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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5577_Библиотеки_им_академика_М_И_Перельмана.pdf
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
Pharmaceutical Data Integrity: issues,
challenges and proposed solutions for
manufacturers and inspectors
Adjunct Associate Professor Sia Chong Hock, BPharm, MSc, Vernon Tay,
BSc (Pharm) (Hons); Vimal Sachdeva, MSc, Associate Professor Chan Lai
Wah, BSc (Pharm) (Hons), PhD
Data Integrity, which is data deemed Attributable, Legible, Contemporaneous, Original, Accurate, Complete, Consistent, Enduring, and
Available (ALCOA-plus), has been the focus of the pharmaceutical
industry in recent years. With the growing use of computerized systems and rising prevalence of outsourcing manufacturing processes,
ensuring data integrity is becoming more challenging in an increasingly complex pharmaceutical manufacturing industry. To address
this issue, multiple legislation and guidance documents such as ‘Data
Integrity and Compliance with CGMP Guidance for Industry’ from
the United States Food and Drug Administration (FDA), ‘GxP’ Data
Integrity Guidance and Definitions from the United Kingdom Medicines & Healthcare products Regulatory Agency (MHRA), and Guidance on Good Data and Record Management Practices from the
World Health Organization”, have been published in recent years.
However, with rising data integrity issues observed by FDA, WHO,
MHRA and other pharmaceutical inspectors even after these guidance documents have been published, their overall eectiveness is
yet to be determined.
Good Documentation Practice and Pharmaceutical Data Integ rity
This paper compares and evaluates the legislation and guidance
currently in existence; and discusses some of the potential challenges
pharmaceutical manufacturers face in maintaining data integrity
with such legislation and guidance in place. It appears that these legislation and guidance are insucient in maintaining data integrity
in the industry when used alone. Last, but not least, this paper also
reviews other solutions, such as the need for a company culture of
integrity, a good database management system, education and training, robust quality agreements between contract givers and acceptors, and performance of eective audits and inspections, to aid in
maintaining data integrity in the manufacturing industry. These
proposed solutions, if successfully implemented, can address the
issues associated with data integrity, and raise the standard of pharmaceutical and biopharmaceutical manufacturing worldwide.
Keywords: ALCOA-plus, audit trail, blockchain technology,
computerized system, data integrity, regulations
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Introduction
Data integrity (DI) in the pharmaceutical manufacturing industry
is the state where data is Attributable, Legible, Contemporaneous,
Original, Accurate, Complete, Consistent, Enduring, and Available
(ALCOA+) [1–3], as outlined in Table 1. Data altered such that it no
longer fulfils these criteria is considered as falsified, regardless of it
being due to human error or generated deliberately [2, 4].
Current legislation, good manufacturing practice (GMP) standards
and guidance on data management and governance published by
organizations such as the United States Food and Drug Administration (FDA) [6–8] and World Health Organization (WHO) [1] aim
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
Table 1: Outline of ALCOA+ [5]
A Attributable
Who performed the action or
acquired the data, and when?
L Legible
Can the data be easily read and
are they indelible?
C Contemporaneous (real time)
Is the data documented at the
time of the activity?
O Original
Is data recorded from an original
observation or a certified
copy?
A Accurate
Is the information complete,
consistent, and correct?
ALCOA+: Attributable, Legible, Contemporaneous, Original, Accurate, Complete,
Consistent, Enduring, and Available.
+ Complete
Are all data, including changes,
included, e.g. testing, re-analysis,
processing, re-processing?
+ Consistent
Is there consistent generation of
records and application of time
stamps?
+ Enduring
Are data recorded in a manner
which will enable them to last
for the intended duration?
+ Available
Are data available for review and
audit during their entire life
cycle?
to guide the industry in ensuring DI is not compromised. These
include the ‘Data Integrity and Compliance with cGMP Guidance
for Industry’ from FDA [9], ‘GXP Data Integrity Guidance and Definitions’ from the United Kingdom Medicines and Healthcare products Regulatory Agency (MHRA) [10], and ‘Guidance on Good Data
and Record Management Practices’ from WHO [1], which were published in recent years. Inspectors from various organizations inspect
the pharmaceutical manufacturing companies to assure compliance to such legislation, standards and guidance, where appropriate
[3, 11, 12]. If violations of regulatory significance are observed, warning letters containing the key violations to be rectified would be
Good Documentation Practice and Pharmaceutical Data Integ rity
sent to the companies [13]. However, with the number of FDA warning letters issued citing DI violations quintupling from 2014 to 2017
[14], and large pharmaceutical companies getting cited for falsifying
data in quality control results and other manufacturing processes,
the eectiveness of such legislation and guidance to maintain DI
remains yet to be seen [15, 16].
