Transcript PHARMACY COMPOUNDING IN THE U.S. Current Status and the

CONTEMPORARY
PHARMACEUTICAL
COMPOUNDING
Loyd V. Allen, Jr., Ph.D., R.Ph.
Editor-in-Chief
International Journal of
Pharmaceutical Compounding
Role of the
Compounding Pharmacist
• “Individualizing Drug Therapy”
IJPC First Issue Cover
OUTLINE
•
•
•
•
•
•
•
Introduction
Compounded Pharmaceuticals
U.S. Pharmacopeia
FDA and Contemporary Compounding
Current USP Compounding Activities
New Drug Delivery Systems
Summary
INTRODUCTION
• History of Pharmacy Compounding in
the United States
• Reasons for the Growth of
Compounding
• Special Patient Populations
• Examples of Pharmaceutical
Compounding
History of Pharmacy
Compounding in the U.S.
• In the past, Compounding Was
Pharmacy
• 1900s gave way to commercially
prepared pharmaceuticals
• Many strengths/dosage forms available
• Economics changed all that
• Limited strengths/dosage forms
• “One Size Fits All” approach
Reasons for the Growth of
Pharmacy Compounding
•
•
•
•
•
Limited dosage forms
Limited strengths
Home health care
Hospice
Nonavailable drug products/combinations
– Discontinued Drugs
– Drug Shortages
•
•
•
•
Orphan drugs
Veterinary compounding
New therapeutic approaches
Special Patient Populations
SPECIAL PATIENT
POPULATIONS
•
•
•
•
•
•
•
•
Pediatrics
Geriatrics
Bioidentical Hormone Replacement Therapy
Pain Management
Dental Patients
Environmentally & Cosmetic Sensitive
Sports Injuries
Veterinary Compounding
– Small, Large, Herd, Exotic, Companion
..
MEETING PATIENTS
NEEDS
• Traditional Dosage Forms
• New Dosage Forms
COMPOUNDED DOSAGE
FORMS
Oral Solids (Capsules, Tablets)
Oral Liquids (Solutions, Susp, Emulsions)
Topicals (Creams, Ointments, Gels)
Suppositories, Inserts
Injectables
Many, many others….
NEWER COMPOUNDED
DOSAGE FORMS
•
•
•
•
Oral
Topical
Parenteral
Specialty
RAPID-DISSOLVING
TABLETS
• Active Drug
• Lactose
• PEG 3350
qs
70 mg
30 mg
• Actual size depends upon mold.
• ‘Bridging’ mechanism
Compounded Gummy Bears
GUMMY GELS
•
•
•
•
•
•
•
Fentanyl citrate
Chewable gummy gel base
Bentonite
Aspartame
Acacia powder
Citric acid monohydrate
Flavor concentrate
1.884 mg
23.35 g
500 mg
500 mg
500 mg
650 mg
10-12 drops
VETERINARY ORAL PASTE
•
•
•
•
•
•
•
Ingredient #1
PEG 300
65
PEG 3350
35
Prop Glycol Molasses
Peanut Butter Hydrog Veg Oil
#2
25
25
50
-
#3
25
25
50
-
#4
65
35
ORAL PASTES
• VANCOMYCIN PASTE
• (VANC PASTE) •
•
•
•
•
•
Vancomycin
Aspartame
Flavor
Sodium benzoate
Methylcellulose 2% Gel
500 mg
200 mg
qs
200 mg
qs100 mL
Compounded Lollipops
LOLLIPOPS
•
•
•
•
•
•
•
•
•
Sodium chloride
Potassium chloride
Calcium lactate
Magnesium citrate
Sodium bicarbonate
Sodium phosphate monobasic
Silica gel
Flavor
PEG 1450
46.56 g
3g
6.12 g
2.04 g
22.44 g
3.84 g
3.6 g
qs
qs
Compounded Popsicles
POPSICLES
•
•
•
•
•
•
•
NYSTATIN POPSICLES•
------------------------------------------Nystatin powder
2,500,000 u
Sorbitol 70% solution
20 mL
Syrup
50 mL
