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Table 3: Comparison of GMP standards between various RAs and IOs
RA/IO WHO PIC/S ASEAN
Provisions
of GMP
standards
Tec hn ica l Report Series
(TRS), No. 957,
Annex 2
• GMP for API
TRS, No. 986, A nnex 2
• GMP for
pharmaceutical
products
TRS, No. 999, Annex 2
• GMP for biolog ical
products
PIC/S GMP Guide Par t I
• Basic requirements for medicinal products
PIC/S GMP Guide Par t II
• Basic requirements for API
PIC/S GMP Guide An nex 2
• Manu facture of biological medicinal prod-
ucts and substances for human use
282
a
FDA NMPA EMA CDSCO
21CFR, part 210-211
• Par t 210: Current
GMP (cGMP) in
manufacturing,
processing, pack-
aging, or holding
of drug s; general
• Par t 211: cGMP
for finished phar-
maceuticals
Guidance for Indus-
try, Q7A
• GMP for API
21 CFR, Part 600
to 680
• Prov isions for
biologicals
21 CFR, Part 1271
• Provisions for
human cells, tis-
sues, and cellular
and tissue-based
products (HCT/P)
Chinese GMP
Annex 3
• GMP for
biological
medicinal
products
EudraLex, Vol. 4
Part I
• Basic require-
ments for medici-
nal products
EudraLex, Vol. 4
Part II
• Basic require-
ments for active
substances
used as starting
materials
EudraLex Vol. 4,
Annex 2
• Ma nufacture of
biological prod-
ucts and active
substa nces for
human use
EudraLex, Vol. 4
Part IV
• GMP
requirements for
ATMPs
Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
Schedule M
• GMP and
requirements of
premises,
plant and
equipment for
pharmaceutical
products
(Continued )
Table 3: (Continued )
RA/IO WHO PIC/S ASEAN
GMP
principles
Emphasis on:
• QR M principles
• Robust manufacturing process
• In-process controls
Remarks • Does not disting uish
between dierent
types of
biopharmaceuticals
• GMP for API does
not include vaccines,
gene therapy and
whole cells; however,
production of APIs of
biologicals is covered
by GMP for biologi-
cal products
• PIC/S GMP
Guide Part II is
analogous to ICH
Q7 – GMP guide
for API
• PIC/S GMP
Guide Annex 2 is
divided into two
parts — general
guidance (Part
A) and fur ther
guidance on
• MRA currently
excludes biopharma-
ceuticals
• AMS have pledged to
use PIC/S
guidelines,
excluding those
pertaining to
biopharmaceuticals
selected types of
biological medic-
inal substances
and products
(Part B)
a
ASEAN compr ises 10 Member States, e ach with its ow n RA.
AMS: ASEAN Member States; API: active pharmaceutical ingredient ; ASEA N: Ass ociation of South East A sian Nations; AT MPs: advanced therapy medicinal produc ts;
CDSCO: Dr ugs Standard Control Organ isation; EM A: Europea n Medicines Agency; FDA: Food and Drug Administ ration; ICH: International Council for Har monisation;
IO: international organization; GMP: good manufact uring practice; NMPA: Nationa l Medica l Products Admi nistration; QRM: quality risk management ; PIC/S: Phar ma-
ceutica l Inspection Co-operation Scheme; RA: reg ulatory authorities; WHO: World Health Organ ization.
a
FDA NMPA EMA CDSCO
— • Being an ICH
member,
NMPA is
expected to
adopt ICH
Q7A as well
• GMP princi-
ples are not
Emphasis on:
• QR M principles
• Robust manufac-
turi ng process
• In-process
controls
• Flexibility
(ATMPs only)
— • GMP does not
Provisions seem
to imply CDSCO
adopts similar
manufacturing
principles
as the well-
established RAs
and IOs
explicitly
mentioned about
biopharmaceu-
ticals. However,
the provisions
seem appropri-
ate.
