FDA's Warning Letter dated 8/2/2013 to inspection of your pharmaceutical manufacturing facility, Posh Chemicals Private Limited, located at Unit II, Plot No. 23, Phase-1, Jeedimetla, Hyderabad, India, Regarding API

can be read here

FDA HAS RAMPED UP INSPECTIONS OF APIs--From FiercePharma Manufacturing: FDA warning to Abbey questions quality of API for sterile drugs Warning Letter lists repeat violation on water quality February 27, 2013 | By Eric Palmer Read more: FDA warning to Abbey questions quality of API for sterile drugs

The FDA says an active pharmaceutical ingredient maker in Philadelphia had yet to qualify that its purified water was in fact pure enough to make APIs two years after the agency noted a deficiency.
Abbey Color was told in a new warning letter posted to the FDA website this week that the agency is dissatisfied with the steps the company has taken to demonstrate that its water is suitable for use in manufacturing fluorescein USP, an API used in sterile drug products.
The inspection was conducted nearly a year ago, but the agency notes the company had promised in 2010 that it would make sure it had a reliable source of quality water. The most recent inspection found Abbey still passes spec endotoxin and total organic carbon test results. But inspectors found the operational parameters and effectiveness of an endotoxin removal unit had not been qualified and that Abbey was not monitoring the microbial and chemical attributes of the feed water.

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Sign up for our FREE newsletter for more news like this sent to your inbox!The FDA also came down on the company for not getting to the root cause of its water-supply issues. The manufacturer was further criticized for not setting up an adequate program to monitor API stability that would determine how the API should be stored.
The FDA has been ramping up inspections of APIs, and drugmakers using additional user fees that kicked in this year from generic manufacturers. But that work is being put to risk by looming across-the-board budget cuts from the current sequestration fight in Congress. A recent Congressional Budget Office (OMB) ruling said that user fees have to be cut as well. Regulatory Focus recently figured the cuts would mean a loss of about $200 million from the FDA's base budget and an estimated $112 million (annualized) in lost user fees.

- here's the warning letter

Read more: FDA warning to Abbey questions quality of API for sterile drugs - FiercePharma Manufacturing http://www.fiercepharmamanufacturing.com/story/fda-warning-abbey-questions-quality-api-sterile-drugs/2013-02-27#ixzz2MAm4Tpmh
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A Question in the New England Compounding Center Meningitis Case No One Seems to Be Asking: Where Did They Get Their API or Bulk Powders From?

One question that investigators may or may not be looking at, and one that news reports have not seemed to pick up on is where did New England Compounding Center buy its active pharmaceutical ingredients (api) or bulk powders or chemicals from.   Previously reported here on August 29, 2012, was this:

Alarming Report About API from China

Melanie Lee and Ben Hirschler at Reuters have written a Special Report: China's "wild east" drug store dated August 28, 2012.  This report contains alarming information about API from China.  It should be read by everyone and serves as a reminder to ask questions about the source of API used by compounders. To read the report click here.

On June 13, 2012, this was reported on the blog:

The Problems With Buying API From Foreign Sources

The Problems With Buying API From Foreign Sources

More than 80 percent of API is imported into the United States. The problem with buying API from foreign sources is that you do not know what you are getting.  For example, a pharmacetuical representative in Arizona may actually obtain its API from countries such as those in Asia or South America.  In some of these places, quality standards are very lax and counterfeit medications are more widespread and common. The identity, purity, potency and safety of drugs purchased from foreign sources is not guaranteed. It is essential that pharmacists know where the API orginated from even if they are purchasing the API from a company in the United States. Using sources of API whether the API comes from a foreign country or the United States without knowing the identity, purity, potency and safety of drugs simply to save money is not worth the exposure in liability, both civil and criminal, if a patient--human or animal--is injuried or dies from the use of these type of API.  All drugs and API distributed in the United States must comply with the Federal Food Drug and Cosmetic Act, regardless of where they are made. Note that it is illegal (with very few exceptions) to ship prescription drugs that are not approved by FDA into the US, regardless of whether the drug is legal to sell in another country. 


For more information click here.  
To see notes from an FDA seminar on imported API click here.
To review a FDA slide presentation on imported API click here.
To read prior testimony about API, click here.
To read news articles click here,  here,  here and  here
To read a 2012 report on India, click here.
To read an article published April 2012, that suggest better safeguards for imported drugs are needed, click here.
To read the FDA's report entitled Pathway to Global Product Safety and Quality, click here

Hopefully the right people are asking the right questions in the New England Compounding Center Meningitis Outbreak case
.

