FDA 2011 Pharmaceutical GMP Enforcement

Press Announcement FDA News Release- Permanent injunction - Hill Dermaceuticals Inc. and Hill Labs, Inc.

McNeil - PPC ....The U.S. Food and Drug Administration announced March 10, 2011 that a consent decree of permanent injunction has been filed against McNeil-PPC and two of its officers for failing to comply with current Good Manufacturing Practice (cGMP) requirements. Multiple manufacturing facilities are involved.

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Pharmaceutical - Warning Letters

SmithKline Beecham Warning Letter:

FDA issued a warning letter on October 7, 2011. Among serveral GMP violations, the firm was issued one of the most frequently issued citations related to microbiological contamination:

"...Your firm has not established appropriate written procedures designed to prevent microbiological contamination of drug products purporting to be sterile [21 C.F.R. 211.113(b)]. "

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Below are Failure Investigation-related excerpts from three recent cGMP Warning Letters listed below:

• “Your firm has not thoroughly investigated the failure of a batch or any of its components to meet its specifications whether or not the batch has already been distributed [21 C.F.R. 211.192] ..."
• “…your firm failed to conduct an investigation after a number of…failed to meet release specifications…”
• “…your firm has yet to address the failure to investigate the Out-of-specification (OOS) results and identify a root cause.”
• “You are responsible for investigating and determining the causes of the violations identified above…”
• “…the root cause analysis provisions do not include extending the investigation to other lots…”
• “Lack of…product failure investigations are repeat violations…”
• “…you did not provide copies of the investigations…”
• “Your firm failed to conduct an investigation for numerous OOS results…”
• “The inspection identified a pattern of your firm failing to follow procedures.”

1. Luitpold Pharmaceuticals  - August 31, 2011
2. Deibel Labs  - September 1, 2011
3. Lonza Biologics - September 1, 2011

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Noven Pharmaceuticals, Inc..... August 25, 2011

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Ningbo Smart Pharmaceutical Co. .... March 30, 2011

Cordis LLC ... February 16, 2011

"We find objectionable that products complying with the release compliance test but failed the...design specification test and your CAPA ... failed to address this nonconformance and allowed products to be released based on the compliance test results only."

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Baxter Healthcare... January 20, 2011

Multiple SHOCKING GMP Violations cited in this Warning Letter. Below are a few excerpts:

"...failed to thoroughly investigate..."

"...your firm released 17 lots of product that were at risk of cross contamination to the market..."

"...insect found in the intravenous solution..."

"...product defects..."

"...dirt reported..."

"Your firm identified the root cause...one year prior to initiating the recall."

"...shipment of product with critical defects to the marketplace..."

"Product defects...began receiving complaints in 2004...at least 199 complaints since then..."

"...your firm identified 542 incidences through consumer complaints of product complaints."

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Scientific Protein Laboratories LLC...January 20, 2011

"Failure to investigate all quality related complaints whether received orally or in writing according to a written procedure. For example, your firm failed to conduct a formal investigation concerning a complaint identifying potential contamination...on October 9, 2008. Your firm did no initiate a formal investigation until September 9, 2009.

"...your firm failed to extend your investigations..."

Related to complaint handling, "The manner in which you addressed this problem is very worrisome with respect to the timeliness of the investigation, the identification of all potentially affected drugs, and implementing appropriate actions to resolve these issues."

"Your firm failed to properly evaluate a contract to ensure GMP compliance of operations occurring at the contact site. For example, our investigators identified that your firm had failed to audit the contact testing laboratory...utilized in testing your...product, as required in your Standard Operating Procedure (SOP)...As a result, your firm conducting an audit of the contract laboratory prior to the close of the FDA inspection and identified "Critical and Major" deficiencies."

"As a result of your failure to ensure that...was in compliance with GMP you submitted data to FDA that was not accurate...in numerous instances (contract testing laboratories)...reporting passing results to your firm after failing results were obtained."

"However, we are concerned about your firm's fundamental understanding of what is required by your Quality Unit and the regulatory expectations for a firm that enters in agreements with contract testing laboratories."

"Failure to have equipment for the manufacture of APIs of appropriate design for its intended use" ...your firm uses inappropriate equipment..."

"In addition, your firm has not demonstrated that the proposed corrective action is adequate to ensure that your product is not contaminated with foreign material."

