concerns related
to the potential for non-microbial contamination headed the overall list of deficiencies.
The incidence of citations in this category
was 8.2 per cent of the total number in
2002–03, falling to 6.8 per cent in 2003–04
and to 3.8 per cent in 2004–05. The highest
number of deficiencies per inspection in
2004–05 concerned quality management.
Data for the past two years show a rise in deficiencies in this category from 14th spot in
2002–03 to third spot in 2003–04 to top spot
last year (Table 2). However, non-compliances
relating to the potential for all types of contamination were the most frequent reason for
recording a deficiency last year.
20 May 2006 The Pharmaceutical Journal (Vol 276) 593
Articles
Tables 3, 4 and 5, respectively, show the top
10 categories of deficiency reported during
inspections of UK industrial manufacturers,
NHS manufacturers and third country manufacturers in 2004–05, ranked in descending
order of incidence, compared with rankings
for the previous three years. Gaps in the tables
indicate that the particular category did not
appear in the top 20 in a particular year.
For UK industrial sites (Table 3) deficiencies related to quality management wer the
main concern last year. Concerns over batch
release and duties of the Qualified Person and
quality system documentation continue to
feature prominently.
For NHS manufacturers (Table 4) deficiencies related to validation documentation form
the highest category.This is a new category for
the deficiency analysis, deficiencies concerning
validation documentation having previously
been assigned to other validation categories.
Concerns related to the design and maintenance of manufacturing facilities at NHS sites
continue to feature prominently and there appears to be a trend towards increasing incidence of deficiencies related to quality system
documentation. Potential for microbial contamination continues to cause concern.
For third country manufacturers concerns
related to potential for microbial contamination continue to dominate the analysis (Table
5). The proportion of reports of deficiencies
related to in-process control and monitoring
of production operations continues to feature
prominently and deficiencies related to finished product testing are increasing. Lack of
evidence to demonstrate compliance with
guidelines related to transmissible spongiform
encephalopathy (TSE) is an increasing concern for UK and third country industrial
manufacturers.
Analysis of GDP deficiencies for
2004–05 The number of serious deficiencies
per inspection reported from visits to wholesale distributors continues to show a downward trend. Serious GDP deficiencies per
inspection were 1.34 in 1999–2000, 0.98 in
2000–01, 0.94 in 2001–02, 0.97 in 2002–03,
0.63 in 2003–04 and 0.38 in 2004–05.
Table 6 shows the GDP deficiencies cited
most frequently in 2004–05 in descending
order of ranking, compared with their
rankings in the previous four years. A dash
against a category indicates that it did not appear in the top 20 categories in that particular year.
For the past four years the largest number
of deficiencies have concerned the control
and monitoring of storage conditions in general warehouse areas (as opposed to cold
stores). Overall, deficiencies related to the
control and monitoring of storage and transportation temperatures of medicines comprised 43 per cent of the total number of
serious deficiencies. There was an increase in
the incidence of reports of unauthorised activities. Deficiencies concerning returns (including returns of cold chain goods) have
increased in prominence.
