Regulators Increasingly Embrace New Rapid Technologies for Viable Air Monitoring
When it comes to air monitoring, manufacturers
have relied on gravitational sampling
by settle plates—a weak methodology.
The value of data generated by settle
plates is highly questionable, considering
that most positive plates are generated
from false-positive results. But real-time
monitoring might offer a solution, driven
by recent regulatory developments.
For example, regulators are turning to
ISO/EN norms as reference documents
detailing methods for the determination
of microbiological and particulate
cleanliness of air, surfaces, etc. (1). With
viable air monitoring, in particular, they
are looking at the ISO 14698 standard
(2). ISO 14698 states that “a sampling
device shall be selected according to
the area being monitored. The selection
for a particular application shall take into consideration the following factors:
expected concentration of the viable
particles, ability to detect low levels of
biocontamination and time and duration
of sampling” (2).
This leads to a vital point: it is virtually
impossible for pharmaceutical customers
to validate viable air samples for biological
or physical collection efficiency as
required in ISO 14698. Only a few laboratories
worldwide can provide the experimental
design and know-how required for
trial testing. Collection efficiency remains
a critical measure that manufacturers of
instruments should provide and demonstrate.
This is where real-time solutions
Rapid or alternative microbiological methods
have been promoted for almost 20 years in the pharmaceutical industry. In
2003, the U.S. FDA guidance on process
analytical technology (PAT) (3) and the
pharmaceutical cGMPS for the 21st century
gave industry a new drive. The concept
of PAT implies the need for collection of
process data in real-time, targeting a realtime
release of drug products. The FDA
guidance, updated in 2015, recommends
“building quality into products” through
science-based facility, equipment, process
and system design for sterile drug manufacture
and emphasizes the importance of
the pharmaceutical industry’s adoption of
new technological advances.
With the continuous effort of regulatory
bodies encouraging the use of alternative
microbiological methods, the need
to understand how these methods could
be implemented in pharmaceutical manufacturing processes grows. All major
pharmacopeias worldwide now include
chapters that describe the validation of
those methods, e.g., USP <1223>, Ph.
Eur. 5.1.60 (4,5). Those chapters continue
to evolve with regular updates.
In recent years, regulators have begun
creating specific pathways to facilitate
the use of modern technologies such as
real-time monitoring. The FDA promotes
the use of “comparability protocols” and
has developed an Emerging Technologies
Team to evaluate change proposals. EMA
has implemented a post-approval change
management protocol and provides an
opportunity to request a “scientific advice
meeting” with experts.
Still, the adoption rate of alternative
methods remains slow, whether due to
hesitation, uncertainty or fear of longer
validation processes. Other factors, such
as difficulty in justifying the return of
investment for implementation, also play
a large part. The key to supporting rapid
technologies lies in recognizing the costs of poor quality. Many of these technologies
offer the potential to offset such costs
as waste, rework, poor inspection findings,
recalls and more.
The key to a strong regulatory framework
around viable air monitoring lies in considering
new technologies like real-time
testing. Global regulators are increasingly
accepting these new technologies for ISO
7 (Grade C) and ISO 5 (Grade B) critical
environments. The right combination of
strategies can lead to substantial improvements,
contributing significantly to cost
savings programs by reducing the “cost of
[Editor’s Note: This is a follow-up to the
article, “Monitor Viable Air with Single-Use, Real-Time Tech,” in the Jan.
2018 PDA Letter.]
- EudraLex, Volume 4, EU Guidelines to Good
Manufacturing Practice, Medicinal Products for
Human and Veterinary Use; Annex 1: Manufacture
of Sterile Medicinal Products. (2008) European Commission.
- ISO 14698-1. (2003). Cleanrooms and associated
controlled environments - Biocontamination control
- Part 1: General principles and methods.
- Guidance for Industry: PAT — A Framework for Innovative
Pharmaceutical Development, Manufacturing,
and Quality Assurance, 2004, U.S. FDA.
- USP 39–NF 34. (2016). Microbiological
Control and Monitoring of Aseptic Processing
Environments. Chapters <1223> and <1756>.
U.S. Pharmacopeial Convention.
- European Pharmacopoeia 9th Edition. (2017).
Alternative Methods for Control of Microbiological
Quality, Chapter 5.1.6., p 540. European
Directorate for the Quality of Medicine &