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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
[90]. However, relying on DBMS alone will not prevent all DI issues.
Firstly, DBMS is unable to ensure data entered was ALCOA-plus,
and audits are required to ascertain that [111]. Secondly, unvalidated
or outdated systems require upgrading, and migration of data while
updating may cause errors to be carried forward unknowingly,
especially for large volume of data [95, 112], leading to an inaccurate
database. Therefore, DBMS alone cannot prevent all DI issues. Continually upgrading DBMS by periodically reviewing documentation and procedures which influence the quality of pharmaceutical
products manufactured against established standards would aid in
promoting DI in the future as well [113–116]. However, audits take
resources to perform, and smaller companies might not be able to
perform frequent and comprehensive self-audits. Nonetheless, having such audits would ensure that the DBMS employed by the company are current and ecient, ultimately promoting DI [95, 114].
Education and training
It is important for employees to undergo DI education and training
for them to understand the importance of maintaining DI and the
consequences if not maintained [117, 118]. More detailed sessions
should be conducted for employees with access to modify processes,
systems, and records, further explaining their responsibilities [114,
118]. Training sessions could also standardize the procedures, terminology, and concepts within the company, reducing DI violations
due to miscommunication [114]. Currently, DI courses from external service providers such as ECA Academy [119] and Reading Scientific Services Ltd (RSSL) [120] exist.
However, training can be costly, especially to smaller companies. To
mitigate part of the cost, a representative could be trained, before
Good Documentation Practice and Pharmaceutical Data Integ rity
training their fellow colleagues, causing a multiplying eect. Furthermore, manufacturers may form associations together, getting
group discounts from DI training providers [120]. To ensure knowledge retention of the training provided, constant refreshers are
needed, be it refresher courses or incentivize maintaining DI with
company culture, otherwise such knowledge might be forgotten if
infrequently used [121].
Robust quality agreements
With an increase in outsourcing of pharmaceutical manufacturing
processes, quality agreements, which are written contracts between
companies to ensure responsibilities and expectations for both parties are agreed upon [122], must be rigorously prepared, mutually
agreed and signed. However, this process can be time-consuming as
reaching a consensus can be challenging. Some guides, such as one
from Rx-360 [123], help expedite this process. By having a concise
understanding of expectations, the contract giver would hence be
able to assure that practices which promote DI would be performed
by the contract acceptor, while the contract acceptor understands
what is expected of them [124].
253
Collaboration between countries
Each country has its own set of legislation. Although the legislation of dierent countries generally overlaps [125, 126], individual
countries may not accept specific documents that originate from
another country, exacerbating DI issues. Hence, collaborative use of
legislation and mutual recognition schemes can help to promote DI
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
[127, 128], with the added benefit of ecient international transactions as DI criteria would have been fulfilled prior to application for
regulatory or other transaction approvals.
Eective and ecient audits and audit trail review
Audits are defined as validation checks conducted on manufacturing protocols and systems that assure quality in the processes, products, and computerized systems at the manufacturing site [129]. This
includes both internal audits self-conducted by the manufacturer
in accordance with Chapter 9 of the PIC/S GMP Guide [130], and
external audits conducted by regulatory auditors including FDA
and MHRA. As audits are limited in duration, meaningful and ecient audits should be conducted [124]. In general, processes or data
that do not aect product safety and compliance, including data on
accounting and finances [131], need not be audited. The audit can
be streamlined by tagging relevant items to allow the auditor to
quickly sieve them out for scrutiny [132, 133]. Audit trails may be
divided into 2 dierent types: Data Audit Trail (DAT), which covers
the raw data recorded, and System Audit Trail (SAT), which covers
the systems in place to maintain DI during documentation.
When auditing DAT, critical quality attributes (CQA) and audit
trail elements must be defined before conducting the audit. CQAs
are the characteristics or properties that can harm patients if not
properly controlled [117]. These attributes are to be defined by the
company, referring to current legislation and guidance such as ICH
Q8(R2) Part 2 [134]. Audit trail elements are the items which aect
CQAs and are to be audited [132]. Other items need not be audited
as frequently nor meticulously [131]. When auditing SAT, assuming
Good Documentation Practice and Pharmaceutical Data Integ rity
Table 7: Suggested review frequencies based on GAMP 5 Software
Category and risk class [49, 131]
GAMP 5 Software Category
Risk Class
High 3 months 6 months 12 months 24 months
Medium 6 months 12 months 24 months As required
Low 24 months 36 months As required As required
5
4 3 1
the current system is validated, auditing for possible indicators
of DI breaches can substitute an audit of the raw SAT data [131].