Flavoring (banana, etc.) 5 mL
Purified water
qs 300 mL
TROCHES/LOZENGES
•
•
•
•
•
•
•
TESTOSTERONE 2 MG TROCHES •
Testosterone
24 mg
Citric acid
300 mg
Stevia powder
250 mg
Saccharin sodium
30 mg
Polyethylene glycol 1450
20 g
Citrus flavor
qs
SUBLINGUAL DROPS
• TESTOSTERONE 10 mg/0.1 mL SL •
•
•
•
•
•
Testosterone
Saccharin
Silica gel
Tangerine oil
Almond oil
qs
1g
100 mg
200 mg
qs
10 mL
Compounded PLO Gels
TOPICAL PLO GELS
• PROMETHAZINE HCL 50 mg/mL PLO
GEL •
• -------------------------------------------------
Promethazine HCl
5g
• Purified water
4 mL
• Lecithin:Isopropyl palmitate 22 mL
• Pluronic F127 30% Gel qs 100 mL
TOPICAL PLO GELS
•
•
•
•
•
•
Capsaicin
75 mg
Ketamine HCl
2g
Ketoprofen
10 g
Ethoxy diglycol
10 mL
Lecithin:Isopropyl palmitate 22 mL
Pluronic F127 30% gel qs 100 mL
RAPID-PENETRATING
TOPICALS
• PROGESTERONE 50 mg/mL
CLEAR SOLUTION •
• Progesterone
5g
• Benzyl alcohol
20 mL
• Alcohol, absolute
20 mL
• DMSO
20 mL
• Propylene glycol qs 100 mL
LIPID CRYSTALS CREAM
• ANTHRALIN 1% IN LIPID CRYTALS •
•
•
•
•
•
•
Anthralin
Glyceryl laurate
Glyceryl myristate
Citric acid
Sodium hydroxide
Purified water
qs
1g
7g
21 g
1g
140 mg
100 g
...
Compounding Parenterals
AMBULATORY PUMP
INFUSION SOLUTION
•
•
•
•
•
CEFTAZIDIME 20 mg/mL •
------------------------------------------Ceftazidime
2.5 g
Sterile water for injection
qs
0.9% Sodium chloride inj qs125 mL
Ambulatory Pumps
INTRATHECAL INJECTION
•
•
•
•
Fentanyl citrate
314 μg
Bupivacaine HCl
100 mg
Baclofen
500 μg
0.9% Sodium chloride inj. qs 20 mL
SPONGE DISKS
• VANCOMYCIN SPONGE DISKS •
• -------------------------------------------• Vancomycin HCl
5 mg
• Sponge (collagen or gelatin) qs
IMPLANTABLE BEADS
• TOBRAMYCIN IMPREGNATED
POLYMETHYLMETHACYLRATE
BEADS •
• -------------------------------------------• Tobramycin sulfate
1.2 g
• Palacos Bone cement
40 g
IONTOPHORETIC SOLUTION
• Dexamethasone
sodium phosphate
400 mg
• Sterile water for injection qs 100 mL
Iontophoresis Unit
Iontophoresis Unit
Iontophoresis Unit
Inside Iontophoresis Unit
Size of a Dupel Iontophoresis
Unit
PHONOPHORESIS
PREPARATIONS
• HYDROCORTISONE 10%
PHONOPHORESIS GEL •
•
•
•
•
•
•
•
Hydrocortisone
Carbopol 940
Propylene glycol
Methylparaben
Propyleparaben
Purified water
qs
Sodium hydroxide 10% Sol
10 g
1.25 g
15 mL
200 mg
100 mg
100 mL
qs
Compounding Oral Inhalation
Solutions
Compounded Oral Inhalation
Solutions
U.S. PHARMACOPEIA
Setting Standards for Drugs in the
U.S. since 1906
Pharmacopeia Development
Pharmacopeia
• Pharmakon
drug
• poiein
to make
• Used together in Pharmacopeia means
any recipe or formula or other standards
required to make or prepare a drug.
• 1580 Bergamo, Italy…..first used in
connection with a local book of drug
standards.
Pharmacopeias
• Local, City and National Pharmacopeias
in Europe
• The London, Edinburgh and Dublin
Pharmacopeias were official until 1864
• Replaced by the British Pharmacopoeia
• How about in the U.S.?
