To: CBER OCOD Consumer Account
Subject: What are the ingredients of vaccine adjuvants?
There are a number of vaccines that list aluminum adjuvant as one of the ingredients. What are the ingredients of that adjuvant?
Boostrix by GlascoSmithKline is one of them. What exactly is in the adjuvant?
Thanks,
Barbara Gregory
Subject: RE: What are the ingredients of vaccine adjuvants?
Date: Thursday, April 30, 2009, 10:28 AM
Dear Ms. Gregory:
Thank you for your inquiry to the Food and Drug Administration's (FDA) Center for Biologics Evaluation and Research (CBER). CBER, one of six centers within FDA, is responsible for the regulation of biologically-derived products, including blood intended for transfusion, blood components and derivatives, vaccines and allergenic extracts, and cell, tissue and gene therapy products.
We hope that the following information helpful:
Aluminum adjuvants are primarily used in vaccines to help enhance or direct an immune response. Aluminum in the form of aluminum hydroxide, aluminum phosphate or alum has been commonly used as adjuvants in many vaccines licensed by FDA for over six decades.
Information related to the adjuvant used in vaccines licensed by FDA can be found in the product labeling. Most of the labels can be found on CBER’s list of licensed vaccines at http://www.fda.gov/cber/vaccine/licvacc.htm. For information not found in the labeling, you may contact the manufacturer of the product of interest directly for additional information.
Protecting and improving public and individual health is the Agency's primary mission. As such, a commitment to ensuring the safety and efficacy of all biological products, including vaccines, is one of our highest priorities.
We hope this information is helpful.
Sincerely,
H.A.
Consumer Safety Officer
Consumer Affairs Branch
Division of Communication and Consumer Affairs
Center for Biologics Evaluation and Research
US Food and Drug
Administration
This communication is consistent with 21 CFR 10.85 (k) and constitutes an informal communication that represents my best judgment at this time but does not constitute an advisory opinion, does not necessarily represent the formal position of FDA, and does not bind or otherwise obligate or commit the agency to the views expressed.
To: CBER OCOD Consumer Account
Subject: Please explain trade secrets
Since you cannot tell me what the actual ingredients are in vaccine adjuvants, I would like to know what the law is as applied to vaccine manufacturers. Please explain what they can and cannot have in vaccines that can be a trade secret.
Thank you,
Barbara F. Gregory
Dear Ms. Gregory:
To the best of my knowledge, aluminum in the form of aluminum hydroxide is the adjuvant used in the production of Boostrix. The antigens used in the formulation are bound to the aluminum hydroxide in order to boost the immune response in the recipient. The amount of adjuvant, as with any other ingredient, within a vaccine formulation may vary by manufacturer. However, they are still required to provide data to FDA demonstrating that the amount of adjuvant, in this case aluminum, is necessary to enhance the antigenicity of the vaccine and that the vaccine containing this amount of aluminum is safe for the indicated use.
Federal regulations pertaining to biological products can be found in Title 21 Code of Federal Regulations (CFR) Parts 600-680. Specific regulations regarding adjuvants can be found in 21 CFR 610.15. I have provided the following links to the CFRs for your convenience. [http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm]
[http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=610.15]
We hope this information is helpful.
If you have further questions feel free to contact our office at ocod@fda.hhs.gov, or by phone 301-827-2000.
Sincerely,
H.A.
Consumer Safety Officer
Consumer Affairs Branch
Division of Communication and Consumer Affairs
Center for Biologics Evaluation and Research
US Food and Drug
Administration
This communication is consistent with 21 CFR 10.85 (k) and constitutes an informal communication that represents my best judgment at this time but does not constitute an advisory opinion, does not necessarily represent the formal position of FDA, and does not bind or otherwise obligate or commit the agency to the views expressed.
[Code of Federal
Regulations]
[Title 21, Volume 7]
[Revised as of April 1, 2008]
[CITE:
21CFR610.15]
TITLE 21--FOOD AND DRUGS
CHAPTER I--FOOD AND DRUG
ADMINISTRATION DEPARTMENT OF HEALTH AND HUMAN SERVICES
SUBCHAPTER
F--BIOLOGICS
PART 610 -- GENERAL BIOLOGICAL PRODUCTS STANDARDS
Subpart B--General Provisions
Sec. 610.15 Constituent materials.
