483 of the week: lying QC manager edition

Via FiercePharma, these tidbits from an FDA inspection (PDF) of Sichuan Deebio Pharmaceutical: 

The Form 483 relays an especially troubling event during the inspection when Sichuan Deebio’s quality control team leader provided “misleading information” about records on the results of a microbiology test.

At first, the quality control chief lied about viewing those test results, logging them and leaving them with another team member on a different floor of the facility, the FDA contends in its report. Then she changed tack, claiming she had not read the results, before switching back to a story similar to her first. At last, the QC chief “finally” admitted that she was “not telling the truth about recording the results on respective data worksheets, and no worksheet existed,” investigators wrote in the Form 483.

To make matters worse, investigators subsequently asked the quality leader how she kept track of the test results, to which she replied that they were “in her ‘mind.’”

There's a lot of lab results in my mind (well, there was), but I usually tried to write them down really quickly.  

Warning Letter of the Week: vermin edition

In a letter to the general manager of Optum Infusion Services, this observation: 

The FDA investigator noted that drug products intended or expected to be sterile were prepared, packed, or held under insanitary conditions, whereby they may have become contaminated with filth or rendered injurious to health, causing your drug products to be adulterated under section 501(a)(2)(A) of the FDCA. For example, the investigator observed that:

1. You did not perform adequate product evaluation and take appropriate corrective action after vermin was observed in your production area. Vermin are a source of microbial contamination. Therefore, your products intended to be sterile were produced in an environment that may not provide adequate protection against the risk of contamination.

Seems bad for a compounding pharmacy!  

Warning Letter of the Week: try, try again edition

In a letter to the Chief Executive Officer of Bioiberica, SAU, the Center for Drug Evaluation and Research notes these issues: 

1. Failure to establish written procedures to monitor the progress and control the performance of processing steps that may cause variability in the quality characteristics of your intermediates and API.

You failed to establish appropriate monitoring and controls for reworking batches of [redacted] USP, API. In 2020 and 2021, approximately 23 batches of [redacted] USP, API were reworked in your industrial [redacted] because of microbiological out-of-specification or non-conforming high [redacted], a class 3 residual solvent, content results. The use of the industrial [redacted] was not part of the established process validation for [redacted] USP, API. The investigator documented this [redacted] was used to rework multiple batches from [redacted] to as many as [redacted] times until acceptable results were obtained. No studies had been performed to establish the effectiveness of this rework step. Additionally, your industrial [redacted] was not equipped with real time [redacted] monitoring or a [redacted] summary to monitor the performance of the [redacted].

No product too holy to be reworked, folks! (Guessing that they chose to use a different piece of equipment than what they laid out earlier.) 

Warning Letter of the Week: dirty homeopathic equipment edition

In an epistle from the Center for Drug Evaluation and Research to the CEO of Mayon's Pharmaceuticals Pvt Ltd in Maharashtra, India:

API Deviations 

1. Failure to clean equipment and utensils to prevent contamination or carry-over of a material that would alter the quality of the API beyond the official or other established specifications. 

Your firm manufacturers homeopathic in process materials and [redacted] from various raw materials. Our investigator observed unidentified debris in the [redacted] of your [redacted] equipment, which is used to process multiple raw materials for homeopathic [redacted], including [redacted] containing [redacted]. This equipment was marked as clean. 

Your response states that you filed a deviation and re-trained your staff. This response is inadequate because you failed to identify the observed debris and perform an impact assessment for the drugs that were manufactured using this dirty equipment.

There are API in homeopathic remedies? How do they test for them? What's the limit of detection?*

*I’m sure there’s some way

Warning Letter of the Week: dancing festival edition

Via a comment at In the Pipeline, this funny missive from the Center for Drug Evaluation and Research to the director of Centurion Laboratories Private Limited (emphasis mine):

3. Your firm failed to follow written procedures for cleaning and maintenance of equipment (21 CFR 211.67(b)). 

During the inspection, our investigator observed that equipment used to manufacture more than one product was inadequately maintained and cleaned. 