Dangers aside, drugmakers can't live without Chinese APIs

September 3, 2012 | By Eric Palmer

When it comes Chinese-made APIs, Western drugmakers are between a rock and a hard place. They know Chinese oversight of bulk APIs is insufficient to snuff out substandard producers, but since China produces more APIs than any other country, they can't live without them.

"If China for some reason decided to stop exporting APIs, within three months all our pharmacies would be empty," Guy Villax, CEO of Hovione, tells Reuters. The Portuguese API supplier has factories in China, as well as the U.S. and Ireland.

After 80 U.S. patient deaths were tied to tainted Chinese heparin in 2008, Chinese authorities pledged to crack down on API suppliers. But a Reuters investigation finds that while China is doing more, the fact that many Chinese APIs are substandard or counterfeit is an open secret. "Illegal ingredients in bulk are a big problem, but nobody talks about it," Villax says.

Read more: Dangers aside, drugmakers can't live without Chinese APIs - FiercePharma Manufacturing http://www.fiercepharmamanufacturing.com/story/dangers-aside-drugmakers-cant-live-without-chinese-apis/2012-09-03#ixzz25iHugod3 
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Health Care Renewal Blog: Entry on Importance of Knowing API Source

The Health Care Renewal blog has a very interesting post entitled Who Really Makes Brand-Name Pharmaceuticals?  dated Wednesday, September 5, 2012.  While this blog entry is geared toward manufactured drugs, the information regarding the API  and problems with API for foreign sources is equally relevant to compounded drugs.  The blog entry can be read here.

Alarming Report About API from China

Melanie Lee and Ben Hirschler at Reuters have written a Special Report: China's "wild east" drug store dated August 28, 2012.  This report contains alarming information about API from China.  It should be read by everyone and serves as a reminder to ask questions about the source of API used by compounders. To read the report click here.

PowerPoint from FDA on API

PowerPoint Presentation on Importation of Active Pharmaceutical Ingredient (API)
Requirements, presented by Bill Nychis, Acting Team Leader, US FDA, Center for Drug Evaluation and Research (CDER), Office of Compliance (OC), Division of New Drug Labeling & Compliance (DNDLC),Import-Export Team and presented 7/16/08 New York API Seminar can be found here.

Report Says China and India are emerging as global superpowers in the API industry

China and India are emerging as global superpowers in the API industry offering promising features, says RNCOS.

According to a new research report by RNCOS, entitled “Global Biotech API Market Analysis”, China and India are emerging as global superpowers in the API industry. The availability of cheap resources, such as infrastructure, labor, raw materials, etc accompanied by the advancing pharma expertise is one of the key factors backing this growth. Both the economies present a very bright opportunity for CRAMS as several pharma manufacturers outsource their APIs and intermediaries to these two low-end economies. While generics are a mainstay for the API industry in both the countries, India is posing a threat to India as its generic API industry has outshone that of China.

The rapidly evolving pharma market and increasing demands for drugs worldwide is primarily driving growth in the global API market. While the generic and the branded APIs represent equal share in the API merchant market, the growth of generics is expected to be incessant. The initiatives by the government to cut down on burgeoning costs have resulted in the active promotion of the generics market. Biotechnological APIs are also expected to evolve in the market. The rising patent expiries among the biopharmaceutical products in Europe and the US will increase the demand for bulk drugs.  Further a latest report by RNCOS, also foresees the worldwide API market size to be likely to register a healthy CAGR of around 8% during 2012-2015.

The report spread in over 55 pages provides a proper understanding of the API market globally along with an idea about its current state. The key industry drivers have been covered in details along with the current and future market projections for the time period of 2012-2015. The major segments and sub-segments of the API industry have been covered along with the description of the API industry in the most promising geographies of India, China, Italy and Taiwan. The report also analyzes the opportunity assessment for companies in the global APIs market in terms of therapeutic segments and countries’ comparative index.  An analysis of the emerging areas, competitive landscape, and regulatory stringency further provides a holistic understanding of the global API market.

For FREE SAMPLE of this report visit: http://www.rncos.com/Report/IM424.htm

 

Source is found here.

India, China plan to jointly oppose EU regulation on API at WTO forum

Joseph Alexander, New Delhi Monday, August 06, 2012, 08:00 Hrs  [IST]

India and China may together move the World Trade Organisation (WTO) against the European Union (EU) regulation on bulk drugs which may affect the current exports of Active Pharmaceutical Ingredients (APIs) from both the countries to Europe. EU has changed the rules for importing active substances into EU for medicinal products for human use and the amended regulation would come into effect fully by July 2013. It would make mandatory the current good manufacturing practices (cGMP) certificate from the local authority for all bulk drugs exports. To read the remainder of the article, click here.

EU's newly-changed rules on cGMP certificate for bulk drug exports may hit Indian exports

To read this article written by Joseph Alexander, New Delhi on July 31, 2012, click here.

