FDA’s CDER LISTING OF TOP NINETEEN OBSERVATIONS FOR 2014

TOP FOUR OBSERVATIONS REMAIN SIMILAR IN NUMBER TO 2013

Each fiscal year the FDA issues the various FDA 483 Observations from the various Centers to include CBER, CDER, CDRH, etc.  This Blog focuses only upon those issued by the Center for Drug Evaluation and Research (CDER) and will concentrate upon those found within 21 CFR Part 211.  Interestingly, while the order of the Observations has remained relatively constant within the top four, the number of Observations has markedly increased in numbers (from 340 in 2012 to 491 in 2013 to 645 in 2014).  This appears to be partially because of the large number of Form FDA 483s arising from citations at various compounding facilities.

21 CFR 211.192 was listed as two sets of Observations.  The first, which was ranked third in 2014, was defined as “investigations of discrepancies/failures” (94 Observations), while the second set was defined as “written record of investigation incomplete” (38 Observations).

Of particular interest to my readers should be 21 CFR 211.113 (b) which pertains to the manufacture of sterile drug products.  In 2012 this Observation was considerably lower in terms of numbers of Observations noted (<43) than 2014 when a total of 109 Observations were recorded.  Please note that within 21 CFR 211.113(b) that two different sets of Observations were recorded wherein 72 referenced “procedures for sterilizing drug products” and 37 referenced “validation lacking for sterile drug products”.

One should also be aware that the FDA, and CDER, in particular, use an internal electronic system to assist in positioning an Observation.  This system called TURBO EIR is designed to provide the most pertinent Observation vs. the information collected by the FDA auditor.  While this system is “painted” by the FDA as providing the most fool-proof method of providing the correct citation, it is especially notable within the area of microbiology that this often does not occur and one should question the number of microbiological citations, i.e., 21 CFR 211.113 (a)/(b) – especially when one studies 21 CFR 211.192 and recognizes that several of citations should not have been “192”, but 211.113(b).

   

 

Reference Number

Short Description   Frequency
21 CFR 211.22(d) Procedures not in writing, fully followed 145
21 CFR 211.160(b) Scientifically sound laboratory controls 109
21 CFR 211.192 Investigations of discrepancies, failures 94
21 CFR 211.100(a) Absence of Written Procedures 87
21 CFR 211.67(b) Written procedures not established/followed 72
21 CFR 211.113(b) Procedures for sterile drug products 72
21 CFR 211.165(a) Testing and release for distribution 64
21 CFR 211.67(a) Cleaning / Sanitizing / Maintenance 63
21 CFR 211.68(a) Calibration/Inspection/Checking not done 54
21 CFR 211.166(a) Lack of written stability program 51
21 CFR 211.110(a) Control procedures to monitor and validate performance 51
21 CFR 211.198(a) Complaint Handling Procedure 47
21 CFR 211.25(a) Training–operations, GMPs, written procedures 46
21 CFR 211.100(b) SOPs not followed / documented 43
21 CFR 211.188 Prepared for each batch, include complete information 43
21 CFR 211.42(c)(10)(iv) Environmental Monitoring System 42
21 CFR 211.63 Equipment Design, Size and Location 41
21 CFR 211.192 Written record of investigation incomplete 38
21 CFR 211.113(b) Validation lacking for sterile drug products 37
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2015 United States Pharmacopeia (USP) Microbiological General and Information Chapters Training Program

7-Part Live Training Program

Starts September 30, 2015

Instructor: Barry A. Friedman Ph.D. Biography>>>

Click Here to Learn More and to Register for this Live Training Program

The United States Pharmacopeia (USP) contains a number of chapters relating to microbiology within its General and General Information Chapters. These Chapters present information that relate to both non-sterile and aseptic processing. Several of these chapters have been recently updated and all have been updated since 2009. Each of these Chapters has relevance to each other and provides a significant knowledge base of microbiological requirements. Several of these have also been harmonized and permit one to not only follow the USP, but simultaneously meet the requirements of both the European and Japanese Pharmacopeia.

This intensive annual live training program on the topic of USP Microbiological General and Information Chapters will consist of 7 live training sessions of 2 hour presentations followed by 30 minutes of live Q&A each. It will include over 17 hours of live presentation and Q&A delivered periodically over the course of 3 months. The method of delivery proves effective in providing trainees with ample time to absorb, process, and put to use the information learned, and then return to the next session with any questions, as opposed to condensing this intensive training program’s curriculum into a short seminar, and thereby saturating the audience with an overload of information.