With an increasing use of computerized systems in the pharmaceutical industry [17, 18], and current regulation of physical data being
more well-defined than regulation of electronic data [19], it is uncertain if the legislation and guidance are still able to maintain DI as
more electronic data are generated. Furthermore, the outsourcing
of pharmaceutical manufacturing activities to improve productivity
and business eciency continues unabatedly [20]. A lack of synergy
and good data management between companies increases the diculty in standardizing protocols and procedures to assure DI [21],
regardless of the legislation and guidance in place [22]. Additionally,
protocols which help maintain DI in parent companies may not
be adopted by their subsidiary companies [23]. Failure to prevent
DI violations could lead to substandard medicinal products being
released into the market, thus causing harm and possibly death to
patients [24, 25] and, in the case of vaccines and biosimilars, loss of
public confidence.
235
Hence, this paper strives to assess the prevalence and trends of recent
DI violations, identify reasons why companies commit DI violations,
evaluate the eectiveness of current legislation, guidance and challenges, and finally, explore solutions which can promote DI in the
pharmaceutical and biopharmaceutical manufacturing industry. A
systematic, scientific and comprehensive literature review, covering
the websites of regulatory authorities, scientific journals, pharmaceutical fora and newsletters, national and international legislation,
236
20
18
16
14
12
10
Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
GMP and other good practices and guidance documents relating to
DI, was conducted. Challenges and issues relating to DI were identified, and solutions to address them, were proposed for the benefit
of the manufacturers, inspectors and the global pharmaceutical and
biopharmaceutical community in general.
Current trends
As reported by the Unger Consulting Incorporation [14], the prevalence of FDA warning letters that cited DI violations has been
increasing exponentially, see Figure 1. This may be due to pharmaceutical inspectors proactively searching for DI violations [26],
inspectors who are now better trained to detect DI issues, more
companies taking risks in violating DI for various reasons, or ignorance and carelessness of operators [27]. It is not easy to analyse the
8
6
4
2
0
2015 2016 2017 2018
Figure 1: Percentage of DI associated warning letters by country (2008 to 2018)
[14, 29, 30]
DI: Data Integrity.
Good Documentation Practice and Pharmaceutical Data Integ rity
root causes of DI violations as the increasing prevalence of DI issues
and eorts to manage them appear to be a recent development [28].
Also, from Tables 2(a) and 2(b), it is noted that most of the DI
violations cited pertain to manual, automatic, mechanical and electronic equipment, which includes ‘failure to calibrate and maintain written records’ and ‘failure to exercise appropriate controls
over computer or related systems to assure that only authorized
personnel institute changes in production and control records, laboratory records or other records’ [31]. The next few most cited DI
violations pertain to quality control of the pharmaceutical product.
The leading countries being issued DI associated warning letters
include India and China [14], see Table 3, where parent pharmaceutical manufacturers in the US and Europe have been known to
translocate their manufacturing plants to these countries to reduce
production costs [20, 23]. It is also important to emphasize that DI
violations are also routinely cited by the FDA during inspections of
domestic manufacturers as well.
237
Reasons for Data Integrity violations (inadvertent and intentional)
Pharmaceutical companies are often under pressure to improve
their key performance indicators (KPIs), especially during economic
downturns. Hence, data are known to be falsified to decrease the
rejection of manufactured batches, with some companies deleting
non-compliant records [32–36], or even churning out records without legitimately performing relevant tests to expedite regulatory
approval [28, 34]. Furthermore, the lack of support from senior
management, due to insucient involvement and resources, can
Table 2(a): Drug GMP Inspections, citation frequency by regulations and year [14, 27, 30, 31]
Citation
Total Form 483s issued using FDA tools for Drug Inspections
§211.22(d) Procedures applicable to the quality unit shall be in
Short Description 2013 2014 2015 2016 2017 2018 2019
690 645 678 691 694 716 779
168 148 165 153 185 208 215
writing and shall be followed
§211.192 Investigations of discrepancies 239 209 250 227 278 183 167
§211.42(c) Facilities shall include defined areas of sucient size 94 125 235 227 148 134 156
§211.160(b) Lab controls should include scientifically sound
199 165 246 133 207 209 145
specifications
§211.166(a) Stability testing 104 82 126 124 72 111 135
§211.100(a) Production and process controls shall be supported
135 107 123 110 116 102 129
by written procedures
§211.67(b) Equipment cleaning and maintenance 83 80 91 102 91 112 124
§211.188 Master production and control records 114 74 110 100 208 93 123