These indicators include multiple logins attempts and read and
write errors [135]. With the recent focus of audits being more SAToriented, coupled with more robust systems that can detect errors
in DAT [131], falsification of data points prior to documentation
may not be detected. As such, both DAT and SAT must be audited
in tandem to achieve a more comprehensive audit outcome.
255
Finally, it must be emphasized that a reliance on periodic audits
from the regulator is grossly inadequate to address DI issues. On
the other hand, overly frequent internal audits may ineciently use
the company’s manpower. For SAT, an approach based on the risks
and implications of DI breaches and the Good Automated Manufacturing Practices (GAMP 5) Software Category [131], as tabulated in
Table 7, is recommended.
Computerized systems validation
Pharmaceutical and biopharmaceutical manufacturers should
validate their computerized systems such that they are fit for
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
their intended purpose, and to ensure that adequate controls are
in place to facilitate tracking and detection of deleted or altered
data. The use of hybrid (paper and computerized) systems should
be discouraged. However, where legacy systems are awaiting
replacement, mitigating controls should be put in place. In such
cases, original records generated during the course of GxP activities must be complete and must be maintained throughout the
records retention period in a manner that allows the full reconstruction of the GxP activities. Replacement of hybrid systems
should be a priority [41].
List of abbreviations
ALCOA+ Attributable, Legible, Contemporaneous, Original,
Accurate, Complete, Consistent, Enduring, and
Available
CAPA corrective and preventive actions
CQA critical quality attributes
DAT Data Audit Trail
DBMS database management system
DI Data Integrity
EU European Union
GAMP 5 Good Automated Manufacturing Practice guide
version 5
GMP good manufacturing practice
ICH The International Council on Harmonisation of
Technical Requirements for Pharmaceuticals for
Human Use
KPIs key performance indicators
PIC/S Pharmaceutical Inspection Convention and
Pharmaceutical Inspection Co-operation Scheme
Good Documentation Practice and Pharmaceutical Data Integ rity
SAT System Audit Trail
UK MHRA United Kingdom Medicines and Healthcare products
Regulatory Agency
Conclusion
With increasingly complex pharmaceutical manufacturing processes,
maintaining DI might become more challenging, and relying merely
on legislation and guidance to maintain DI might be insucient.
Some possible solutions to tackle this challenge include having a company culture of integrity, having a good DBMS, education and training, forming eective quality agreements, collaborations between
countries, and performing ecient audits. Together with existing legislation and guidance, these measures can help manage DI issues in
the pharmaceutical manufacturing industry, improve the standard
of pharmaceutical manufacturing worldwide, and ultimately, produce safe and quality medicinal products for patients internationally.
257
Competing interests: None.
Provenance and peer review: Not commissioned; externally peer
reviewed.
Authors
Adjunct Associate Professor Sia Chong Hock1, BSc (Pharm), MSc
Vernon Tay
Vimal Sachdeva
(Pharm) (Hons), PhD
1
, BSc (Pharm) (Hons);
2
, MSc Associate Professor Chan Lai Wah1, BSc
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
1
Department of Pharmacy, National University of Singapore,
18 Science Drive 4, Singapore 117543
2
Technical Ocer (Senior Inspector), World Health Organization,
Prequalification Team, Regulation of Medicines and Other Heath
Technologies (RHT), Essential Medicines and Health Products
(EMP), Health Systems and Innovation, 20 Avenue Appia, CH-1211
Geneva 27, Switzerland
References
This article has 135 references which can be found at https://gabijournal.net/pharmaceutical-data-integrity-issues-challenges-andproposed-solutions-for-manufacturers-and-inspectors.html.
Part III
Manufacture and Supply,
Science and Regulation of
Medicinal Products
Chapter 9
Manufacture and Supply, Science
and Regulation of Biopharmaceutical
Products
261
9.1. Pharmaceuticals versus Biopharmaceuticals
iopharmaceutical products are also referred to as biological medicinal products, or simply as biologics, biologicals
or biopharmaceuticals. Let us compare a pharmaceutical
B
tons) with a biopharmaceutical product such as Immunoglobulin
G (molecular weight: 150,000 Daltons).
Pharmaceuticals are relatively small, simple molecules produced
through chemical synthesis while biopharmaceuticals are generally
large, complex proteins produced in living cells. Pharmaceuticals
have defined structures and are easier to characterize or analyze,
product such as Lovastatin (molecular weight: 404.5 Dal-