September
16, 1998
Jane
Axelrad
Associate
Director for Policy
Center
for Drug Evaluation and Research
Food
and Drug Administration
1451
Rockville Pike, Room 6027
Rockville,
Maryland 20852
RE: FDA Modernization Act 1997. Compounding Provision.
Dear
Jane:
Please find enclosed material for
the docket ( I believe 98D-0272). I
request that this material be put on the internet.
Sincerely,
John
H. Perrin, Ph.D.
Professor
of Medicinal Chemistry
Cc: Rep Karen Thurman
Comments on Drugs Difficult to Compound and the Quality of Chemicals to be used in Compounding.
Comments on Drugs Difficult to Compound and the Quality of Chemicals to be used in Compounding.
J.H. Perrin,
Ph.D.
Professor of Medicinal Chemistry
University of Florida
1.SUSTAINED RELEASE PRODUCTS
These should never be
compounded. I have recently read that it
takes companies whose business is solely the design of sustained release oral
products, five to seven years to successfully develop a new product, the longer
time being necessary for the more water soluble molecules.
They why can a compounding
pharmacist make any drug into a sustained release product regardless of water
solubility, pharmaco kinetic parameters etc from a general formula provided by
a supply company in ten minutes? Mixing
with hydroxymethyl cellulose or related substance and lactose and placing in a
capsule is the prefered method with no testing of total drug content or rate of
dissolution. The commonest drugs sold by
compounding pharmacists in this way are morphine sulfate, oxycodone
hydrochloride and verapramil, although theophylline a drug on many negative
formularies has been compounded. I have
already written that such sustained release products can be expected to release
the active ingredient far too quickly and may not release all the active ingredient
in the end. This has been confirmed in
data for verapramil sent to my graduate student from a pharmacy school,
receiving support from a supply company, which teaches students how to compound
sustained release capsules and determines their dissolution characteristics. This data also confirmed what had been
reported on national television using data obtained in the commercial
laboratory regarded as the leaders in evaluating sustained release
products. I know of two pharmacies that
make sustained release methylphenidate capsules. Parents have told me that they can tell how
much water their child has consumed by the behavior of the child. Isn’t this also predictable? Of course, that the release of the active ingredient
from a manufactured sustained release product must be independent of food and
water intake is never mentioned at the cult meetings of compounding
pharmacists. They were also making
sustained release Fen Phen products with both drugs in the same capsule. Of course the main target of compounding
pharmacists is the vulnerable elderly in the form of sales of sustained release
morphine and oxycodone to nursing homes hospices etc in the Sun Belt. These sales result in huge profits for the
nursing homes and compounding pharmacists, helped by the overpricing by the
legitimate manufacturer. In any other
industrialized nation and in most of the third world, pharmacists making their
own sustained release products would lose their license for life, in the US
they become leaders of the profession.
Compounding pharmacists also make slow release estrogen implants. No slow release product should ever be
compounded.
PRODUCTS MANUFACTURED TO BE RECONSTITUTED BY THE PHARMACIST
Here we have mostly pediatric suspensions and
injections. It costs the manufacturer
much more to produce these products for reconstitution than it would if they
sold a finished drug. So, compounders,
there must be a reason for the sale of product to be reconstructed, it is
stability, something which you totally ignore.
The worst case is probably Augmentin.
The pH profile of molecules are never looked at by compounding
pharmacists, the patient’s parent is simply asked what is the child’s favorite
flavor. I have had calls from parents
who have had several products reflavored and their child has become very sick. The child has recovered when the original
drug was correctly reconstituted in a chain pharmacy. A sample of one proves nothing but any
thoughtful pharmacist should see a red flag when reconstitution is
involved. The matter is not simply one
of pH, as has been stated to compounders, but also involves potential catalysis
by all added components and most importantly of all the solubility of the
hydrolysable molecule, the solubility also being influenced by pH and the
presence of all other ingredients. In
some compounding pharmacies seats are provided for children to watch their
medicine being made or perhaps mutilated.
No active ingredient supplied in a form to be reconstituted, should ever
be involved in the preparation of another liquid dosage form.