§211.113(b) Control of microbiological contamination 119 109 157 118 92 71 121
§211.25(a) Personnel qualifications 132 115 119 99 113 47 113
§211.67(a) Equipment shall be cleaned/ sanitized or sterilized 71 94 113 94 54 81 99
§211.110(a) Sampling and testing of in-process materials and
79 74 85 65 68 86 94
final product
§211.165(a) Appropriate lab tests shall be used to determine
66 64 80 73 64 56 90
conformance to specifications
§211.68(a) Automatic, mechanical, and electronic equipment 69 64 72 80 67 60 67
§211.100(b) Contemporaneous documentation of activities 84 62 72 70 65 60 54
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
Good Documentation Practice and Pharmaceutical Data Integ rity
Table 2(b): Frequent Data Integrity violations and regulation citations in FDA
warning letters [30]
Number Of
21 CFR
Reference
Times Cited Title of CFR section
211.194 10 Laboratory Records, Review of All Data
211.188
211.165 (a) and (b)
211.192
6
5
5
Batch Production and Control Records
Testing and Release for Distribution
Production Record Review, Deviations
and Investigations
211.68
2
Automatic, Mechanical and Electronic
Equipment
Table 3: Number of Data Integrity associated warning letters by country (2008
to 2018)
2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 TOTAL
China
USA 1 2 1 1 1 0 7 15 8 36
India 1 1 2 6 7 10 9 12 6 54
Europe 1 1 2 6 3 1 14
Brazil 3 3
Japan 1 2 1 3 7
Thailand 1 1
Canada 1 1 2 1 5
Mexico 2 1 1 4
UAE 1 1
Jamaica 1 1
South Korea 2 4 6
Singapore 1 1
Australia 1 1
Taiwan 1 1
Dominican
Republic
TOTAL 4 5 5 4 6 6 10 15 41 56 42 194
UAE: United Arab Emirates.
1 1 3 1 2 2 14 19 15 58
1 1
239
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
aggravate the situation. Also, some employees may fear retrenchment due to unachieved KPIs [37, 38]. Thus, they may release the
product without following internal protocols requiring them to
seek approvals from authorized personnel [33], or alter records if
given access to the database [35, 39]. Occasionally, and in particular,
for systems involving manual transfer of data to the company database using hybrid computerized systems, transcription errors can
occur, leading to inaccurate data records [40].
An example of a hybrid approach is where laboratory analysts use
computerized instrument systems that create original electronic
records and then print a summary of the results. Where hybrid
approaches are used, appropriate controls for electronic documents,
such as templates, forms and master documents, that may be
printed, should be available. However, during on-site inspections of
the laboratory systems, it has been discovered that data were being
falsified on an industrial scale, using a variety of means, such as
copy and paste, manipulation of weights, and unauthorized manual
integration of chromatograms. The root cause is often a chromatographic data system (CDS) whose audit trail had been deliberately
turned o, and therefore, cannot track who had falsified what data,
and when [41].
Assuring and promoting Data Integrity via legislation and guidance documents
Legislation
In this article, regulations from the FDA and the European Union
(EU) EudraLex, are discussed and compared. As DI in pharmaceutical
Good Documentation Practice and Pharmaceutical Data Integ rity
manufacturing is strongly associated with Good Manufacturing
Practice (GMP), it is important to understand the GMP regulatory
framework and its impact on DI. The GMP legislative framework
from FDA comprise the 21 CFR 210, 211, 212, 600, and 820, while
those from EU comprise Commission Directive 2003/94/EC and its
regulatory statute EudraLex Volume 4 [42]. 21 CFR 210 provides a
very generic regulation on the safety, identity, strength, quality, and
purity of pharmaceutical products [7]. EU Commission Directive
2003/94/EC gives a general over view of GMP for the pharmaceutical
manufacturing companies [43]. 21 CFR 211 and EudraLex Volume 4
are similar, regulating the required documentation for personnel
qualifications and training, equipment protocols, inspections and
maintenance, labelling and distribution processes, and even protocols for recalls, and corrective and preventive actions (CAPA) [8, 43],
with EudraLex Volume 4 dedicating Chapter 7 to contract requirements for outsourced manufacturing activities [43], whereas such
requirements are not explicitly stated in 21 CFR 211. 21 CFR 212 and
600 regulate specifically radiological [44] and biological pharmaceutical products [45] respectively. In general, they require more accurate and attributable information to be kept for a longer time to
retrace and recall when issues pertaining to the manufacture of the
product arise. 21 CFR 820 dictates requirements to ensure quality is
maintained throughout the manufacturing process, specifying the
documentations required to validate such processes [46]. Clearly,
these legislations cover many aspects where proper documentation
and DI should be enforced.
241
There are also legislation specifically promoting DI in pharmaceutical manufacturing. For example, 21 CFR 11 specifically targets
requirements for electronic documentation, stating that these electronic documentations are as significant as paper records, and in certain cases can be used in lieu of them [6]. It regulates computerized