Doing Business in China - Considerations for Effectively Leveraging Emerging Markets

The U.S. economic slowdown and the Eurozone debt crisis have created pressure in the pharma industry that shows no signs of relenting. Yet, with the global pharma market forecasted to languish in single digit growth, emerging markets such as Brazil, China, India, Mexico, Russia and Turkey anticipate double digit growth nearing 14 percent through to 2014. 1
It is clear that China and other emerging markets are set to occupy an expanding share of pharma’s geographical portfolio. Of these, China has emerged as central to many U.S. pharma strategies. According to a recent market analysis by IMS, the compound annual growth rate of the Chinese pharmaceutical market over the next five years will be 23.2 percent. Growth has been rapid: China is on course to become the world’s third-largest prescription medicines market, after the U.S. and Japan. 2

To continue reading this article published August 1, 2012, click here.

Market Research Estimates European Active Pharmaceutical Ingredients (API) Market Growth at 6% CAGR Through 2017

To review this World News Article click here.

Cipla to set up API facilities

To read the article in the Economic Times, date August 5, 2012, click here.

Exit the dragon Indian drug makers are trying to shake off their dependence on China

Geetanjali Shukla Edition: May 27, 2012
It's a no-brainer that buying from a Chinese supplier is cheaper than from a Japanese one, right? Pravin Herlekar, Chairman of Omkar Speciality Chemicals, a Rs 100-crore bulk drug maker based in Badlapur, near Mumbai, learned the hard way that it is not always true. His company dumped its Japanese supplier of selenium when it found a cheaper source in China. But, Herlekar says, the Chinese suppliers resisted inspection of shipments before delivery. Within a few months, the intermediates that Omkar made using Chinese selenium began to suffer from quality issues. The company went back to sourcing selenium from Japan.

"Chinese suppliers often don't agree to third party inspections which help keep a check on quality," says Herlekar. Selenium derivatives are used to make an active pharmaceutical ingredient (API) or bulk drug. Bulk drugs are used to make medicines. For instance, intermediate compounds such as isobutyl benzene, aluminium chloride and sodium dichromate are used to make ibuprofen, the principal ingredient in formulation brands such as Combiflam.

With strong advantages such as economies of scale and government funding, Chinese companies have been flexing their muscles by resisting inspections, neglecting quality issues and raising prices. Many Indian companies are finding or creating alternatives to Chinese suppliers"
Lower prices offered by Chinese companies have caught the attention of many Indian drug makers. "In the last five years, API imports by Indian companies have doubled. In 2010/11, imports crossed $7 billion, of which China has a 60 per cent share," says O.R.S. Rao, Director, Cygnus Business Consulting and Research. "In the same period, India's bulk drug production has fallen to 35 per cent of its consumption, from about 70 per cent." The Hyderabad-based research firm releases a study on the Indian bulk drug industry every two years; the last edition was published in 2011. The Indian bulk drug market is valued at $13.5 billion, and its Chinese counterpart at $30 billion.

China and India are the leading players in bulk drugs, accounting for more than 40 percent of global bulk drug production. China is the largest bulk drug supplier, and India is second. Part of China's competitive advantage comes from the operating environment (lower interest rates, access to power and other infrastructure) and government aid (cheaper land, government funding). This has enabled Chinese manufacturers to benefit from economies of scale. China is also better endowed with raw materials such as phosphorous, potassium and sulphur. So it can produce bulk drugs at 10 percent of the cost in developed countries.

In 2010/11, bulk drug imports by Indian companies crossed dollar 7 billion, of which China has a 60 per cent share: O.R.S. RaoGiven their strong advantages, Chinese companies have been flexing their muscles by not allowing inspections, neglecting quality issues and raising prices. And Indian pharma seems to have finally decided that it needs to stop depending on China. Some Indian companies are integrating their operations backward to increase control over bulk drugs and intermediates. And, as price increases by Chinese manufacturers squeeze margins, Indian companies are trying to move up the value chain into the high-margin formulations business. Dependence on China has generated enough concerns for the Indian Drug Manufacturers' Association (IDMA) to call for anti-dumping duties on some bulk drugs and intermediates from China. IDMA also wants the government to set up a $700-million fund for bulk drug manufacturers. "Low-priced Chinese APIs are attractive, but this phenomenon can only be temporary," says Manish Doshi, President, IDMA.

"Nothing can stop them from raising prices once they know that Indian API manufacturers have closed down due to cut-throat competition. It is the government's duty to protect the industry from such dumping tactics by China." Doshi is also Managing Director at Amoli Organics and Umedica Laboratories, companies which were set up by his father and which make intermediates, bulk drugs and finished drugs. Naresh Gupta, who heads Lupin Laboratories's bulk drug unit, also argues that the government should try to level the playing field for Indian manufacturers. Incidentally, Lupin is the only Indian pharma major that exports bulk drugs to China.

