AAPS Open Pub Date : 2016-07-07 , DOI: 10.1186/s41120-016-0007-0 Adel H. Karara
The statement made by Debra Schotik Chan in 2001 (Chan 2001) regarding the regulations for use of bulk drugs in animals being unclear was probably true until last year. In May 2015 FDA issued a draft guidance on compounding animal drugs from bulk drug substances (Guidance for Industry (Draft) (#230) 2015). The guidance included specific FDA mandated conditions for animal drug compounding for each of: 1) state-licensed pharmacies, 2) licensed veterinarians or 3) outsourcing facilities. Since many pharmacy professionals and pharmaceutical scientists work at outsourcing facilities, this guidance is certainly of importance as it is expected to be finalized in 2016.
The compounding of animal drugs from bulk drug substances results in a new animal drug that must comply with the FD&C Act’s approval and indexing requirements (Steinschneider 2012). FDA has long had a concern regarding the unrestricted compounding of animal drug products as it raises the same concerns as other unapproved animal drugs (Steinschneider 2012). If the compounded drug is for a food-producing animal, it may pose a risk to the animals or humans if unsafe tissue residues should occur or it may be ineffective in the animal (Steinschneider 2012). Also for these products, there is no mandatory reporting to the FDA of adverse events drug experiences (Steinschneider 2012). Additionally, these products may undermine the incentives to develop and submit new animal drug applications to FDA containing data and information to demonstrate that the product is safe, effective, properly manufactured, and accurately labeled (Guidance for Industry (Draft) (#230) 2015).
Although there has been an increase in the number of approved veterinary products on the market, it is still well recognized that extemporaneous drug formulation is essential to provide optimal pharmaceutical care to veterinary patients especially when medications are not available in the desired dosage form. Lack of commercially available products, drug dose adjustment, high cost of finished drug products especially those for certain neoplastic and immune-mediated diseases, ease of administration and flavor compounding to make medication taste better and enhancing compliance are typically the main drivers for veterinary compounding. Under the proposed guidance, FDA does not intend to take action under sections 512(a), 501(a)(5), and 501(a)(2)(B) of the FD&C Act (FD&C Act Chapter V) if an outsourcing facility compounds animal drugs from bulk drug substances in accordance with the defined applicable conditions published in the document (Guidance for Industry (Draft) (#230) 2015).
Key features of the conditions mandated by guidance include (Guidance for Industry (Draft) (#230) 2015):
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When finalized the document will be populated with a list of bulk drug substances (Appendix A of FDA guidance) for use by outsourcing facilities
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The veterinarian’s prescription specifies that the drug is intended to treat the species and condition(s) for which the substance is listed in Appendix A
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The drug is not intended for use in food-producing animals and that it is compounded under cGMP
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Providing FDA with biannual reports on outsourcing activities
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Mandatory reporting to FDA of serious-adverse events
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Adequate labeling of compounded animal drug (Guidance for Industry (Draft) (#230) 2015).
Appendix A of FDA guidance containing the list of bulk drug substance is probably the center piece of this guidance. Public input was sought for nominating bulk drug substances for the list. FDA established a set of criteria that had to be met for a drug candidate to be added to the list. Those criteria included no marketed approved animal drug that can be used as labeled to treat the condition, there is no marketed approved animal or human drug that could be used under section 512(a)(4) or (a)(5) and 21 CFR Part 530 to treat the condition (extralabel use), the drug cannot be compounded from approved animal or human drug, immediate treatment with compounded drug is necessary to avoid animal suffering or death and FDA has not identified a significant safety concern specific to the use of bulk drug substance (Guidance for Industry (Draft) (#230) 2015). Outsourcing facilities seeking to compound animal drug should be registered under section 503B of the FD&C act(Guidance for industry 2014). The compounding facility would need to have a prescription from a veterinarian for an individually identified animal patient or an order from veterinarian for veterinarian office use (Guidance for Industry (Draft) (#230) 2015).