Pharmacopoeias of the U.S.
• 1778
Lititz Pharmacopeia
– First Pharmacopeia in the U.S.
– Published in Lititz, Pennsylvania for use by
the Military Hospital of the U.S. Army
• 1808
Massachusetts Medical Society
– published a 272 page pharmacopeia with
information on 536 drugs and preparations
Pharmacopoeias of the U.S.
• Jan 1817
•
•
•
•
•
•
•
Dr. Lyman Spalding
Submitted a plan
Medical Society of the County of New York
Creation of a national pharmacopeia
---Divided U.S. into 4 geographical districts
Medical schools and societies were to develop a
pharmacopeia and appoint delegates to a
general convention to be held in Washington,
DC
Pharmacopoeias of the U.S.
• Jan 1820
First U.S. Pharmacopeial
Convention
– Only 2 districts submitted plans
– These were reviewed, consolidated and adopted.
• Dec 1820 First U.S. Pharmacopeia was
published
– 272 pages containing 217 drugs/preparations
USP I
• Preface:(in part)
• It is the object of the Pharmacopeia to select
from among substances which possess
medicinal power, those, the utility of which is
most fully established and best understood;
and to form from them preparations and
compositions, in which their powers may be
exerted to the greatest advantage……..
USP AND CONTEMPORARY
COMPOUNDING
U.S. PHARMACOPEIA AND
FDAMA
• 1985 USP Convention
– Resolution 4
• Compounding Information in the USP
– Resolution 5
• Standards for Repackaged and Compounded
Parenterals
• 1990 USP Convention
– Established the Expert Advisory Panel on
Pharmacy Compounding
Resolution #4
• Be it resolved that the COR examine the
desirability and feasibility of developing, with
a view to inclusion in the USP, the following
types of information:
• 1. The short-term stability of drugs when
dissolved in common diluents and stored in
common standardized containers and/or
delivery systems at room, refrigerator and
freezer temperatures;
Resolution #4 (cont’d)
• 2. pKa and minimum solubility of drugs
in common diluents; and
• 3. pH, osmolality and osmolarity of
reconstituted injectables and liquid
dosage forms.
Resolution #5
• Be it resolved that the COR be charged
with the responsibility for providing
standards and test methods;
specifications for packaging, labeling,
and storage; guidelines for appropriate
documentation; and, where necessary,
procedures for compounding parenteral
preparations.
PSD Subcommittee
• Expert Advisory Panel on Pharmacy
Compounding was formed to advise the
PSD Subcommittee
• Also, the Review Panel on Pharmacy
Compounding Practices was formed to
assist the Expert Advisory Panel by
providing immediate expert review on
materials produced by the Panel
Expert Advisory Panel
• Oct 1993
First meeting
• Organized into 2 groups
– General Chapter Group
• to prepare a general informational chapter on
compounding
– Monograph Group
• develop monographs for specific preparations
– those widely compounded but not available
commercially
U.S. PHARMACOPEIA AND
FDAMA
• 1993-2000 Expert Advisory Panel
Activities
• I. General Chapter Group
– <795> Pharmacy Compounding
• II. Monograph Group
– develop monographs for specific
preparations
FDA AND CONTEMPORARY
COMPOUNDING
FDA ACTIVITIES
• Mid 1990s
FDA began investigating
a number of pharmacies that were
compounding large quantities of selected
drug products.
