Monday, June 11, 2012

FDA Field Guidance: Detention Without Physical Examination of Heparin and Related Products for Current Good Manufacturing Practices

In April 2012, the FDA issued the following field guidance:
 
Import Alert Name:
Detention Without Physical Examination of Different Forms of Heparin and Heparin- 
Related Products for CGMP Issues

Reason for Alert:
Heparin is a widely used anti-coagulant and is commonly used during surgical procedures and for those undergoing dialysis. There are an estimated 12 million Americans that use heparin each year. In 2008, a number of deaths in the United States were associated with either contaminated or adulterated heparin. The adverse events have included allergic or hypersensitivity-type reactions, with symptoms such as low blood pressure, angioedema, shortness of breath, nausea, diarrhea, and abdominal pain. 

The vast majority of crude heparin, heparin intermediates, and heparin API used in finished drug product in the United States is imported from other countries. The phrase "different forms of heparin and heparin-related products" is used for brevity to refer to articles such as crude heparin, heparin intermediates, heparin active pharmaceutical ingredient (API), heparin products, and heparin-containing products. 

As part of FDA's activities intended to protect the health and safety of U.S. consumers, FDA often conducts inspections of foreign establishments that produce FDA-regulated articles intended for use in the United States. One basis for detention without physical examination is that the firm's quality system is inadequate for the prevention of contamination or otherwise does not conform to CGMP. Heparin contaminated with oversulfated chondroitin sulfate (OSCS) clearly indicates that the "methods used in" or the "controls used for" the "manufacture, processing, packing, or holding do not conform to or are not operated or administered in conformity" with CGMP. OSCS is not part of the manufacturing process for heparin and its presence suggests that somewhere in the supply chain OSCS has been added intentionally to heparin for financial reasons because it is a very cheap material prepared by a simple synthetic process. In addition, it mimics certain heparin properties so that it would pass then current United States Pharmacopeia (USP) specifications for Heparin Sodium USP. (The USP has since revised in 2009 its monograph for Heparin Sodium USP to incorporate tests that can detect the presence of OSCS). 

Manufacturers must have adequate traceability, qualification, and testing systems in place in order to satisfy applicable CGMP requirements. Where there is an inspection that identifies an inadequate system in this regard, the firm's drug(s) or other products appear to be adulterated and are subject to imports refusal per 801(a)(3). 

Furthermore, if the firm appears to have been responsible for introducing contaminated forms of heparin or heparin-related products into the supply chain, then there is an appearance that the firm's quality system is inadequate or otherwise does not conform to CGMP. If the firm demonstrates that they have appropriate controls in place, the firm's drugs or other products may no longer appear to be adulterated. 

The attachment to this alert identifies firms for which we have information indicating that the different forms of heparin or heparin-related products appear to be adulterated for one of the reasons described above. It appears per 801(a) that the methods used in and controls used for the manufacture, processing, packing, or holding of the drugs or other products from the firms listed in the attachment do not appear to conform to current good manufacturing practices within the meaning of Section 501(a)(2)(B); therefore such articles are subject to refusal of admission into the United States.

Guidance:
Districts may detain without physical examination all forms of heparin and heparin-related products from the firm(s) identified on the attachment to this import alert. 

Since the article appears to be adulterated due to inadequate GMPs and is subject to Refusal of Admission per Section 801(a)(3) of the Act, FDA considers reconditioning or submission of analytical results to be insufficient to overcome the appearance of the violation. Drugs and other products offered for importation from the firm(s) listed on the attachment to this import alert are subject to detention without physical examination until FDA is satisfied that the appearance of a violation has been removed, either by inspection, reinspection, submission of documentation, and/or other actions requested by the FDA. 

Firms may provide copies of inspection reports for inspections performed by third parties to assist FDA in prioritizing inspection requests. An establishment wishing to schedule an FDA inspection or to provide a copy of an inspection report conducted by a third party, should do so by submitting a request or documentation to the following address: 

Food and Drug Administration 
Division of Import Operations and Policy (HFC-170) 
12420 Parklawn Drive, ELEM-3109 
Rockville, MD 20857 

Or via email: Importalerts2@fda.hhs.gov

Product Description:
Different Forms of Heparin and Heparin-Related Products (e.g., Crude Heparin, Heparin Intermediates, Heparin Active Pharmaceutical Ingredient (API), Heparin Products, and Heparin-Containing Products) from the firms listed below. 

PROBLEM: Good Manufacturing Practices

Charge:
"The article is subject to refusal of admission pursuant to Section 801(a)(3) in that the methods used in and controls used for the manufacture, processing, packing, or holding of drugs and other products do not appear to conform to current good manufacturing practices within the meaning of Section 501(a)(2)(B)." 

