FDA CDER Most Frequent Form FDA 483 Observations Fiscal Year 2012

COMMENT

Each year CDER summarizes the number of significant Observations obtained from Form FDA 483s.  Enclosed are the “top fifteen” Observations.  The Observations within the top fifteen usually do not change — although their frequency and ranking may vary. Please note that the frequencies of various Observations have markedly increased in FY 2012.  Where a specific section is indicated, the Reference Number indicates the overall paragraph. You may wish to review this list with your own facility operations.  Please review 21 CFR Part 211 for additional specifics. 

Ref No	Freq	Short Description
21   CFR 211.22(d)	169	Procedures not in writing, fully followed
21   CFR 211.192	119	Investigations of discrepancies, failures
21   CFR 211.100(a)	116	Absence of Written Procedures
21   CFR 211.160(b)	115	Scientifically sound laboratory controls
21   CFR 211.110(a)	89	Control procedures to monitor and validate performance
21   CFR 211.67(b)	73	Written procedures not established/followed
21   CFR 211.68(a)	69	Calibration/Inspection/Checking   not done
21   CFR 211.25(a)	65	Training–operations, GMPs, written procedures
21   CFR 211.67(a)	65	Cleaning/Sanitizing/ Maintenance
21   CFR 211.100(b)	64	SOPs not followed/documented
21   CFR 211.165(a)	62	Testing and release for distribution
21   CFR 211.188	56	Prepared for each batch, include complete information
21   CFR 211.25(a)	54	GMP Training Frequency
21   CFR 211.63	54	Equipment Design, Size and Location
21   CFR 211.113(b)	47	Procedures for sterile drug products

APOTEX INC RECEIVES WARNING LETTER FOR MULTIPLE CANADIAN SITES (2/21/13) PART II

FDA INVESTIGATOR FINDS INACCURATE REPORTING OF MICROBIOLOGICAL DATA

The FDA, during August and October 2012 inspected two Apotex, Inc. sites.  This Blog only discusses the facilities located at 150 Signet Drive, Toronto, Canada.  The U.S. Food and Drug Administration (FDA) identified significant violations of current good manufacturing practice (CGMP) regulations during the audit for finished pharmaceuticals, Title 21, Code of Federal Regulations, Part 210 and 211.

Observation 1 was previously discussed earlier this week.  Observation 3, another relating to microbiology, is noted below.

“3. Your firm failed to ensure that laboratory records included complete data derived from all tests necessary to assure compliance with established specifications and standards (21 CFR 211.194(a)).

For example, on August 22, 2012, an FDA investigator observed your microbiologist reading an environmental monitoring (personnel) plate. The microbiologist reported the result for that plate as zero; however, our FDA investigator observed one (1) colony forming unit (CFU) on the plate.  Your microbiologist corrected this observation on the form WI-MI-150-108-J Microbiology Laboratory after the FDA investigator pointed it out to him.  Your firm did not take further action to investigate and determine the impact of inaccurate reporting of your microbiological plate readings on the release of your batches.

The failure to document positive results for a microbial plate that was confirmed as containing microbial growth raises concerns about the accurate reporting of results in your records.  Accurate and reliable microbial data management is essential to support the reliability of your aseptic manufacturing of finished drug products intended for distribution in the United States.

COMMENT

An investigation and determination of the impact of inaccurate reporting of microbiological plate readings on the release of batches is essential – especially when a FDA investigator, during an investigation of the Client’s site, discovers a non-conformance that the on-site microbiologist has failed to notice.  

As noted within the FDA commentary associated with this Observation, “the failure to document positive results for a microbial plate that was confirmed as containing microbial growth raises concerns about the accurate reporting of results in your records.  Accurate and reliable microbial data management is essential to support the reliability of your aseptic manufacturing of finished drug products intended for distribution in the United States.” 

While the information listed within this Observation does not specify where the positive was observed –only that it came from an “environmental monitoring personnel plate”, the Investigator deemed the missed count to be sufficiently significant to ultimately raise the concern to the level of an Observation within a Warning Letter.  The information provided is insufficient to determine whether it was obtained during a critical operation.  However, the assumption is that it was obtained from an ISO 5 environment. 