For example, our investigator observed in the [redacted] room a [redacted] identified as “cleaned.” However, this [redacted] was found to have visible product build-up inside the [redacted] and [redacted] of the [redacted]. Furthermore, the air filter of the equipment was damaged with multiple holes. This equipment was used to manufacture finished drug products shipped to the United States such as [redacted] tablets, [redacted] tablets, [redacted] tablets, and [redacted] tablets. Additionally, a memo provided during the inspection stated these cleaning and equipment maintenance deficiencies were because of a shortage in manpower related to a nine-day dancing festival and government holiday. Inadequately cleaned and maintained equipment can lead to cross-contamination and variability of drug products.

Must have been a good time. 

Warning Letter of the Week: dead legs and rusty pipes edition

From a letter from the Center for Drug Evaluation and Research to the Chairman of the Board of Guangzhou Tinci Materials Technology Co., Ltd.:

Your [redacted] and distribution systems appear to have multiple dead-legs, which can foster the development of biofilms. The piping and installation diagrams for your [redacted] system in your response lack adequate information regarding the slope of the piping. 

Moreover, your [redacted] system lacks proper maintenance. For example, there were visible corrosion on pipes, brackets, fittings, valves, and tanks in the utilities area, which is covered but not completely enclosed from outside elements. During the inspection, you stated that some poorly maintained equipment and piping in the [redacted] utility area is not currently in use. However, during the inspection it appeared that the poorly maintained equipment and piping was still connected to the [redacted] system you use to make components of drugs.

I genuinely didn't know the FDA disapproves of dead legs, although biofilms are a perfectly good reason why. 

Warning Letter of the Week: unorganized office edition

From a note from the Center for Drug Evaluation and Research to the owner and general Manager of Yibin Lihao Bio-technical Co., Ltd. in Sichuan, China: 

2. Failure to establish, document, and implement an effective system for managing quality that involves the active participation of management and appropriate manufacturing personnel. 

During the inspection, the investigator observed your firm did not adequately control critical documentation pertinent to the traceability of crude heparin manufactured at your facility. During the walkthrough on July 31, 2019, our investigator observed numerous records on the floor, desks, and cabinets of the Quality Assurance (QA) Office on the third floor of the office building. Some of these records included batch production records for heparin. 

During the inspection, one of your employees stated that these records were generated to support an application for government funding, but the crude heparin batches specified in the records had not actually been manufactured. However, later during the inspection, on August 2, 2019, your firm stated that all the records in the QA Office were in fact associated with genuine crude heparin batches. 

Additionally, even though your Crude Heparin Sodium Inventory and Distribution Record indicated your firm manufactured [redacted] batches of crude heparin (CU190601 to CU190730) from June 1, 2019, to July 30, 2019, your firm was only able to provide complete batch records for two batches, CU190728 and CU190730. 

Traceability of crude heparin is a critical part of managing quality. You must ensure that a complete contemporaneous record of each batch of drug manufactured is retained for CGMP purposes. Your system for managing quality is inadequate and calls into question the traceability of all drugs, including crude heparin. manufactured at your facility.

It's a good thing the FDA hasn't seen my desk...

Warning Letter of the Week: scraps of paper edition

In a letter to the general manager of Sunstar Guangzhou Ltd. in Guangdong, Guangzhou, China from the Center for Drug Evaluation and Research, this amusing tidbit:

4. Failure to establish an adequate quality control unit and the responsibilities and procedures applicable to the quality control unit are not in writing and fully followed. (21 CFR 211.22(a) and 211.22(d)). 

Your quality unit (QU) failed to ensure that you have adequate procedures and did not provide adequate oversight of your manufacturing activities. For example: ·

• You lack adequate control over the issuance, use, and reconciliation of manufacturing batch records and equipment maintenance sheets. Uncontrolled copies of manufacturing batch records and in-process control forms were pre-printed and kept in a room with unrestricted access.

• Several test reports of your drug product assay were reviewed and the raw data for the standard curve could not be located. It was noted that scrap pieces of paper were used to record data which was later entered to calculate the [redacted] concentration for the assay test.