Overall the draft guidance tightens FDA control of compounding animal drugs from bulk drug substances. The new documentation requirements represent added paper work burden on compounding outsourcing facilities, pharmacies and the veterinarian. For the prescribing veterinarian, it will require justification based on clinical evidence in the individually identified animal patient that the compounded drug effect would be different from that of the FDA approved animal or human drug product. That may not be an easy case to make. It is true that if the approved drug dose is too large for the intended animal patient and the dosage form cannot be divided or diluted into the small dose required then that would be a good justification for requiring a compounded drug and expecting a clinical difference from a lower dose (Chan 2001). However, there may be cases where it is difficult to dose the approved formulation in a particular animal. That may be the case especially for cats which are hard to dose in general but also it could be due to the volume of the dose of medication that needs to be smaller, or removing the bitter taste by adding an appealing flavor (Davis 1997). The prescribing veterinarian should provide a statement accompanying the prescription documenting the clinical difference for the individually identified animal patient. Methimazole, a drug commonly used for the treatment of feline hyperthyroidism is available as oral coated tablets. The twice-a-day regimen chronic treatment as might be expected can be difficult for the owners of uncooperative animals which has led to the development of transdermal options for drug administration. Results from several clinical studies have shown that while the transdermal gel is not as effective as the oral dosage from it is still a viable alternative in the treatment of feline hyperthyroidism (Lecuyer et al. 2006; Sartor et al. 2004). This represents an opportunity for compounding pharmacies and outsourcing facilities seeking to satisfy an unmet need for veterinary patients. It should also be noted that compounding facilities that are engaged in compounding sterile preparations have to comply with USP Chapter <797> to minimize contamination risks to patients. One new restriction in the guidance deals with compounded drug products for “office use”. Under the draft guidance every animal prescription to be compounded from bulk drug substance has to correspond to an individually identified animal patient. Limitations on the amount of compounding done in advance of receipt of a prescription were specified. That amount should not exceed the amount of drug product that the state-licensed pharmacy compounded based on a patient-specific prescriptions and the history of receipt of such patient-specific prescriptions for that drug product over any consecutive 14-day period within the previous 6 months (Guidance for Industry (Draft) (#230) 2015). Some veterinary state boards already restrict having compounded drugs from a compounding pharmacy kept at the veterinarian clinic for “office use” (State of the State of Drug compounding on Minnesota). For the compounding pharmacist, documentation is needed that the compounded drug cannot be made from the FDA-approved drug(s). For example, if a manufacturer discontinues a product or a prolong shortage is expected but the specific animal medication need still exist. Other cases may include the pharmacist noting a potential physicochemical incompatibility when the approved product is to be mixed or diluted with other ingredients per the veterinarian prescription. The pharmacy should confirm that compounded drug is not intended for use in food-producing animals by checking that the prescription or accompanying document contains the statement “This patient is not a food-producing animal”. The new guidance will require both the compounding pharmacist and the prescribing veterinarian to engage in more communication/coordination which is to the benefit of the animal patient. It should be noted that many of the conditions set by FDA are standard practice that most compounding facilities would be expected to be observing including good compounding practices, code of ethics (Code of ethics- International Academy of Compounding) and operating in accordance with USP/NF Chapters <795> and <797>.
It is the hope that once populated with bulk drug substances, Appendix A would reflect a comprehensive and diverse list of bulk drug substances from which compounded products can offer therapies that are currently not available to animal patients. Personalized medicine should not be a theme restricted to the human population. Outsourcing facilities serving the compounding needs for the veterinary patient play an important role in providing optimal pharmaceutical care in that special population.
Chan DS (2001) Regulatory issues for the use of bulk drugs in veterinary compounding. IJPC 5(2):97–100
Code of ethics- International Academy of Compounding. http://www.iacprx.org/?6. Accessed 28 Feb 2016
Davis JL (1997) Marketing to veterinarians. IJPC 1(4):236–240
FD&C Act Chapter V: Drugs and Devices http://www.fda.gov/RegulatoryInformation/Legislation/FederalFoodDrugandCosmeticActFDCAct/FDCActChapterVDrugsandDevices/. Accessed 28 Feb 2016
Guidance for Industry (Draft) (#230): “Compounding Animal Drugs from Bulk Drug Substances” May 19, 2015. http://www.fda.gov/ucm/groups/fdagov-public/@fdagov-av-gen/documents/document/ucm446862.pdf. Accessed 28 Feb 2016
Guidance for industry: “Fees for Human Drug Compounding Outsourcing Facilities Under Sections 503B and 744K of the FD& C Act”, November 2014. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM391102.pdf accessed 28 Feb 2016
Lecuyer M, Prini S, Dunn ME, Doucet MY (2006) Clinical efficacy and safety of transdermal methimazole in the treatment of feline hyperthyroidism. Can Vet J 47:131–135
Sartor LL, Trepanier LA, Kroll MM, Rodan I, Challoner L (2004) Efficacy and safety of transdermal methimazole in the treatment of cats with hyperthiodism. J Vet Intern Med 18:651–655
State of the State of Drug compounding on Minnesota. https://mn.gov/boards/assets/Spring%202014%20Newsletter_tcm21-26525.pdf. Accessed 29 Feb 2016
Steinschneider J. Compounding regulatory perspective. Office of surveillance & compliance, FDA, Center for veterinary medicine. USP Veterinary Drugs Stakeholder Forum November 9, 2012. http://www.usp.org/sites/default/files/events/stakeholder_forums/2012/meeting-1/6a-animal-drug-compounding-fda-perspective-2012-11-09.pdf. Accessed 28 Feb 2016
The author declares that he has no competing interests.