The concern regarding the missing of counts within controlled and classified environments has a predecessor within several other Warning Letters that have previously appeared within this Blog.  Within these individual Blogs, several Indian companies, one of which was located in India and the other which was located in Mexico, were cited for having “nil” colonies, where the term “nil” suggested zero counts.  The FDA Investigator, however, noted in both of these situations that bacteria were actually present.  For additional information please review the Cadia Healthcare Ltd India (July 19, 2011) and the Aurobindo Pharma Ltd (August 22, 2011) Blogs that were presented within my WordPress site.

 

 

APOTEX INC RECEIVES WARNING LETTER FOR MULTIPLE CANADIAN SITES (2/21/13)

FIRM FAILED TO ESTABLISH AND FOLLOW PROCEDURES DESIGNED TO PREVENT MICROBIOLOGICAL CONTAMINATION (21 CFR 211.113(b))

The FDA, during August and October 2012 inspected two Apotex, Inc. sites.  This Blog only discusses the facilities located at 150 Signet Drive, Toronto, Canada.  The U.S. Food and Drug Administration (FDA) identified significant violations of current good manufacturing practice (CGMP) regulations during the audit for finished pharmaceuticals, Title 21, Code of Federal Regulations, Part 210 and 211.

1. “Your firm failed to establish and follow appropriate written procedures that are designed to prevent microbiological contamination of drug products purporting to be sterile, and that include validation of all aseptic and sterilization processes (21 CFR 211.113(b)).
For example, you failed to perform adequate unidirectional airflow pattern studies (i.e., smoke studies) for the aseptic filling line used for the production of (b)(4) Injection. The smoke studies did not include examination of airflow during set-up and at points of process intervention.  Moreover, your airflow pattern studies for the class 100 area of the (b)(4) filling line show clear evidence of turbulent airflow in your filling line located in Room (b)(4) both above the (b)(4) just prior to entry into the filling zone and over the stopper bowl adjacent to the filling zone. Although this lack of unidirectional airflow can compromise sterility, you failed to take appropriate action to ensure that your parenteral drug products were protected from these contamination hazards.

COMMENT

Smoke studies in Aseptic Processing Areas (APA) have continued to “gain traction” from the regulatory authorities over the past several years.  Once the APA is “buttoned up”, smoke testing should commence.  As noted above, the studies should be initiated as early as set-up and definitely occur during any process interventions which need to be noted during any aseptic filling activities.  Any lack of unidirectional flow may compromise the integrity of the fill and problems around a stopper bowl are especially notable.

An in situ air pattern analysis should be conducted in all critical areas under dynamic conditions, to demonstrate unidirectional airflow and sweeping action at critical work areas.
These studies should evaluate the impact of aseptic manipulations (e.g., interventions) and equipment design, document the activities performed, and include written conclusions. In your response to this letter, provide a copy of your new smoke study recordings along with supporting documentation.”
“According to your September 14, 2012 response, you committed to conduct smoke studies by December 31, 2012.  In your response to this letter, provide an update of all airflow pattern studies conducted, your evaluation of the results, and your proposed corrective and preventive actions.  In addition, provide your risk assessment for all sterile products within expiry that were manufactured under these unacceptable conditions.”

COMMENT

When regulatory agencies determine that sterile products may not have been manufactured under acceptable conditions, it is not unusual for them to request a risk assessment for all sterile products that have not expired that were manufactured under these adverse conditions.  In addition, while it is not noted here, regulators also often request a separate “scientific rationale” as to why these products should not be recalled.  While the FDA has requested an update of the data and an evaluation of the results, there is also no mention of a demonstration of the successful completion of these studies through visual monitoring (photographic results) of successful smoke studies to include a script that describes each of the scenes, e.g., the historic movement of smoke around the stopper bowl and the activities that were completed to demonstrate the changes that were initiated within this critical area.

“In addition, your firm failed to establish maximum holding times for vials used in media fills, prior to incubation. Your media fill protocol for batch (b)(4) does not establish a set timeframe between completion of filling vials and placing filled vials in the incubators.  Our investigator found that, during a media fill operation you filled the vials on July 24 and July 25, 2012, and did not incubate them until July 30, July 31, and August 1, 2012. Your manager attributed the delay to lack of space to perform the visual inspection and to personnel resource constraints.  Upon completion of filling the media fill vials, the vials should be incubated under conditions (time and temperature) adequate to allow detection of microorganisms that might otherwise be difficult to culture.  Data should be maintained to show monitoring of, and conformance to, those conditions.