594
The Pharmaceutical Journal (Vol 276) 20 May 2006
Table 3: Trends in the top 10 categories of deficiency for UK industry
Category of deficiency
Quality management
Batch release and duties of the QP
Quality system documentation
Design and maintenance of premises
Environmental monitoring
Process validation
Evidence of compliance with TSE guidelines
Cleaning validation
Potential for microbial contamination
Potential for non-microbial contamination
Ranking by year
01–02
02–03
03–04
04–05
17
15
4
3
–
10
12
–
13
1
17
4
1
9
12
6
–
20
10
2
3
1
6
13
–
12
–
17
–
4
1
2
3
4
5
6
7
8
9
10
Table 4: Trends in the top 10 categories of deficiency for NHS sites
Category of deficiency
Validation documentation
Design and maintenance of premises
Quality system documentation
Potential for microbial contamination
Environmental monitoring
Sterility assurance
Batch release
Failure to respond to previous inspection findings
Potential for non-microbial contamination
Design and maintenance of equipment
Ranking by year
01–02
02–03
03–04
04–05
–
1
8
2
4
12
13
–
6
14
–
1
5
2
3
10
11
19
15
8
–
2
3
4
13
14
17
11
8
18
1
2
3
4
5
6
7
8
9
10
Table 5: Trends in the top 10 categories of deficiency for third country manufacturers
Category of deficiency
Potential for microbial contamination
Evidence of compliance with TSE guidelines
Validation documentation
In-process control and monitoring of production
operations
Potential for non-microbial contamination
Batch release
Cleaning validation
Equipment validation
Finished product testing
Handling and control of packaging components
Ranking by year
01–02
02–03
03–04
04–05
8
6
–
2
15
–
2
13
–
1
2
3
1
2
–
18
10
–
17
8
1
–
7
–
–
9
3
1
–
10
7
18
12
4
5
6
7
8
9
10
Discussion
Manufacturers Serious deficiencies reported by the MHRA’s medicines inspectors
from inspections of UK and third country
manufacturers have shown a number of
trends in recent years. Inspectors’ concerns related to quality management have come to
the fore for UK industrial manufacturers,
while deficiencies related to batch release and
duties of the Qualified Person continue to
cause concern.
Corrective action concerning quality system documentation remains a priority for
manufacturers and there appears to be an increasing incidence of deficiencies regarding
cleaning validation. Deficiencies related to
the potential for non-microbial contamination show a decreasing trend that may reflect
increasing attention paid to this area by UK
industry. Handling and control of packaging
components did not feature in the top 10 in
2004–05, although defects related to packaging, labels and leaflets continued to comprise
the most common reason for batch recall in
the UK.
A number of hospitals and NHS trusts in
the UK hold manufacturer’s specials licences
which authorise the manufacture of unlicensed medicinal products to fulfil special
clinical needs.These facilities are inspected at
the same frequency and to the same standards
as UK industrial manufacturers and it is,
therefore, not surprising that similar categories of deficiency are recorded in each sector.The main differences seen in the data for
2004–05 are in the categories of validation
documentation, sterility assurance and failure
to respond to previous inspection findings,
which do not appear in the top 10 for UK industry. The latter category of deficiency
shows an increasing trend for NHS manufacturing facilities.
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Articles
Table 6: Trends in the most frequently reported GDP deficiencies
Description of deficiency
Ranking by year
00–01
01–02
02–03
3
4
1
–
2
8
–
13
9
5
1
4
3
–
2
10
–
17
7
6
1
11
2
–
3
5
7
–
4
6
General storage — temperature control and
monitoring
Returns
Lack of or inadequate written procedures
Unauthorised activity
Cold storage — temperature control and monitoring
Housekeeping and pest control
Cold chain transportation
Customer status
Premises, equipment and calibration
Duties of Responsible Person
Table 7: Most frequently reported GMP
deficiencies in 2004–05 for IMP sites
Category of GMP deficiency
Incidence (%)
1
7
2
–
4
6
8
–
3
5
1
2
3
4
5
6
7
8
9
10
Vaccine (%) All (%)
14.3
14.3
10.7
7.1
7.1
7.1
7.1
3.6
3.6
3.6
GMP inspections are carried out by UK
inspectors of manufacturing sites in third
countries which are nominated as manufacturers or potential manufacturers of products
that have UK marketing authorisations and in
some cases those that have marketing authorisations issued by the European Medicines
Agency (EMEA). Potential for microbial contamination has been a major concern at these
sites for the past three years, with validation
documentation and batch release procedures
featuring for the first time in the top 10. As
with UK industrial manufacturers, potential
for non-microbial contamination appears to
be decreasing in incidence.
