An analysis is presented of the serious deficiencies reported on inspections by the United Kingdom Medicines Control Agency of pharmaceutical manufacturers and distributors in the UK and countries outside the European Union or European Economic Area during 1998-99. The primary purpose of this paper is to provide an indication to manufacturers and wholesale distributors of the most common failures to comply with the EU guidance on Good Manufacturing Practice and Good Distribution Practice, as recorded by MCA GMP inspectors. The findings and the uses to which they may be put are discussed
This paper reports the nature and frequency of serious deficiencies in compliance with Good Manufacturing Practice (GMP) and Good Distribution Practice (GDP) found on inspections by the Medicines Control Agency (MCA) during the year 1998/99. It covers industrial sites in the United Kingdom and in third countries (ie, countries not in the European Union or European Economic Area (EEA) and sites where the National Health Service (NHS) is the licence holder. Similar information has been collected since 1994 and was first published for the year 1996/97.1
Method
Deficiencies reported in this paper are those categorised as “critical”
or “major” in the report to the licence holder; other deficiencies,
often minor, are not considered here. Each deficiency is assigned to one of
39 categories. The analysis, which has been previously described,1
was improved for 1998/99: for example, the previous category of “cross-contamination”
referring to both chemical and microbial contamination has been divided into
“chemical/physical contamination” and “microbial contamination”.
Findings of the analysis of deficiencies for 1998/99 are given below. 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 analysed.
Findings
Analysis of GMP deficiencies for 1998/99 Data from 387 inspections,
comprising 330 inspections of UK manufacturers (including 87 NHS sites) and
57 third country manufacturers were analysed. Table 1 shows the numbers of deficiencies
recorded in each sector. Although more deficiencies were recorded per inspection
of third country sites than UK sites, the number decreased in comparison with
the figures for previous years as is seen in Table 2. Viewed against a two-year
inspection cycle of UK manufacturers, comparison of the figures for 1995/96
and 1997/98, and for 1996/97 and 1998/99 suggest an increasing trend in the
number of deficiencies reported per inspection for a number of individual companies.
 |
Table 3 shows the categories and the number of the 20 GMP deficiencies most
frequently reported in 1998/99. These represent 82 per cent of the total number.
In 1996/97 and 1997/98, concerns over the potential for contamination during
the manufacturing process headed the overall list of deficiencies. It still
does, but we considered this category to be too broad and for the 1998/99 analysis
divided it into potential for chemical/physical contamination and potential
for microbial contamination. As a result, deficiencies relating to quality system
documentation and written procedures moved from third place in 1996/97 and 1997/98
to become the most cited deficiency in 1998/99. However, the potential for all
types of contamination remains the most frequent reason for a deficiency at
14.4 per cent, similar to that for 1997/98 (14.2 per cent) but higher than that
reported for 1996/97 (11.9 per cent). Deficiencies relating to validation continue
to be a general concern across all sectors of manufacturer and their combined
incidence of 9.4 per cent would place them as the second most frequently recorded
group of deficiencies after potential for contamination. The past three years
have seen a downward trend in the proportion of deficiencies relating to the
design and maintenance of premises, process validation and environmental monitoring.
Tables 4, 5 and 6, respectively, show the top 10 categories of deficiency reported
during inspections of UK industrial manufacturers, NHS manufacturers and third
country manufacturers in 1998/99, ranked in descending order of incidence, compared
with rankings for the previous two years. For UK industrial sites (Table 4)
deficiencies related to potential contamination have been the chief concern
for the past two years. Concerns over the handling and control of packaging
components and quality system documentation continue to figure prominently.
There is a trend towards a higher incidence of reporting of deficiencies relating
to line clearance, segregation and potential for mix-up
For NHS manufacturers (Table 5), deficiencies related to potential contamination
have been the chief concern for the past three years, while the numbers of deficiencies
related to quality system documentation and design and maintenance of equipment
recorded during 1998/99 exceeded those recorded during previous years.
For third country manufacturers, concerns relating to potential contamination
also continue to dominate the analysis (Table 6). The proportion of reports
of deficiencies relating to in-process control and monitoring of production
operations shows a trend in ranking position from fifth in 1996/97 through fourth
in 1997/98 to second in 1998/99. A trend towards a higher incidence of deficiencies
related to audit of suppliers and technical agreements is also seen; this category
was not ranked in the top 20 in 1996/97.
Analysis of GDP deficiencies for 1998/99 Ten critical and 272
major deficiencies were recorded during inspections of 260 wholesale dealers,
including importers, during 1998/99. The number of serious GDP deficiencies
reported per inspection was 1.08, compared with 1.22 for 1997/98 and 1.07 for
1996/97.
 |
Table 7 shows the GDP deficiencies cited most frequently in 1998/99 in descending
order of ranking, compared with their rankings in the previous two years.
As in previous years, the largest number of deficiencies related to written
procedures, either because they did not exist, they were inadequate for their
purpose or they were not effectively controlled. Deficiencies relating to the
control and monitoring of storage conditions continue to cause concern to inspectors.
Returns procedures and records figured previously outside the top 10 ranked
deficiencies, but this category featured more prominently in the rankings in
1998/99. Although not appearing in the top 10, an increasing incidence was seen
of unlicensed activities (such as unauthorised assembly) being carried out by
wholesale dealers. Of the 15 serious deficiencies reported in this category,
five were classified as critical.
Discussion
Manufacturers Comparison of the findings for UK industrial manufacturers
for the past three years shows that the incidence of reported deficiencies relating
to potential for contamination, including cross-contamination, has increased
since 1996/97 to become the most cited category in 1997/98 and 1998/99. Handling
and control of packaging components and quality system documentation continue
to figure prominently and a review of trends in inspection findings suggest
that deficiencies relating to line clearance, segregation of activities and
potential for product mix-up are on the increase. It is interesting to compare
findings from the deficiency analysis with the list of reported quality defects
investigated and confirmed by the MCA’s defective medicines report centre
during 1998/99.
