Exempt Sections within the Food, Drug, and Cosmetic Act If a "traditional compounder", defined as a licensed pharmacist or licensed physician, meets ALL conditions within Section 503A, the compounder is exempt from THREE sections within the Food, Drug, and Cosmetic Act; (1) Section 501(a)(2) (concerning current good manufacturing practices); (2) Section 502(f)(1) (concerning labeling or drugs with adequate directions for use); and (3) Section 505 (concerning the approval of drugs under new drug applications or abbreviated new drug applications). If a facility meets ALL conditions within Section 503B, the outsourcing facility is exempt from TWO sections within the Food, Drug, and Cosmetic Act: (1) Section 502(f)(1) (concerning labeling of drugs with adequate directions for use): and (2) Section 505 (concerning the approval of human drug products under new drug applications (NDAs) or (ANDAs). Bulk Ingredients A drug product may be compounded if the licensed pharmacist or licensed physician if they (A) compounds the drug product using bulk drug substances, as defined in regulations of the Secretary published at section 207.3(a)(4) of title 21 of the Code of Federal Regulations (i) that - comply with the standards of an applicable United States Pharmacopoeia or National Formulary monograph, if a monograph exists, and the United States Pharmacopoeia chapter on pharmacy compounding; OR - if such a monograph does not exist, are drug substances that are components of drugs approved by the Secretary; OR - if such a monograph does not exist and the drug substance is not a component of a drug approved by the Secretary, that appear on a list developed by the Secretary through regulations issued by the Secretary under subsection (d) of this section; AND - that are manufactured by an establishment that is registered under section 360 of this title (including a foreign establishment that is registered under section 360(i) of this title); AND - that are accompanied by valid certificates of analysis for each bulk drug substance. If a facility chooses to register with the FDA, the facility must comply with the following requirements regarding bulk drug substances: - The drug is compounded in an outsourcing facility that does not compound using bulk drug substances unless: (1) the bulk drug substance appears on a list established by the Secretary OR (2) the drug compounded from bulk drug substances appears on the drug shortage list; AND - Where an applicable monograph exists under USP, the National Formulary, or another compendium or pharmacopeia recognized by FDA, the bulk drug substances each comply with the monograph; AND - The bulk drug substances are each manufactured by an establishment recognized under section 510; AND - The bulk drug substances are each accompanied by a valid certificate of analysis. **FDA is currently soliciting nominations for this list. Nominations are due to the FDA no later than 4 March 2014. Ingredients other than Bulk Ingredients **FDA previously published a proposed rule listing bulk drug substances that may be used in pharmacy compounding. FDA intends to reconsider the bulk drug substances that were proposed for inclusion on the list and seek additional nominations and propose. Nominations are due to the FDA no later than 4 March 2014. Compounds the drug product using ingredients (other than bulk drug substances) that comply with the standards of an applicable United States Pharmacopoeia or National Formulary monograph, if a monograph exists, and the United States Pharmacopoeia chapter on pharmacy compounding; The Secretary, in consultation with the United States Pharmacopoeia Convention, shall promulgate regulations identifying drug substances that may be used in compounding under subsection (b)(1)(a)(i)(iii) of this section for which a monograph does not exist or which are not components of drug products approved by the Secretary. The Secretary shall include in the regulation the criteria for such substances, which shall include historical use, reports in peer reviewed medical literature, or other criteria the Secretary may identify. Ingredients must comply with standards of USP or National formulary monograph if such monograph exists, or another compendium or pharmacopeia recognized by FDA. (c) 2014. International Academy of Compounding Pharmacists. All Rights Reserved. Page 1 of 6
Withdrawn or Removed from Market - Do Not Compound List Shall not compound a drug product that appears on a list published by the Secretary in the Federal Register of drug products that have been withdrawn or removed from the "Shall not compound a drug product that appears on a list published by the Secretary in the Federal Register of drug products that have been withdrawn or removed from the market because such drug products or components of such drug products have been found to be unsafe or not effective. **FDA promulgated a Final Rule codified at 21 CFR 216.24, which lists drug products that may not be compounded because they have been withdrawn or removed from the market because the drug products or components of the drug products were found to be unsafe. Until the previously published list is updated, all traditional compounders are expected to follow the list published in 2002. The Secretary has authority to include drugs on a list that cannot be compounded of drugs that have been withdrawn or removed from the market because such drugs or components of such drugs have been found to be unsafe or not effective. Commercially Available Shall not compound regularly or in inordinate amounts (as defined by the Secretary) any drug products that are essentially copies of a commercially available drug product. For purposes of this Section, the term essentially a copy of a commercially available drug product does not include a drug product in which there is a change, made for an identified individual patient, which produces for that patient a significant difference, as determined by the