"Failure to follow procedures for evaluating suppliers of critical materials. For example, your firm failed to audit your suppliers at least once every two years as required by your SOP..."

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Hawkeye-Jensen, Inc. ...February 8, 2011

Warning Letter outlining several Part 211 violations related to process validation. Here are some excerpts

"Your firm has not validated the water system used in the manufacture of drug products..." Water analysis results "...insufficient to demonstrate your water system is in a state of control."

Your firm... "was using ...media plates for microbiological assessment that were seven years past expiration with no validation data to support this action."

"In your August 2010 response, your firm states you will validate the cleaning process...We are concerned about the length of time your firm has needed to develop and implement cleaning validation plans..."

Here's another except from the same warning letter on Feb. 8th with a Part 211 Subpart B- Organization and Personnel violation:

"Your firm has failed to follow written responsibilities and procedures applicable  to the quality control unit. - 21 C.F.R. 211.22(d)"

"At the time of inspection, your Quality Manager repeatedly stated that QCU responsibilities were not fulfilled due to a lack of resources (e.g. money, time, personnel). Be advised that a lake of resources is not an acceptable response for your firm's failure to comply with CGMP regulations. It is a requirement under 21 C.F.R. 211.25 (c) to ensure that your firm has an adequate number of qualifed personnel to perform daily operations."

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New GMP Guidance Document

Download FDA's Newly issued Process Validation Guidance Document - Click here  

See bottom of this page for process validation warning letter excerpts...

Pharmaceutical GMP Regulations

Current Good Manufacturing Practice In Manufacturing, Processing, Packing or Holding of Drugs: General Part 210 -Click Here

Current Good Manufacturing Practice For Finished Pharmaceuticals - Part 211 - Click Here

Help ensure your company's compliance with FDA regulations with the Part 211 e-Textbook.

Electronic Records; Electronic Signatures - Part 11 - Click Here

FDA Enforcement of Process Validation is increasing...

Recent Warning Letters excerpts:  

 
“There was no process validation study…” 
Smith & Nephew 
 
“…you had not performed validation of the manufacturing process…” 
Synbiotics 
 
“…nor had you established a process design, a validation plan, or qualification protocols” 
CP Pharmaceuticals
 
“Your firm failed to provide validation protocols that evaluated the impact of the increasing batch size on product quality…Further, your firm uses a “Master Validation Plan” for process validation on all products. Validation must be demonstrated for each product and process.” 
Contract Pharmacal Corp. 
 
“Failure to validate (product) to ensure that devices conform to defined user/patient needs and intended uses, as required by 21 C.F.R. § 820.30(g).”
 
“Failure to establish procedures and to validate a process whose results can not be fully verified by subsequent inspection and test, as required by 21 C.F.R. § 820.75(a).”
OsteoSymbionics 
 
“…your firm failed to perform process validation for three USP products: This is a repeat observation.  The June 2001 FDA inspection reported that your firm failed to conduct process validation studies for (product) a USP product manufactured at your facility. “
 
“Your firm failed to perform stability studies for (product) to support the (product) year expiration date currently assigned.  This is a repeat observation.  The June 2001 FDA inspection documented your failure to perform stability studies on (product), a USP product manufactured at your facility.”
 
“Your firm failed to perform cleaning validation studies to support the use of "city water" to clean all your equipment.” 
Macco Organiques 
 
“Your firm has failed to establish and document the accuracy, sensitivity, specificity, and reproducibility of test methods [21 C.F.R. § 211. 165(e)]. 
 
For example, your firm performed analytical method transfers for 236 protocols without determining whether those methods had been properly validated by your clients.”
Advanced Testing Laboratory 
 
“…your firm has not conducted performance qualification for the unit-dose packaging machine to ensure its proper performance.” 
 
Your “…response is inadequate in that it fails to adequately describe how and on which pieces of equipment qualification will be performed.” 
Shamrock Medical Solutions Group 
 
“…you have not validated the manufacturing processes for the following drug products…” 
Benev Company 
 
“…during the process qualification stage of the process validation for (product) you made equipment and process modifications without adequate change control.” 
IriSys, Inc. 
 
“…we are concerned about the length of time your firm has needed to develop and implement its Validation Prioritization Plan …” 
Hospira 
 
“We disagree with your assessment and we do not consider your process validated. Your investigation report conclusion was based on finished product test results alone, and did not consider in-process testing and analyses.” 
Gilead Sciences