The design and preparation of this program’s content is a result of years of practical industry experience on the part of the presenter, Dr. Friedman, ensuring that trainees will be provided with the most up to date and practical information on the topic. This multi-part live training program is instructed by Dr. Barry Friedman, who has over thirty years of experience in pharmaceuticals, biotechnology and regulatory compliance. He has worked with both large and small pharmaceutical and biotechnology companies on various aspects of non-sterile and sterile microbiology to include auditing, method validation and regulatory compliance.

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VUAB PHARMA, CZECH REPUBLIC, RECEIVES WARNING LETTER (MAY 27, 2015, con’t)

Objectionable Bacillus spp. Found During Customer Sampling 

During the FDA’s inspection of VUAB Pharma a.s., Vltayska 53, Roztoky, Czech Republic, from June 09, 2014, through June 13, 2014, an investigator from the U.S. Food and Drug Administration (FDA) identified significant deviations from current good manufacturing practice (CGMP) for the manufacture of active pharmaceutical ingredients (APIs). On May 27, 2015 the FDA subsequently issued a Warning Letter. This followed the issuance of an Import Alert on April 10, 2015.

During the June 2014 audit, the investigator observed specific violations during the inspection, including, but not limited to, the following. The enclosed represents “Part B” of Observation 1.

In April 2014, your firm received a customer complaint concerning Bacillus spp. contamination of (b)(4), API lot (b)(4). Your tests of the returned customer samples confirmed microbial contamination, including both high levels of bioburden and Bacillus spp. contamination.  During your investigation, your firm did not extend the investigation to any other batches potentially affected. In addition, deficient sampling procedures compromised your firm’s ability to detect the contamination your customer found. Your firm sampled (b)(4) per batch and had no statistical justification that this sample was representative of the entire batch.

COMMENT: 

21 CFR 211.192 Production Record Review states that “investigation shall extend to other batches of the same drug product and other drug products that may have been associated with the specific failure or discrepancy. A written record of the investigation shall be made and shall include the conclusions and follow-up.”  In this particular Warning Letter, this did not occur.  211.192 represents one of the ten most common Observations that the FDA lists on an annual basis.  Please visit my Blog site to view its frequency as well as the frequency of other oft cited Observations. Statistical evaluations based on the American Society for Quality (ASQ) also represent a reliable source for statistical justification.

While your response focuses on detecting future contaminations prior to release, it fails to adequately identify the potential root causes of the contamination. Your response states that you have updated your Final Product Adjustment SOP and Product Homogenization SOP to add a step: (b)(4), API. However, you have no data to support this will adequately remediate the contamination issues.

Your response states that you will now sample from (b)(4) those samples before testing. While your response proposes using (b)(4) samples, your customer complaint shows that (b)(4) samples are not representative. For example, the returned sample from lot (b)(4) container number (b)(4) had gross contamination of 4,800 cfu/g; while returned samples from the other (b)(4) containers ranged from (b)(4) to (b)(4) cfu/g, within specification.   We are concerned that testing a (b)(4) sample could mask an out-of-specification (OOS) result for a single container.

In response to this   letter, provide data and information from a detailed root cause investigation into the source of this contamination. In addition, provide a summary of your investigation into other batches potentially affected by this contamination, including testing of retain samples of all potentially affected batches. Furthermore, revise your sampling plans to ensure they are statistically appropriate and non-uniform contamination can be detected. The revisions should encompass finished API testing, in-process testing, and raw material acceptance testing. 

COMMENT:

Non-uniform contamination represents a difficult area when it comes to microbiological detection of organisms.  Individual containers must be tested and cannot be composited in these cases where it is suspected because of the potential for one container with “gross contamination” masking the balance of the tested containers.

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VUAB PHARMA, CZECH REPUBLIC, RECEIVES WARNING LETTER (MAY 27, 2015)

Objectionable Anaerobe Found During Customer Sampling

During the FDA’s inspection of VUAB Pharma a.s., Vltayska 53, Roztoky, Czech Republic, from June 09, 2014, through June 13, 2014, an investigator from the U.S. Food and Drug Administration (FDA) identified significant deviations from current good manufacturing practice (CGMP) for the manufacture of active pharmaceutical ingredients (APIs). On May 27, 2015 the FDA subsequently issued a Warning Letter. This followed the issuance of a Import Alert on April 10, 2015.

During the June 2014 audit, the investigator observed specific violations during the inspection, including, but not limited to, the following.

  1. Failure to adequately investigate and resolve all quality-related customer complaints, and to investigate other batches that may have been associated with specific failures.

