TABLE 1
Recommended action limits for microbial contamination in controlled areas in operation*
Grade
Volumetric air sample
(CFU/m 3 )
Settle plates
(diameter 90mm)
(CFU/plate, 4 hours
exposure)
Contact plates
(diameter 55mm)
(CFU/plate)
Glove or garment
contact plates
(diameter 55mm)
(CFU/plate)
A (ISO 5)
<1
<1
<1
<1
B (ISO 7)
10
5
5
5
C (ISO 8)
100
50
25
–
D
200
100
50
–
*After EU Guidelines to Good Manufacturing Practice (GMP) Annex 1 Manufacture of Sterile Medicinal Products, and the FDA Guidance for
Industry: Sterile Drug Products Produced by Aseptic Processing – Current Good Manufacturing Practice. Note: The US and EU air cleanliness
classifications are not truly equivalent. CFU: colony-forming unit
The Massachusetts Department of Public Health
collaborated with the CDC and FDA on a multistate
investigation of fungal meningitis among
patients who received an epidural steroid injection
to control back pain. The pharmacy involved NECC
and recalled three lots consisting of a total of 17,676
single-dose vials of the steroid, preservative-free
methylprednisolone acetate (MPA).
The contaminating fungus was established as
Exserohilum, a fungus so rare in human infection
that the Tennessee State Health Commissioner
described it as a fungus most physicians never
see it in a lifetime of practising medicine.
According to the ASM Manual of Clinical Microbiology,
phaeohyphomycosis of the skin, subcutaneous
tissue, cornea, nasal sinuses and the brain have been
documented with this fungus. As of the final CDC
update in October 2015, this multi-state outbreak
resulted in 753 fungal meningitis infections in at
least 20 states and 64 deaths due to Exserohilum
rostratum from contaminated preservative-free MPA
steroid injections.
Establishing an environmental monitoring
programme might be a new activity for some
sterile compounding pharmacies. This review
briefly summarises the requirements for microbial
monitoring as well as associated release testing.
These will differ by regulation responsibility in
the United States; for example, a state board of
pharmacy expects the compounding pharmacies
to comply with USP <797> (following Section 503A
sterile compounding pharmacies), and the US FDA
regulates compounding pharmacy that have to
comply with pharmaceutical good manufacturing
practices (following Section 503B outsourcing sterile
compounding facilities).
Sterile compounding pharmacies in the US
Section 503A sterile compounding pharmacies
must comply with the requirements found in
USP <797> Pharmaceutical compounding: sterile
preparations in terms of the location and frequency
of environmental monitoring in their sterile
compounding and support areas. These general
requirements are summarised in Table 1.
Frequency of sampling
According to the current chapter <797> air
sampling shall be performed at least semi-annually
(that is, every six months) as part of the recertification
of facilities and equipment. USP <797>
is currently undergoing revision and it is likely
that the frequency of monitoring will be increased
from semi-annually to monthly routine monitoring.
Contrast this frequency to every manufacturing shift
in pharmaceutical drug product manufacturing.
Selection of sampling sites
USP <797> requires that an appropriate
environmental sampling plan is developed for
airborne viable particles based on a risk assessment
of compounding activities performed. The risk
assessment should take into consideration the
compounding processes and the compounding
products. The focus should be on high-risk locations
where significant movement of people, airflow, or
product exposure occur during the compounding.
Selected sampling sites shall include locations
within each ISO Class 5 environment (Grade A) and
in the ISO Class 7 and 8 environments (Grades B
and C), and the segregated compounding areas at
greatest risk of contamination (for example, work
areas near the ISO Class 5 environment, counters
near doors, pass-through boxes). The plan should
include sample location, method of collection,
frequency of sampling, volume of air sampled, and
time of day as related to activity in the compounding
area and action levels.
Qualification and re-evaluation of
compounding personnel
All compounding personnel working in ISO Class
5 and 7 environments (Grades A and B) shall
successfully complete an initial competency
evaluation and gloved fingertip/thumb sampling
procedure (zero CFU) no less than three times
before initially being allowed to manufacture
CSPs for human use. More specifically to ISO Class
7 environment (Grade B), the garment can also
be sampled (for example, forearms, chest, head).
This can be slightly different for compounding
in isolators. Re-evaluation of all compounding
personnel for this competency shall occur at least
annually for personnel who compound low- and
medium-risk level CSPs and semi-annually for
personnel who compound high-risk level CSPs using
one or more sample collections during any media-fill
test procedure before they are allowed to continue
compounding CSPs for human use.
Microbiological growth media
A general microbiological growth medium such as
soybean–casein digest agar (also known as trypticase
soy broth agar (TSA)), is used to support the growth
36 | Issue 91 | 2019 | hospitalpharmacyeurope.com