OASIS Charge Code: DRUG GMPs

 


 

 


 

The Following companies are subject to this guidance:
CHINA
Casing Factory Jintan City
Date Published : 02/22/2012

7 Bei Huan West Road , Jin Chen , Jintan City, CHINA
55 R - - -- Pharm Nec (Mfr)
Date Published: 02/22/2012

Desc:Heparin and Heparin-related products 
Notes:Aliases;Jintan Yongmao Casing Co. LtdJintan Caliber Casing Co. Ltd
61 L - - -- A-Coagulant
Date Published: 02/22/2012

Desc:Heparin and Heparin-related products 
Notes:Aliases; Jintan Yongmao Casing Co. Ltd Jintan Caliber Casing Co. Ltd

Changsha Wulipai Food Stuff Factory
Date Published : 02/22/2012

"No 8 Bayi Road , Changsha, , Hunan, CHINA
55 R - - -- Pharm Nec (Mfr)
Date Published: 02/22/2012

Desc:Heparin and Heparin-related products
61 L - - -- A-Coagulant
Date Published: 02/22/2012

Desc:Heparin and Heparin-related products

Changzhou SPL Company, Ltd.
Date Published : 02/22/2012

3 Changhong West Rd., , Hutang Township, Wujin City , Changzhou, Jiangsu Province CHINA
55 R - - -- Pharm Nec (Mfr)
Date Published: 02/22/2012

Desc:Heparin and Heparin-related products
61 L - - -- A-Coagulant
Date Published: 02/22/2012

Desc:Heparin and Heparin-related products

Chongqing Baijie Changhong Casing Co., Ltd
Date Published : 04/04/2012

Baijie, , Chongqing, CHINA
55 R - - 75 Crude Heparin (Pharmaceutic Necessity)
Date Published: 04/04/2012

Desc:Heparin and Heparin-Related Products
55 R - - 99 Pharmaceutic Necessities, N.E.C.
Date Published: 04/04/2012

Desc:Heparin and Heparin-Related Products
61 L - - 08 Heparin Sodium (Anti-Coagulant)
Date Published: 04/04/2012

Desc:Heparin and Heparin-Related Products
61 L - - 22 Anti-Coagulant Heparin Sol
Date Published: 04/04/2012

Desc:Heparin and Heparin-Related Products
61 L - - 26 Ardeparin Sodium (Anti-Coagulant)
Date Published: 04/04/2012

Desc:Heparin and Heparin-Related Products
61 L - - 27 Dalteparin Sodium (Anti-Coagulant)
Date Published: 04/04/2012

Desc:Heparin and Heparin-Related Products
61 L - - 29 Enoxaparin Sodium (Anti-Coagulant)
Date Published: 04/04/2012

Desc:Heparin and Heparin-Related Products
61 L - - 30 Heparin Calcium (Anti-Coagulant)
Date Published: 04/04/2012

Desc:Heparin and Heparin-Related Products
61 L - - 35 Tinzaparin Sodium (Anti-Coagulant)
Date Published: 04/04/2012

Desc:Heparin and Heparin-Related Products
61 L - - 99 Anti-Coagulant, N.E.C.
Date Published: 04/04/2012

Desc:Heparin and Heparin-Related Products
74 L - - IS Heparin Coating Chemicals
Date Published: 04/04/2012

Desc:Heparin and Heparin-Related Products

Chongqing Imperial Bio Chem Co
Date Published : 02/22/2012

5 Yanghe Sancun , 19-7 Citic Bank Building, Jiangbei Dist. , Chongqing, CHINA
55 R - - -- Pharm Nec (Mfr)
Date Published: 02/22/2012

Desc:Heparin and Heparin-related products
61 L - - -- A-Coagulant
Date Published: 02/22/2012

Desc:Heparin and Heparin-related products

Chongqing Paiquiang Agribyproduct Co., Ltd
Date Published : 02/22/2012

158 Gonglongpo , Yudong , Chongqing, CHINA
55 R - - -- Pharm Nec (Mfr)
Date Published: 02/22/2012

Desc:Heparin and Heparin-related products
61 L - - -- A-Coagulant
Date Published: 02/22/2012

Desc:Heparin and Heparin-related products

HEILONGJIANG YUANGUANG CASING CO., LTD.
Date Published : 02/22/2012

7 Bohai Rd., Jizhong District , Haping Rd. Develop. District , Harbin, CN-23 CHINA
55 R - - -- Pharm Nec (Mfr)
Date Published: 02/22/2012

Desc:Heparin and Heparin-related products 
Notes:Alias;Heilongjiang Yuanguang Caliber Casing Co.; LtdAlternate Address;No.7 Bohai East Road;Jizhong District HeilongjiangChina
61 L - - -- A-Coagulant
Date Published: 02/22/2012