• Your firm failed to establish and follow procedures for calculating production yields.

In your response, you stated" ... starting July 2019, relevant personnel will be handed just enough blank forms on a [redacted] basis and they must account for the whereabouts of all blank forms at the [redacted]." You stated that all documents will be archived and procedures will be drafted and/or updated to meet CGMP requirements.

"Scraps of paper" may have described some of my grad school jotted notes, but definitely not my experience in a QC lab...

Warning Letter of the Week: Excel spreadsheet edition

A note from the Center for Drug Evaluation and Research to the Chief Executive Officer of Tismor Health and Wellness Pty Limited in Kingsgrove, New South Wales:

3.   Your firm failed to establish laboratory controls that include scientifically sound and appropriate specifications, standards, sampling plans and test procedures designed to assure that components, drug products conform to appropriate standards of identity, strength, quality, and purity (21 CFR 211.160(b)). 

Your firm failed to validate the Excel spreadsheet used to perform the assay calculation for your “[redacted].” Your procedures lacked guidance on how to check and manually verify the calculation sheets. During the inspection, our investigator identified a calculation error within the spreadsheet. The incorrect formula for averaging the Internal Standard peak area was used. 

There is no assurance that the associated assay results recorded are reliable and accurate.
In your response, you stated that you have retrospectively tested products in the market using correct procedures and will update the validation master plan to ensure that spreadsheets are included within the scope of validation efforts. You created a new procedure which details the approach for validating spreadsheets as well as protecting the file from accidental changes. You also stated all Excel spreadsheet calculations for your [redacted] batches have been retrospectively reviewed. 

During the review, you identified another error within your Excel spreadsheets. The assay test result for [redacted] batch [redacted] was incorrect due to a transcription entry error for active peak area. Your firm used a new spreadsheet and entered the correct active peak area. The result was recalculated, and the final result was reported. The product had already been released with test results using the incorrect calculation, although the recalculated test result was still within specification. You have committed to manually check calculations until the spreadsheet has been validated. 

Your firm relied on Excel spreadsheets to calculate assay and determine the reportable result for final batch release. Your computerized systems must perform their functions satisfactorily and that your firm establish a written program to ensure ongoing proper system performance. 

Your response is inadequate. You have not fully assessed the potential impact of using data from unvalidated, unsecured spreadsheets for critical CGMP functions.

Excel spreadsheets are so useful, and who knew they had to be validated? (answer: lots of people)

(who among us have not transposed a number on Excel?)

Warning Letter of the Week: aborted HPLC run edition

From a missive from the Center for Drug Evaluation and Research to the managing director of GPT Pharmaceuticals Private Ltd in Balanagar, India:

3.  Your firm failed to exercise appropriate controls over computer or related systems to assure that only authorized personnel institute changes in master production and control records, or other records (21 CFR 211.68(b)). 

Our investigator observed your laboratory equipment lacked appropriate controls. For example, from January 1, 2018, to June 25, 2019, audit trails from [redacted] Agilent 1260 Infinity Series II high-performance liquid chromatography (HPLC) instruments showed a pattern of aborted runs and single run entries for testing [redacted]. Single run entries included analyses of multiple peaks or split peaks without documented investigations or adequate scientific justifications. Your employees used the Agilent Service Account login, with full administrative privileges, to abort HPLC testing runs without being attributable to a specific individual. 

Your response identified the number of deleted, aborted, and single runs during your HPLC testing. However, your response did not provide adequate investigations or evidence of corrective actions put in place to prevent these data integrity issues from recurring.

Clever move, with the extra account. 

Warning Letter of the Week: Dollar Tree edition

From an epistle from the Center for Drug Evaluation and Research to the President and CEO of Greenbrier International, Inc dba Dollar Tree (emphases mine):

The U.S. Food and Drug Administration (FDA) inspected your corporate headquarters, Greenbrier International, Inc. (Greenbrier) (FEI 3005269673) at 500 Volvo Parkway, Chesapeake, Virginia, from January 14 to 18, 2019 after FDA inspections revealed violative conditions at multiple foreign drug manufacturers that supplied drugs to your distribution network. Firms inspected by FDA included contract manufacturers used to manufacture Dollar Tree's Assured Brand drugs…. 