Your quality unit released API with objectionable microbial contamination into distribution. For example,

  1. In January 2014, your firm received a customer complaint regarding microbial contamination of (b)(4), API lot (b)(4). Your customer tested samples of this lot produced by your firm and identified Clostridium sphenoides. During your customer complaint investigation, you were unable to detect the contamination in the samples your customer returned. Your customer’s May, 2014, on-site audit of your firm revealed differences in microbiological test methods: your test method was inadequate to detect Clostridium sphenoides growth. Once you modified the test method per your customer’s recommendation, your firm confirmed Clostridium sphenoides contamination in your retain sample. However, you failed to identify the source of the contamination or to implement meaningful corrective actions to prevent future microbial contamination.

COMMENT: 

Correct test methodology is quite important to assuring that a procedure is being properly performed.  Several USP test methods to include USP<61> and USP<62> are available to assist with the proper testing protocol. However, as noted within the above paragraph, the microorganism that was avoiding detection was an anaerobe, and would have required modifications to the standard USP<61>/<62> methodologies. Thus, when attempting to follow a USP monograph, it remains quite important to understand both what is within as well as what remains outside of the monograph.

Test results exhibiting objectionable microbial contamination represent a significant deficiency in the safety and quality of your APIs. Since microbial contamination is typically non-uniform, the risk of patient exposure to a contaminated drug is exacerbated by low detectability of a test of limited sample size.  In addition, your customers may not perform any additional microbiological testing upon receipt of your API.  Furthermore, objectionable microbiological contamination in your API, which is intended for (b)(4) and (b)(4) suspensions, indicates a significant failure in your capability to prevent microbiological contamination in your operation.

COMMENT: 

21 CFR 211.160 General Requirements (b) states that “laboratory controls shall include the establishment of scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that components, drug product containers, closures, in-process materials, labeling, and drug products conform to appropriate standards of identity, strength, quality and purity…(b)(1) Samples shall be representative and adequately identified…(b)(2) Such samples shall be representative and properly identified. “

And although a non-U.S. customer made this complaint, the Agency is concerned about your firm’s poor investigation because you manufacture (b)(4), API, using common equipment, materials and personnel in the operation, regardless of the destination of a given batch.

Your response states that you will retroactively test (b)(4) batch per (b)(4) to cover January, 2013, to June, 2014, when you implemented the modified test method. However, your rationale for testing (b)(4) batch per (b)(4) is not scientifically sound. This approach does not evaluate all batches that could be contaminated with objectionable organisms. It relies on the false assumption that retroactively testing a limited number of API batches will assure that all batches distributed to customers were of acceptable quality. Your investigation did not sufficiently pursue or determine root causes. Corrections you have described are insufficient.

COMMENT: 

When perform testing for Out of Specifications (OOS) or Corrective/Preventive Actions (CAPA), one must recall that this is not the time to use ASQ skip lot testing techniques. Nor is it the time to take samples that are less than of a scientifically sound size.

In addition, you do not mention any improvements to your procedure for deviation and corrective action and preventive action (CAPA) management. Please note that your senior management is responsible for ensuring the quality and safety of your APIs.  Additionally, your senior management is responsible for assuring quality defects are thoroughly investigated and resolved quickly as well as for preventing the distribution of defective APIs.

In response to this letter, provide an accelerated timeline for completing retroactive testing of all potentially affected batches and a commitment to respond with all results promptly. Also provide a detailed update on whether your firm has determined root cause of this contamination problem and implemented any further risk controls. Provide your improved deviation and CAPA management procedure, as well as a review of all microbial test methods to ensure they are suitable for their intended use. Finally, provide documentation of all changes implemented as a result of your review and remediation of these issues.

COMMENT: 

Microbial contamination problems are often difficult to determine as to the “root cause”. The microbial test methods can be verified or validated; however, even assuring that they are acceptable for the intended method may not assure the determination of the “root cause”.

 

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INSPECTION TRACKER: DRUG MANUFACTURING ESTABLISHMENTS (CANADA)

 

Health Canada Begins Publishing Information Regarding Emerging Issues

As part of Health Canada’s ongoing commitment to openness and transparency, the Department recently began publishing information regarding emerging issues identified through the drug inspection program.

This tracker provides a snapshot of the potential health and safety issues Health Canada is tracking with companies that fabricate, package/label, test, wholesale, distribute or import drugs for sale in Canada. The information in the chart will expand to eventually include details about affected Canadian companies and products.