COMMENT

Media fills should have Batch Records and SOPs to support them.  The time that is set between the final filled vial and placing the vials within an incubator should be set by the SOPs and/or the Batch Record.  Lack of space for the incubation of media vials is unacceptable.  Gantt Charts or other time lines should be in place to assure that the Company understands any limitations or “bottlenecks” with the incubation of their media fills.  If incubators are lacking, media fills should not be initiated.
Your response indicates that you initiated a change control to have a maximum hold time of (b)(4) from end of filling to start of incubation of the media fill vials.  In your response, provide your justification for the (b)(4) maximum hold time.  In addition, specify the required storage conditions for the media vials during this hold period and their justification.  In your response please also provide a summary of your assessment regarding whether the vial hold conditions between filling and incubation for batch (b)(4) affected the conclusions of your media fill studies, including whether you plan to repeat the studies and the rationale supporting this decision.
COMMENT

The prior paragraph is loaded with potential “bombshells” waiting to explode.  Moving away from standard practices to adapt to a “one of a kind” issue is only going to create problems.  The last sentence “including whether you plan to repeat the studies and the rationale supporting this decision” needs to be considered very carefully — especially if the media studies are not repeated.

JUBILANT HOLLISTERSTIER RECEIVES WARNING LETTER (2/13/13)

ASEPTIC FILLING FACILITY RECEIVES SIGNIFICANT OBSERVATIONS

Jubilant HollisterStier located in Kirkland, Quebec, Canada was audited by the FDA on March 19-26, 2012.  Following the receipt of the Form FDA 483, the Company responded on April 13, 2012 to the Observations and subsequently on May 1, June 1, and August 9, 2012.  The various violations caused the drug products to be adulterated as per Section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act.

For example:

1. Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed (21 CFR 211.192).

For example, on multiple occasions, you failed to perform failure investigations for rejected batches or implement any preventive actions.

The inspection found that your firm failed to perform an investigation for the failure of (b)(4) Injection (b)(4) mg/ml lot (b)(4) to meet in-process pH requirements. This failing pH result was confirmed by your QC laboratory.

Additionally, you rejected filled (b)(4) Injection lot (b)(4) when sub-lots failed to meet the particle in-process acceptance criteria, but did not conduct an adequate investigation into that failure. In your response, you stated that the “…process is known to generate occasional out of limit in-process (b)(4) aggregate particle density results…” However, you did not provide your determination of actual root cause for this failure to meet in-process limits. Additionally, you noted that the sponsor of this product is planning (b)(4) activities for this process and will target consistent particle results as part of the validation of the new process. Please note that your firm is expected to conduct thorough investigations for each failure to meet specifications, regardless of future plans for validation.

In your response to this letter, provide a copy of your revised procedure requiring a thorough failure investigation when in-process or finished product testing shows that your product fails to meet established specifications.

In addition, our investigator found that you do not determine and implement corrective and preventive actions (CAPAs) in a timely manner to prevent recurrence of manufacturing deviations. For example, the inspection noted that some CAPAs remained open for approximately 500-700 days (one was open for 761 days) without implementation of corrections. Your firm’s response stated that you have now completed these CAPAs. However, you failed to address why you had not completed these CAPAs in a timely manner to prevent repetition of manufacturing problems. We are concerned that your response corrects the FDA 483 observation, but does not provide for a systematic and sustainable correction to ensure timely and effective CAPAs.

COMMENT

21 CFR 211.192 represents an all encompassing citation frequently utilized by the FDA.  The terminology “failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specification, whether or not the batch has already been distributed” is used within the Agency whenever any issue arises within a batch record and may include areas as far flung as the laboratory or environmental monitoring.

In this particular citation the Agency remains concerned that failure investigations were not performed on a timely basis “when in-process or finished product testing shows that your product fails to meet established specifications”.

The “investigator found that you do not determine and implement corrective and preventive actions (CAPAs) in a timely manner to prevent recurrence of manufacturing deviations. For example, the inspection noted that some CAPAs remained open for approximately 500-700 days (one was open for 761 days) without implementation of corrections”.

“Your firm’s response stated that you have now completed these CAPAs. However, you failed to address why you had not completed these CAPAs in a timely manner to prevent repetition of manufacturing problems. We are concerned that your response corrects the FDA 483 observation, but does not provide for a systematic and sustainable correction to ensure timely and effective CAPAs.”