Omkar Speciality Chemicals isn't waiting for the government act, however. Its strategy is to meet international standards. Its Badlapur factory has good manufacturing practices (GMP) status from the US Food and Drugs Administration. Regulatory authorities in many countries grant GMP status, but the most important for Indian companies are the US and British authorities, besides Indian regulators. Omkar will also seek GMP status for its factory coming up in Chiplun, Maharashtra. Herlekar says his advantage will be quality. "Indian formulations majors are increasingly sourcing from India, as they don't have to maintain large stocks and quality can be controlled," he says. "Most Indian API and intermediates manufacturers get their facilities audited by their customers, so quality isn't much of an issue."

Another strategy is backward integration. Shasun Chemicals and drugs, a Chennai-based Rs 1,000-crore company, has decided to manufacture some intermediates at its Andhra Pradesh plant, rather than importing them from China. Managing Director S. Abhaya Kumar says: "We have earmarked Rs 70 crore to move production of some of our key intermediates to India. The shift should be complete by December." He adds that intermediate prices in China have increased by 10 per cent in the last three months, because of rising petroleum prices and pressure on China to adhere to environmental norms. Shasun is the largest producer of ibuprofen in the world. It is developing 13 APIs for a few billion-dollar drugs whose patents expire in the next five years.

Another way to integrate backward is to acquire a bulk drug maker. For example, Mumbai-based Aanjaneya Lifecare bought intermediates manufacturer Apex Drugs in February for Rs 250 crore. The aim is to reduce dependence on third parties and reduce its vulnerability to fluctuations in price and supply. Similarly, Indoco Remedies, also based in Mumbai, acquired bulk drug maker La Nova Chem in 2006. The contribution of bulk drugs to overall revenues is negligible, but Indoco plans capital expenditure of Rs 55 crore over the next couple of years in its bulk drug factory at Patalganga, near Mumbai.

To counter the Chinese, big Indian drug makers such as Dr. Reddy's, Ranbaxy and Lupin have been moving up the value chain, from intermediates and bulk drugs to generics. But not everyone finds it easy to walk away from China.

"Only intermediates that have an impact on the quality of the finished product are manufactured in India or inhouse," says Sanjay Bhanushali, Head of International Business at Cipla. Procurement from China has increased five to eight per cent every year for the last three years." Cipla is looking at stronger alliances with other Indian or overseas companies to avoid sudden shocks. It is also open to dealing with companies in other markets, such as Brazil, Argentina, and Vietnam.

Lupin's Gupta says his company's Japanese operations are looking to shift all bulk drug manufacturing to India. "Despite price volatility in some inputs, the company was able to insulate itself due to hedging," he adds. Quality and research differentiate India from China. India has more than 175 plants approved by the US FDA - the highest number outside the US. Focus on quality has helped Indian companies increase their presence in developed markets. According to a report published in April by HSBC Global Research, half the Drug Master Files (DMF) in the first three months of this year are from Indian companies, compared to China's share of 14 per cent. DMF documents contain complete information about a drug's chemistry and manufacturing process, among other things, and enable a company to protect its intellectual property.

Many medium-sized bulk drug manufacturers have, with investments in research and development, shifted focus to late-stage intermediates and complex synthetic APIs. Chandigarh-based Parabolic Drugs , a Rs 900-crore company, recently commissioned a facility to manufacture bulk drugs in new therapy areas such as oncology and lifestyle ailments such as diabetes. The facility is likely to generate revenues of Rs 50 crore to Rs 75 crore in the current financial year and when fully operational, can generate up to Rs 300 crore.

But in the near future, it looks as if Chinese companies will continue to bleed Indian bulk drug makers. The capital-intensive nature of operations and extended working capital cycles have suppressed their return on capital. "Many bulk drug manufacturers are struggling financially," says Ajit Mahadevan, Partner - Life Sciences, Ernst & Young. "A lot of them are looking for funds and finding it difficult to manage them in these times." It may be a while before they are strong enough to fend off the dragon.
Article is located here.