(a)Ingredients, preservatives, diluents, adjuvants. All ingredients used in a licensed product, and any diluent provided as an aid in the administration of the product, shall meet generally accepted standards of purity and quality. Any preservative used shall be sufficiently nontoxic so that the amount present in the recommended dose of the product will not be toxic to the recipient, and in the combination used it shall not denature the specific substances in the product to result in a decrease below the minimum acceptable potency within the dating period when stored at the recommended temperature. Products in multiple-dose containers shall contain a preservative, except that a preservative need not be added to Yellow Fever Vaccine; Poliovirus Vaccine Live Oral; viral vaccines labeled for use with the jet injector; dried vaccines when the accompanying diluent contains a preservative; or to an Allergenic Product in 50 percent or more volume in volume (v/v) glycerin. An adjuvant shall not be introduced into a product unless there is satisfactory evidence that it does not affect adversely the safety or potency of the product. The amount of aluminum in the recommended individual dose of a biological product shall not exceed:
(1) 0.85 milligrams if determined by assay;
(2) 1.14 milligrams if determined by calculation on the basis of the amount of aluminum compound added; or
(3) 1.25 milligrams determined by assay provided that data demonstrating that the amount of aluminum used is safe and necessary to produce the intended effect are submitted to and approved by the Director, Center for Biologics Evaluation and Research or the Director, Center for Drug Evaluation and Research (see mailing addresses in 600.2 of this chapter).
(b)Extraneous protein; cell culture produced vaccines. Extraneous protein known to be capable of producing allergenic effects in human subjects shall not be added to a final virus medium of cell culture produced vaccines intended for injection. If serum is used at any stage, its calculated concentration in the final medium shall not exceed 1:1,000,000.[The problem with this is ANY protein along with the adjuvant can cause allergenic effects in human subjects!!! - bfg]
(c)Antibiotics. A minimum concentration of antibiotics, other than penicillin, may be added to the production substrate of viral vaccines.
[38 FR 32056, Nov. 20, 1973, as amended at 46 FR 51903, Oct. 23, 1981; 48 FR 13025, Mar. 29, 1983; 48 FR 37023, Aug. 16, 1983; 49 FR 23834, June 8, 1984; 50 FR 4134, Jan. 29, 1985; 51 FR 15607, Apr. 25, 1986; 55 FR 11013, Mar. 26, 1990; 70 FR 14985, Mar. 24, 2005]
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=610.15
I'm really not interested in the aluminum in the adjuvant. I am interested in the oils used in the adjuvant. The way I read the regulations, as long as the oil meets your purity standards it is fine to use and does not have to be listed on the package insert?
And protein in the culture medium... the way I read that is the final culture medium is not to contain extraneous protein but the earlier culture mediums could contain a variety of protein?
Thanks,
Barbara F. Gregory
From:
"CBER OCOD Consumer Account"
Dear Ms. Gregory:
First let me extend my sincerest apologies for the delayed response. Although we make every effort to respond to each inquiry that we receive in a timely manner, on occasion there are number of contributing factors that impede our ability to achieve that goal.
It is unclear from your email exactly what oil you are referring. Again, the aluminum is the adjuvant. Aluminum in the form of alum, aluminum hydroxide or phosphate is the only adjuvants used in U.S. licensed vaccines and there is no oil in those adjuvants. The adjuvant, as well as, certain inactive ingredients [That's right... only certain inactive ingredients not all of them. And peanut oil was considered totally safe for injection from the skin prick tests so it doesn't have to appear!! - bfg] must appear on the package label. General requirements for the package labeling can be found in 21 CFR 610.61.
Regarding cell culture medium, 21 CFR 610.15 states, "extraneous protein known to be capable of producing allergenic effects in human subjects shall not be added to a final virus medium of cell culture produced vaccines intended for injection." It would be inaccurate to infer that earlier culture mediums used in production could contain various proteins. [How can it possibly be inaccurate? It isn't illegal. - bfg] However, some of the package inserts for cell cultured vaccines do provide information on protein contents used in the manufacturing of the product.
