FDA Warning Letters for International APIs in 2011

The following blog post can be found here.

FDA Warning Letters for International APIs in 2011

January 8, 2012

FDA issued at least ten Warning Letters to international manufacturers of active pharmaceutical ingredients in FY-2011. Manufacturers in both China and India, the world’s largest exporters of APIs, received three Warning Letters each from FDA. Manufacturers in Spain, the UK, Canada, and Japan each received one Warning Letter from FDA. These metrics show both the domination of China and India in the API market as well as the continued dependence on international manufacturers for APIs destined for the U.S. market.
Deficiency Categories:
The violation that dominated the charges cited by FDA in FY-2011 related to quality control, cited in four Warning Letters, two to China and one each to Canada and Japan.
Another violation that is sure to cause concern with FDA is the failure to prevent cross-contamination. When I attended FDA API inspection training in 2000 cross-contamination, particularly with anti-biotics, was a major concern. It continues to be with API manufacturers in both India and China being cited for the “Failure to have appropriate procedures in place to prevent cross-contamination.”
Out of specification (OOS) laboratory results are always a concern of FDA and landed on Warning Letters to manufacturers in India and Spain. Other citations include:
= Water purification for APIs used in parenterals
= Failure to establish a stability program to monitor APIs
= Failure to perform at least one identity test of each batch of incoming material
= Validation of analytical methods used to test APIs
There are no big surprises here but it shows that regular surveillance of API vendors is an absolute necessity for the manufacture of quality drug products. What is of interest is that GxP Perspectives couldn’t find any domestic Warning Letters for APIs. That doesn’t mean they don’t exist, only that they couldn’t be easily located. Unfortunately, FDA lists API Warning Letters in any number of classifications for GMPs for finished pharmaceuticals. However, they don’t seem to list them for APIs. With all the razzle-dazzle taking place on FDA’s website, you would think they could come up with a consistent way to list API Warning Letters. Who knows, maybe next year.
by Carl Anderson, GxP Perspectives
Research by Francesca Carreras-Perez, GxP Perspectives
====

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
.

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 

FDA Alert 66-66; "APIs That Appear To Be Misbranded Under 502(f)(1) Because They Do Not Meet The Requirements For The Labeling Exemptions In 21 CFR 201.122"

(Note: This import alert represents the Agency's current guidance to FDA field personnel regarding the
manufacturer(s) and/or products(s) at issue. It does not create or confer any rights for or on any person,
and does not operate to bind FDA or the public).

Import Alert # 66-66

Published Date: 04/10/2012

Type: DWPE

Import Alert Name:

"APIs That Appear To Be Misbranded Under 502(f)(1) Because They Do Not Meet The
Requirements For The Labeling Exemptions In 21 CFR 201.122"

Reason for Alert:

OASIS records indicate that a large volume of bulk chemicals which can be used as APIs in human
medicines that require NDAs, ANDAs, or INDs are being offered for entry into the U.S.

NDA Imported APIs labeled for further manufacturing and processing or labeled as chemical
substances are frequently destined for pharmaceutical processors that formulate finished drug
products. These drug substances, consigned to individuals or processors who formulate and
distribute human drugs, may be misbranded under Section 502(f)(1).

AIND Sponsors of investigational new drug applications frequently import from foreign
countries either the dosage form or the API for use in laboratory research or clinical trials.

Some persons importing APIs have found that they could obtain entry of these articles if they
simply supply an NDA or IND number at the point of entry. Districts should be alert to the
possibility that: 1) the NDA or IND number provided does not cover the source of the particular
API or 2) the persons importing the API have no authorization to refer to the particular NDA or
IND number. In the past, the persons importing an API have referred to legitimate numbers to
get their APIs released, but the APIs were not destined for use in the application referenced.

CDER and ORA are in the process of making the Establishment Evaluation System (EES)
available to the field. When available, field offices should utilize EES to search and verify the
status of an API, its manufacturer, whether it has been referenced in a valid NDA or whether
it is the subject of a valid IND. Districts that do not have access to EES should contact
DIOP, 301-443-6553 to verify this status.

(OASIS entry records can be compared to CDER records for NDAs, ANDAs, and IND
exemptions to verify the source and status of an API.)

EXEMPTION UNDER 21 CFR 201.122

API labeling invariably lacks adequate directions for use as required by Section 502(f)(1)
of the Act. However, such drugs may be subject to an exemption under 21 CFR subpart 201.122.
This regulation requires specific labeling on the package when adequate directions for use are
missing, such as "Caution: For manufacturing, processing, or repacking."

However, the exemption under 21 CFR 201.122 will not apply to a substance intended for a
use in the manufacture, processing, or repacking of the API which causes the finished article
to be a new drug, unless:

A. an approved NDA covers the production and delivery of the API to the application holder
by persons named in the application; or

B. if no application is approved with respect to the API, the label statement "Caution: For
manufacturing, processing, or repacking" is immediately supplemented by the words "in the
preparation of a new drug or new animal drug limited by Federal law to investigational use,"
and the delivery is made for use only in the manufacture of such new drug or new animal
drug limited to investigational use as provided in 21 CFR part 312 or part 511.1.

The API/manufacturer combinations listed in Attachment A appear to represent importations
of APIs to be used for the manufacture, processing, or repacking of drugs which the Act
and regulations require to be the subject of an approved NDA or a valid IND. However,
either the person receiving the API or the person importing the API appears not to meet the
statutory and/or regulatory requirements regarding labeling. Further, it appears that the Agency
has never inspected the declared manufacturer's GMPs for that imported API.