Desc:Heparin and Heparin-related products 
Notes:Alias; Heilongjiang Yuanguang Caliber Casing Co.; Ltd Alternate Address; No.7 Bohai East Road; Jizhong District Heilongjiang China

Henan Zhengping Huixin
Date Published : 02/22/2012

Fuzhuang Yangying Town , "Zhengping, , Henan, CHINA
55 R - - -- Pharm Nec (Mfr)
Date Published: 02/22/2012

Desc:Heparin and Heparin-related products 
Notes:Aliases;Henan Zhengping Huixin
61 L - - -- A-Coagulant
Date Published: 02/22/2012

Desc:Heparin and Heparin-related products 
Notes:Aliases; Henan Zhengping Huixin

Hubei Anlu Food Stuff Factory
Date Published : 02/22/2012

Xinli Village, Zhuzhan Town , Xiaogan City, , Hubei, CHINA
55 R - - -- Pharm Nec (Mfr)
Date Published: 02/22/2012

Desc:Heparin and Heparin-related products
61 K - - -- A-Cholinergic
Date Published: 02/22/2012

Desc:Heparin and Heparin-related products

Jiangsu Long Life Group
Date Published : 02/22/2012

No. 216 Renshou Rd. , Rucheng Town, Rugao, , Jiangsu, CHINA
55 R - - -- Pharm Nec (Mfr)
Date Published: 02/22/2012

Desc:Heparin and Heparin-related products
61 L - - -- A-Coagulant
Date Published: 02/22/2012

Desc:Heparin and Heparin-related products

Junan Hengxing Foodstuff Co., Ltd
Date Published : 02/22/2012

No. 126 Meishan Rd , Ju'nan County, , Shandong, CHINA
55 R - - -- Pharm Nec (Mfr)
Date Published: 02/22/2012

Desc:Heparin and Heparin-related products
61 L - - -- A-Coagulant
Date Published: 02/22/2012

Desc:Heparin and Heparin-related products

Nanjing Maohai Biotech Co.
Date Published : 02/22/2012

8 Developing Zone , Yaxi Town, Gaochun County , Nanjing, Jiangsu Province, CHINA
55 R - - -- Pharm Nec (Mfr)
Date Published: 02/22/2012

Desc:Heparin and Heparin-related products
61 L - - -- A-Coagulant
Date Published: 02/22/2012

Desc:Heparin and Heparin-related products

Nantong Jianhua Casing Co. Ltd
Date Published : 02/22/2012

Linjiang Village/Langshan Town, , Nantong, , Jiangsu , CHINA
55 R - - -- Pharm Nec (Mfr)
Date Published: 02/22/2012

Desc:Heparin and Heparin-related products
61 L - - -- A-Coagulant
Date Published: 02/22/2012

Desc:Heparin and Heparin-related products

Qingdao Hualu Foods Co., Ltd
Date Published : 02/22/2012

Industrial Park of Jiaodong Town , Jiaozhou, , Qingdao, CHINA
55 Q - - -- Pharm Nec (Mfr)
Date Published: 02/22/2012

Desc:Heparin and Heparin-related products
61 L - - -- A-Coagulant
Date Published: 02/22/2012

Desc:Heparin and Heparin-related products

Shandong Union Food Stuff Qingzhou Branch*
Date Published : 02/22/2012

Mojiacun Subu Town , Qingzhou, , Shandong, CHINA
55 R - - -- Pharm Nec (Mfr)
Date Published: 02/22/2012

Desc:Heparin and Heparin-related products 
Notes:Aliases;Qingzhou United
61 L - - -- A-Coagulant
Date Published: 02/22/2012

Desc:Heparin and Heparin-related products 
Notes:Aliases; Qingzhou United

Shanghai Biochemial And Pharmaceutical Co Ltd
Date Published : 02/22/2012

Room A403, No. 494 Zhongxing Road , Shanghai, CHINA
55 R - - -- Pharm Nec (Mfr)
Date Published: 02/22/2012

Desc:Heparin and Heparin-related products
61 L - - -- A-Coagulant
Date Published: 02/22/2012

Desc:Heparin and Heparin-related products

Shanghai No. 1 Biochemical & Pharmaceutical Co., Ltd.
Date Published : 02/22/2012

387 Shangqui Road , Shanghai, CHINA
55 R - - -- Pharm Nec (Mfr)
Date Published: 02/22/2012

Desc:Heparin and Heparin-related products
61 L - - -- A-Coagulant
Date Published: 02/22/2012