prescribing practitioner, between the compounded drug and the comparable commercially available drug product. The drug shall not be essentially a copy of one or more approved drugs. For this Section, essentially a copy of an approved drug" means -- (A) a drug that is identical or nearly identical to an approved drug, or a marketed drug not subject to section 503B and not subject to approval in an application submitted under section 505, unless, in the case of an approved drug, the drug appears on the drug shortage list in effect under section 506E at the time of compounding, distribution, and dispensing; OR (B) a drug, a component of which is a bulk drug substance that is a component of an approved drug or a marketed drug that is not subject to section 503B and not subject to approval in an application submitted under section 505, unless there is a change that produces for an individual patient a clinical difference, as determined by the prescribing practitioner, between the compounded drug and the comparable approved drug. For this Section, the term "approved drug" means -- a drug that is approved under section 505 and does not appear on the list described in subsection (a)(4) of drugs that have been withdrawn or removed from the market because such drugs or components of such drugs have been found to be unsafe or not effective. (c) 2014. International Academy of Compounding Pharmacists. All Rights Reserved. Page 2 of 6
Demonstrable Difficulties - Do Not Compound List Section 503A - Traditional Compouner A drug product may be compounded only if such drug product is not a drug product identified by the Secretary by regulation as a drug product that presents demonstrable difficulties for compounding that reasonably demonstrate an adverse effect on the safety or effectiveness of that drug product. **This provision is not enforceable until FDA promulgates an implementing regulation. FDA is seeking nominations of "demonstrably difficult" drugs or drug classes for review and evaluation by the Pharmacy Compounding Advisory Committee. The drug can be compounded if it's not identified on a do not compound list by FDA through the regulatory process. The list can include drugs or categories of drugs that present demonstrable difficulties for compounding that are reasonably likely to lead to an adverse effect on the safety or effectiveness of the drug or category of drugs, taking into account the risks and benefits to the patients; OR Is compounded in accordance with all applicable conditions identified on the list by FDA as conditions that are necessary to prevent the drug or category of drugs from presenting demonstrable difficulties. This list must be developed through the regulatory process AND before issuing regulations, FDA must convene and consult an advisory committee on compounding. The advisory committee must include representatives from NABP, USP, the US Pharmacopeia, pharmacists with current experience and expertise in compounding, physicians with background and knowledge in compounding, and patient and public health advocacy organizations. Risk Evaluation and Mitigation Strategy (REMS) Prohibition on Wholesaling No language addresses the compounding of drug products which are currently subject to a REMS program. No language addresses wholesaling within 503A - however, state wholesaling language may be applicable. In the case of a drug that is compounded from a drug that is subject to a risk evaluation and mitigation strategy approved with elements to assure safe use or from a bulk drug substance that is a component of such drug, the outsourcing facility must demonstrate to FDA prior to beginning compounding that such facility will utilize controls comparable to the controls applicable under the relevant REMS. The drug cannot be sold or transferred by an entity other than the outsourcing facility that compounded such drug. This section does not prohibit office use and the administration of a drug in a health care setting or dispensing a drug pursuant to a prescription. (c) 2014. International Academy of Compounding Pharmacists. All Rights Reserved. Page 3 of 6
Labeling No label requirements within 503A. Compounded medications must be labeled with the following: -This is a compounded drug or a reasonable comparable alternative statement; - The name, address, and phone number of the applicable outsourcing facility; - With respect to the drug -- the lot or batch number, the established name of drug, the dosage form and strength, the statement of quantity or volume, the date that the drug was compounded, the expiration date, the storage and handling instructions, the National Drug Code number, the statement not for resale or office Use only where applicable, and a list of active and inactive ingredients identified by established name and the quantity or proportion of each ingredient. - With respect to the container the container from which individual units are removed for dispensing or for administration shall include: a list of active and inactive ingredients, identified by established name and quantity or proportion of each ingredient where there is no space on the label, information to facilitate adverse event reporting, and directions for use, including as appropriate dosage and administration. - In addition, any other information determined necessary by FDA through a regulatory process must be included on the label. Registration Requirements None within 503A. When a facility chooses to register with the FDA, the registration must occur on an annual basis between October 1 and December 31. The facility must register its name, place of business, and unique facility identifier and a point of contact email address. The facility shall indicate whether the outsourcing facility intends to compound a drug that appears on the drug shortages list during the subsequent calendar year. FDA must make this registration information available to the public and post a list on the FDA s website of