Affiliations
Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland Eastern Shore, 11868 Academic Oval, Princess Anne, MD, 21853, USA
Adel H. Karara
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Cite this article
Karara, A.H. FDA draft guidance on compounding animal drugs from bulk drug substances: a commentary. AAPS Open 2, 5 (2016). https://doi.org/10.1186/s41120-016-0007-0
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Keywords
- Drug Product
- Compounded Drug
- Mandatory Reporting
- Draft Guidance
- Human Drug
中文翻译：
FDA关于从原料药中混合动物药物的指南草案：评论
Chan Debra Schotik Chan在2001年（Chan 2001）发表的关于在动物中使用散装药物的法规尚不明确的声明可能直到去年才是正确的。FDA在2015年5月发布了关于从原料药中混合动物药物的指南草案（《工业指导（草案）（2015年第230号））》。该指南包括FDA规定的以下每种动物药配混的特定条件：1）国家许可的药房，2）许可的兽医或3）外包设施。由于许多药房专业人员和药房科学家在外包机构工作，因此该指南无疑很重要，因为该指南有望在2016年完成。
将动物药与原料药混合制成一种新的动物药，必须符合FD＆C法案的批准和索引要求（Steinschneider 2012）。FDA长期以来一直对动物药产品的无限制配混感到担忧，因为它引起了与其他未经批准的动物药相同的担忧（Steinschneider 2012）。如果该复合药物是用于生产食物的动物，则如果会出现不安全的组织残留物或对动物无效，可能会对动物或人类构成危险（Steinschneider 2012）。对于这些产品，也没有向FDA强制报告不良事件药物经历（Steinschneider 2012）。此外，这些产品可能会破坏开发和向FDA提交新的动物药品申请的动机，其中包含的数据和信息证明该产品是安全，有效，正确制造和准确标记的（工业指导（草案）（＃230）2015年））。
尽管市场上批准的兽药产品的数量有所增加，但仍众所周知，即期药物制剂对于为兽药患者提供最佳的药物护理至关重要，尤其是在无法以所需剂型获得药物时。缺乏市场上可买到的产品，调整药物剂量，制成品的高成本（尤其是某些肿瘤和免疫介导疾病的产品），易于给药和添加调味剂以使药物的口感更好并增强依从性通常是兽药配制的主要驱动力。根据建议的指南，FDA并不打算根据《 FD＆C法案》（FD＆C法案第V章，第512（a），501（a）（5）和501（a）（2）（B）节采取行动。）如果外包设施根据文件中规定的适用条件（《工业指导（草案）（＃230）2015）》将原料药中的动物药与动物药进行了复合。
指南规定的条件的主要特征包括（工业指导（草案）（＃230）2015）：
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最终确定后，该文件将填充供外包设施使用的原料药清单（FDA指南附录A）
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兽医处方规定，该药物旨在治疗该物质在附录A中列出的物种和状况。
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该药物不适用于食用动物，并且根据cGMP配制
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向FDA提供有关外包活动的半年度报告
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强制向FDA报告严重不良事件
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适当标记复合动物药物（工业指导（草案）（＃230）2015）。
包含大宗药物清单的FDA指南附录A可能是该指南的中心部分。寻求公众意见提名该清单中的原料药。FDA建立了一套标准，必须将候选药物添加到列表中。这些标准包括没有上市的可批准用于治疗疾病的批准的动物药品，没有上市的根据第512（a）（4）或（a）（5）和21条使用的批准的动物或人类药物。 CFR第530部分，用于治疗该疾病（标签外使用），该药物不能与获批准的动物或人类药物混合使用，必须立即用复合药物进行治疗以避免动物遭受痛苦或死亡，并且FDA尚未针对该用途确定严重的安全隐患原料药的生产（工业指导（草案）（＃230）2015）。寻求复合动物药的外包设施应根据FD＆C法案（2014年工业指南）第503B条进行注册。复合设施需要向兽医开具针对个体识别的动物患者的处方，或从兽医开具用于兽医办公室的订单（工业指导（草案）（＃230）2015）。
