www.biopharminternational.com September 2019 BioPharm International eBook 13
Regulatory Sourcebook Good Manufacturing Practices
y o u ' r e g u e s s i n g ," C i u r c z a k
explains. If one could place hidden
cameras in many oral solid-dosage
form facilities today, he says, one
might often see operators taking
material from the top of the last
drum, scooping it out and calling
it representative of the entire last
batch, instead of sampling every
drum at different levels using dif-
ferent sample thieves.
One obv ious solut ion wou ld
be to use PAT, but many manu-
fac t u rers st i l l a ren't, Ciu rc za k
says. "Wit h PAT, you have in-
process tests and the potential of
100% analysis. There are online
options that can automatically
examine 100,000 tablets an hour,
and there is zero excuse for not
using them." Ciurczak also sees a
need for cGMPs to specify better
calibration methods. "GMPs are
based on 1950s technology, and
they don't stress raw material qual-
it y enough," he says, at a time
when most materials are being
sourced from regions where regu-
latory practices are still evolving.
For instance, cGMP practice still
accepts the use of compendial test-
ing, even though some older United
States Pharmacopeia (USP) tests have
proven to be fallible, as was seen
during the heparin recall of 2007.
"Spot and color tests for heav y
metals might have been okay when
pharmacists were making things in
their back rooms and selling them
locally, but now you're sourcing
materials from halfway across the
world and the identity tests won't
show whether they are even use-
able," says Ciurczak.
The biggest problem with cGMPs,
Ciurczak says, is that they are "one
size fits all." FDA, however, cannot
mandate the approaches that com-
panies use to meet requirements.
"Measurements, process release,
and in-process measurements are
not mandatory. PAT methods may
reduce variability in commercial
product, but how the manufac-
turer achieves required targets is
up to them," says Ritchie. However,
he notes, when something tragic
happens, it's usually lawyers who
point out that management knew
that other options were available
but chose not to use them. This
may prove to be grounds for future
liability and accusations of negli-
gence, he suggests.
STRUCTURAL CHANGE NEEDED
S o me b e l ie ve t he p r o ble m i s
much bigger than cGMPs alone,
and requires that drug develop-
ment and manufacturing, and the
chemistr y, manufact ur ing, and
controls, and manufacturing func-
tions become more closely con-
nected. "These companies placed
the end user of their products at
the center and developed a value
chain to deliver on their needs in
terms of value for money. They
achieved incredible improvements
in quality by placing the respon-
sibilit y for defec ts on the pro -
duction operators, rather than a
'quality function.' The production
operators were given the tools of
statistical process control and they
used them to great effect, achiev-
ing six-sigma quality levels (i.e.,
3.4 defects per million opportuni-
ties)," he says. Amgen is one of a
few biopharmaceutical and phar-
maceutical manufacturers that has
achieved this level of quality.
At the same time, Rees explains,
forward-thinking manufacturers
in other industries began to design
fo r m a nu f a c t u r e, a s o p p o s e d
to throwing processes "over the
wall." They adopted a collabora-
tive approach, he says, in which
desig n a nd produc t ion depa r t-
ments worked together to achieve
the crucial balance between inno-
vation and production feasibility
and economics. "The results were
transformational," says Rees, who
has commented on some of these
issues in his new book, Taming the
Big Pharma Monster, published in
May 2019 (9). Rees sees the answer
as going back to a simpler time,
and to vertical integration. But
one might ask: How can decades
of industry change be reversed?
For now, it remains to be seen if
and how regulators will address
the need to clarify industry's inter-
pretation of cGMPs. Hussain sug-
gests breaking the problem down
into smaller bites. "The cGMPs
for nutritional supplements, com-
pounding, and tobacco are still
evolving. Perhaps the first order
of business is to bring some san-
ity to the definition of adequate
education, training, and experi-
ence, since the entire system rests
on this foundation," he says.
REFERENCES
1. C. Ballentine, "Sulfanilamide Disaster,"
FDA Consumer Magazine (June 1981),
www.fda.gov/media/110479/download
2. JP Swann, Pharm Hist. 41(1) 16-25
(1999).
3. R. Pepling, Chemical & Engineering
News 83 (25), (June 20, 2005).
4. K. Stone, Current Good Manufacturing
Practices, thebalance.com, March 7,
2019.
5. FDA, "Pharmaceutical cGMPS for the
Twenty-First Century: A Risk-Based
Approach," Report (September 2004),
www.fda.gov/media/77391/download.
6. FDA, Guidance for Industry,
PAT—A Framework for Innovative
Pharmaceutical Development,
Manufacturing, and Quality Assurance,
(Rockville, MD, September 2004).
fda.gov, www.fda.gov/media/71012/
download
7. FDA, Guidance for Industry, Process
Validation: General Principles and
Practices (Rockville, MD, January
2011), fda.gov, www.fda.gov/
media/71021/download.
8. 7.G. McNally, "A Practical Approach to
Effective Life Cycle Implementation
of Systems and Processes for
Pharmaceutical Manufacturing,"
presentation at the Pharmaceutical
Quality Systems (ICH Q10) Conference,
Arlington, VA, Oct. 4–6, 2011, www.
fda.gov/media/84787/download.
9. H. Rees, Taming the Big Pharma
Monster, amazon.com, May 2019,
www.amazon.com/Taming-Big-
Pharma-Monster-Speaking-ebook/dp/
B07R3FYJQH
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