Table 1 (p593) records the number of serious deficiencies per inspection over the past
six years. A higher incidence of serious deficiencies continues to be recorded at inspections in third countries than in the UK. The
reasons for this are two-fold. First, inspections
in third countries are product-related and
thus more intensively focused than general
GMP inspections in the UK and, second,
some third country manufacturers, particularly sites nominated on UK/EMEA marketing authorisations for the first time, may not
be familiar with EU GMPs and thus the standards which EU inspectors expect of them.
The data for UK manufacturers include
the results of inspections of the manufacture
of investigational medicinal products (IMP)
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04–05
Table 8: Comparison of GMP deficiencies
for vaccine manufacturers and all sterile
product manufacturers 2004–05
Category of GMP deficiency
Manufacturing documentation
Handling and control of packaging
components
Quality management
Evidence of compliance with TSE
guidelines
Line clearance, segregation and potential
for mix-up
Validation documentation
Failure to respond to previous inspection
findings
Batch release
Cleaning validation
Potential for non-microbial
contamination
03–04
Potential for microbial
contamination
Design and maintenance of premises
Quality management
Quality system documentation
Design and maintenance of
equipment
Environmental monitoring
Starting material and packaging
component testing
Validation documentation
Process validation
Evidence of compliance with TSE
guidelines
21
15
12
9
5
3
4
4
9
8
2
5
8
5
3
2
2
3
2
3
which is now a statutory requirement.Table 7
shows the top 10 serious GMP deficiencies
from these manufacturers, in descending order
and, together with Table 8, demonstrates how
the deficiency database can be used to look at
specific manufacturing activities. In view of
the importance of documentation and packaging for IMPs, it is not surprising that these
categories are prominent in the list. In other
respects the list includes similar categories to
that for other manufacturers.
During 2004–05 much attention was focused on vaccine manufacture and the supply
situation of influenza vaccine in the UK and
the US.That interest continues today with regard to vaccines to provide immunity against
a potential influenza pandemic. It is interesting to compare the findings from inspections
of vaccine manufacturers with those from all
sterile product manufacturers. Table 8 does
this.
The figures (rounded up or down) show a
significantly higher incidence of deficiencies
in regard to vaccine manufacture in the categories of potential for microbial contamination and design and maintenance of premises.
Furthermore, higher incidences are demonstrated in eight of the top 10 categories of deficiency for vaccine manufacturers. The
differences may be attributable to the particular and unique processes involved in vaccine
manufacture and the facilities involved.
Wholesale distributors It is important
for distributors of medicinal products to bear
in mind that their actions or omissions can
have a significant effect on the quality of the
products that they handle. Storage and transportation temperatures have more influence
than any other factor on maintaining the
quality of products throughout the distribution network and it is of major concern that
inspectors continue to report deficiencies in
these areas.The MHRA’s concerns in this regard are not restricted to those products that
are commonly referred to as “cold chain
products”. It is also concerned that “temperate chain products”, ie, those whose recommended storage temperatures range up to
30C, are also protected from extremes of
temperature during storage and transportation.The agency has contributed to a number
of open seminars and conferences on this
subject and in July 2001 it published detailed
recommendations on the control and monitoring of storage and transportation temperatures of medicinal products.4 There is an
increasing trend in the reporting of deficiencies related to returns, and deficiencies concerning written procedures continue to
feature.
Reports of unauthorised activities by
wholesale distributors have resulted in this
category entering the top 10 for the first
time. Examples include unlicensed assembly,
use of unlicensed premises for storage and
unauthorised importation of unlicensed
medicines. Trading other than in accordance
with an appropriate licence may result in adverse licensing action or enforcement action
against the organisation concerned, or both.