总体而言，指南草案加强了FDA对从原料药中混合动物药物的控制。新的文件要求代表了复合外包设施，药房和兽医增加的书面工作负担。对于开处方的兽医，将需要根据个体识别的动物患者的临床证据证明其复合药物作用与FDA批准的动物或人类药物产品不同。这可能不容易做到。的确，如果对于目标动物患者而言，批准的药物剂量过大，并且无法将剂型划分或稀释为所需的小剂量，那么这是需要复合药物并期望与药物的临床差异的充分理由。较低的剂量（Chan 2001）。但是，在某些情况下，可能难以在特定动物中给药批准的制剂。特别是对于一般难以配药的猫来说可能是这种情况，但这也可能是由于所需药量较小，或者是通过添加吸引人的味道来消除苦味而引起的（Davis 1997）。开处方的兽医应在处方后提供说明，以证明针对个体识别的动物患者的临床差异。甲硫咪唑是常用于治疗猫甲状腺功能亢进的药物，可以口服包衣片的形式获得。对于不合作的动物的主人来说，一天两次的长期治疗可能很难做到，这导致了透皮药物选择的发展。多项临床研究的结果表明，尽管透皮凝胶的效果不如口服剂量有效，但在治疗猫甲状腺功能亢进症方面仍然是可行的选择（Lecuyer等，2006； Sartor等，2004）。）。这为寻求满足兽医患者未满足需求的药房和外包设施提供了机会。还应注意，用于配制无菌制剂的配制设备必须符合USP <797>章的规定，以最大程度地降低对患者的污染风险。该指南中的一项新限制涉及用于“办公用途”的复合药品。在指导草案中，要从原料药中调配的每只动物处方都必须与个体识别的动物患者相对应。规定了在收到处方之前要进行的混合量的限制。2015）。一些兽医局已经限制在兽医诊所为“办公室使用”而从混合药店购买混合药物（明尼苏达州混合药物州））。对于混合药剂师，需要证明不能从FDA批准的药物中制成混合药物。例如，如果制造商停产产品或预期长期短缺，但仍需要特定的动物药物。其他情况可能包括药剂师在按照兽医处方将批准的产品与其他成分混合或稀释时注意到潜在的物理化学不相容性。药房应通过检查处方或随附文件是否包含“该患者不是食用动物”的声明，来确认该复合药物不打算用于食用动物。新指南将要求配混药剂师和开处方的兽医都进行更多的交流/协调，这对动物患者有利。应当注意，FDA设定的许多条件是标准惯例，大多数复合设施都应遵守，包括良好的复合惯例，道德规范（道德规范-国际复合材料研究院（International Academy of Compounding），并根据USP / NF第<795>和<797>章进行操作。
希望附录A一旦填充了散装原料药，便会反映出散装原料药的全面而多样的清单，复合产品可以从这些清单中提供动物患者目前无法获得的疗法。个性化医学不应成为仅限于人群的主题。满足兽医患者复合需求的外包设施在为特殊人群提供最佳药物护理方面发挥着重要作用。
Chan DS（2001）兽药配合中使用散装药品的管理问题。IJPC 5（2）：97-100
道德规范-国际复合学会。http://www.iacprx.org/?6。2016年2月28日访问
Davis JL（1997）面向兽医的营销。IJPC 1（4）：236–240
FD＆C法案第五章：药品和器械http://www.fda.gov/RegulatoryInformation/Legislation/FederalFoodDrugandCosmeticActFDCAct/FDCActChapterVDrugsandDevices/。2016年2月28日访问
工业指南（草案）（＃230）：“从散装毒品物质中提取兽药”，2015年5月19日。http://www.fda.gov/ucm/groups/fdagov-public/@fdagov-av-gen/ document / document / ucm446862.pdf。2016年2月28日访问
行业指南：“ FD＆C法案第503B和744K条规定的人用药品复合外包设施的费用”，2014年11月。http: //www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM391102.pdf已获得28 2016年2月
Lecuyer M，Prini S，Dunn ME，Doucet MY（2006）经皮甲巯咪唑治疗猫甲亢的临床疗效和安全性。可以投票J 47：131–135
Sartor LL，Trepanier LA，Kroll MM，Rodan I，Challoner L（2004）透皮甲巯咪唑在猫高硫血症猫中的疗效和安全性。兽医医学杂志18：651–655
明尼苏达州的毒品复合州。https://mn.gov/boards/assets/Spring%202014%20Newsletter_tcm21-26525.pdf。2016年2月29日访问
Steinschneider J.复合监管观点。FDA监督与合规办公室，兽药中心。USP兽药利益相关者论坛2012年11月9日。http://www.usp.org/sites/default/files/events/stakeholder_forums/2012/meeting-1/6a-animal-drug-compounding-fda-perspective-2012- 11-09.pdf。2016年2月28日访问
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马里兰大学东海岸药学院药学院药物科学系，11868学术椭圆，安妮公主，医学博士，21853，美国
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AH，Karara，美国食品和药品管理局（FDA）关于从原料药中混合动物药物的指南草案：评论。AAPS 第2、5（2016）期。https://doi.org/10.1186/s41120-016-0007-0
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关键词
- 药品
- 复合药物
- 强制性报告
- 指导草案
- 人用药物
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