explicitly
stated, but
inferred
Manufacture and Supply, Science and Reg ulation of Biopha rmaceutical Products
283
284
Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
Furthermore, the National Medical Products Administration
(NMPA) of China has a GMP guideline for API that is not entirely
relevant to biopharmaceutical APIs. This guideline provides recommendations on API produced by classical fermentation, which typically do not employ biotechnological processes and requires less
stringent control on the manufacturing processes [80]. In addition,
the APIs produced by classical fermentation, such as antibiotics,
amino acids and vitamins, are generally of low molecular weights
[77]. Instead, GMP pertaining to biopharmaceuticals and their APIs
are covered under the Chinese GMP Annex 3 only. NMPA, being a
regulatory member of the International Council for Harmonization
(ICH), is expected to implement ICH Q7 guideline — GMP Guide
for API [81]. Hence, NMPA’s GMP guideline on API is likely to be
harmonized with international standards. However, since NMPA is
not expected to implement ICH Q5 guideline — Quality of Biotechnological Products, it is dicult to ascertain whether NMPA’s GMP
standards on finished biopharmaceuticals are harmonized with
international standards.
The Central Drugs Standard Control Organization (CDSCO) of India,
for instance, does not explicitly mention about the inclusion of biopharmaceuticals within the scope of its GMP guide-line (Schedule M)
[82]. However, the provisions appear to be adequate for biopharmaceuticals and also suggest that CDSCO adopts similar GMP principles
as the well-established RAs and IOs. There is an additional guideline
document for biopharmaceuticals on the CDSCO website, but it was
inaccessible at the time of writing this review. It is worth mentioning that both China and India are currently undergoing regulatory
reforms and have expressed interest to join PIC/S [83]. There are also
reports that Chinese and Indian manufacturers are improving their
Manufacture and Supply, Science and Reg ulation of Biopha rmaceutical Products
product quality to meet international standards [84, 85], signaling
their strong commitment to GMP.
Within ASEAN, the biopharmaceutical industry is at a nascent stage.
Vaccines are the main biopharmaceuticals manufactured due to the
high prevalence of infectious diseases [86]. In addition, there have been
reports of vaccine shortages in ASEAN which may necessitate prioritizing vaccines over other biopharmaceuticals [87]. The review of ASEAN
GMP standards reveals that the majority of AMS adopt PIC/S GMP
recommendations for biopharmaceuticals [88–91]. The lack of unified
adoption can be attributed to the current exclusion of biopharmaceuticals from the scope of the ASEAN Mutual Recognition Arrangement
(MRA) [92]. In addition, some AMS are emphasizing on generic pharmaceutical manufacturing [93, 94] and medical devices [95], which may
also contribute to the lack of GMP guidelines for biopharmaceuticals.
However, eorts have been made, such as the recent agreement on the
ASEAN common technical requirements of biological products [96],
to include biopharmaceuticals for harmonization in the future [97].
285
Overall, the dierences in the scope of GMP standards observed is
not surprising in view of the diversity of biopharmaceuticals being
manufactured, and that GMP guidance is contextualised to the
respective countries. It is however heartening to know that most
RAs and IOs share similar GMP principles for regulating biopharmaceuticals. With concerted eorts, the outlook on harmonization
is bright. Nonetheless, it must be emphasized that the adequacy of
GMP and quality standards adopted by the various RAs and IOs,
will ultimately depend on the extent of compliance by the biopharmaceutical manufacturers, and the robustness of enforcement of
the standards by the RAs and IOs.