Again, this above comment represents the often observed “silo effect” wherein the immediate problem is considered, but is not expanded to review the overall effect of the total issue.

 

MEDI-FARE DRUG AND HOME HEALTH CENTER, BLACKSBURG, SC RECEIVES WARNING LETTER (3/7/13)

SERIOUS DEFICIENCIES ARE NOTED IN THE PRACTICE OF PRODUCING STERILE DRUGS

BACKGROUND

Recently the FDA has been criticized for its management of the New England Compounding Center.  The following Warning Letter represents one of the first Warning Letters that the Agency has issued in a similar area since the issue of Compounding Pharmacies has become a national topic.

The document highlighted below provides insight as to how the FDA is now managing this problem.  Of note is the fact that even though the State of South Carolina lifted a suspension of Medi-Fare’s pharmacy license, the FDA, in a teleconference with the Client “informed you (the Client) that you should not resume production of sterile drugs until you implement appropriate corrective actions”.

“Between December 10, 2012, and January 18, 2013, U.S. Food and Drug Administration (FDA) investigators conducted an inspection of your facility, Medi-Fare Drug and Home Health Center, Inc., located at 300 W. Pine Street in Blacksburg, South Carolina 29702. During the inspection, the investigator noted that you were not receiving valid prescriptions for individually-identified patients for a significant number of drug products you were producing. In addition, the investigator observed serious deficiencies in your practices for producing sterile drug product, which could lead to contamination of the products, potentially putting patients at risk. These observations and others were noted on an FDA Form 483 issued on January 18, 2013. We acknowledge receipt of your firm’s letter to FDA dated December 12, 2012, as well as your firm’s response to the FDA Form 483 dated January 29, 2013.

On February 28, 2013, we held a teleconference with you. Among other issues discussed, we expressed our concerns related to the design of your firm’s aseptic fill areas, which places sterile products at considerable risk of microbial contamination. As evidenced by photographs taken by the FDA investigator during the inspection your firm’s aseptic fill area is (b)(4) In addition, other activities, including labeling and weighing of non-sterile ingredients, are performed in this same room where sterile product is manipulated, creating a risk of contamination.

We are aware that the South Carolina Board of Pharmacy has recently lifted a suspension of your pharmacy license to produce sterile products. During our February 28, 2013 teleconference, we informed you that you should not resume production of sterile drugs until you implement appropriate corrective actions. You stated that you did not intend to resume production of sterile drugs until appropriate corrective actions have been implemented. We expect that you will notify this office before resuming production of sterile drugs.

Based on this inspection, it appears that you are producing drugs that do not fall within the exemptions for compounded drugs described in section 503A of the Federal Food, Drug, and Cosmetic Act (FDCA) or within the agency’s exercise of enforcement discretion set forth in Compliance Policy Guide 460.200 on Pharmacy Compounding (CPG) (2002).1

A. Compounded Drugs Under the FDCA

Currently, there are conflicting judicial decisions regarding the applicability of section 503A of the FDCA [21 U.S.C. § 353a), which exempts compounded drugs from several key statutory requirements if certain conditions are met.2 Nevertheless, receipt of valid prescriptions for individually-identified patients prior to distribution of compounded drugs is relevant for both section 503A of the FDCA and the agency's CPG. During the FDA inspection, the investigator observed that your firm does not receive valid prescriptions for individually-identified patients for a significant number of the drug products you produce. Based on this factor alone, those drugs are not entitled to the statutory exemptions for compounded drugs described in section 503A of the FDCA and do not qualify for the agency's exercise of enforcement discretion set forth in the CPG.3 In addition, we remind you that there are other conditions that must be satisfied to qualify for the exemptions in section 503A of the FDCA, as well as other factors that FDA considers in determining whether to exercise enforcement discretion under the CPG.4

Because the drug products that you manufacture and distribute without valid prescriptions for individually-identified patients are not the subject of approved applications, they are unapproved new drugs and misbranded drugs in violation of sections 505(a) and 502(f)(1) [21 U.S.C. §§ 355(a) and 352(f)(1)] of the FDCA, respectively. In addition, because you manufacture and distribute drugs without valid prescriptions for individually-identified patients, the manufacture of those drugs remains subject to FDA’s Current Good Manufacturing Practice (CGMP)regulations for Finished Pharmaceuticals, Title 21, Code of Federal Regulations (CFR), Parts 210 and 211. FDA investigators observed significant CGMP violations at your facility, causing such drug product(s) to be adulterated within the meaning of section 501(a)(2)(B) of the FDCA [21 U.S.C. § 351(a)(2)(B)].”