Desc:Heparin and Heparin-related products

Shanghai No. 1 Biochemical & Pharmaceutical Co., Ltd.
Date Published : 02/22/2012

1317 Jianchuan Road, , Minhang District , Shanghai, CHINA
55 R - - -- Pharm Nec (Mfr)
Date Published: 02/22/2012

Desc:Heparin and Heparin-related products
61 L - - -- A-Coagulant
Date Published: 02/22/2012

Desc:Heparin and Heparin-related products

Sichuan Shuangliu Food Stuff Factory
Date Published : 02/22/2012

61 Wujiaba Nort Street , Shuangliu, , Sichuan, CHINA
55 R - - -- Pharm Nec (Mfr)
Date Published: 02/22/2012

Desc:Heparin and Heparin-related products
61 L - - -- A-Coagulant
Date Published: 02/22/2012

Desc:Heparin and Heparin-related products

Sichuan Zhongjiang Xiongjian Casing Co.
Date Published : 04/04/2012

"Kanjiang, , Zhongjiang, , Sichuan, CHINA
55 R - - 75 Crude Heparin (Pharmaceutic Necessity)
Date Published: 04/04/2012

Desc:Heparin and Heparin-Related Products
55 R - - 99 Pharmaceutic Necessities, N.E.C.
Date Published: 04/04/2012

Desc:Heparin and Heparin-Related Products
61 L - - 08 Heparin Sodium (Anti-Coagulant)
Date Published: 04/04/2012

Desc:Heparin and Heparin-Related Products
61 L - - 22 Anti-Coagulant Heparin Sol
Date Published: 04/04/2012

Desc:Heparin and Heparin-Related Products
61 L - - 26 Ardeparin Sodium (Anti-Coagulant)
Date Published: 04/04/2012

Desc:Heparin and Heparin-Related Products
61 L - - 27 Dalteparin Sodium (Anti-Coagulant)
Date Published: 04/04/2012

Desc:Heparin and Heparin-Related Products
61 L - - 29 Enoxaparin Sodium (Anti-Coagulant)
Date Published: 04/04/2012

Desc:Heparin and Heparin-Related Products
61 L - - 30 Heparin Calcium (Anti-Coagulant)
Date Published: 04/04/2012

Desc:Heparin and Heparin-Related Products
61 L - - 35 Tinzaparin Sodium (Anti-Coagulant)
Date Published: 04/04/2012

Desc:Heparin and Heparin-Related Products
61 L - - 99 Anti-Coagulant, N.E.C.
Date Published: 04/04/2012

Desc:Heparin and Heparin-Related Products
74 L - - IS Heparin Coating Chemicals
Date Published: 04/04/2012

Desc:Heparin and Heparin-Related Products

Weifang Legang Food Ltd.
Date Published : 02/22/2012

No. 1 Honghe Street , Honghe Town, Changle County , Weifang , Shandong, CHINA
55 R - - -- Pharm Nec (Mfr)
Date Published: 02/22/2012

Desc:Heparin and Heparin-related products
61 L - - -- A-Coagulant
Date Published: 02/22/2012

Desc:Heparin and Heparin-related products

Xinjiang Lanshanbinggong Food Factory
Date Published : 02/22/2012

No31 QinjianRoad , Gumudi Town, Miquan City, , Xinjiang, CHINA
55 R - - -- Pharm Nec (Mfr)
Date Published: 02/22/2012

Desc:Heparin and Heparin-related products
61 L - - -- A-Coagulant
Date Published: 02/22/2012

Desc:Heparin and Heparin-related products

Xuzhou City Mianshang Fengxian Shengda Casing Factory
Date Published : 02/22/2012

Zhangshicheng Village , Zhaozhuang Town , Xuzhou, Jiangsu, CHINA
55 R - - -- Pharm Nec (Mfr)
Date Published: 02/22/2012

Desc:Heparin and Heparin-related products
61 L - - -- A-Coagulant
Date Published: 02/22/2012

Desc:Heparin and Heparin-related products

Zhejiang Casing Animal By-Products Co.,Ltd.
Date Published : 02/22/2012

369 Dong Xing Road , Tonglu Economic Developing District , Hangzhou, Zhejiang Province CN-33 CHINA
55 R - - -- Pharm Nec (Mfr)
Date Published: 02/22/2012

Desc:Heparin and Heparin-related products
61 L - - -- A-Coagulant
Date Published: 02/22/2012

Desc:Heparin and Heparin-related products

Zhengzhou Yuanlong Casing Co., Ltd
Date Published : 04/04/2012

"Renmin Road, , Zhengzhou, , Henan, CHINA
55 R - - 75 Crude Heparin (Pharmaceutic Necessity)
Date Published: 04/04/2012