286
Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
Challenges in the regulation of biopharmaceuticals
Resource-intensive evaluation of biosimilarity
The standard approach for approving generic conventional
chemical-based pharmaceuticals, or generics, is not appropriate for
biosimilars. For the approval of generics, manufacturers only need to
demonstrate that the generics have identical molecular structure and
is bioequivalent to the reference product [98]. However, the inherent
variability of biopharmaceuticals makes it impossible for biosimilars
to exactly replicate the reference product. Manufacturers may have
to modify the manufacturing process based on the reference product with appropriate optimization such that the CQAs of biosimilars are highly similar to that of the reference product [99]. There
will be dierences, albeit slight, in the processing that can aect the
end-product of biological nature. Hence, a ‘totality-of-the-evidence’
approach is used to evaluate biosimilarity. This approach considers
the entirety of the information submitted in the biosimilar application, such as data from analytical, preclinical, clinical studies and
lot-to-lot variabilities, to evaluate the biosimilarity to the reference
product [100]. The approval of biosimilars places more emphasis on
extensive characterization of the API [101], with supplementary data
from animal studies, clinical pharmacology or clinical trials to rule
out any residual uncertainty from the characterization process [102].
Compared to chemical-based pharmaceuticals, the evaluation process
clearly demands more time and expertise for the RAs. In addition,
doubts have been cast on the suitability of the guidance for biosimilarity evaluation in assessing more complex biopharmaceuticals such
as ATMPs [103]. Such uncertainty thus raises the need for more harmonization between dierent regulatory perspectives.
Manufacture and Supply, Science and Reg ulation of Biopha rmaceutical Products
Diering perspectives on interchangeability
Dierences exist between FDA and EMA perspectives on
inter-changeability. For FDA, biopharmaceuticals that are highly
similar to the reference product can be classified as biosimilar
product or interchangeable product. For the product to be classified as interchangeable, additional data on the safety and ecacy of
switching from the reference product must be provided [104]. Once
an interchangeable product is approved, the reference product may
be substituted with the interchangeable product by the pharmacist without consulting the prescriber. In comparison, EMA does
not require additional studies to determine if a biosimilar is interchangeable. However, EMA distinguishes the act of interchanging
between reference product and biosimilar, or between biosimilars, into switching and substitution: switching is done at the prescriber level while substitution is done at the pharmacy level [14].
Dierences in definition can lead to unnecessary confusion when
manufacturers want their products approved for use in dierent
countries. While the requirement for a switching study can provide better safety assurance of the interchangeable product, this
also increases the production cost and possibly negate any cost savings it has over the reference product. This may also explain why
there has been no interchangeable products approved by FDA currently [105, 106]. In addition, the vast clinical experience of EMA in
approving biosimilars has demonstrated that biosimilars have similar ecacy and safety profiles as their reference product [107]. This
is also supported by a systematic review which did not show any
safety or ecacy risk from switching between reference products
and biosimilars [108]. Thus, the requirement by FDA for a switching study to demonstrate interchangeability is debatable.
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
Growing number of data integrity lapses
‘Data integrity is the degree to which a collection of data is complete,
consistent and accurate throughout the data life-cycle. The collected
data should be attributable, legible, contemporaneously recorded,
original or a true copy, and accurate (ALCOA). Assuring data integrity requires appropriate quality and risk management systems,
including adherence to sound scientific principles and good documentation practices’ [109, 110]. FDA has noted an increasing number
of GMP violations pertaining to data integrity in recent years [111].
Compromised data integrity can lead to missing and inaccurate
information that are vital considerations in the regulatory approval
for market authorization [112], as well as jeopardizing product quality assurance [113]. Lapses can be due to unintentional errors such
as lack of awareness as well as inadequate standard operating procedures (SOPs) [114]. In more serious cases, deliberate data manipulations, such as data falsification instructed by upper management,
have been reported [115, 116]. A review of the warning letters issued
by the Center for Biologics Evaluation and Research (CBER) reveals
that data manipulation can occur despite the implementation of
legislative guidelines, SOPs and controls [117–119], hinting a possible
lack of a quality-focused culture within these organizations.
Proposed solutions to challenges of biopharmaceuticals
Optimizing biopharmaceutical manufacturing with Industry 4.0
Industry 4.0, or the Fourth Industrial Revolution, is a broad concept
that involves the amalgamation of physical and digital technologies
Manufacture and Supply, Science and Reg ulation of Biopha rmaceutical Products
to generate a constant flow of information, allowing real-time data
access [120]. These data can then be applied to generate analytical
tools such as algorithms and models to allow better process and
product understanding [121]. Consequently, this allows more eective implementation of Quality-by-Design (QbD) approach in process development and optimization [122]. According to ICH, QbD
is a “systematic approach to development that begins with predefined objectives and emphasizes product and process understanding
and process control, based on sound science and quality risk management” [76]. With QbD, process capability is improved with better product and process understanding, which in turn reduces the
inherent variation in quality of biopharmaceuticals [123].