The entire Warning Letter may be found at: http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2013/ucm343340.htm

CAPCO CUSTOM PACKAGING INC RECEIVES WARNING LETTER (02/20/13)

DIETARY SUPPLEMENT MANUFACTURING FACILITY FAILS TO ADEQUATELY PERFORM MICROBIOLOGICAL TESTING; FDA CITES INCORRECT USP CHAPTER 

COMMENTS 

Dietary Supplement Warning Letters have within the past several months been issued at a frequency of two to three each week.  Many of these Warning Letters demonstrate that the recipient fail to follow even the most basic Dietary Supplement regulations (21 CFR Part 111) which, in itself, remains quite interesting given that the regulations have now been in the public domain for several years. 

Many of the Observations provided by the FDA to various Companies are quite basic and should be capable of being met by simply reading the regulations.  However, when these Observations are reviewed, one gains the impression that the cited Companies have never even looked at them (21CFR Part 111). 

The enclosed Observation, taken from the February 20, 2013 Warning Letter is more unique than many since it confuses USP<61> with USP<2021> and USP<2022>.  What makes this Observation even more interesting is because the investigators, reviewers and those within the FDA issuing this Warning Letter appear to be ignorant that USP<2021>, and <2022> even exist.  Even if the Client had used USP<61>, the FDA should have corrected the Company by reminding them that Dietary Supplement manufacturers should be using the USP “2000” series, not the less than “1000” series.  It would have also represented an excellent opportunity on the part of the FDA to remind its Clients of the existence of these sections to include USP<2023> within the USP and that they pertain to Dietary Supplements.  

The following discusses Observation #2 issued to Capco Custom Packaging. 

2.  “The United States Food and Drug Administration (FDA) inspected your firm located at 10225 Greenleaf Ave, Santa Fe Springs, California, from May 4 – 18, 2012. Our investigation revealed significant violations of the Current Good Manufacturing Practice (CGMP) regulation for dietary supplements, Title 21, Code of Federal Regulations, Part 111 (21 CFR Part 111). These violations cause your dietary supplement products to be adulterated under Section 402(g)(1) of the Federal Food, Drug and Cosmetic Act (the Act), 21 U.S.C. § 343(g)(1), because they have been prepared, packed, or held under conditions that do not meet the CGMP regulations for dietary supplements.”

“These observations were presented to you in an FDA-483 at the conclusion of our inspection on May 18, 2012. We have reviewed your responses dated June 11, 2012 and July 7, 2012, and specifically address your June 11, 2012 response below as it addresses violations of 21 CFR Parts 111 and 211.

Specific violations observed during the inspection include, but are not limited, to the following:”

2.  “You failed to determine whether the specifications you established for limits on contamination that may adulterate or may lead to adulteration of the finished batch of dietary supplement were met, as required by 21 CFR 111.73. (NOTE: 21 CFR 111.73     refers to “determining whether established specifications are met”, not whether one adheres to a USP method.)  For example, your laboratory does not follow the USP Microbial Limits Method for Total Plate Count and Yeast and Molds as referenced in      your batch records. Your total aerobic counts are not performed in duplicate in accordance with the USP. Additionally, your sample volumes for total aerobic count were 1mL and not 10mL as indicated in the USP.

We have reviewed your response letter, dated June 11, 2012, and have determined your response to be inadequate because you did not provide documentation to show that you have amended your protocols. You state in your letter that you commit to following the procedures in USP <61> for the Microbial Limits Method for Total Plate Count and Yeast and Molds, and to changing your protocols to be consistent with the USP procedure, including correct sample volumes and the performance of the analytical experiments in duplicate.

You also state in your letter that you commit to completing the amendment of your protocols for the Microbial Limits Method for Total Plate Count and Yeast and Molds by the end of the third quarter of 2012. However, as of November 1, 2012, we had not received a copy of your proposed new protocols. Therefore we could not evaluate the adequacy of your modified protocols.