...Our inspection and review of import data revealed the following: 

2. lmport records reviewed indicated that your firm received various [redacted] and [redacted] drug products from Hangzhou Zhongbo Industrial Company, Ltd., FEI 3008229416, from October through December of 2018. An inspection of Hangzhou Zhongbo Industrial Company, Ltd. in April of 2018 revealed significant CGMP violations, including the failure to test each batch of drug for conformance with specifications prior to release (21 CFR 211.165(a)). As a result of this and other violations, Hangzhou Zhongbo lndustiial Company, Ltd. was placed on Import Alert 66-40 on September 28, 2018 and was issued a warning letter on November 27, 2018. FDA copied your COO on the outgoing warning letter.... 

...We also note that Greenbrier has, at various points in time, used contract manufacturers and suppliers with histories of significant drug CGMP violations. For example, our inspections revealed that beyond the facilities detailed above, your firm has used the following contract manufacturers and suppliers: 

2. Bicooya Cosmetics Limited, FEI 3010671652, which was issued a warning letter on August 11, 2017. This firm was also placed on Import Alert 66-40 on June 29, 2017, for, among other things, not testing finished drug products prior to distribution and for rodent feces found throughout the manufacturing facility. FDA copied your COO on the warning letter.

What’s a little rodent feces between friends? 

Warning Letter of the Week: lost in the move edition

A missive from the Center for Drug Evaluation and Research to the president of Bingbing Pharmaceutical Co., Ltd (emphasis mine):

1.    Your firm failed to maintain written production, control, or distribution records specifically associated with a batch of a drug product for at least one year after the expiration date of the batch (21 CFR 211.180(a)). 

You manufactured drugs at your Wuhan facility at Building [redacted], No. 5, Kangda Street, Longyang Avenue, Hanyang District, Wuhan, and then transferred drug production to your Hubei facility and closed the Wuhan facility. Your firm failed to maintain manufacturing records, raw material and finished product testing records, retain samples, stability samples, and other CGMP records for your over-the-counter (OTC) [redacted] drug products manufactured at your Wuhan facility. During the inspection at the Hubei facility, you stated that you lost CGMP manufacturing documentation and drug product samples during the transfer of your manufacturing facility from Wuhan to Hubei in May 2018.

Yep, happens all the time in moves. You put your batch records in the box, the box gets loaded onto a truck, stuff gets moved around, it gets lost! 

Warning Letter of the Week: gritty cracking edition

A missive from the Center for Drug Evaluation and Research to the Chairman & Managing Director of Glenmark Pharmaceuticals Limited in Mumbai, India: 

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 the batch has already been distributed (21 CFR 211.192). Your firm failed to ensure your investigations identify appropriate root causes and you failed to implement sustainable corrective action and preventive action (CAPA). 

a. You failed to thoroughly investigate multiple complaints of grittiness for your topical [redacted] cream USP, [redacted]%. Since November 2017, you rejected 20 batches and received at least 38 complaints about product grittiness. Product grittiness has been an ongoing formulation issue since 2010 and was a deficiency cited in the previous inspection of your facility. You proposed specific remediation for this formulation issue in your response at that time. In your response to the most recent inspection, you stated that the product grittiness issue was remediated during product reformulation in November 2018. Your response is inadequate. You did not provide sufficient data to demonstrate the robustness of the new formulation... 

d. You failed to adequately investigate more than 70 consumer complaints associated with punctures, cracks, and holes in [redacted] for various drug products including, but not limited to, [redacted] ointment USP, [redacted]%, [redacted] cream USP, and [redacted] ointment USP, [redacted]%. Your investigations failed to adequately address the scope and cause of these serious container/closure system defects and evaluate other drug products that have similar manufacturing quality signals such as complaints, or that use the same supplier. 