We hope this information is helpful.
Feel free to provide a contact number so that we can discuss your specific questions and/or concerns. Otherwise, you may contact our office directly toll free at 800-835-4709.
Sincerely,
H.A.
Consumer Safety Officer
Consumer Affairs Branch
Division of Communication and Consumer Affairs
Center for Biologics Evaluation and Research
US Food and Drug
Administration
This communication is consistent with 21 CFR 10.85 (k) and constitutes an informal communication that represents my best judgment at this time but does not constitute an advisory opinion, does not necessarily represent the formal position of FDA, and does not bind or otherwise obligate or commit the agency to the views expressed.
To:
Merck & Co., Inc.
One Merck Drive
P.O. Box 100
Whitehouse Station, NJ 08889-0100 USA
Date: June 18, 2009
Re: Ingredients of vaccines
Hello,
I have a few questions regarding the ingredients of the vaccines that you manufacture.
Recombivax HB lists as ingredients: produced in yeast cells, cloned into yeast, complex fermentation medium which consists of an extract of yeast, soy peptone, adjuvanted with amorphous aluminum , hydroxyphosphate sulfate, may contain not more than 1% yeast protein
1. Won’t the combination of yeast and aluminum adjuvant cause a yeast allergy in some people?
2. Won’t the soy peptone and the aluminum adjuvant cause a soy allergy in some people?
3. What are the ingredients of the aluminum adjuvant? Does it include a liquid oil or water as an ingredient?
Varivax lists monosodium L-glutamate as an ingredient.
1. Is that the same thing that people who have Chinese Restaurant Syndrome are sensitive to?
Thank you,
Dear Ms. Gregory:
Thank you for contacting Merck & Co., Inc.
As a pharmaceutical manufacturer, Merck is not in a position to provide general medical information regarding your inquiry. We encourage you to direct questions regarding disease and its management towards your physician.
If you have a question about a specific Merck product, please visit the Merck Product Information link at www.Merck.com or contact the Merck National Service Center at 1-800-NSC-MERCK (1-800-672-6372) and reference your service request number 1-3334249111.
Again, thank you for contacting Merck.
Trace amounts of food protein in vaccines
Tuesday, April 20, 2010 9:59 AM
From: "Barbara Gregory"
To: ocod@fda.hhs.gov
Please verify for me that the FDA allows trace amounts of food protein in vaccines. The sources are from the culture medium and the GRAS “pharmaceutical grade” food oils.
Regarding the oils… the way I understand it, the FDA approved highly refined peanut oil to be GRAS and made it voluntary for pharmaceutical companies to list it as an ingredient. The FDA also gave the pharmaceutical companies the power to decide that other ingredients are GRAS without having to submit anything to the FDA.
Culture mediums as the source:
[Code of Federal Regulations]
[Title 21, Volume 7]
[Revised as of April 1, 2008]
[CITE: 21CFR610.15]
TITLE 21--FOOD AND DRUGS
CHAPTER I--FOOD AND DRUG ADMINISTRATION
DEPARTMENT OF HEALTH AND HUMAN SERVICES
SUBCHAPTER F--BIOLOGICS
PART 610 -- GENERAL BIOLOGICAL PRODUCTS STANDARDS
Subpart B--General Provisions Sec. 610.15 Constituent materials. (b)Extraneous protein; cell culture produced vaccines. Extraneous protein known to be capable of producing allergenic effects in human subjects shall not be added to a final virus medium of cell culture produced vaccines intended for injection. If serum is used at any stage, its calculated concentration in the final medium shall not exceed 1:1,000,000.
Note that is says “FINAL virus medium of cell culture.” Up until the FINAL medium, food waste can be used:
..In contrast, complex media will use extracts of a variety of things, including left-over animal parts (cow brains and hearts), yeast (from brewing) or digests of plants or animal slurries (peptones are one example of this category). The exact composition of these extracts is often unknown. The sources of these extracts often take advantage of waste products from other industries to save money....
