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.

**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.