INJECTABLES
By law injectables should
be sterile and pyrogen free. The
Millipore filters and generic equivalents used by compounding pharmacists are
excellent for helping maintain sterility during transfer of one sterile solution
to another, they are not designed as a primary method of sterilization and they
do not remove pyrogens. Of the several
injections made by compounding pharmacies the worst example is morphine sulfate
for intrathecal use sometimes with the addition of clonidine. It is well documented that the spinal fluid
is very much more susceptible to pyrogens than is the blood. Why is this popular I have been told by a
very reliable person that if someone knowingly takes advantage of loopholes in
medicare payments methods then they are guilty of medicare fraud. Thus medicare fraud is the reason for
compounders making morphine sulfate injections for intrathecal use. The Merck Index gives a water solubility of
morphine sulfate as around 64 mg per ml at room temperature. A commercial product, ie one proved to be
sterile and pyrogen free, of 50 mg per ml is available. There is absolutely no need to compound these
products other than to take advantage of the ridiculous amount paid by medicare
for the compounding of morphine sulfate injection. You can read how to make these injections in
an early issue of the International Journal of Pharmaceutical Compounding. No analysis of the finished product is
recommended in the article but occasional testing of sterility and freedom from
pyrogens. This journal accepts
advertising from supply companies, I have been told that the editor has been
involved with a supply company for years, and he is supposedly representing the
USP on this committee. A major, major,
major conflict of interest I think, but apparently not in the eyes of the FDA
or USP. There is need to make injections
very occasionally in an institutional setting, but these should never be
released until tested for sterility and pyrogens as well as undergoing chemical
analysis. It is criminal to make
injections for intrathecal use without testing for at least pyrogens and
sterility. Testing drugs, by using
caveman type technology, ie using five senses as suggested by a prominent
member of the Florida affiliate of the American Pharmaceutical Association on
national television is hardly adequate as we approach the third millenium.
INHALATION FLUIDS
I
personally would only use a sterile inhalation fluid provided in a sealed unit
dose container. The active ingredients
of inhalation fluids are notoriously fragile molecules. Their decomposition can be accelerated by
filter materials, plastic, glass and metals used during production. Every new supply of filter materials container
materials has to be tested by the manufacturer for compatibility with each
active ingredient and any preservative to be added. One type of cheap container cannot be used
for all inhalations fluids, as is done by compounding pharmacists. I have been told by students, of benzalkanium
solutions being produced in plastic milk cartons in a pharmacy making 30,000
vials a day. Apparently no one considers
that the surface active benzalkonium can remove plasticisers from the
carton. They also used albuterol
manufactured in a third world country and already yellowing. Using chemicals manufactured in third world
countries and of unknown quality is common in compound pharmacies. Mixing two active ingredients is not a good
idea. For example I have a patient talking
to me about a mixture of ipratropium and albuterol containing benzalkonium.
A medicaid patient. At first she
used commercial products , ie separate active ingredients in sealed vials ( the
best). Then she was persuaded to have
the prescription compounded in a single vial, benzalkonium being added. This very sick patient now found that the
interval between doses was shortened considerably, and what once was a
prescription for a month now left her several days short. On returning to the original chain pharmacy
and obtaining the manufactured separate drugs, the problem disappeared. The potency was thus reduced in the
compounded mixture. This is not due to
any pharmacological activity of benzalkonium a problem which has been
overstated. The problem is due to poor
weighing or stability, probably the latter.
Others have told me and will publish information that their laboratories
has found a loss of potency in the mixture of albuterol and iprotropium when
certain benzalkoniums are added. This
can occur even if all three ingredients are of USP quality. Which emphases the point that the USP allows
considerable range of ingredients in the mixture called benzalkonium,
manufacturers carefully screen every
batch of benzalkonium to see if it satisfies the problems in their particular
environment. Clinical pharmacy and
physician specialists using inhalation fluids have told me that they see no
reason to compound inhalation fluids as the proven manufactured products are
adequate. Why are they compounded? Again, medicare fraud. Some pharmacies make as many as 100,000 vials
a day using 1940’s techniques for the delicate molecules of the 1990’s. This proves they are compounding not
manufacturing. Again the ridiculous fees
paid for compounded inhalation fluids by HCFA are the reason for the
compounding. Many pharmacies receive several
million dollars a year from HCFA for compounded inhalation fluids. It seems to amount to over half a billion
dollars a year, nationally. The figures
are in the public domain and make interesting reading, many prominent
pharmacists i.e. big shots in the state affiliates of the American
Pharmaceutical Association are involved.
All inhalation fluids should be sterile, the FDA is dragging its heels
on this issue following pressure from the leading manufacturer who uses
outdated containers. There is absolutely
no reason to compound inhalation fluids.
We read of the increased treatment of asthma at emergency rooms. Is it not possible that this is associated
with the increased usage of homemade inhalation fluids of unproven quality?
COPYING OF COMMERCIAL PRODUCTS
Compounders
have long ignored patents, orphan drugs statuses etc. This must be stopped. Excuses like, the child must be allergic to
an ingredient are just excuses to compound.
There is absolutely no literature to support these statements and of
course no tests are ever conducted on the patient. The copying of commercial products is not
allowed in any other industrialized nation and must be stopped in the US.
Before
Viagra, we had a prostaglandin injection.
