having to list any side-effect even if
none have proven to be a direct result
of the drug substance, invites both expensive lawsuits and generates fear of
the drug, causing non-compliance on
the part of a patient.
3. Clinical studies: a) necessary: we
need to know about activity (
bioavailability), elimination, modes
of action, and possible toxicity; b.
negative aspects: most trials tend
to use young, white males. Thus,
an awful lot of new drugs are not
tested on people with the actual
illness or geriatric, female, or pediatric trial subjects. Also, long-term
effects cannot be studies over the
short-term of the study; the Agency depends on feedback from patients over time.
This is not to say that, for over forty
years, GMPs have not served us well. In
an industry as complicated as producing drugs for ill people, firm guidelines
(Guidances) are necessary. Unfortunately, over time, the way of doing things
becomes ossified. Since the late 1950s,
the manner in which we produced solid
dosage forms has become routine. While
there have been small, incremental improvements—larger, faster production
equipment, better analytical methods—
a person who retired from a production
position in 1975, would only need a few
days’ training to become familiar with
From the point of view of rapidly
gaining approval from the Agency, a set
of templates—in any given company,
most dosage forms have similar DNA for
formulation purposes—allows for rapid
development of a new product: merely
insert a NCE (new chemical entity) into
one of the proven tablet, caplet, or cap-
sule templates and crank out the prod-
uct. We can change the color, coat or not
coat, emboss or imprint, but whatever
we generate, it will not be too different
from previous products. The physical
parameters of the new dosage form can
almost be written before actual produc-
tion +/- a slight variation.
With all that being true, when the
FDA—fueled by Ajaz Hussain—held a
massive workshop/information gathering event in early 2002 to encourage
modernization and better control of the
finished product through control of the
process, a number of “traditionalists”
balked at the radical changes. Perhaps
the one phrase that chaffed the Quality
Assurance people was “using their best
judgement” in lieu of “written in stone”
SOPs. The draft Guidance took much
longer than “typical” Guidances to be
approved. The document drew up, until
that time, a record number of comments
Keep in mind that two “products”
emerge from production for every lot produced: the tablets/capsules that are sent to
the hospital/pharmacy for distribution to
patients; and the MMF (master manufacturing formula) with all the weights and
signatures for the batch.
Now, the former could have an ab-
solutely wonderful distribution of API,
In the face of this mindset, we are en-
couraging manufacturers to implement
PAT, with monitors/controllers at each
step. As the PAT Guidance states, “each
batch may be considered a validation
batch.” Not three lots and chisel the batch
instructions in stone, but perform each
step until the pre-determined quality is
achieved. E.g., we are to mix until blended,
not for a set time.
How, you might ask, can we justify PAT
and QbD under the law—cGMPs are the
law. Well, to quote/paraphrase the GMPs,
there are two requirements that are beg-ging for more measurements and control:
1. “Meaningful in-process tests shall be
performed.”Well, in 1978, the best we
had were friability, hardness, weight,
disintegration, and appearance. All
destructive and time consuming…
and not actually controlling the process, since, by the time results are
gleaned, many thousands of dosage
units have been produced. Therefore,
not really a control strategy.
2.“A statistically significant number of
units must be tested from every lot.”
Now, I don’t know where you learned
your statistics, but at my school,
20 tablets from a 1, 2, 5, or 10-mil-
lion tablet lot is not to be considered
significant, no matter how you trust
So, when you are considering whether
a PAT/QbD program violates cGMPs, I
submit that they are the only way to fulfill
our legal requirements—1 and 2 above.
So, as the benefits of a modern fully con-
trolled, in-compliance PAT/QbD pro-
gram begin to accrue—faster production
times, fewer rejects, real-time release—
you can rest assured that your program/
product is fully covered by both the letter
and spirit of Good Manufacturing Prac-
tices. No, I submit you will be following
Better Manufacturing Practices. Welcome
to the 21st century and be prepared for
more business. CP
GMP GENESIS TIMELINE
1. Part 210: cGMP in Manufacturing, Processing, Packing, or Holding of Drugs;
General (1963; revamped 1978).
2. Part 211: cGMPs for Finished Pharmaceuticals (1963; revamped 1978) – Part
226: cGMPs for Type A Medicated Articles (1975).
3. Part 606: cGMPs for Blood and Blood Components (1975).
4. Part 225: cGMPs for Medicated Feeds (1976).
5. Part 110: cGMP in Manufacturing, Packing, or Holding Human Food (1986).
6. Part 820: Quality System Regulation (1996).
7. Part 216: Pharmacy Compounding (1999).
8. Part 1271.145-320: Current Good Tissue Practice [for HCT/Ps] (2001).
9. Part 111: cGMP in Manufacturing, Packaging, Labeling, or Holding Operations
for Dietary Supplements (2007).