FDA Seminar Materials on Importation of API Requirements

The material below may be found here.
Importation of Active Pharmaceutical Ingredients (APIs) Requirements
7-16-08 FDA NYK-DO API Seminar Presentation Notes (Tab A)
7-16-08 FDA NYK-DO API Seminar Presentation Notes (Tab A) - 0
TAB CONTENTS
A. GENERAL IMPORTATION: Definitions (Page 1)
B. REGISTRATION AND LISTING: FRN (Page 2)
C. API EXEMPTIONS (Page 4)
D. MISBRANDING: Labeling Requirements & Exemptions (Page 6)
E. MARKETING: Requirements & Useful Information (Page 6)
OTC, Pharmacy Compounding, Pre-Submission Batches, and Rx
F. DATABASE: Drug Master Files (DMFS)/Establishment Evaluation
System (EES) (Page 8)
G. PRE-LAUNCH ACTIVITIES IMPORTATION REQUEST (PLAIR)
(Page 9)
H. CONTACTS (Page 9)
Importation of Active Pharmaceutical Ingredients (APIs) Requirements
7-16-08 FDA NYK-DO API Seminar Presentation Notes (Tab A)
7-16-08 FDA NYK-DO API Seminar Presentation Notes (Tab A) - 1

A. DEFINITIONS:
1. “Drug” [FD&C Act Section 201(g)(1)]:
• Articles intended to diagnose, cure, mitigate, treat or prevent disease in man
or other animals
• Articles (other than food) intended to affect the structure or any function of
the body of man or other animals
• Articles intended for use as a component of a drug
2. "New" drug [FD&C Act Section 201 (p) & 505]:
• "any drug.... the composition of which is such that such drug is not generally
recognized, among experts qualified by scientific training and experience....,
as safe and effective for use under the conditions prescribed, recommended
or suggested in the labeling."
• A “new drug” must be covered by an approved new drug application
(NDA/ANDA) to be marketed in the U.S. or by an investigational new drug
application (IND)
• Applies to both Rx and OTC drugs
3. Over-the-counter drug products (OTC):
• All other drugs that can be used safely without medical supervision
Example: Medications for fever such as aspirin and acetaminophen,
preparations for the common cold or allergies, antacids, and some
first aid antibiotics
4. Prescription (Rx) drug products (Rx) [FD&C Act Section 503(b)(1)]:
• These drugs cannot be used safely without medical supervision
Example: Injectable drugs or drugs to treat serious conditions like heart
disease, cancer, or fertility problems
Importation of Active Pharmaceutical Ingredients (APIs) Requirements
7-16-08 FDA NYK-DO API Seminar Presentation Notes (Tab A)
7-16-08 FDA NYK-DO API Seminar Presentation Notes (Tab A) - 2
5. Active Pharmaceutical Ingredient (API) a.k.a. bulk drug substance
[21 CFR 207.3]
• "any substance that is represented for use in a drug and that, when used in
the manufacturing, processing, or packaging of a drug, becomes an active
ingredient or a finished dosage form of the drug“
• "term does not include intermediates used in the synthesis of such
substance"
6. Adequate Directions for Use [21 CFR 201.5]: “directions under which a
layman can use the drug safely….”
B. REGISTRATION & LISTING:
1. Requirements for Foreign Establishments:
• FFDCA Section 510(i) [21 U.S.C. 360]
• 21 CFR 207.40
• FFDCA Section 502(o) [21 U.S.C. 352]
• FFDCA Section 801(o) [21 U.S.C. 381]
2. Foreign firms that manufacture, prepare, propagate, compound, or process
a drug imported or offered for import into the U.S. are required to…
a. Register name and place of business
b. List all drugs imported or offered for import into the U.S.
c. Designate a U.S. Agent
- Each foreign drug establishment shall designate only one United States
agent
- Must be physically located in the U.S.
- Point of contact between FDA and foreign firm on all drug registration &
listing matters and requirements
- Letter of designation must:
o Be prepared on the foreign firm's letterhead
o Signed by authorizing official of the firm
o Contain: Name of the firm's designated U.S. Agent, Address,
Telephone/ fax numbers, and E-mail address
Importation of Active Pharmaceutical Ingredients (APIs) Requirements
7-16-08 FDA NYK-DO API Seminar Presentation Notes (Tab A)
7-16-08 FDA NYK-DO API Seminar Presentation Notes (Tab A) - 3
3. Registration must be renewed annually
4. Registration required before any application is approved
5. Listing information must be updated:
a. Every June and December or
b. Discretion of the registrant or
c. When any change occurs
6. National Drug Code Number (NDC #):
a. Assigned to each listed product
b. Identifies manufacturer/distributor, drug, and trade package size/type
c. FDA requests but does not required to appear on the product label or
labeling:
- If the NDC # appears on the label it must comply with