• Manufacturing under the guise of
compounding
• “New Drugs”
Food and Drug Administration
Activities
• FDA considered compounded
preparations as “New Drugs” and
subject to the New Drug Provisions
–
–
–
–
IND
NDA
Safety
Efficacy
• Enforcement Activities
FDAMA 97 Passage
•
•
•
•
Pharmacy professional organizations
U.S. Congress
FDAMA 97
Compounding provisions
FOOD AND DRUG
ADMINISTRATION
MODERNIZATION ACT
• New Drug Requirements
– shall not apply to a drug product if the drug
product is compounded for an individual
patient based on the unsolicited receipt of a
valid prescription order…..if the compounding
is by:
– a licensed pharmacist
– a licensed physician
FOOD AND DRUG
ADMINISTRATION
MODERNIZATION ACT
• Anticipatory Compounding
• Physician-Patient-Pharmacist “Triad”
FOOD AND DRUG
ADMINISTRATION
MODERNIZATION ACT
• Compounding must be done using the
following sources of ingredients:
• USP/NF monographs
• Commercial products
• Bulk Drug Substances List (being
developed)
FOOD AND DRUG
ADMINISTRATION
MODERNIZATION ACT
• Compounding cannot be done from:
• Drugs on the “Negative List”
– drugs that have been withdrawn due to
safety or efficacy reasons
– List was developed
FOOD AND DRUG
ADMINISTRATION
MODERNIZATION ACT
• Cannot compound regularly or in
inordinate amounts any drug products
that are essentially copies of
commercially available products
FOOD AND DRUG
ADMINISTRATION
MODERNIZATION ACT
• Cannot compound a drug product that
“presents demonstrable difficulties for
compounding that reasonably
demonstrate an adverse effect on the
safety and effectiveness of that drug
product”. (list)
FOOD AND DRUG
ADMINISTRATION
MODERNIZATION ACT
• Memorandum of Understanding
– Distribution of inordinate amounts
interstate
– Handling of complaints
FOOD AND DRUG
ADMINISTRATION
MODERNIZATION ACT
• Advertising
– The pharmacy, pharmacist or physician
cannot advertise or promote the
compounding of any particular drug, class
of drug, or type of drug.
FDA Modernization Act of 1997
• FDA Advisory Committee on
Compounding
• Function: to advise the FDA in the areas
of bulk drug substances, safety and
efficacy and difficult-to-compound
products.
• FDA Pharmacy Compounding Steering
Committee (Internal to FDA)
FDA Modernization Act of 1997
Three Lists
• Products not to be compounded because
they were withdrawn from the market
based on safety and efficacy concerns
• Bulk drug substances of proven quality
accepted for use in pharmacy
compounding
• Difficult-to-compound products
IMPLEMENTATION OF
FDAMA
• Ongoing since 1997
• FDA Steering Committee (Internal)
• FDA Compounding Advisory
Committee (External)
• Work with USP
USP I
• Preface:(in part)
• It is the object of the Pharmacopeia to select
from among substances which possess
medicinal power, those, the utility of which is
most fully established and best understood;
and to form from them preparations and
compositions, in which their powers may be
exerted to the greatest advantage……..
FDAMA IMPLEMENTATION
AND THE USP
• <1161>Pharmacy Compounding Practices
became
<795 Pharmacy Compounding
• Monographs of accepted bulk drug substances
are being developed
• <1206> Sterile Preparations-Pharmacy
Practices has been recommended as guidelines
for sterile preparations compounding…being
renumbered as <797>
• New chapters being written
Current USP Compounding
Activities
USP 2000-2005
• New structure from Committee of Revision to
Expert Committees
• Compounding Pharmacy Expert Committee
– General Chapters, incl <795>
– Nonsterile preparation monographs
• Parenteral Products--Compounding and
Preparation Expert Committee
– General Chapters, incl <1206>
– Sterile preparation monographs
USP Convention 2000
• Resolution
• Continue to develop and institute, in
collaboration with other organizations as
appropriate, specific initiatives focused on the
development of appropriate compounding
guidelines and monographs for noncommercially available, but commonly
prescribed, medicines and dosage forms for
use in special populations, notably neonatal,
pediatric, geriatric, and terminally ill patients.
U.S. PHARMACOPEIA AND
FDAMA
•
•
•
•
•
Activities to date:
15 official compounding monographs
8 more stability studies underway
6 formulas being processed through PF
2 official chapters and 2 additional
chapters in process:
– Pharmacy Calculations
– Good Compounding Practices
CURRENT ACTIVITIES OF
PHARMACY COMPOUNDING
EXPERT COMMITTEE
• Survey of compounding pharmacists in
hospitals, community pharmacies and
long-term care facilities (August 2000)
• List of over 150 preparations, mostly
pediatric, that need to be considered.
• 2000 Resolution:
U.S. PHARMACOPEIA
• 2001
• Recent survey listed over 1000 other
preparations need monographs
• Well over 5,000 different formulations
routinely compounded
FDAMA and the 9th District
• Early 2001
– the Ninth Circuit ruled that the FDAMA
section dealing with compounding was
invalid in the 9th Circuit District (NV, CA,
WA, OR, MT, ID, AZ, AK, HI) but still in
effect in the rest of the US.