Real-time data access can be achieved with process analytical
technologies (PAT). FDA considers PAT as “a system for designing,
analyzing, and controlling manufacturing through timely measurements, i.e. during processing, of critical quality and performance
attributes of raw and in-process materials and processes, with the
goal of ensuring final product quality” [124]. The general methodology of PAT begins with the collection of data using robust, rapid
and sensitive analytical tools and sensors, such as HPLC, dynamic
light scattering, pressure gauge and flow meter [125]. This is followed
by the modelling of these data to generate useful process-related
information and ends with the goal of using the generated data to
influence the manufacturing processes [126]. For instance, PAT has
been used to optimize downstream processing. This is achieved by
combining the screening of previously validated chromatographic
conditions with scientifically sound experiments to generate a chromatographic model that is able to predict critical process parameters for downstream optimization [127, 128]. In addition, deviations
captured during routine monitoring can also be used to generate
algorithms that can better categorize human errors or facilitate
289
290
Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
more eective corrective actions and preventive actions (CAPAs),
thereby reducing the occurrence of failed batches as well as the cost
of implementing CAPAs [129].
Industry 4.0 has allowed greater interconnectivity through platforms such as the Internet of Things (IoT), providing worldwide
access to data to facilitate better process understanding. For instance,
a better understanding of the CHO cell genome is achieved by pooling data from various assemblies generated by the other researchers using sequencing technologies such as short-read Illumina and
single molecule real time (SMRT) sequencing [130]. With a better
understanding of the genome, manufacturers may manipulate the
gene more eectively and improve host-cell stability, consequently
leading to more consistent product quality.
Enhanced harmonization eorts on biosimilar guidelines
With the expected influx of biosimilars due to patent expiry of the
reference product, there is a need for RAs to develop guidelines
that facilitate the clinical decision to choose between the reference
product and biosimilars, switching between reference product and
biosimilars, or switching between biosimilars as a potential therapeutic option. Although EMA does not provide recommendations
on interchangeability and leave the development of substitution
policies to its Member States [131], countries such as Germany, The
Netherland and Scotland have endorsed the interchangeability of
biosimilars [132]. In general, these countries recommend that the
decision of switching should be based on shared decision making
Manufacture and Supply, Science and Reg ulation of Biopha rmaceutical Products
between the patient and prescriber on the potential risks of switching, along with appropriate monitoring for early detection of adverse
event [14, 133–135]. Such perspective is logically sound as it ensures
that any clinical decision made is in the patient’s best interest. It
is worthwhile to encourage RAs of these countries to share their
regulatory experience so that other RAs can make a more informed
choice when developing guidelines relating to the use of biosimilars.
Such concerted eorts will promote harmonization of guidelines.
Enhancing data integrity with a culture of quality (quality culture)
Without a culture of quality, even the simplest and preventable
data integrity-related violations can occur [136]. This is because the
organizational culture directly impacts routine operations which
have a downstream influence on data and product quality, and
senior management is responsible for creating a culture of quality
[137]. A critical element of quality culture is the “transparent and
open reporting” of data integrity-related violations at all organizational levels [109]. Measures such as an independent reporting
channel, anonymous or identifiable, or rewarding employees who
report quality-related issues can help to incentivize employees to
voice out their concerns [138]. A culture of quality can be created
by first incorporating the “Leader 5Vs” that correlate with a positive influence on quality culture [139], which are further explained
in Table 4 [140]. In essence, the table emphasizes on the importance of senior management in creating a vision, leading by example, empowering their employees towards quality excellence. Senior management is encouraged to look at WHO guidance on data
291