21 CFR 207.35 (b)(3)
7. Does not indicate FDA’s approval of a firm or its products
8. The Bioterrorism Act of 2002:
Requires foreign drug establishments whose drugs are imported into the U.S. to
submit certain information with the annual registration (This is in addition to
the regular registration requirements):
- Each importer/consignee of each drug in the U.S. known to the manufacturer
at time of registration
- Each person who imports or offers to import the manufacturer’s drugs
- The name and contact information of U.S. Agent
9. Non-listed products are misbranded [502(o)] & in violation of 801(a)(3)
10. Firms that are not in compliance with 510(i) are in violation of 801(o)
11. Listing Requirements – Exemptions:
a. Inactive ingredients
b. Intermediates (non-API)
c. Drug products not for importation into the U.S.
d. Drugs imported or offered for import under an Investigational New Drug
Application (IND) [21 CFR 312]
e. Components of drugs imported under 801(d)(3) - Import for Export (IFE)
Importation of Active Pharmaceutical Ingredients (APIs) Requirements
7-16-08 FDA NYK-DO API Seminar Presentation Notes (Tab A)
7-16-08 FDA NYK-DO API Seminar Presentation Notes (Tab A) - 4
12. Information:
a. FDA Forms: www.psc.gov/forms
b. NDC Directory: www.fda.gov
c. Guidance Annual Registration:
www.fda.gov/cder/drls/registration_listing.htm
d. Annual Registration Status: www.fda.gov/cder/dfars/default.htm
e. Registration & Listing contact number: 301-210-2840
f. Draft Guidance: E-Registration & Listing: FRN Vol. 73, No. 134, 7/11/08,
Page 39964
SUMMARY: The Food and Drug Administration (FDA) is announcing the
availability of a draft guidance for industry entitled ``Providing Regulatory
Submissions in Electronic Format--Drug Establishment Registration and
Drug Listing.'' This draft guidance document establishes a Pilot Program for
industry to voluntarily submit drug establishment registration and drug
listing information in an electronic format that FDA can process, review, and
archive. The document provides guidance on what required and FDArecommended
information related to drug establishment registration and
drug listing to submit and on how to electronically prepare and submit the
information to FDA.
C. API EXEMPTIONS:
1. 21 CFR 201.122(a):
a. API is intended for use in a product approved in a NDA, ANDA, or
supplement
b. API is manufactured by the supplier approved in the new drug application
c. Prescription (Rx) and over-the-counter (OTC) drugs covered by an approved
application
d. Labeling (Must):
• “Caution: for manufacturing, processing, or repacking” &
• “Rx only”- when most dosage forms in which the API may be used are
subject to prescription [503(b)(1)]
e. Useful Information:
• API product name and NDC number
• Name and address of the API manufacturer
• Number of approved NDA/ANDA or supplement
• Finished dosage drug product name and NDC number
Importation of Active Pharmaceutical Ingredients (APIs) Requirements
7-16-08 FDA NYK-DO API Seminar Presentation Notes (Tab A)
7-16-08 FDA NYK-DO API Seminar Presentation Notes (Tab A) - 5
2. 21 CFR 201.122(b):
a. API is intended for use in a product subject to an IND (for clinical use)
b. Must be covered by an active IND
c. Must be going to person(s) authorized in the IND
d. Labeling (Must):
• “Caution: for manufacturing, processing, or repacking in the preparation
of a new drug or new animal drug limited by federal law to
investigational use”
e. Useful Information:
• IND number
• Sponsor’s name
• Name of the product
3. 21 CFR 201.122(c):
a. API is intended for use in a product subject to a pending NDA or ANDA or
supplement
b. API is manufactured by the supplier included in the pending NDA, ANDA,
or supplement.
c. Applies to prescription (Rx) and over-the-counter (OTC) drugs
d. Labeling (Must):
• “Caution: for manufacturing, processing, or repacking” &
• “Rx only”- when most dosage forms in which the API may be used are
subject to prescription [503(b)(1)]
e. Useful Information:
• API product name and NDC number
• Name and address of the API manufacturer
• Number of pending NDA/ANDA or supplement
• Finished dosage drug product name and NDC number (if applicable)
• Written commitment that products manufactured with the API will not be
introduced in commercial distribution until they are approved
4. 21 CFR 201.125:
a. API is intended for use in teaching, law enforcement, research, and analysis
b. Includes both APIs and finished drug products
c. Cannot be used in human research
d. API product name and NDC number
e. Name and address of the API manufacturer
f. Name and address of U.S. Consignee