COMMENT 

Aside from using the incorrect USP General Chapter , the Observation demonstrates how one must follow a USP monograph, and, if not followed, can readily lead to an Observation.  From the information within this Warning Letter, it appears that the Client did not perform standard testing in duplicate nor  used the correct volume of sample for the testing (total aerobic count) that they were performing.  Further, if they were following current USP<61>, the Client would be performing a mesophilic count (quantitative enumeration of mesophilic bacteria and fungi that may grow under aerobic conditions) , not a Total Aerobic Count which includes a much greater temperature range than the mesophilic count.  Had the Client indicated that they were using USP<2021>  Microbial Enumeration Tests—Nutritional and Dietary Supplements,  they would have been correct in using the term “Total Aerobic Count” — even though its use does not correctly define “Total Aerobic Count” as presently used in practice.

 

 

ABBEY COLOR, PHILADELPHIA, PA RECEIVES WARNING LETTER (FEBRUARY 19, 2013)

API MANUFACTURING FACILITY IS CITED FOR SEVERAL REPEAT WATER RELATED OBSERVATIONS

During the time frame of March 13 to March 23, 2012 the FDA inspected Abbey Color, an active pharmaceutical ingredient (API) manufacturing facility in Philadelphia, PA.  Following a detailed review of the firm’s response, dated April 12, 2012, the FDA concluded that the response lacked sufficient corrective actions.

Specific violations included the following:

1. Failure to validate and monitor the water purification system to ensure that water is of appropriate quality.

Specifically, “your firm failed to demonstrate that your purified water system can consistently produce water that is suitable for use in the manufacture of this API.  This is a repeat observation from the July 21-August 8, 2010 inspection. … you continued to get periodic out-of-specification (OOS) endotoxin and total organic carbon (TOC) test results.  …you indicated your firm’s intention to conduct a comprehensive gap analysis of the purified water system. However, you have failed to indicate when you will initiate this gap analysis and when it will be completed.

Your firm also failed to detail how you will determine the source(s) of high endotoxin and TOC in your purified water and how your firm will remedy identified problem(s). We note that, for example, your firm installed an endotoxin removal unit on your purified water system in January 2011 in response to the OOS results for endotoxin in the water used for API. However, your firm has not demonstrated that the water produced by the purified water system is now suitable for use in production.  The operational parameters and effectiveness of the new endotoxin removal unit have not been qualified. Your firm does not monitor the microbial and chemical attributes of the feed water, and have no assurances that the purified water system is capable of consistently producing water that meets specifications for a given quality of feed water. Your gap analysis should also include evaluation of factors such as feed water quality, whether each component of the purified water system is meeting its performance specifications, and whether the system’s output is reproducible. Your firm has not determined the source of the endotoxin failures in the past, and it is essential that you demonstrate that changes in design and operational procedures have resulted in a reliable water system.”

COMMENT

Repeat Observations in today’s FDA environment have become a very successful mode for inviting Warning Letters.  Historically, the FDA often required three Repeat Observations before they would issue a Warning Letter.  That is no longer the norm.

Observation 1 suggests that the Company has little understanding of how to perform an investigation of a contaminated water system.  Their lack of sampling of each Unit operation, the lack of attention to feed water quality, and the use of a endotoxin removal filter that acts as a “band aid” or a “quick fix”, rather that determining the root cause of the problem suggest that the Company study how to attack a problem using the FDA Guidance for Industry re: Out of Specifications.

2.  Failure to adequately investigate and document OOS test results.

“For example, your rinse water from cleaning equipment used to manufacture (b)(4) lots of Fluorescein, USP from October 2010, to December 2011, had (b)(4) results that were OOS for endotoxin and/or total organic carbon (TOC). Your firm failed to document that these were OOS results, conduct an investigation to determine the root cause of these recurring failures, or implement corrective actions.  Executive management of your firm is responsible for assuring quality system effectiveness.  A basic part of this responsibility is prompt identification and remediation of problems that indicate manufacturing control problems, including an evaluation of the impact of these deviations on the quality of your APIs.”

COMMENT

In this Observation, the Client again is encountering OOS results for both endotoxin and total organic carbon.  From the above paragraph, it appears that the Client did not realize that the Company was experiencing these problems and neither documented them as OOS nor conducted an analysis to determine the root cause of these recurring failures  — much less implemented corrective actions.