FDAMA and the 9th District
• April 29, 2002
• U.S. Supreme Court ruled the
advertising restrictions unconstitutional
and the section not severable.
• Entire 503a now is thrown out and
nonenforceable
SUMMARY
• Pharmacy compounding is now legally
recognized by the FDA, the Supreme Court,
Congress, etc. as a necessary component of
quality health care
• Emphasis on quality of compounding is
increasing with documentation of quality
being recommended and required
• Clinical pharmacy becomes more of a reality
with compounding pharmacy
A LOOK INTO THE NEAR
FUTURE
New Compounded Drug Delivery
Systems (DDS)
Future Trends
•
•
•
•
•
•
Adhesive Site-Specific DDS
Antibody-Based DDS
Biocompatible Microsphere DDS
Biodegradable Polymers DDS
Biologic-Based DDS
Electromagnetic/RadiationActivated DDS
Future Trends
• Immunomodulator DDS
• Implant-Enhanced DDS
• Microorganism-Containing
Microcapsule DDS
• Lipid Microcylinders
• Liposome Enhancements
• Living-Cell Therapies
Future Trends
•
•
•
•
•
•
•
Magnetic System DDS
Maze-Escape DDS
Monoclonal Antibody DDS
Novel Nasal DDS
New Osmotic DDS
Transmucosal DDS
Polymer Drug Complex DDS
Future Trends
•
•
•
•
Pulsatile DDS
Resealed Erythrocyte DDS
Respiratory DDS
Self-Assembling Controlled-Release
DDS
• Programmed Skin-Surface DDS
NANOTECHNOLOGY:
The Ultimate Alchemy
NANOTECHNOLOGY
• The art and science of building molecular
structures so they are sufficiently large and
complex to function as machines or devices
• Atomically precise, functional machine
systems developed on the scale of the
nanometer
• Builds objects atom by atom, molecule by
molecule
POTENTIAL PRODUCTS
• Activated Pharmaceuticals (Magic Bullets)
• Cell-herding machines to stimulate rapid
wound healing
• Nanosurgeons to repair damaged cellular
parts
• Nanocruisers to attack viruses and bacteria
FORECASTS: 2-5 YEARS
• Inexpensive handheld biosensors built
on the basis of nanoscale ion channel
switches
• Simple detection of diseases, within
minutes, from a small sample of saliva
or blood
FORECASTS
• DNA vaccines will begin to be available in the
next 5-10 years
• Superior and safer than traditional vaccines
• Ability to directly mimic body components
and can “rebuild” worn, defective, damaged,
diseased cells/tissues/organs
• Blood products, artificial skin products,
bioartificial organs, blood vessels
FORECASTS
• IF a breakthrough to a universal
assembler occurs during the next 10-15
years, an entirely new field of
“nanomedicine” and “nanopharmacy”
will emerge by 2020.
NANOMEDICINE
• Monitoring, repair, construction and
control of human biological systems at
the molecular level, using engineered
nanodevices and nanostructures.
NANOPHARMACY
Preparation and delivery of ultra-small
pharmaceuticals, therapeutic substances
and delivery systems.
NANOPHARMACY AND
NANOPHARMACEUTICALS
• Motors consisting of, for example,
ATPase molecules with a metallic
substrate and a chemical “propeller” on
the other. As the ATP breaks down, the
biomotor moves.
• This motor may be able to compound
tiny quantities of drugs and pump them
directly to the target tissues.
NANOPHARMACY AND
NANOPHARMACEUTICALS
• The uses of biomolecular motors
could be used for sensing or placing
in living cells as a pharmacy to
deliver medicine when required.
NANOPHARMACY AND
NANOPHARMACEUTICALS
• New formulations and routes for
drug delivery
• Pharmaceuticals based on an
individuals genome
CONCLUSIONS
• We must live in today and prepare for
tomorrow
• Compounding pharmacists roles in
“individualizing drug therapy” is
preparing the foundation for the
“NANOPHARMACY” of tomorrow.