Desc:Heparin and Heparin-Related Products
55 R - - 99 Pharmaceutic Necessities, N.E.C.
Date Published: 04/04/2012

Desc:Heparin and Heparin-Related Products
61 L - - 08 Heparin Sodium (Anti-Coagulant)
Date Published: 04/04/2012

Desc:Heparin and Heparin-Related Products
61 L - - 22 Anti-Coagulant Heparin Sol
Date Published: 04/04/2012

Desc:Heparin and Heparin-Related Products
61 L - - 26 Ardeparin Sodium (Anti-Coagulant)
Date Published: 04/04/2012

Desc:Heparin and Heparin-Related Products
61 L - - 27 Dalteparin Sodium (Anti-Coagulant)
Date Published: 04/04/2012

Desc:Heparin and Heparin-Related Products
61 L - - 29 Enoxaparin Sodium (Anti-Coagulant)
Date Published: 04/04/2012

Desc:Heparin and Heparin-Related Products
61 L - - 30 Heparin Calcium (Anti-Coagulant)
Date Published: 04/04/2012

Desc:Heparin and Heparin-Related Products
61 L - - 35 Tinzaparin Sodium (Anti-Coagulant)
Date Published: 04/04/2012

Desc:Heparin and Heparin-Related Products
61 L - - 99 Anti-Coagulant, N.E.C.
Date Published: 04/04/2012

Desc:Heparin and Heparin-Related Products
74 L - - IS Heparin Coating Chemicals
Date Published: 04/04/2012

Desc:Heparin and Heparin-Related Products

To view entire guidance, click here.
 
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Agreement Between FDA and China

FDA - SFDA

Agreement between
the Department of Health and Human Services
of the United States of America
and the State Food and Drug Administration
of the People's Republic of China on
the Safety of Drugs and Medical Devices

The Department of Health and Human Services (“HHS”) of the United States of America ("United States") and the State Food and Drug Administration ("SFDA") of the People’s Republic of China ("China") (hereinafter referred to together as "the Parties"):
Understanding the mutual benefits of protecting the public health through improved cooperation between the Parties with regard to monitoring and regulating the safety of drugs and medical devices;
Desiring to work together to better ensure the safety and quality of Drugs, Excipients, and Medical Devices; and
Recognizing that such cooperation can improve the health of the citizens of both the United States and China and enhance confidence in the regulation of Drugs, Excipients, and Medical Devices in both countries;
Have agreed as follows:
Article I    Purpose
The purpose of this Agreement is to establish methods of cooperation between the Parties that will provide the Food and Drug Administration within HHS (“HHS/FDA”) with additional information about products exported from the customs territory of China to the United States, provide SFDA with increased sharing of information about products exported from the United States to China, and encourage further regulatory cooperation between the Parties regarding Drug and Medical Device regulation.
Article II    General Principles
  1. The Parties shall engage in regulatory cooperation regarding the export of Drugs, Excipients, and Medical Devices from the customs territory of China to the United States and Drugs, Excipients, and Medical Devices produced in the United States and exported to the customs territory of China as set out in Article VI and as further defined in Work Plans to be agreed upon by the Parties.
  2. The Parties shall engage in information-sharing to improve their mutual understanding of, and to gain greater confidence in, each Party’s regulatory system as set out in Article V and as further defined in Work Plans to be agreed upon by  the Parties.  As specified in Article V, each Party shall share relevant information with the other Party, including on relevant laws, regulations, areas of jurisdiction, and public health and safety.
  3. The Parties shall engage in regulatory cooperation regarding improving the authenticity, quality, safety, and effectiveness of Drugs, Excipients, and Medical Devices as set out in Articles IV and VI and as further defined in Work Plans to be agreed upon by the Parties. 
The Parties shall commit to annual meetings between senior Agency leaders to discuss and evaluate progress under this Agreement, among other things.
For purposes of this Agreement the following definitions shall apply:
  1. "API" or "Active Pharmaceutical Ingredient" means any substance or mixture of substances intended to be used in the manufacture of a drug (medicinal) product and that, when used in the production of a drug, becomes an active ingredient of the drug product.  Such substances are intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure and function of the body.  
  2. "Counterfeit Drugs and Medical Devices" means a product that is deliberately and fraudulently mislabeled with respect to identity and/or source.  Counterfeiting can apply to branded and generic products and may include products with correct ingredients, with wrong ingredients, without active ingredients, with incorrect quantity of active ingredient, or with fake packaging.
  3. "Designated Drugs and Designated Medical Devices" means a Drug (including APIs) and Excipients or Medical Device, respectively, designated for inclusion in each phase of implementation, based on criteria established in Article IV. A.
  4. "Drug" means any material commonly used for human pharmaceutical use.  The term includes the following materials:
    1. Finished-dosage forms (including both over-the-counter ("OTC") and prescription drugs);
    2. Drug substance, or active pharmaceutical ingredients ("APIs");
    3. Biologic drugs (e.g., vaccines and monoclonal antibodies); and
    4. Products taken by mouth intended to supplement the diet that:
      1. bear or  contain one or more of the following dietary ingredients: a vitamin; a mineral; an herb or other botanical; an amino acid; a dietary substance for use in humans to supplement the diet by increasing the total dietary intake; ora concentrate, metabolite, constituent, extract or combination of any of the above; and
      2. meet any one of the following characteristics:
            - are not clearly labeled as dietary supplements; or
            - contain claims to diagnose, cure, mitigate, treat, or prevent disease; or
            - contain substances that are regulated by HHS/FDA as APIs.