Caverject was a protected product but was copied immediately by
compounding pharmacists who shipped prefilled syringes and multidose vials
around the country. There were many
complaints about ineffectiveness and of the subsequent prescription being of
different potency than the first. Much
of the active ingredient was made in the Czech Republic and was of unproven
quality. Why did the FDA take no action
against the supply companies providing the prostaglandin or the pharmacies
shipping their products around the country?
Why did the state boards of pharmacy totally ignore the problem?
OTHER
Currently there is a growing business of
compounding mixed estrogens, the composition apparently being frequently
determined by the pharmacist. The
patients are told that the components are natural, I think they are synthetic
or at least seminsynthetic. These are
molecules which have limited water solubility and some skill in the formulation
of these products is necessary to obtain an adequate dissolution rate. You can read how to make these products is an
issue of the International Journal of Pharmaceutical Compounding, no
dissolution or stability data is included.
Antibiotics
should only be sold as supplied by the manufacturer, ie as the original dosage
form on as prepared following the manufacturer’s instructions for
reconstitution.
Reflavoring should not be done, not
only for stability reasons mentioned above but also for safety reasons. There is a great danger of cross
contamination in the working conditions of a compounding pharmacy, I do not
imagine any have a room dedicated to working with a single antibiotic. I believe that pharmacies are exempt OSHA
rules for legitimate reconstitution, but once manipulation of the antibiotic
starts, whether for a capsule, a crushed tablet on the powder for
reconstitution then OSHA rules apply.
Manipulation of antibiotics must be stopped. I believe that pharmacists have contributed
to what has been interpreted in a given microenvironment as bacterial
resistance, the possibility that the local pharmacist has destroyed the
antibiotic never being considered.
As in the
other cases the compounding pharmacist hides behind expression like,
individualized doses, practicing pharmaceutical care and being part of the
triad. Does the compounding pharmacist
ever tell the patient and physician that the product has not been tested for
quality or performance and if the active ingredients have been manufactured in
a third world country? Just what does
individualized dosing mean: for example
18.5mg sustained release methylphenidate?
What appropriate measurements are made to determine this dose? Do all compounders just observe the patient
like the pharmacist from Oklahoma seen on television?
QUALITY OF CHEMICALS USED IN COMPOUNDING
The USP monograph on compounding is
embarrassing, the worst section being on quality of chemicals used. No pharmacist is trained to make judgement on
the quality of chemicals to be used in drugs.
I suspect only two members of this committee one an internationally
respected technologist and the other a practicing pharmacists have the
necessary experience to make these judgements.
To suggest that buying a chemical from a chemical supply company is
satisfactory is nonsense, experience has taught me that the impurities are
invariably not the same and certainly not in the same concentrations as the
form sold for the manufacture of drugs.
The certificate of analysis suggestion is also stupid. Just what does a certificate of analysis
originating with a minor, non approved company, in a third world country
mean? Nothing. Representatives of supply companies have been
heard to say we check the melting point and run an infrared on all our
chemicals. This is meaningless and shows
a complete lack of understanding of the problem. Incidentally, certificates of analysis can be
purchased for any chemical off the internet, I suspect compounding pharmacists
are or will be the main clients for this service. The Quality of chemicals to be used to make
drugs must be as accepted in the original NDA unless legally modified. USP specifications are no longer
satisfactory.
CONCLUSIONS
Sustained release products and
inhalation fluids should never be compounded.
Injections should only be prepared in an institutional environment and
only in extenuating circumstances.
Before release they should be assayed for content and pass sterility and
pyrogen tests. Active ingredients
supplied in forms for reconstitution should never be reformulated. A new set of standards or improved USP
monographs must be produced to in order to stop the use of low quality of
ingredients in drugs. Technology has
been downplayed in pharmacy schools for the last twenty five years, we are not
training pharmacists to make value judgements on what can and cannot be
compounded, and yet compounding is the fastest growing branch of the
profession. We certainly do not train
pharmacists to make value judgements in the quality of chemicals used in the
preparation of drugs. The US public has
been very poorly served by the FDA and the Boards of Pharmacy, the FDA has had
the information necessary to stop the supply questionable quality chemicals and
of unproven drugs, but has taken no action.
Why? Even worse is the situation
in the states with the Boards of Pharmacy.
The boards seem intimidated by compounding pharmacists the supply
companies and the politicians supporting both.
Their has been no leadership from the admittedly of no legal
consequence, National Association of Boards of Pharmacy, although the head
spoke out recently on the ABC Evening News.
I am hoping he will continue to do so, and lead the committee to make
decisions, which are in the best interest of the US public, not to just to keep
3000 unnecessary pharmacies in existence.
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