the name of each facility registered as an outsourcing facility, the State in which each facility is located, whether the facility compounds from bulk drug substances, and whether any such compounding bulk drug substances is for sterile or non-sterile drugs. **FDA recently released proposed guidance regarding 503B registration and is currently soliciting comments. In terms of interim registration, FDA encouraged facilities to use FDA's electronic registration system but since this is a new requirement, FDA is proposing to allow outsourcing facilities that register to register under an alternative interim registration by submitting required information in an email to edrls@fda.hhs.gov. FDA encourages OFs to begin using this alternative method no later than September 30, 2014. *** An OF can currently register without paying a fee until October 1, 2014. (c) 2014. International Academy of Compounding Pharmacists. All Rights Reserved. Page 4 of 6
Reporting Requirements None within 503A. After voluntarily registering with the FDA, the outsourcing facility during June and December of each year must submit a report to FDA. The report must: - Identify the dugs compounded by such outsourcing facility during the previous 6 months; and - For each drug provide the active ingredient, source of active ingredient, the National Drug Code number of the source drug or bulk active ingredient, if available, the strength of the active ingredient per unit, the dosage form and route of administration, the package description, the number of units produced, and the National Drug Code number of the final product, if assigned. Advisory Committee Before issuing regulations to implement subsections on BULK DRUG SUBSTANCES, DO NOT COMPOUND LIST FOR REMOVED OR WITHDRAWN FROM MARKET, or DO NOT COMPOUND LIST FOR DEMONSTRABLY DIFFICULTY, the Secretary shall convene and consult an advisory committee on compounding unless the Secretary determines that the issuance of such regulations before consultation is necessary to protect the public health. The advisory committee shall include representatives from the National Association of Boards of Pharmacy, the United States Pharmacopoeia, pharmacy, physician, and consumer organizations, and other experts selected by the Secretary. ** FDA recently released interim reporting guidance and is soliciting comments. ***In order to encourage facilities to register and report with FDA, if a facility register before June 2, 2014, FDA does NOT intend to immediately enforce the requirement to report product information at the time of initial registration, as long as the facility submits its report within 2 months after the date of that initial registration. The BULK DRUG SUBSTANCES and DEMONSTRABLY DIFFICULT do not compound list must be developed through the regulatory process AND before issuing regulations on DEMONSTRABLY DIFFICULT, FDA must convene and consult an advisory committee on compounding. The advisory committee must include representatives from NABP, USP, the US Pharmacopeia, pharmacists with current experience and expertise in compounding, physicians with background and knowledge in compounding, and patient and public health advocacy organizations. Fees None within 503A. Beginning in 2015 and on an annual basis, outsourcing facilities must pay annual establishment fees as well as reinspection fees. In addition, if an outsourcing facility chooses to continue to practice as a pharmacy, the outsourcing facility is also responsible for all fees owed to the state Boards of Pharmacy. Fee amounts will be published not later than 60 calendar days before the start of each year. Amount of the annual establishment fee will be $15,000 multiplied by the inflation adjustment factor. The amount of any reinspection fee will be equal to $15,000 multiplied by the inflation adjustment factor. Reduced Fee for Small Businesses Number of small business that will pay a reduced amount for the establishment fee will be determined by the Secretary. An outsourcing facility with gross annual sales of $1 million or less in the 12 months ending April 1 of the fiscal year preceding the fiscal year in which fees are due, shall pay 1/3 the amount of the establishment fee for a non-exempt outsourcing facility. (c) 2014. International Academy of Compounding Pharmacists. All Rights Reserved. Page 5 of 6
Shipping Restrictions The drug product must be compounded in a State (i) that has entered into a memorandum of understanding with the Secretary which addresses the distribution of inordinate amounts of compounded drug products interstate and provides for appropriate investigation by a State agency of complaints relating to compounded drug products distributed outside such State; OR (ii) that has not entered into the memorandum of understanding described in clause (i) and the licensed pharmacist, licensed pharmacy, or licensed physician distributes (or causes to be distributed) compounded drug products out of the State in which they are compounded in quantities that do not exceed 5 percent of the total prescription orders dispensed or distributed by such pharmacy or physician. The Secretary shall, in consultation with the National Association of Boards of Pharmacy, develop a standard memorandum of understanding for use by the States. None within 503B For the Administration in a Health Facility - Office Use **FDA is currently drafting the MOU and recently announced that FDA does not intend to enforce the 5% limit on interstate distribution until 90 days after FDA has finalized an MOU and made it available to the States for their consideration and signature. Language within 503A states that a "drug product is compounded for an identified individual patient." No reference to "office use" compounding appears in 503A. An 503B may or may not obtain prescriptions for identified individual patients. Thus, office-use is allowed. (c) 2014. International Academy of Compounding Pharmacists. All Rights Reserved. Page 6 of 6