To read the rest of the agreement, click here.
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Independent Laboratory Testing Demonstrates Important Quality Differences Between FDA-Approved Makena® and Compounded 17P Formulations

Independent Laboratory Testing Demonstrates Important Quality Differences Between FDA-Approved Makena® and Compounded 17P Formulations

 
 

FDA Issues Statement on Makena® on November 8, 2011

ST. LOUIS, Nov. 8, 2011 /PRNewswire/ -- Recent testing conducted by independent laboratories, commissioned by Ther-Rx Corporation, a subsidiary of K-V Pharmaceutical Company (the "Company") (NYSE: KV.A/KV.B), shows that multiple samples of both compounded 17P drug formulations and active pharmaceutical ingredient (API) that may be used in compounded 17P failed to meet certain established standards for potency and purity. These findings, which have been submitted to the U.S. Food and Drug Administration (FDA), demonstrate important quality differences in these compounded 17P formulations when compared to FDA-approved Makena® (hydroxyprogesterone caproate injection).
"We commissioned this research because moms and healthcare providers deserve to know whether medications prescribed during pregnancy meet FDA's quality standards," said Greg Divis, President and CEO of K-V Pharmaceutical Company. "This research demonstrates important differences in product quality between FDA-approved Makena® and these compounded 17P formulations. Healthcare providers and patients have no practical way of ensuring that compounded 17P formulations meet FDA's quality standards. Now that FDA-approved Makena® is available, America's high-risk moms deserve a product that consistently meets FDA's standards."
On Nov. 8, 2011, the FDA issued a statement on Makena® acknowledging it has received information from the Company regarding the potency and purity of samples of bulk hydroxyprogesterone caproate APIs and compounded hydroxyprogesterone caproate products. FDA stated, "According to the analysis of this information provided by K-V, there is variability in the purity and potency of both the bulk APIs and compounded hydroxyprogesterone caproate products that were tested." The agency has begun its own sampling and analysis of compounded hydroxyprogesterone products and the bulk APIs used to make them. In FDA's statement, the agency "reminds healthcare providers and patients that before approving the Makena® new drug application, FDA reviewed manufacturing information, such as the source of the API used by the manufacturer, proposed manufacturing processes and the firm's adherence to current good manufacturing practice. Therefore, as with other approved drugs, greater assurance of safety and effectiveness is generally provided by the approved product than by a compounded product."  
The full text of the FDA statement is available athttp://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm279098.htm
Overview of Research
The active pharmaceutical ingredient in FDA-approved Makena®, hydroxyprogesterone caproate, is sourced exclusively from the same FDA-registered and FDA-inspected manufacturer that supplied the API used in the NICHD study that served as part of the basis for FDA approval of Makena®. To the Company's knowledge, this is the only manufacturer of hydroxyprogesterone caproate known to have an active Drug Master File with the FDA.  
Research commissioned by Ther-Rx shows that the API used in compounded 17P formulations originates primarily from facilities in China that are neither registered with nor inspected by the FDA. This research also found that the vast majority of entities claiming to be original manufacturers of hydroxyprogesterone caproate are actually re-packagers, re-sellers, brokers or distributors of hydroxyprogesterone caproate that is actually manufactured in China.
The Company also commissioned independent laboratory testing to assess samples of API and compounded 17P formulations and, as such, does not purport to assess the quality of all of the various compounded 17P formulations and hydroxyprogesterone caproate API available on the market. Specifically, the laboratory testing included:
  • 10 samples of API used in compounded 17P formulations provided by 10 different suppliers of API. Seven of the suppliers were determined to be original manufacturers of API that are located in China and that, to the Company's knowledge, do not appear to have been registered with or inspected by the FDA. The other three were identified as U.S.-based resellers of API, whose product is also believed to originate from China.
  • 30 vials of compounded 17P formulations, prepared by 30 different compounding pharmacies across 15 states.
The independent laboratories measured the quality of each API sample and compounded 17P vial against certain quality standards required by FDA for Makena®. The samples also were evaluated by these labs against certain U.S. Pharmacopeia (USP) standards for hydroxyprogesterone caproate and hydroxyprogesterone caproate injection, because some compounding pharmacies claim that their compounded formulations meet USP criteria. The laboratories analyzed the API and compounded 17P drug formulations to assess potency, chemical impurities and drug identity.