Sanctions
The large majority of deficiencies reported to
the manufacturer or wholesaler are remedied
within an acceptable period without further
action by the regulatory authority. However,
where critical deficiencies are reported, or
where a number of major deficiencies have
resulted in a critical systems failure, more formal action may be required in order to protect public health. The MHRA’s Inspection
Action Group (IAG) considers referrals from
GMP and GDP inspectors resulting from adverse inspection findings that indicate an unacceptable patient risk. The group also
considers referrals from inspectors and enforcement officers concerning breaches of
medicines legislation. If the IAG considers
that licensing action, or action concerning a
Qualified Person or a Responsible Person is
indicated, a recommendation will be made to
the UK licensing authority for action to be
taken.This can include suspension or revocation of a manufacturing authorisation or
wholesale dealer’s licence, compulsory variation of the authorisation or licence to exclude certain activities or categories of
product, compulsory variation of a marketing
authorisation to remove a particular site of
manufacture, or censure of a QP or RP.
Thirteen GMP and GDP inspections for
which critical deficiencies were recorded
20 May 2006 The Pharmaceutical Journal (Vol 276) 595
Articles
Drug alerts
A drug alert is classified into one of four
categories, depending on its criticality and the
speed with which action should be taken by the
recipient.
A Class 1 alert is issued when a defect is
potentially life-threatening or presents a serious
risk to health. The response to a Class 1 drug alert
should be immediate, on receipt.
A Class 2 alert (action within 48 hours) is
issued when a defect could cause illness or
mistreatment, but which is not Class 1.
A Class 3 alert (action within five days) is one
that, although not posing a significant hazard,
nevertheless requires action.
Where a defect poses no threat to patients, or
is unlikely to impair product use or efficacy, the
DMRC may issue a Class 4 “caution in use” alert.
In addition to national distribution, Class 1 and
Class 2 alerts are also sent by way of an
established rapid alert system to EU/EEA member
states, countries that have a mutual recognition
agreement with EU, members of the
Pharmaceutical Inspection Co-operation Scheme
and agencies such as the EMEA and the US Food
and Drug Administration.
Defective medicines
Listening Friends
The MHRA’s Defective Medicines Report
Centre (DMRC) plays a major part in the
protection of public health by minimising the
hazard to patients arising from the distribution of defective medicinal products. It does
this by providing an emergency assessment
and communications system between suppliers of medicinal products, the regulatory authorities and the users. It achieves this by: (i)
receiving and assessing reports of suspected
defective medicines, (ii) monitoring and, as
necessary, advising and directing appropriate
actions by the responsible licence/authorisation holder, and (iii) communicating the details of this action as necessary and with
appropriate urgency to recipients of the
products and other interested parties in the
UK and elsewhere by means of drug alerts.
A defective medicine may be defined as
one that is likely to be harmful under normal
conditions of use, one that is not in compliance with its marketing authorisation, one
that is lacking in therapeutic efficacy or one
that has been manufactured other than in accordance with GMP. Recalls are normally
carried out by the marketing authorisation
holder with help and advice from the
DMRC who may issue a drug alert to recipients within and outside the NHS to support
the recall. Not every substantiated defect results in a drug alert. Some organisations are
able to identify every customer that received
the defective product (for example, some hospital-only products) and where the MHRA
has assurance that all customers can be
reached, the DMRC may decide not to issue
a drug alert to support the recall. However,
the MHRA must be advised of any defect
that could result in a recall and organisations
596
must not undertake a recall without first discussing it with the DMRC. The DMRC receives reports of suspected defective
medicines from a variety of sources, including
manufacturers, distributors, hospitals, pharmacies, GPs and the general public. During
2005 the DMRC received 271 reports of suspected defective medicines of which 41 were
substantiated.These resulted in the issue of 25
drug alerts, including two at Class 1.
Defects related to labels and leaflets (nine
alerts), contamination, stability and packaging
(four alerts each), and sterility assurance, efficacy, product mix-up and counterfeit products (one alert each).
The Class 1 drug alerts were associated
with a lack of sterility assurance and product
mix-up.The recall of a counterfeit product in
2005 followed two recalls of counterfeit
products in 2004.