How the Inspection Tracker Works

  1. Health Canada responds to potential risks as soon as they learn about them whether from their own inspections, the companies themselves, adverse reaction reports or from various regulatory partners.
  2. The tracker highlights actions Health Canada is taking such as: requests for voluntary quarantine, stop sales, import restrictions, or product recalls. It also indicates those circumstances where no action has been warranted.
  3. Even if a company is listed on the tracker, it doesn’t necessarily mean there is an immediate risk to the health of Canadians. It means Health Canada is looking into a potential issue.
  4. Health Canada will continue to take action to manage risks identified to the health of Canadians using the most appropriate level of intervention, proportional to the risk to health.
  5. This tracker currently doesn’t list specific drugs and health products affected but links to Recalls & Safety Alerts if a risk has been linked to specific products on the Canadian market.
  6. This tracker is updated regularly.
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Sagent Pharmaceuticals Recall due to FDA Observations Pertaining to Aseptic and GMP Practices at the Manufacturer’s Site Potentially Impacting Product Sterility

Sagent Pharmaceuticals, Inc. Schaumburg, IL announced on February 23, 2015 the voluntary nationwide recall of two lots of Atracurium Besylate Injection, USP, 50mg/5mL single-dose vials (NDC 25021-659-05) and four lots of Atracurium Besylate Injection, USP, 100mg/10mL multi-dose vials (NDC 25021-672-10) manufactured by Emcure Pharmaceuticals Ltd. and distributed by Sagent.

Sagent has initiated this voluntary recall of Atracurium Besylate Injection, USP, 50mg/5mL and 100mg/10mL to the user level due to FDA observations pertaining to aseptic and GMP practices at the manufacturer’s site potentially impacting product sterility. Non-sterility of a drug administered via the intravenous route has the potential to result in infections, which could be fatal, especially in patients who are immunocompromised.

Sagent has transferred the manufacture of this product to its own facility and this product manufactured at the Sagent facility will not be impacted by the recall.

Sagent is not aware of any adverse patient events resulting from the use of the subject product lots.

The lot numbers being recalled are VATA012, VATA015 (50mg/5mL) and VATB012, VATB013, VATB014, VATB017 (100mg/10mL) which were distributed to hospitals, wholesalers and distributors nationwide from February 2014 through February 2015.

Atracurium Besylate Injection, USP, 50mg/5mL and 100mg/10mL is indicated, as an adjunct to general anesthesia, to facilitate endotracheal intubation and to provide skeletal muscle relaxation during surgery or mechanical ventilation, and is supplied in single-dose and multi-dose vials.

 

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2015 United States Pharmacopeia (USP) Microbiological Training Program — 9-Part Live Training Program Instructor: Barry A. Friedman Ph.D.

STARTS THURSDAY, MARCH 19, 2015

The United States Pharmacopeia (USP) contains a number of chapters relating to microbiology within its General and General Information Chapters. These Chapters present information that relate to both non-sterile and aseptic processing. Several of these chapters have been recently updated and all have been updated since 2009. Each of these Chapters has relevance to each other and provides a significant knowledge base of microbiological requirements. Several of these have also been harmonized and permit one to not only follow the USP, but simultaneously meet the requirements of both the European and Japanese Pharmacopeia.

This intensive 9-Part annual live training program on the topic of Microbiological General and General Information Chapters will consist of 9 live training sessions of 2 hour presentations followed by 30 minutes of live Q&A each. It will include over 22 hours of live presentation and Q&A delivered periodically over the course of five months. The method of delivery proves effective in providing trainees with ample time to absorb, process, and put to use the information learned, and then return to the next session with any questions, as opposed to condensing this intensive training program’s curriculum into a short seminar, and thereby saturating the audience with an overload of information. The design and preparation of this program’s content is a result of years of practical industry experience on the part of the presenter, Dr. Friedman, ensuring that trainees will be provided with the most up to date and practical information on the topic. This live training program is instructed by Dr. Barry Friedman, who has over thirty years of experience in pharmaceuticals, biotechnology and regulatory compliance. He has worked with both large and small pharmaceutical and biotechnology companies on various aspects of non-sterile and sterile microbiology to include auditing, method validation and regulatory compliance.

The complete course agenda detailing each individual session can be found below at:  http://www.pharmawebinars.com/usp-microbiological-training-program-9 

http://www.pharmawebinars.com/usp-microbiological-training-program-9

Posted in FDA Compliance, Microbiological Issues, New Guidances for Industry, On-Site Training | Tagged , , , , , , | Leave a comment