Key Laboratory Testing Findings
Active Pharmaceutical Ingredient (API)
  • One API sample sent from a Chinese manufacturing facility was not the correct active pharmaceutical ingredient. Although the package was sent to the United States labeled in Chinese as hydroxyprogesterone caproate (HPC), the active ingredient failed the drug identity test for HPC. Further laboratory analysis conclusively proved that the substance was glucose instead of HPC.
  • 80 percent (8 of 10) of the API samples failed to meet at least one FDA standard for unknown impurities.
  • 50 percent (5 of 10) of the API samples failed to meet the USP standard for potency.
  • The paperwork (certificates of analysis) that arrived with API shipped from China was often missing or incomplete. Such gaps in paperwork can make it difficult to track back specific product to specific manufacturing facilities, which is critically important should a problem with the medication arise.


Compounded 17P Formulations
  • 27 percent (8 of 30) of the compounded 17P vials tested failed to meet the USP standard for potency. The potency values of the compounded 17P vials ranged from just over half to a level more than 2.5 times the labeled potency. If these vials were administered to patients, some patients would not have received the dose of 17P that was reviewed and subsequently approved by FDA for safety and efficacy in this patient population. This variability in potency was comparable to those found in FDA's limited survey of compounded drug products conducted in 2006, which is available at:  http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/PharmacyCompounding/ucm204237.htm
  • 53 percent (16 of 30) of the vials of compounded 17P had levels of unknown impurities that exceeded at least one standard required by the FDA for Makena®. The potential toxic effects of these unidentified compounds in the intended patient population are unknown.  
  • Taken together, two-thirds (20 of 30) of the compounded 17P vials failed to meet at least one USP requirement (a standard used by some compounding pharmacies) or at least one FDA quality standard required of Makena® for potency and/or purity levels. Information was not obtained regarding the sterility of, or potential presence of endotoxins in, the compounded 17P vials.  
  • FDA-approved Makena® must meet FDA's quality standards before release for patient use.
Article is found here
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Sunday, June 10, 2012

K-V prompts FDA Investigation into Compounding Pharmacies--Makena--API Source from China

K-V prompts FDA Investigation into Compounding Pharmacies--Makena--API Source from China
To read article, click here 

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Friday, June 8, 2012

Wedgewood Village Pharmacy, Inc.: The 2005 Third Circuit Decision

The Wedgewood Village Pharmacy, Inc. (Wedgewood) decision, a critical case dealing with compounding and the FDA's jurisdiction, was rendered in the Third Circuit Court of Appeals in 2005.  The Third Circuit has appellate jurisdiction over,
Eastern District of Pennsylvania

The beginning of that case provides a good summary of what the case is about.  The beginning provides:
Wedgewood Village Pharmacy appeals the District Court's order affirming the Magistrate Judge's denial of Wedgewood's motion to quash an administrative warrant issued to agents of the Food and Drug Administration.   Wedgewood argues that it is exempt from FDA inspection under provisions of the Food, Drug, and Cosmetic Act (the “FDCA”), 21 U.S.C. § 301 et seq.   Wedgewood also contends that it was denied procedural due process.  For the reasons that follow, we hold that Wedgewood was not exempt from FDA inspection under the FDCA, and that issuance of the warrant did not deny Wedgewood procedural due process.  Accordingly, we will affirm the decision of the District Court.
To read the entire decision, click here.
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U.S. Pharmcopeial Compounding Expert Committee and Focus Areas

The U.S. Pharmacopeial Convention (USP) has a compounding expert committee with focus areas.  The members and focus areas are listed below.  The committee's work plan can be downloaded here.