The Listening Friends Scheme offers free
telephone help to pharmacists under stress.
A call to the scheme will put the pharmacist
in touch with a fellow pharmacist who will be
there to give time to talk about the problems that
are causing stress. The Listening Friend will have
insight into the particular pressures that apply in
pharmacy but the service is also there to help
with problems not related to work, such as
illness, disability, bereavement and relationship
issues.
The service is run by a team of volunteer
pharmacists, who are all mature and experienced
professionals in their field of practice. They have
all been trained in listening skills and may be
able to direct pharmacists under stress to more
specialist help if needed.
The Pharmaceutical Journal (Vol 276) 20 May 2006
Contact with the Listening Friends is made
initially by telephoning 020 7572 2442 where a
voicemail answering service will take details of a
first name, a telephone number and a convenient
time to call. A Listening Friend will then call back,
usually on the evening of the same day or within
24 hours. Arrangements will be made to make
further calls if the pharmacist would like more
telephone time with the Listening Friend.
The scheme is supported by the Royal
Pharmaceutical Society’s Benevolent Fund and
is part of the fund’s aims in supporting
pharmacists in need.
For additional information about the scheme,
or the fund and the services it offers, call 01327
264739 or 01323 890135 or e-mail
benevolent.fund@rpsgb.org
Summary
The objective of regulatory medicines inspection is to contribute to the protection of
public health through the assessment of compliance by manufacturers and distributors of
medicines with standards of good manufacturing practice and good distribution practice. Although there have been some changes
in the incidences of reported serious GMP
and GDP deficiencies in recent years, the lists
of those most frequently cited categories for
each manufacturing sector and for wholesale
distributors continue to include categories for
which concerns have been recorded in past
inspections. Failure to comply with GMP and
GDP can have a profound effect on product
quality and patient safety and where this occurs the MHRA will take appropriate action
in support of its prime objective. Those organisations that have issued product or batch
recalls will be aware not only of the risks that
they may have exposed patients to but will
also be aware of the costs involved in a recall.
The data reported above indicate to manufacturers and distributors areas on which
they may wish to continue to focus their
training programmes, internal audit and quality improvement.
ACKNOWLEDGEMENTS We acknowledge that the data presented in this paper
were generated by MHRA’s GMP and GDP
Inspectors.
References
1. Taylor J, Turner J, Munro G. Good manufacturing practice and
good distribution practice: an analysis of regulatory
inspection findings. Pharmaceutical Journal
1998;261:748–51.
2. Taylor J, Turner J, Munro G, Goulding N. Good manufacturing
practice and good distribution practice: an analysis of
regulatory inspection findings for 1998/99. Pharmaceutical
Journal 2000;265:686–9.
3. Taylor J, Munro G, Lee G, McKendrick A. Good manufacturing
practice and good distribution practice: an analysis of
regulatory inspection findings for 2001–02. Pharmaceutical
Journal 2003;270:127–9.
4. Taylor J. Recommendations on the control and monitoring of
storage and transportation temperatures of medicinal
products. Pharmaceutical Journal 2001;267:128–31.
Ownership changes
were referred to the IAG in 2004–05. Ten of
these resulted in recommendations to the UK
licensing authority for action. As a consequence, five notices of intention to suspend
an authorisation or licence were issued resulting in four suspensions pending the implementation of appropriate corrective action
and one revocation. Five letters of censure
were issued to QPs or RPs.
When buying a pharmacy business the
purchaser must contact the Royal
Pharmaceutical Society prior to taking
over the business to obtain the necessary
“Application for transfer of ownership”
form. Until this form is completed and
returned to the Society, the Register will
continue to show the premises as
registered by the previous owner.
A legal problem could arise from the
new owner not advising the Society of a
change of ownership. Section 76(3) of the
Medicines Act 1968 provides that the
existing registration automatically
becomes void at the end of 28 days from
the date on which a change of ownership
occurs.
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