Guidance:

Detain without physical examination the APIs from the manufacturers identified in the
Red List to this Import Alert.

Districts may detain without physical examination APIs from the persons identified in the
Red List because it appears that the API is misbranded based on its lack of adequate
directions for use as required by section 502(f)(1) of the Act and its failure to meet the
requirements of the exemption found in 201.122. Persons importing these APIs may obtain
release of the detained articles if these persons can supply evidence establishing that the article is:

1. intended for pharmacy compounding that meets the requirements of section 503A of the
Act, including that the API:

a. is accompanied by a valid certificate of analysis,

b. is manufactured by an establishment registered under section 510 of the Act,

and

c. does not appear on a list of drugs identified in 21 CFR 216.24, that have been withdrawn or
removed from the market for reasons of safety or effectiveness.

2. intended for use in the manufacture, processing, or repacking of an over-the-counter
product or prescription product that does not require an NDA;

or

3. a new animal drug, or intended for use in the manufacture, processing, or repacking of a new
animal drug, subject to an NADA;

and, therefore, the API is not subject to this import alert.

OR

Persons importing APIs may obtain release of the detained articles by supplying evidence
establishing that the article is:

1. intended for use in the manufacture, processing, or repacking of a human drug that is itself
the subject of an approved NDA, and that the API is from the appropriate source; or

2. it is covered by IND requirements at 21 CFR 312.110(a).

For questions or issues concerning science, science policy, sample collection, analysis,
preparation, or analytical methodology, contact the Division of Field Science at (301) 796-6600.

This guidance is not intended to address new animal drugs or investigational new animal drugs addressed
by Import Alert number 68-09. If the imported APIs are intended for use in an NADA or INAD, refer
to Import Alert number 68-09.

If the APIs are intended for the compounding of finished drugs by pharmacies, persons
importing the APIs must comply with the requirements in 503A of the FDCA.

This guidance does not apply to excipients or APIs intended for use in OTC drugs or prescription drugs
that do not require a new drug application.

Product Description:

Active Pharmaceutical Ingredients (APIs)

Charge:

"The article is subject to refusal of admission pursuant to section 801(a)(3) in that it appears to be misbranded in that it lacks adequate directions for its intended use. [Misbranding, Section 502(f)(1)]."

OASIS Charge Code - DIRECTIONS

NOTE: Under 502(f)(1), an API must have labeling that lists adequate directions for its use unless the API is subject to exemptions from labeling found in 201.122.

For a list of firms and their products subject to detention without physical examination (DWPE) under this import aller (a.k.a. Red List), click here and scroll to the bottom of the page.

FDA Division of Compliance: Inspecting Businesses that May be Manufacturing Under Guise of Compounding

The Division of Compliance of the United States Food and Drug Administration (FDA) has issued assignments to conduct inspections of firms, including internet pharmacies, who may be engaged in the practice of manufacturing under the guise of pharmacy compounding.  The FDA web site contains the following statement regarding Veterinary Drug Compounding.

Inspections, Compliance, and Criminal Investigations

.9.2 - VETERINARY DRUG ACTIVITIES

CVM is responsible for inspections of therapeutic and production drugs, and Active Pharmaceutical Ingredients (APIs). Therapeutic drugs are used in the diagnosis, cure, mitigation, treatment or prevention of disease. Production drugs are used for economic enhancement of animal productivity. Examples include: growth promotion, feed efficiency and increased milk production.
Preapproval inspections are conducted pursuant to pending NADA or ANADA applications.

Post approval inspections of veterinary drugs are conducted to determine compliance with the Current Good Manufacturing Practices (CGMPs) for Finished Pharmaceuticals under 21 CFR Part 211³. These cGMPs apply to both human and veterinary drugs. Information on veterinary drugs approved can be found in the "Green Book" database accessed through CVM's website.

APIs are active pharmaceutical ingredients. Many of the APIs used to manufacture dosage form drugs are imported from foreign countries. The intended source for an API must be indicated in NADA/ANADA submissions for new animal drug approvals. Any change in a source for an API would require a supplement to the application.

Extra label drug use refers to the regulations in 21 CFR Part 530⁴ codified as a result of the Animal Medicinal Drug Use Clarification Act⁵ (AMDUCA) of 1994. These regulations set forth the requirements that veterinarians must meet to prescribe extra label uses of FDA approved animal and human drugs. The regulations describe what is a valid veterinary-client-patient relationship as well as what is considered illegal extra label use. 21 CFR Part 530 addresses issues regarding extra label use in non-food as well as food producing animals. 21 CFR 530.41⁶ contains a list of drugs that cannot be used in an extra label manner in food-producing animals. During an inspection or investigation if you encounter any situations on suspected illegal extra label use of any FDA approved animal or human drugs or those prohibited for extra label use in food animals, you should contact CVM's Division of Compliance (HFV-230) (240-276-9200).

21 CFR Part 530 also addresses compounding of products from approved animal or human drugs by a pharmacist or veterinarian. The regulations clearly state compounding is not permitted from bulk drugs. This would include APIs. CVM has an existing CPG on Compounding of Drugs for Use in Animals (CPG 608.400⁷). A copy can be found on CVM's website. The Division of Compliance (HFV-230) has issued assignments to conduct inspections of firms, including internet pharmacies, who may be engaged in the practice of manufacturing under the guise of pharmacy compounding. You should contact the Division of Compliance (HFV-230) at 240-276-9200 to report instances of compounding or to seek guidance on inspectional issues, or regulatory and enforcement policies.