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Research Letters |

Over-the-Counter and Compounded Vitamin D: Is Potency What We Expect? FREE

Erin S. LeBlanc, MD, MPH; Nancy Perrin, PhD; Jeffery D. Johnson, PhD; Annie Ballatore, MS; Teresa Hillier, MD, MS
[+] Author Affiliations

Author Affiliations: Kaiser Permanente Center for Health Research, Portland, Oregon (Drs LeBlanc, Perrin, and Hillier); and Eagle Analytical Services, Houston, Texas (Dr Johnson and Ms Ballatore).


JAMA Intern Med. 2013;173(7):585-586. doi:10.1001/jamainternmed.2013.3812.
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Published online

Because vitamin D insufficiency can be harmful to health,13 supplementation is often prescribed. However, the Food and Drug Administration (FDA) does not regulate vitamin D supplements, so potency may not be well evaluated. In a recent trial examining vitamin D in menopausal women, we found that compounded vitamin D3 (cholecalciferol) supplements varied significantly in potency. Only one-third of our compounded study pills met US Pharmacopeial (USP) Convention standards, which require that compounded pills contain 90% to 110% of the active ingredient.4 This variability in compounded cholecalciferol pills led us to additionally investigate over-the-counter (OTC) cholecalciferol pills, in which we also found variability.

We randomly selected 5 pills from 15 sealed bottles of OTC cholecalciferol dietary supplements (1000 IU, 5000 IU, and 10 000 IU) purchased at 5 stores in Portland, Oregon. We next randomly selected 1 pill from 5 bottles with the same lot number and 1 pill from 5 bottles with different lot numbers. We also analyzed compounded study cholecalciferol pills (1000 IU and 50 000 IU), compounded on 3 occasions over 4 months. Testing was done at variable times (0-6 months) after compounding.

Pill potency was analyzed using high performance liquid chromatography (HPLC) (Rapid Separation LC [RSLC] Ultimate 3000 UHPLC System; Dionex) (see eAppendix). To validate our laboratory testing accuracy, we split pills and sent them to a second laboratory. The values from the second laboratory were within 10% of the results of our laboratory.

We describe pill accuracy using the percentage of expected potency. We averaged overall potency of 5 pills from the same bottle and calculated the standard deviation. To standardize variability and compare across doses, we calculated the coefficient of variation (CV)—the ratio of the standard deviation to the mean.

The OTC pills contained 52% to 135% of expected dose (Table). When averaged over 5 pills, two-thirds of bottles met USP Convention standards for OTC cholecalciferol solution,5 which state that contents should be within 90% to 120% of the stated dose. In approximately one-fourth of bottles, all 5 pills met USP Convention standards. Two-thirds of bottles had less than 10% variability (CV). The one manufacturer that was USP verified (No. 4) was highly accurate (101.7%), and all 5 pills tested were within 10% of expected dose.

Table Graphic Jump LocationTable: Vitamin D3 (Cholecalciferol) Potency of 5 Pills From 1 Bottle

When we took 1 pill from each of 5 bottles with the same lot number, potency ranged from 57% to 138% of the stated amount (eTable 1). When pills in each lot were averaged, potencies ranged from 99.7% to 107%. Only the 5000 IU dose of the USP-verified manufacturer had pills from the same lot that all tested within 90% to 120% of the expected amount. The 1000 IU pills of that manufacturer were more variable (97% to 135% of the expected dose; CV, 13.0%). Variability of pills from the remaining manufacturers ranged from 7.1% to 27.9%; only 1 had less than 10% variability.

The potency of pills from different lots ranged from 9% to 140% of the stated dose; mean potencies over 5 lots ranged from 89% to 105% (eTable 2). Only the USP-verified manufacturer had pills from different lots that were all within 90% to 120% of the expected dose (CV, 5.5%). The 1000-IU pills from the USP-verified manufacturer were more variable—potency ranged from 70% to 140% (CV, 23.3%). The pills from different lots of the remaining manufacturers were also variable (CVs, 11.3% to 58.2%).

The compounded 50 000-IU cholecalciferol tablets contained 52% to 105% and the 1000 IU compounded tablets 23% to 146% of the expected dose. Only one-third of pills were within 10% of the expected dose, which is the USP Convention standard for compounded pills.4 Variation in storage time did not explain potency differences.

The cholecalciferol content of OTC and compounded vitamins was highly variable; potency ranged from 9% to 146%. In our test, just over one-half of OTC pills and only one-third of compounded pills met USP Convention standards. The manufacturer that was USP verified (No. 4) was generally more accurate and less variable. Lack of accuracy in cholecalciferol dosing may not cause harm in most consumers. However, supplementation may be less effective and dose adjustments inaccurate in inconsistent users,6 which may harm women with severe vitamin D deficiency. Pill variability may also threaten validity of vitamin D trials that use compounded pills to blind participants. As more people take vitamin D supplements, it is critical that health care providers and patients understand that cholecalciferol potency may vary widely. Products that are USP verified may have better accuracy but may be sparsely distributed. On the basis of our study, we agree with a recent editorial calling for increased regulation of dietary supplements.7

Correspondence: Dr LeBlanc, Kaiser Permanente Center for Health Research, 3800 N Interstate Ave, Portland, OR 97227 (erin.s.leblanc@kpchr.org).

Published Online: February 11, 2013. doi:10.1001/jamainternmed.2013.3812

Author Contributions:Study concept and design: LeBlanc. Acquisition of data: LeBlanc, Johnson, and Ballatore. Analysis and interpretation of data: LeBlanc, Perrin, and Hillier. Drafting of the manuscript: LeBlanc. Critical revision of the manuscript for important intellectual content: LeBlanc, Perrin, Johnson, Ballatore, and Hillier. Statistical analysis: LeBlanc and Perrin. Obtained funding: LeBlanc. Administrative, technical, and material support: Johnson and Ballatore.