US Patent 6953574 - Method for producing a fermented hydrolyzed medium containing microorganisms Vegetables preferably used are of leaf and root types e.g. various cabbages, beets, rutabaga, carrot, pumpkin, spinach, beet, watermelon, melon, peanut, artichoke, eggplant, pepper sweet, asparagus, and tomato. Fruits to be preferably used are apples, pears, kiwi, plums, citrus, apricots, grapes/raisins, mango, guava, bananas, biwa, cornel, fig, cherry plum, quince, peach, pomegranate, avocado, pineapple, date, papaya. Berries preferably include raspberry, bilberry, guelder rose, dog rose, ash berry (red and black), currant (red, black, and white), sea-buckthorn berries, gooseberry, schizandra, blackberry, cowberry, bird cherry, cranberry, sweet cherry, cherry, and strawberry. Preferred herbs and their roots are ginseng, celery, parsley, dill, dandelion, nettle, ginseng, and spinach. Preferred high protein products are offals including spleen, kidney, heart, liver, brains, maw, and stomach as well as mushrooms, sea products (fish, mussel, plankton for example), eggs or nuts. Preferred products of beekeeping are propolis, honey, royal jelly, and pollen of flower.
There is no testing done to check for food protein remaining in the vaccine from the pre-final culture medium.
The other source of food protein in vaccines and pharmaceuticals is from GRAS (generally recognized as safe) ingredients that do not have to appear on the package insert or be listed as ingredients anywhere: Aluminum in the form of alum, aluminum hydroxide or phosphate is the only adjuvants used in U.S. licensed vaccines and there is no oil in those adjuvants. The adjuvant, as well as, certain inactive ingredients must appear on the package label. General requirements for the package labeling can be found in 21 CFR 610.61. Email from CBER OCOD Consumer Account, Monday, June 15, 2009 1:51 PM Note that it says only CERTAIN inactive ingredients VLP. Drug delivery vehicles, adjuvants, and excipients shall not be deemed to be "active ingredients", except in the case where such delivery vehicle, adjuvant, or excipient is recognized as an active ingredient in accordance with 21 C.F.R. 210.3(b)(7).
FDA should improve GRAS oversight, says GAO
By Caroline Scott-Thomas, 08-Mar-2010
The FDA needs to improve its oversight of GRAS (generally recognized as safe) food ingredients, claims a new report from the Government Accountability Office (GAO). The Food and Drug Administration (FDA) no longer ‘approves’ food ingredients as GRAS, but does review their safety if a company submits a research dossier including the findings of an independent scientific panel. Following review, the FDA can issue a letter of no objection, leading to what is commonly referred to as FDA GRAS. However, the company remains responsible for ensuring the ingredient is safe and that it complies with all regulatory requirements.
Alternatively, a company can self-affirm GRAS after conducting all necessary research and forming an independent panel to determine its safety. To self-affirm, the company needs to be confident that it could defend the safety of its ingredient based on this process. No ‘systematic’ checks since 1980s But the GAO said the FDA should be made more aware of self-affirmed GRAS products, and should systematically review the safety of current GRAS ingredients as new scientific data comes to light. “FDA is not systematically ensuring the continued safety of current GRAS substances,” the report said. “While, according to FDA regulations, the GRAS status of a substance must be reconsidered as new scientific information emerges, the agency has not systematically reconsidered GRAS substances since the 1980s.” FDA officials countered they are continuously reviewing the scientific literature and take action on particular substances if information is brought to their attention that causes them to doubt an ingredient’s safety.
How are excipients "approved" for use in pharmaceutical products? Under U.S. law, an excipient, unlike an active drug substance, has no regulatory status and may not be sold for use in food or approved drugs unless it can be qualified through one or more of the three U.S. Food and Drug Administration (FDA) approval mechanisms that are available for components used in food and/or finished new drug dosage forms.
These mechanisms are: 1. determination by FDA that the substance is "generally recognized as safe" (GRAS) pursuant to Title 21, U.S. Code of Federal Regulations, Parts 182, 184 or 186 (21 CFR 182, 184 & 186); p>