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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5855_Библиотеки_им_академика_М_И_Перельмана.pdf
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
MKT is not an easy concept to understand and to apply. By definition, MKT is a single derived temperature that, if maintained over a
defined period of time, aords the same thermal challenge to a drug
substance or drug product as would be experienced over a range
of both higher and lower temperatures for an equivalent defined
period. MKT is higher than the arithmetic mean temperature. The
following formula of Haynes, based on the Arrhenius equation, can
be used to calculate MKT for a defined period:
Calculation of mean kinetic temperature
Legend and Symbols
is the MKT calculated in degrees Kelvin. The final MKT result
• T
K
(in degree Celsius) can be calculated by doing a simple subtraction, i.e., T
– 273.15°.
K
• ΔH is the activation energy which describes the reaction rate for
degradation of the active ingredient. A default value of 83.144
kJ/mol is typically used as a good approximation for most pharmaceutical compounds. The use of a default value also simplifies
the mathematics.
• Please note that it is possible to use a dierent ΔH value that is
specific to a given active ingredient (or pharmaceutical product)
if the information is available from experimental studies.
• R is the universal gas constant, which equals 8.3144 J/°K/mol.
• n is the total number of storage temperatures recorded during
the observation (study) period.
Stability and Shelf-Life Testing of Medicinal Products
• T1 = the (average) temperature, in degrees Kelvin, during the
first time point.
• T
= the (average) temperature, in degrees Kelvin, during the sec-
2
ond time point.
• T
= the (average) temperature, in degrees Kelvin, during the nth
n
measured time point.
7.10 . Calculating MKT during Storage and
Transportation
The US FDA and pharmacopeias have published methods to calculate MKT during storage and transportation. However, the easiest
and most meaningful way to get an MKT value is by letting the
data loggers and software do the work for you. It is of course possible to do the calculation yourself, but remember that you need to
gather an extensive amount of data and a calculation tool (for example Microsoft Excel). The manual calculations can be overwhelming. So, we should let the data loggers and software do the work for
us. However, it should be remembered that any tool employed for
calculation of MKT for use in GMP/GDP environment and the associated decision-making would require validation.
223
The UK MHRA advocates the use of MKT in GDP. The agency recognizes that it is not possible to obtain a meaningful MKT value
from daily readings of simple maximum-minimum thermometers
as temperature fluctuation is not a linear function. Continuous
monitoring of temperature data can provide a more meaningful
MKT value. Many data loggers and building management systems
are capable of recording multiple/continuous temperature readings,
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
and calculating the MKT over a given time period. Today, there are
many monitoring systems which can automatically calculate MKT,
using any historical data set. Simply select the timespan you are
interested in and the MKT values will appear in the software window automatically.
7.1 1. Conclusion
This chapter on stability testing can be summarized as follows:
• Stability tests are carried to ensure that a product is safe, eective and of good quality throughout its shelf life.
• Current regulations, science and technology are adequate to
cover all conditions which products are subjected to during storage, transportation and use.
• Stability tests should be carried out following proper scientific
principles and understanding of current regulations and as per
relevant climatic zones.
• MKT is a useful tool to help assure product quality during distribution, especially if storage temperature does not exceed 25°C
or 30°C, or go below refrigeration temperature.
• The inclusion of more recorded temperature-time points in the
formula of Haynes would give a more accurate prediction of the
MKT value.
• Regardless of whether the MKT calculations are used or not, all
temperature excursions should be investigated.
Chapter 8
Good Documentation Practice and
Pharmaceutical Data Integrity
225
8.1. Christopher Columbus versus the Vikings
hat has Good Documentation Practice got to do
with Christopher Columbus and the Vikings? The
short answer is: Good Documentation Practice
W
pher Columbus. He was acknowledged as the discoverer of America instead of the Vikings who probably reached America earlier
than Columbus. The Vikings were prolific explorers, navigators and
discoverers. Some historians believed that the Vikings, led by Leif
Erikson, reached America around the year 1000, which was about
500 years earlier than Columbus. But they did not keep good
records. So, they had no robust proof of where they had been and
their voyage to America was deemed to be anecdotal, rather than a
historical fact.
changed the course of history in favor of Christo-
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
On the other hand, Christopher Columbus was known to be a
meticulous explorer who kept good and extensive records. In 1492,
Columbus landed on a New World. Evaluation of historical records
showed that he reached America. Hence, Columbus is acknowledged as the discoverer of America. You could say that Columbus
knew about the paramount importance of Good Documentation
Practice. He was ahead of his time!
8.2. Documentation and Good Manufacturing
Practice
Documentation is an integral part of Good Manufacturing Practice (GMP). In fact, documentation has always been a significant
and distinct chapter in all national and international GMP standards. Documentation and Good Documentation Practice have been
part of GMP ever since the US FDA published the world’s first GMP
standard in 1962, namely, the US cGMP Regulations for Finished
Pharmaceutical Products, following the Kefauver-Harris Amendment to US Food, Drug and Cosmetic Act. Good Documentation
Practice and GMP as a quality system standard may be crystallized
into the four statements on the next page.