In your response, you stated that the root cause for the complaints was improper “handling by folding and refolding of the [redacted]” by consumers. In addition, you stated that because the complaint rate is insignificant, there is no risk to marketed batches. However, you closed more than 50 of the complaints, without CAPA to prevent recurrence of similar quality defects.

I like the "blame the root cause on the customer" approach - that's a new one.  

Warning Letter of the Week: pre-approved batch records

A missive from the Center for Drug Evaluation and Research to the President of Enprani Co., Ltd. in Seoul, South Korea (emphasis mine) 

2. Your firm failed to establish an adequate quality control unit with the responsibility and authority to approve or reject all components, drug product containers, closures, in-process materials, packaging materials, labeling, and drug products (21 CFR 211.22(a)). 

During the inspection, our investigator observed that your quality unit (QU) lacks adequate oversight for the manufacture of your OTC [redacted] drug products. For example:

• Your QU failed to review entire batch records, including raw data and calculations for accuracy, before making appropriate release determination.
• Your batch records were pre-printed as “approved” indicating the assay results were in specification, even before these values are recorded.
• Label review and line clearance were not performed and documented in batch production and control records.

Pre-printing approvals - how come I never thought of that? 

Warning Letter of the Week: naughty sonicator edition

From a letter to the Director of CTX Lifesciences Private Ltd. from the Center for Drug Evaluation and Research: 

2.    Failure to adequately investigate out-of-specification results and implement appropriate corrective actions. 

You invalidated an out-of-specification (OOS) related substances test result for API [redacted] batch [redacted], listed in a pending drug application, without scientific justification. 

In your response, you stated that you performed an investigational hypothesis study to evaluate the effect of sonication on API [redacted] batch [redacted]. You concluded that [redacted] generated an unknown impurity at the same relative retention time (RRT) and similar percentage peak area as the OOS result. 

Your response is inadequate because you did not adequately investigate all potential causes of the unknown impurity. You attributed the OOS result to degradation caused by [redacted], a sample preparation step performed during your test procedure. You also did not provide adequate scientific justification for your OOS result root cause. We note that three other batches of API [redacted] followed this [redacted] preparation and analysis procedure during the same sequence with no OOS results for these [redacted] batches.

Blaming the sonicator is a new one on me! 

Warning Letter of the Week: tell-tale PLC edition

In a note to the Chairman of Indoco Remedies Limited, Mumbai, India, the Center for Drug Evaluation and Research says:

1.  Your firm failed to prepare batch production and control records with complete information relating to the production and control of each batch of drug product produced (21 CFR 211.188). 

Compression machine process control values were not adequately reported in your batch production records during the manufacture of [redacted]mg tablets intended for the U.S. market. Your quality unit used these deficient records to release batches of this drug product. 

While multiple batch records of [redacted]mg tablet included handwritten values routinely within process parameters, the values recorded by the programmable logic controller (PLC) of your compression machine were frequently outside your established process parameters. For example, [redacted]mg batch [redacted]had compression force values handwritten [redacted]in the batch record ranging from [redacted](your limit was (b)(4)). 

However, the PLC data recorded individual values ranging from [redacted]for the same time period. In addition to compression force values, handwritten values for filling depth and automatic weight control (AWC) did not accurately reflect the values within the PLC data. 

An inspection conducted by the [redacted]in March 2018 found similar discrepancies between the compression force values in batch records and PLC data.

I feel like the last few letters have shown a fair bit of detective work by the inspector - looking up PLC values couldn't have been super easy....

Warning Letter of the Week: inadvertent scrap yard edition

In a missive from the Center for Drug Evaluation and Research to the Managing Director of Strides Pharma Science Limited in Bangalore, India: 

1.  Your firm failed to establish an adequate quality control unit with the responsibility and authority to approve or reject all components, drug product containers, closures, in-process materials, packaging materials, labeling, and drug products (21 CFR 211.22(a)). 

Your quality unit (QU) lacks appropriate responsibility and control over your drug manufacturing operations. 