Table 8 shows a correlation between the top three ranked quality defects and
their equivalent deficiency categories.
In the GMP deficiency analysis for all sectors, the combined categories of handling
and control of packaging components and line clearance, segregation and potential
for mix-up gives rise to the largest number of reported deficiencies. These
findings arise mainly in packaging operations, and inspectors’ concern
here would seem to be justified as this is also the operation giving rise to
the largest number of confirmed quality defects. The defect category of non-compliance
with specification correlates with the next most frequently cited group of deficiencies
formed by combining those relating to process validation and in-process control,
which are those most likely to lead to a product which does not comply with
its finished product specification. Non-
microbial contamination, in third place in the defect analysis, compares to
the fourth highest ranking of deficiency, that is those relating to the potential
for chemical/ physical contamination. Perhaps this correlation is not surprising
but it does give an indication that the focus of inspections is on those operations
which, in practice, still cause most problems. We are exploring these findings
further as more data are collected.
The findings of the past three inspections of a random selection of 40 United
Kingdom
manufacturers (including 16 NHS manufacturers) were examined for any trends
in the numbers of reported deficiencies. The review covered a broad cross-section
of companies, from multinationals to small NHS units. Consecutive increases
in the number of deficiencies reported per inspection were seen for 20 manufacturers,
consecutive decreases were seen for seven and the remainder showed no definite
trend. It is not possible to reach any firm conclusions based on these findings
at this stage. Increases in the number of product-related inspections and in
the number of unannounced inspections carried out in recent years may be contributory
factors towards an overall increase in the number of reported deficiencies.
Findings for manufacturers in third countries for 1996-1999 show that deficiencies
relating to potential contamination remain the greatest concern. There appears
to be a trend towards an increased incidence of deficiencies relating to in-process
controls and monitoring of production operations, but the figure of 11 per cent
of the total number of reported deficiencies for 1998/99 is still below the
overall figure for contamination and cross-contamination (17 per cent).
Deficiencies relating to risk of contamination also continue to dominate the
findings for NHS manufacturers. The overall incidence for 1998/99 was 16 per
cent, with the major contributor being the potential for microbial contamination
(as opposed to UK industrial manufacturers, where the major contributor is the
potential for chemical/ physical contamination). Concerns over premises and
environmental monitoring continue to feature strongly in inspection reports
of NHS manufacturing units. This may reflect the range of products made, being
those more at risk from microbial contamination.
In an industry characterised by batch production of many different products,
often on non-dedicated plant except for the more potent or sensitising products,
it is right that inspectors focus on the risk from contamination and expect
high standards in the measures taken by manufacturers to control this risk.
It is difficult to detect actual contamination by testing if, as is often the
case, it is distributed irregularly within a batch. While the methods of detection
are increasingly sensitive, the clinical importance of trace impurities in most
cases is difficult to estimate. Nevertheless, where inspectors are concerned
that processes, actions or omissions present a potential risk of contamination
they are recorded as deficiencies not only to emphasise that corrective action
is necessary, but also to advise companies, where appropriate, of the need to
implement preventive action before a situation becomes critical.
Wholesalers There has been little change in the pattern of deficiencies recorded during inspections of wholesale dealers over the past three years; deficiencies relating to written procedures remain the most frequently cited concern. Storage and transit 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. MCA has contributed to a number of open seminars and conferences on this subject, the British Association of Pharmaceutical Wholesalers has introduced a protocol for its members2 and advice has been published for the industry by the MCA.3
Action The purpose of this paper is not to consider consequential
actions arising from the inspection findings. Nevertheless, it may be helpful
to address these briefly. The large majority of deficiencies reported to the
manufacturer or wholesaler are remedied within an acceptable time without further
action by the regulatory authority. Provided this is done and product quality
is not considered to be at untoward risk, these deficiencies are not considered
grounds for adverse licensing action. Compliance with GMP is stated in a letter
from the inspector and is confirmed at the next inspection. More formal action
is taken in a minority of cases, either because of the nature or extent of the
deficiencies or the licence holder’s response or previous record, or a
combination of these. This can include suspension or revocation of the licence,
compulsory variation of the licence to exclude certain activities or categories
of product, or suspension of a Qualified Person. In 1998/99, seven cases involved
the use of the licensing authority’s established procedure for instituting
formal adverse licensing action. The actions recommended are summarised in Table
9.
After further investigations, including follow-up inspections to assess corrective
actions and consideration of representations from the licence holders, adverse
licensing action was taken in three cases. These comprised the suspension of
the manufacturer’s licence in one case and withdrawal of approval of a
third country manufacturing site in two cases.
The objective of 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 minor changes in the incidences of reported serious
GMP and GDP deficiencies in recent years, the most frequently cited categories
for each manufacturing sector and for wholesale distributors have not changed
markedly. The data reported above reinforce the findings reported in our previous
paper1 and indicate to manufacturers and distributors areas
on which they may wish to focus for training, internal audit and quality improvement.
Acknowledgments The authors acknowledge that the data presented in this paper were generated by the MCA’s medicines inspectors. Caroline Beaumont was responsible for recording inspection findings on the deficiency database.
Gordon Munro is head of the inspection and enforcement division of the Medicines Control Agency. John Turner is group manager for policy, borderline and standards, John Taylor is a senior inspector in this group and Nigel Goulding is the pharmaceutical assessor in the defective medicines report centre. Correspondence to Mr Taylor at the Medicines Control Agency, Market Towers, 1 Nine Elms Lane, London SW8 5NQ