Conflict of Interest Disclosures: None reported.

Funding/Support: This study was funded through Kaiser Permanente internal funding.

Additional Contributions: Jill Pope, BA, and Carol Ayres, MA, helped edit the manuscript, and Christine Wilkins helped with manuscript preparation.

Holick MF, Binkley NC, Bischoff-Ferrari HA,  et al; Endocrine Society.  Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline.  J Clin Endocrinol Metab. 2011;96(7):1911-1930
PubMed   |  Link to Article
Dobnig H. A review of the health consequences of the vitamin D deficiency pandemic.  J Neurol Sci. 2011;311(1-2):15-18
PubMed   |  Link to Article
Wimalawansa SJ. Vitamin D in the new millennium.  Curr Osteoporos Rep. 2012;10(1):4-15
PubMed   |  Link to Article
US Pharmacopeia.  Pharmaceutical compounding—nonsterile preparations. 2012.http://www.pharmacopeia.cn/v29240/usp29nf24s0_c795.html. Accessed October 15, 2012
US Pharmacopeial Convention.  Cholecalciferol Solution: USP 35–NF 30. Rockville, MD: US Pharmacopeial Convention; 2012:2653
Pfister AK, Welch CA, WuLu JT Jr, Hager KA, Saville PD. An assessment of postmenopausal women's adherence to calcium with vitamin D supplements.  J Appl Res. 2008;8(2):143-150
Cohen PA. Assessing supplement safety—the FDA's controversial proposal.  N Engl J Med. 2012;366(5):389-391
PubMed   |  Link to Article

Figures

Tables

Table Graphic Jump LocationTable: Vitamin D3 (Cholecalciferol) Potency of 5 Pills From 1 Bottle

References

Holick MF, Binkley NC, Bischoff-Ferrari HA,  et al; Endocrine Society.  Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline.  J Clin Endocrinol Metab. 2011;96(7):1911-1930
PubMed   |  Link to Article
Dobnig H. A review of the health consequences of the vitamin D deficiency pandemic.  J Neurol Sci. 2011;311(1-2):15-18
PubMed   |  Link to Article
Wimalawansa SJ. Vitamin D in the new millennium.  Curr Osteoporos Rep. 2012;10(1):4-15
PubMed   |  Link to Article
US Pharmacopeia.  Pharmaceutical compounding—nonsterile preparations. 2012.http://www.pharmacopeia.cn/v29240/usp29nf24s0_c795.html. Accessed October 15, 2012
US Pharmacopeial Convention.  Cholecalciferol Solution: USP 35–NF 30. Rockville, MD: US Pharmacopeial Convention; 2012:2653
Pfister AK, Welch CA, WuLu JT Jr, Hager KA, Saville PD. An assessment of postmenopausal women's adherence to calcium with vitamin D supplements.  J Appl Res. 2008;8(2):143-150
Cohen PA. Assessing supplement safety—the FDA's controversial proposal.  N Engl J Med. 2012;366(5):389-391
PubMed   |  Link to Article

Correspondence

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Manufacturer Identifications
Posted on February 12, 2013
Patrick Proctor
Medical Student, University of North Carolina at Chapel Hill
Conflict of Interest: None Declared
This is very useful information for clinicians who regularly advise patients to take OTC vitamin D supplements. Knowing the identities of the manufacturers included in your study would allow immediate application of your findings by avoiding the least conforming manufacturer and/or recommending the most consistent product, such as that from manufacturer #4. Is it possible for you to release this information?
There are fully tested Vitamin D supplements available
Posted on February 12, 2013
Erin S. LeBlanc, Nancy Perrin, Jeffery D. Johnson, Annie Ballatore, Teresa Hillier, Jason Theodosakis,
University of Arizona College of Medicine
Conflict of Interest: Principle, Supplement Testing Institute, Inc. Testing, Manufacturing.

I agree that supplements with a narrow therapeutic window, such as Vitamin D3, require stringent manufacturing procedures. Increased regulation isn't necessary. What is necessary is enforcement of existing cGMPs. Old regulations state 90-110% of label claim is acceptable. The current regulations require a product to have 100% of the label claim at the end of the expiration date. Consumers can ask a manufacturer for test results, including third party test results for each batch of each product. If it's not given, get the product from another company. There are a few, including DrTheos.com, who provide such information. You can also ask for shelf-life/stability testing. This exceeds the standards for OTC and Pharma drugs. No one should have to guess that the product they take meets label claims, nor assume that USP or another certifying organization is assuring that every batch checks out (because they don't). Furthermore, supplements should not have to have regulations that exceed drug manufacturing standards. The same testing information should be available to consumers of OTC and prescription drugs. Perhaps this would improve safety and help prevent some of the recalls we've seen in the industry.


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Supplemental Content

LeBlanc ES, Perrin N, Johnson JD Jr, Ballatore A, Hillier T. Over-the-counter and compounded vitamin D: is potency what we expect? JAMA Intern Med. Published online February 11, 2013. doi:10.1001/jamainternmed.2013.3812

eAppendix. Chemical Analysis of Vitamin D Pills

eTable 1. Vitamin D3 Potency in Pills From Different Bottles: Results From 5 Different Bottles With Same Lot Numbers.

eTable 2. Vitamin D3 Potency in Pills From Different Bottles: Results From 5 Different Bottles With Different Lot Numbers

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