g. Written commitment that the quantity offered for import is reasonable for
the contemplated research, teaching, analysis, etc.
Importation of Active Pharmaceutical Ingredients (APIs) Requirements
7-16-08 FDA NYK-DO API Seminar Presentation Notes (Tab A)
7-16-08 FDA NYK-DO API Seminar Presentation Notes (Tab A) - 6
5. 21 CFR 312.160:
a. API is intended for investigational (IND) use in laboratory research animals
or in-vitro testing
b. To conduct R&D work prior to the submission of an IND
c. Product cannot be used in humans
d. Must comply with all the requirements under 21 CFR 312.160
e. Includes both APIs and finished drug products
f. Labeling (Must):
• “Caution: Contains a new drug for investigational use only in laboratory
research animals, or for tests in-vitro. Not for use in humans”
g. Useful Information:
• API product name
• Name and address of API manufacturer
• API label content demonstrating compliance with 21 CFR 312.160
D. MISBRANDING - Adequate Directions for Use [502(f)(1) & 21 CFR
201.5]: “directions under which a layman can use the drug safely”
1. All drugs, including APIs, must bear “adequate directions for use” or meet one
of the exemptions. If not, then misbranded [502(F)(1)].
2. Only OTC finished drug products can meet this requirement. All other drugs
must meet one of the exemptions
E. MARKETING – REQUIREMENTS & USEFUL INFORMATION:
1. OTC pending and final monograph drugs:
a. Labeling (Must):
• “Caution: for manufacturing, processing, or repacking”
b. Useful Information:
• Name and NDC # of product to be manufactured with the API
• A statement justifying why an approval is not required for the finished
drug product
• API label content demonstrating compliance with 21 CFR 201.122
Importation of Active Pharmaceutical Ingredients (APIs) Requirements
7-16-08 FDA NYK-DO API Seminar Presentation Notes (Tab A)
7-16-08 FDA NYK-DO API Seminar Presentation Notes (Tab A) - 7
2. Pharmacy Compounding
a. Labeling (Must):
• “For Prescription Compounding”
• “Rx only”
b. Useful Information:
• API is a component of an FDA approved drug
• API meets official compendial requirements when applicable
Example: Certificate of Analysis
• Drug has not been withdrawn or removed from the U.S. market for public
health reasons (list in CPG 460.200)
• API product name and NDC #
• Name of API manufacturer and registration number
• A written commitment that the API will be sold and used solely for
pharmacy compounding by a state licensed pharmacy or federal facility
• A written commitment that the drug has not been withdrawn or removed
from the U.S. market for public health reasons
3. Pre-Submission Batches: (Batches used to conduct the studies necessary to
generate data required to submit an application or supplement
Example: Bioequivalence, bioavailability, and stability batches)
a. Useful Information:
• API product name and NDC #
• Name and address of the API manufacturer
• Name and address of U.S. consignee
• Product must be labeled as per 21 CFR 201.122
• For supplements - may include number of NDA/ANDA to be
supplemented and NDC # of finished product
b. Written commitment that product manufactured with API will not be
introduced in commercial distribution until approved
c. Explanation that API is intended to generate data to submit an application/
supplement
Example: Bioequivalence and/or bioavailability batches
Importation of Active Pharmaceutical Ingredients (APIs) Requirements
7-16-08 FDA NYK-DO API Seminar Presentation Notes (Tab A)
7-16-08 FDA NYK-DO API Seminar Presentation Notes (Tab A) - 8
4. Prescription (Rx) drugs not currently subject to application requirements:
a. Labeling (Must):
• “Caution: For manufacturing, processing, or repacking”
• “Rx only”
b. Useful Information:
• Name and NDC # of product to be manufactured with the API
• A statement justifying why an approval is not required for the finished
drug product
• API label content demonstrating compliance with 21 CFR 201.122
F. DATABASES:
1. Drug Master Files (DMFs):
a. Contain API chemistry and manufacturing control information
b. Are submitted to FDA voluntarily by the API manufacturer
c. NDA/ANDA sponsors may elect to refer to a an API DMF in their
application
d. Are not approved by FDA
e. They are reviewed by FDA in reference to a submission and are judged to be
either adequate or inadequate with regard to that submission
f. May be referenced in multiple applications
g. May be associated with both approved and unapproved applications
h. A DMF number is not sufficient to show that the API supplier is approved in
an application

