Pharmacy Compounding |
Report: Limited FDA
Survey of
|
Analytical Test Performed |
Dosage Form Sampled |
||||
---|---|---|---|---|---|
Sterile Injectable |
Pellet Implant |
Solution or Ointment for Ophthalmic Administration |
Inhalation Products |
Oral Dosage Forms |
|
Sterility |
X |
X |
X |
||
Identity |
X |
X |
X |
X |
X |
Assay (potency) |
X |
X |
X |
X |
X |
Endotoxin (LAL) |
X |
||||
Particulates |
X |
||||
Release rate |
X |
||||
pH |
X |
||||
Microbial limits |
X |
||||
Contaminants |
X |
||||
Dissolution |
X |
||||
Content uniformity |
X |
For chemistry tests, original and check (repeat) analyses were performed for each sample, with the repeat analyses conducted by laboratory personnel different from those who performed the original analyses. Sample failure was based on the type of analytical tests performed in this survey (i.e., chemistry tests and microbiological tests). A sample was deemed to have failed a specific chemistry test if it failed both the original and the repeat analyses. Chemistry tests performed on the samples collected were identity, assay, content uniformity, dissolution, and pH tests. Microbiological tests performed on the samples collected were sterility, Limulus Ameobocyte Lysate (LAL), microbial limits, and particulates tests. Repeat testing was not required for microbiological analyses. A sample was deemed to have failed a specific microbiological test if it failed an original analysis.
Samples were assayed for sterility using the USP method (USP 24, pp. 1818-1824). All but three of the samples were assayed for potency using the appropriate USP Monograph (USP 24). Because there was no applicable USP monograph, the three other samples (two injectable products and one inhalation product) were assayed for potency in accordance with methodology contained in an ANDA or NDA for the product, respectively. An additional product (i.e., Alprostadil injection) was assayed for potency in accordance with the Pharmacopeial Forum (PF), Vol. 27(3) May-June 2001, pp. 2509, 2512-14, and another product (i.e., TriMix injection containing Papaverine, Phentolamine, and Prostaglandin E1) was assayed for potency via a method modified from that of Tu et. al. (American Journal of Hospital Pharmacy, 1987; 44:2524-2527) and validated by the FDA laboratory. This latter method was utilized because of the nature of the specific product and the fact that there was no applicable USP monograph or NDA/ANDA methodology.
The microbial limits assay was performed according to USP 24, Chapter <61>, pp. 1814-1818 and USP 24, Chapter 71, pp. 1820, 1822. The LAL test for endotoxin was conducted using the procedure described in a USP 24, Chapter 85, pp. 1829-1231. Particulate matter was determined in accordance with USP 24, Chapter 788, pp. 1971-1977, and uniformity of dosage units (UDU) analyses were performed according to USP 24, Chapter 905, 2nd Supplement, pp. 2904-2906.
D. Results
Ten (34%) of the 29 sampled products failed one or more standard quality tests performed. Nine of the ten products with failing analytical results failed assay or potency testing. All of the sampled products that failed potency analyses had subpotent results, indicating that the products analyzed contained less of the active ingredient(s) than expected (as described in the product's label). The average percent of declared potency for these nine products was calculated from the original and repeat analyses performed for each sample, with a range of 59 percent to 89 percent of expected potency. In addition to the potency failures described, two other analytical test failures were noted during the survey (i.e., a failed LAL test for an injectable product and a content uniformity failure for an oral product that also failed potency testing).
None of the compounded products analyzed in this survey failed identity testing. In addition, none of the compounded products sampled and subjected to sterility testing (sterile injectables, pellet implants and ophthalmic products) or testing for microbial limits (the single inhalation product) failed these analytical tests. Appendix A lists the specific compounded products sampled for the survey, the expected concentration of active ingredient as listed on the product's label, a notation for the compounding pharmacy from which the product was obtained, and the type of analytical test failed.
CONCLUSIONS
Each year, FDA routinely samples drug products made by commercial manufacturers and analyzes these samples in FDA laboratories. More than 3,000 drug products from commercial manufacturers have been sampled and analyzed by FDA since fiscal year 1996. The analytical testing failure rate for commercially produced samples has been less than 2 percent. When compared to this failure rate, the percentage of sampled compounded products failing analytical testing in this survey (i.e., 34 percent) was higher than expected.
This survey had several limitations including a small sample size, the inability to collect and complete original and repeat analyses on all product samples originally identified for the survey, and the fact that the compounding pharmacies selected for the survey were limited to those permitting Internet purchase of the drug products chosen for sampling. Despite these limitations, this survey provided valuable, preliminary information on the quality of selected compounded drug products currently marketed. The findings also highlight the importance of carefully and properly compounding drug products to minimize risks to consumers.
Appendix A: Specific Compounded Products Sampled in FDA's Survey and List of Failed Analytical Test Results
Compounded Product |
Concentration |
Pharmacy |
Type of Analytical Test Failed |
---|---|---|---|
Sterile Injectables |
|||
Alprostadil |
20 mcg/ml |
H |
LAL |
Betamethasone |
3 mg/ml |
A |
Assay/Potency |
Dipyridamole |
5 mg/ml |
E |
None |
Dipyridamole |
5 mg/ml |
F |
None |
Droperidol |
5 mg/ml |
A |
None |
Hyaluronidase |
150 U/ml |
D |
None |
Hyaluronidase |
150 U/ml |
K |
Assay/Potency |
Iron Dextran |
50 mg/ml |
F |
None |
Iron Dextran |
50 mg/ml |
F |
None |
Papaverine HCl |
30 mg/ml |
A |
Assay/Potency |
Progesterone |
50 mg/ml |
D |
Assay/Potency |
Progesterone |
50 mg/ml |
L |
None |
TriMix - Papaverine - Phentolamine - PGE1 |
17.65 mg/ml 0.59 mg/ml 5.9 mcg/ml |
I |
None |
Pellet Implants |
|||
Estradiol |
25 mg pellet |
D |
None |
Estradiol |
25 mg pellet |
I |
None |
Ophthalmic Solutions and Ointments |
|||
Atropine SO4 |
1% Preservative Free (PF) solution |
G |
None |
Atropine SO4 |
1% PF solution |
J |
None |
Betaxolol |
0.125% PF solution |
G |
None |
Carbacol |
1% PF solution |
G |
None |
Ciprofloxacin |
0.3% PF solution |
G |
Assay/Potency |
Ciprofloxacin |
0.3% PF solution |
J |
None |
Dexamethasone |
0.05% PF ointment |
G |
None |
Dexamethasone |
0.1% PF solution |
J |
Assay/Potency |
Timolol Maleate |
0.25% PF solution |
G |
Assay/Potency |
Inhalation |
|||
Tobramycin |
60 mg/ml |
E |
Assay/Potency |
Oral |
|||
Progesterone |
200 mg |
I |
None |
Estradiol |
2 mg tablet |
B |
None |
Progesterone |
300 mg capsule |
I |
Assay/Potency |
Progesterone |
100 mg capsule |
M |
None |
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FDA/Center for Drug Evaluation and Research
Last Updated: January 28, 2003
Originator: ORP
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