8.3. PIC/S Guide to GMP for Medicinal Products —
Chapter 4
Chapter 4 of the Pharmaceutical Inspection Convention/Co-operation Scheme (PIC/S) Guide to GMP for Medicinal Products deals
with the broad topic of Documentation. It includes elements such
Good Documentation Practice and Pharmaceutical Data Integ rity
as good documentation practices, generation and control of documents, retention of documents, types of documents such as Standard Operating Procedures (SOPs), specifications, batch manufacturing records and many other mandatory records. For example,
Chapter 4.3 specifies that documents should be approved, signed and
dated by authorized persons, and the eective date of a document
should be defined. In eect, it emphasizes the need for documents
to be “attributable”. Chapter 4.7 specifies that entries of records
should be made in a clear, legible, indelible way. In eect, this subchapter requires records to be “legible”. Chapter 4.8 states that
records should be made at the time of action, and be traceable,
that is “contemporaneous” recording. In addition, Chapter 4.9
states that any alteration of records should permit reading of original information and all alterations should be signed and dated.
Additionally, the reason(s) for the alteration of records should be
highlighted and documented. This is in essence the need to maintain “original” and “accurate” records.
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
8.4. Pharmaceutical Data Integrity and ALCOA
Whether it is the US FDA, PIC/S or World Health Organization GMP
standard, it is indeed mandatory for documents, records and data
to be ALCOA, namely, Attributable, Legible, Contemporaneous, Original
and Accurate, without the GMP standards explicitly saying so. Data
Integrity is the degree to which data are ALCOA, making the set
of data complete and trustworthy. Assuring data integrity requires
Good Documentation Practice for both paper and electronic data,
with application of quality risk management and scientific principles, and by people of integrity.
In her book Bottle of Lies published in 2019, author Katherine Eban
described vividly and in great detail the data integrity scandal and
whistleblowing by Dinesh Thakur, a senior employee of Ranbaxy,
then India’s largest pharmaceutical company. In her book, it was
revealed that “fraud and trickery had been deeply entrenched in
Ranbaxy and there was rampant disregard for pharmaceutical data
integrity by the company, including its top management. The company had been fabricating the test results of its medicinal products, and endangering millions of patients in India and around the
world.” Dinesh Thakur decided to resign and turned whistleblower
to the US FDA, which was one of the medicines regulators that Ranbaxy had been dealing with. The book described at great length how
the “multibillion-dollar behemoth was ultimately brought down to
its knees”. It was a sensational case of how one of the world’s corporate success stories fell from grace because of fraud, trickery and
disregard for pharmaceutical data integrity.
Good Documentation Practice and Pharmaceutical Data Integ rity
229
Today’s pharmaceutical manufacturing industry is highly globalized, automated and computerized. It is important to note that a
computerized system comprises not just the hardware and software
components. A computerized system includes the associated personnel, such as the operators or users, process owner, system owner,
and the system administrators. A computerized system also includes
rd
the 3
erized system (comprising the hardware, software, people and 3
party suppliers and service providers. Collectively, a comput-
rd
parties) fulfils a specific manufacturing or quality control function.
Increasingly, computerized systems are bespoke or customized.
They are not purchased o the shelf but are designed on a turnkey
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
basis for a company or organization, from scratch. Annex 11 of the
PIC/S GMP standard covers the topic of Computerized Systems Validation. The overarching objectives of Computerized Systems Validation is to ensure the accuracy, reliability and consistency of the
computerized system, that is, the ability of the validated computerized system to assure data integrity, including discerning authentic
data from falsified ones.
Computerized systems in pharmaceutical manufacturing
8.5. Article(s) on Pharmaceutical Data Integrity
In summary, the increasing concerns regarding pharmaceutical
data integrity are most probably due to the globalization of the
pharmaceutical industry and the associated outsourcing of critical components of manufacturing activities to dierent parts of
the world, often with a compromised or diminished inspection
oversight. There is a need for the pharmaceutical manufacturing
Good Documentation Practice and Pharmaceutical Data Integ rity
industry to appreciate the impact of computerized systems, digital
technologies and organization culture on quality. Robust quality
agreements need to be in place to eectively manage outsourcing
of activities such as contract testing, analysis and manufacturing.
A supply chain is only as strong as its weakest link. And last but not
least, there is also a need to be aware of economic dark clouds and
downturns which can emerge from time to time. This can erode the
quality culture of a company leading to cutting corners, resulting in
a PERFECT STORM!
With current strict regulations and GMP standards in place to
assure data integrity, why have there been so many concerns regarding pharmaceutical data integrity in recent years? It is against this
background that the authors and their collaborators published the
article entitled “Pharmaceutical Data Integrity: issues, challenges
and proposed solutions for manufacturers and inspectors” in
GaBI Journal (Volume 9 | 2020 | Issue 4). Copyright © 2020 Pro Pharma
Communications International. This article has been reproduced
with permission from the publisher of GaBI Journal, and it appears
immediately after this introduction.
231
A related section entitled “Computerized Systems, Digital Technology and Pharmaceutical Data Integrity” is discussed in Chapter 25 on
Industry 4.0 and Emerging Trends in Pharmaceutical Manufacturing.