Guidance Regarding Importation of API into the United States

A 2008 FDA seminar provided the following information regarding importation of API into the United States:
Pharmacy Compounding
a. Labeling (Must):
• “For Prescription Compounding”
• “Rx only”
b. Useful Information:
• API is a component of an FDA approved drug
• API meets official compendial requirements when applicable
Example: Certificate of Analysis
• Drug has not been withdrawn or removed from the U.S. market for public
health reasons (list in CPG 460.200)
• API product name and NDC #
• Name of API manufacturer and registration number
• A written commitment that the API will be sold and used solely for
pharmacy compounding by a state licensed pharmacy or federal facility
• A written commitment that the drug has not been withdrawn or removed
from the U.S. market for public health reasons

The remainder of the seminar outline can be found here.

FDA Warning Letter to Sichuan Pharmaceutical Co., Ltd./ API from China

Warning Letter

VIA UPS MAIL

WL: 320-11-019

September 09, 2011

Mr. Wang Gouping
General Manager
Sichuan Pharmaceutical Co., Ltd.
No. 189 Hualong Road
Pengzhou, Sichuan, China 611930

Dear Mr. Gouping:

During our June 23 to 29, 2010 inspection of your active pharmaceutical ingredient (API) manufacturing facility, Sichuan Pharmaceutical Co., Ltd. located at No. 189 Hualong Road, Pengzhou, Sichuan, China, an investigator from the Food and Drug Administration (FDA) identified significant deviations from Current Good Manufacturing Practice (CGMP) for the manufacture of APIs. These deviations cause your API(s) to be adulterated within the meaning of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (the Act) [21 U.S.C. § 351(a)(2)(B)] in that the methods used in, or the facilities or controls used for, their manufacture, processing, packing, or holding do not conform to, or are not operated or administered in conformity with, CGMP.

We have reviewed your firm’s response of August 05, 2010 and December 13, 2010, and note that it lacks sufficient corrective actions.
Specific deviations observed during the inspection include, but are not limited, to the following:

1. Failure to have appropriate procedures in place to prevent cross-contamination.

From September 2008 to July 2009 your firm manufactured (b)(4) API in workshop (b)(4), which is adjacent to workshops (b)(4) and (b)(4) where you manufactured (b)(4) API and (b)(4) injection, respectively. However, you failed to have adequate controls and monitoring program to prevent cross-contamination between these adjacent workshops.

In addition, your firm manufactures a (b)(4) API ((b)(4) (API) in a facility that was previously used to manufacture (b)(4) without conducting adequate decontamination, renovation, and activation of the facility. Your firm has failed to conduct adequate assessment of the cross-contamination risks.

Please note that analytical testing of a product for possible contamination with (b)(4) is not sufficient to ensure adequate conditions for (b)(4) manufacture. In your response to this letter include your plans for decontamination, renovation, and reactivation (if appropriate) of your facility including the decontamination agent, decontamination plans, analytical methodology for environmental and product testing, and the data obtained to support the effectiveness of the decontamination plan.

The deviations detailed in this letter are not intended to be an all-inclusive statement of deviations that exist at your facility. You are responsible for investigating and determining the causes of the deviations identified above and for preventing their recurrence and the occurrence of other deviations. If you wish to continue to ship APIs to the United States, it is the responsibility of your firm to ensure compliance with all U.S. standards for CGMP and all applicable U.S. laws and regulations.

Additionally, your firm is neither registered nor has it listed every API in commercial distribution in the United States with FDA, as required by 21 C.F.R. § 207.40 and section 510(i) of the Act [21 U.S.C. § 360(i)]. Information on how to register and list is available at the following internet website:http://www.fda.gov/cder/drls/registration_listing.htm. You must complete the required registration and listing and provide evidence that you have fulfilled these requirements in your response to this letter.

Until all corrections have been completed and FDA has confirmed corrections of the deviations and your firm’s compliance with CGMP, FDA may withhold approval of any new applications or supplements listing your firm as an API manufacturer. In addition, failure to correct these deviations may result in FDA refusing admission of articles manufactured at Sichuan Pharmaceutical Co., Ltd. located at No. 189 Hualong Road, Pengzhou, Sichuan, China into the United States. The articles are subject to refusal of admission pursuant to section 801(a)(3) of the Act [21 U.S.C. § 381(a)(3)] in that the methods and controls used in their manufacture do not appear to conform to Current Good Manufacturing Practice within the meaning of section 501(a)(2)(B) of the Act [21 U.S.C. § 351(a)(2)(B)].

Within fifteen working days of receipt of this letter, please notify this office in writing of the specific steps that you have taken to correct deviations. Include an explanation of each step being taken to prevent the recurrence of deviations and copies of supporting documentation. If you cannot complete corrective action within fifteen working days, state the reason for the delay and the date by which you will have completed the correction.

Additionally, your response should state if you no longer manufacture or distribute (b)(4) API and provide the date(s) and reason(s) you ceased production. Please identify your response with FEI # 3002808073.

If you have questions or concerns regarding this letter, contact Milva E. Meléndez, Compliance Officer, at the below address and telephone number.

U.S. Food and Drug Administration
Center for Drug Evaluation and Research
Office of Manufacturing and Product Quality
Division of International Drug Quality
White Oak, Building 51
10903 New Hampshire Ave
Silver Spring, MD 20993
Tel: (301) 796-0662
Fax: (301) 847-8741

Sincerely,

/Steven Lynn/
Steven Lynn
Director
Office of Manufacturing and Product Quality
Office of Compliance