During the inspection, our investigator observed discarded CGMP documents and evidence of uncontrolled shredding of documents. For example, multiple bags of uncontrolled CGMP documents with color coding indicating they were from drug production, quality, and laboratory operations were awaiting shredding. Our investigator also found a blue binder containing CGMP records, including batch records for U.S. drug products, discarded with other records in a 55-gallon drum in your scrap yard. CGMP documents in the binder were dated as recently as January 21, 2019: seven days before our inspection. Your QU did not review or check these documents prior to disposal. 

...The uncontrolled destruction of CGMP records, and your lack of adequate documentation practices, raise questions about the effectiveness of your QU and the integrity and accuracy of your CGMP records. 

In your response you state the binder of CGMP documents in your scrap yard was “inadvertently come [sic] to scrap yard” and that you were investigating the issue....

You hate it when controlled documents end up in a 55-gallon drum in a scrap yard... 

Warning Letter of the Week: short attention span edition

In a note to the Managing Director of Aurobindo, this amusing comment from the Center for Drug Evaluation and Research (emphasis mine):

1.  Changes to methods or controls were not reported to FDA through a supplement to an approved [redacted]. (21 CFR 314.97(a) and 314.70(c)(6)(i)) 

...Investigators observed, in your [redacted] API, non-carcinogenic impurities of [redacted] and [redacted] at levels up to [redacted]% and [redacted]%, respectively, in residual solvent testing for [redacted] API batches. These impurities are present in drug substances at levels exceeding the [redacted] USP specification limit for Any other individual impurity (i.e. NMT [redacted]%). These impurity levels are also above the ICH Q3A(R2) reporting threshold for drug substance impurities. 

Your Quality Unit failed to report to FDA these impurities, which were also above your internal reporting threshold limit of no more than [redacted]%. You updated the information in your Drug Master File (DMF) only after FDA investigators communicated during the inspection that you should be reporting all observed impurities above the reporting threshold.  

In your response, you explained a “scheduled regulatory update skipped our attention.” In addition, you stated you would undertake an additional CAPA for controls of residual solvents. Your response is inadequate, as you did not commit to conduct a full review of all impurities observed in all your APIs above the reporting threshold and ensure that your DMFs and [redacted] are updated accordingly...

I hate it when things skip my attention. 

Warning Letter of the Week: casual batch record edition

Via an epistle from the Center for Drug Evaluation and Research to the Plant Manager of Vida International, Inc. in Taipei City, Taiwan:

The batch production record for lot [redacted] of [redacted] is deficient because it does not represent the formula and ingredients that the product purports on its label. Specifically, the batch record does not list all inactive ingredients included on the product label. The batch record also lacked the actual amounts of each active and inactive ingredient used during manufacturing, a calculation of theoretical or actual yields, documentation of the equipment used, and critical manufacturing parameters such as [redacted] speeds and [redacted] times.

Eh, just throw the stuff in there, let it stir around for a while, take it out. 

Warning Letter of the Week: no confusion edition

A letter from the Center for Drug Evaluation and Research to the Director of Centurion Laboratories Private Limited in Gujarat, India: 

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

On October 24, 2018, our investigator observed torn documents of stability study data, analytical testing sheets, analysis calculations, and release forms that were placed into clear trash bags. Stability study documents for three batches of [redacted] mg tablets were salvaged from the trash and compared to the official and approved records. Out-of-specification (OOS) results were among the data found, however the official results were recorded as within specification. Additionally, it was observed that blank stability study forms were prepared, pre-signed, and approved by the quality unit before recording the test data. 

In your response, you acknowledged the multiple trash bags containing torn quality control documents and the practice of signing documents before recording the data. You stated the torn documents were from scale-up batches in which you tore the documents so as “not to create confusion in the mind of the investigator.” Your response was inadequate because you did not explain the discrepancies between the torn documents with OOS values and the documents retained by the quality control laboratory that included passing values. Additionally, you did not complete a retrospective evaluation of all potentially affected quality-related records to determine the scope of data integrity practices, including, but not limited to, the signing of blank documents before performing laboratory tests.

That. Is. Amazing. Unreal.