2010–2015 Compounding Expert Committee

Focus Areas include: 

 

Human Drug Compounding (Sterile and Nonsterile)

Veterinary Drug Compounding

Radiopharmaceuticals Compounding

Compounding Flavorings


Expert Committee Members


Gigi S. Davidson, B.S. Pharm., DICVP, Chair
Lisa D. Ashworth, B.S. Pharm., R.Ph., Vice Chair
Loyd v. Allen, Ph.D.
Edmund J. Elder, Jr. Ph.D.
Maria do Carmo M Garcez, B.S. Pharm.
Deborah R. Houston, Pharm.D.
Ken Hughes, R.Ph.
Eric S. Kastango, B.S.Pharm., M.B.A.
Patricia C. Kienle, M.P.A.
Keisha D. Lovoi, B.S.Pharm.
Linda F. McElhiney, Pharm.D.
William A. Mixon, M.S.
David W. Newton, Ph.D.
Alan F. Parr, Pharm.D., Ph.D.
Regina F. Peacock, Ph.D.
Robert P. Shrewsbury, Ph.D.
Keith St. John, M.S.
Government Liaisons
Ian F. Deveau, Ph.D.
Edisa Gozun
Martine Hartogenesis, DVM
John W. Metcalfe, Ph.D.
Terrance W. Ocheltree, Ph.D., R.Ph.
Judith McMeekin, Pharm.D.
Yichun Sun, Ph.D

USP Documentary Standards Staff
Shawn Becker, M.S., R.N.
Anthony DeStefano, Ph.D.
Donna Goldberg, M.Ph.
Rick Schnatz, Pharm.D.
Ivonne Zuniga
 
Primary Points of Contact
Rick Schnatz, Pharm.D. (rxs@usp.org)
Jeanne Sun, Pharm.D. (jhs@usp.org)

 

 

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Compounding Concerns for Animals Near and Dear

A article by Alice Villalobos, DVM that appears in the Veterinary Practice News, which can read here, makes some very good points about compounding for animals.

First, Villalobos asks:

Competitive pricing, counterfeit drugs, unreliable sources for drugs and the honesty that our profession must maintain present an everyday dilemma. How can veterinarians avoid being tarnished by scandals of adulterated and contaminated food and drugs and still maintain the public’s trust?

Next, Villalobos points out a number of the current issues regarding compounding for animals:

The hundreds of compounding pharmacies nationwide do not use standardized methods or bases for their compounded products. Only a few pharmacies run tests on the stability of their purchased and outsourced compounds.
Some are illegally manufacturing medications under the guise of pharmacy compounding. The field has sprawled into a confusing crossover situation for veterinarians. We have human pharmacists preparing products for animals. If they do not respect and understand the human-animal bond, they might purchase “bargain” bulk or raw chemical preparations made in China and other unreliable sources to save money. Without testing these bargain agents for reliability, stability and contaminants, our patients are at risk.
For instance, potassium bromide, cisapride and diethylstilbestrol and other discontinued or no-longer-approved human drugs can be prepared only from bulk chemicals for veterinary medicine, and they are loosely supervised. We need to protect our veterinary patients from being victimized by this potential hazard. 

Proper Handling
For example, Pergolide for horses is available only through compounding pharmacies. Compounded Pergolide is stable for 30 days and must be kept in a temperature-sensitive environment. Many pharmacies sell Pergolide with a six-month dating, and the product is not stored adequately to ensure its stability.
Finally, Villalobos makes an excellent point, with quotes from Gigi Davidson, RPh, Dipl. ICVP, director of clinical pharmacy services at North Carolina State University, about the Veterinarian ultimately being responsible:
 “Ultimately, the veterinarian is accountable for what happens to the patient.""Veterinarians must realize that even if evidence abounds regarding the safety and efficacy of a compound, they are responsible for determining whether the compound is achieving the desired therapeutic effect,” Dr. Davidson wrote in a recent article for AAHA News.


“Veterinarians should keep track of the results for their patients who have been prescribed compounds and make sure they know what exactly is going into each prescription.” 
Davidson cited the case of a canine patient treated with pyridostigmine (Mestinon) solution for myasthenia gravis at the N.C. State College of Veterinary Medicine's teaching hospital. The dog was doing well on the treatment but returned several months later weak and unable to stand.
"Apparently the owner had taken her prescription for pyridostigmine solution to a compounding pharmacy and the well-intentioned pharmacist had offered to compound a more dog-friendly flavor of the pyridostigmine," Davidson said. "Unfortunately, the pharmacist included methylcellulose in the vehicle which completely bound the pyridostigmine, making it unavailable for absorption. Luckily, we realized the mistake before the dog was euthanized."






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Thursday, June 7, 2012

Idaho Board of Pharmacy Plans to Adopt Sterile Product Compounding Rules

The Idaho Board of Pharmacy looks to adopt sterile product compounding rules in 2012 as stated in its strategic plan found here.  Part of that plan states:

The Board envisions regulating the practice of compounding pharmacy.  This practice has traditionally been regulated by the United States Food and Drug Administration (FDA), however, the FDA’s authority has been challenged in court recently, leaving such regulation to the states.  The Board envisions promulgating sterile product compounding rules in 2012 and additional compounding rules in 2013, reviewing such rules annually.    
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