Warning Letters

A leading pharma company received the warning letter for the significant violations of cGMP. Detailed warning letter is presented below.

DATE: 8/15/2023

WARNING LETTER – Case #: 655929

This warning letter summarizes significant violations of Current Good Manufacturing Practice (CGMP) regulations for finished pharmaceuticals. See Title 21 Code of Federal Regulations (CFR), parts 210 and 211 (21 CFR parts 210 and 211).

During our inspection, our investigator observed specific violations including, but not limited to, the following.

1.Your firm failed to validate and establish the reliability of your component supplier’s test analyses at appropriate intervals (21 CFR 211.84(d)(2)).

Your firm failed to qualify your suppliers and adequately test the components used to manufacture your finished drug products, including pediatric over-the-counter (OTC) (b)(4) products. For example,

A. (b)(4), one of your active ingredients is sourced from an unqualified supplier and was approved for use without establishing the reliability of your suppliers’ certificate of analysis (COA).

B. The microbiological testing of (b)(4)excipient in your supplier qualification document only included a general statement that it should be free from pathogens but lacked any further specificity on microorganisms that your firm considers to be objectionable.

C. You lacked a specific identity test to detect (b)(4)and (b)(4) in all shipments, containers, and lots of (b)(4)and (b)(4) before use in the manufacturing of drug products. Some of your drug products containing these ingredients are intended for oral use in pediatric populations.

2. Your firm’s quality control unit did not review and approve written procedures for production and process control, including any changes to them, designed to ensure that the drug products you manufacture have the identity, strength, quality, and/or purity they purport or are represented to possess (21 CFR 211.100(a)).

A. You failed to adequately validate your production and process controls. You did not have assurance that you are capable of consistently manufacturing OTC drug products with defined quality attributes. During the inspection, you acknowledged that none of your initial process validation studies (i.e., process performance qualification (PPQ)) were complete.

B. You also failed to adequately qualify and test your (b)(4)system to assure the (b)(4)produced from the system consistently meets chemical and microbiological standards and is suitable for use as a raw material in drug manufacturing or for cleaning.

C. You have not thoroughly validated your cleaning processes and your cleaning verification program does not adequately detect potential cross-contamination between products or microbiological contamination.

3.Your firm failed to establish adequate written responsibilities and procedures applicable to the quality control unit and to follow such written procedure (21 CFR 211.22(d)).

Your quality unit (QU) did not provide adequate oversight for the manufacture of your OTC drug products. For example,

A.You replaced the inactive ingredient with another inactive ingredient, without documented scientific rationale and justification, in multiple batches of your OTC drug products. For example, while manufacturing (b)(4)batch (b)(4), you replaced (b)(4)with (b)(4), without appropriate documentation or a product risk assessment. Your firm failed to perform adequate change management. You failed to perform stability studies to show equivalency between the original and substituted ingredient. Additionally, you failed to update the product label to list the actual inactive ingredient used.

You also used multiple specification ranges for the same quality attribute in the same OTC drug product.

B. Analysts documented original laboratory data on uncontrolled sheets of paper. Analysts also recorded raw data in pencil and changed written data using correction

Ineffective Quality Systems

Significant findings in this letter demonstrate that your firm does not operate an effective quality system in accord with CGMP. In addition to the lack of effective production operations oversight to ensure reliable facilities and equipment, we found your quality unit is not enabled to exercise proper authority and/or has insufficiently implemented its responsibilities. You should immediately and comprehensively assess your company’s global manufacturing operations to ensure that systems, processes, and the products manufactured conform to FDA requirements.

Quality Unit Authority

Significant findings in this letter indicate that your quality unit is not fully exercising its authority and/or responsibilities. Your firm must provide the quality unit with the appropriate authority and sufficient resources to carry out its responsibilities and consistently ensure drug quality.

Conclusion

The violations cited in this letter are not intended to be an all-inclusive list of violations that exist at your facility. You are responsible for investigating and determining the causes of any violations and for preventing their recurrence or the occurrence of other violations.

A detailed warning letter can be accessed through link Gadal Laboratories Inc. – 655929 – 08/15/2023 | FDA 

Warning Letter 320-23-20 -July 28, 2023

This warning letter summarizes significant violations of current good manufacturing practice (CGMP) regulations for finished pharmaceuticals. See Title 21 Code of Federal Regulations (CFR), parts 210 and 211.

During our inspection, our investigators observed specific violations including, but not limited to, the following.

1. Your firm’s quality control unit failed to exercise its responsibility to ensure drug products manufactured are in compliance with CGMP, and meet established specifications for identity, strength, quality, and purity (21 CFR 211.22).

–           failed to ensure reliability of data

–           inadequate oversight of original CGMP documents,

–           deficient controls over computerized systems

–           insufficient laboratory investigations

–           aborted chromatographic sequences.

Senior facility managers failed to exercise their authority and responsibility to ensure reliable data, leading to severe data integrity deficiencies in your production and laboratory departments.

2.You failed to assure integrity of analytical testing data. Some examples include:

1. Our investigators observed plastic bags filled with torn and discarded original CGMP documents in your quality control (QC) scrap area under a stairwell, in your general parenteral scrap room, and on a truck outside your facility.
2. An analyst destroyed CGMP records by pouring acetic acid in a trash bin containing analytical balance slips for testing the standardization of (b)(4). A QC employee stated he observed the same analyst destroy KF titration curves and balance printouts.
3. An analyst weighed out the same samples of amitriptyline hydrochloride tablets USP 100 mg batches multiple times for (b)(4)by (b)(4)test. The analyst stated to our investigator that he did not report all the test results, further stating that in some instances balance printouts were discarded in the trash. In addition, the time stamp on each of the analytical balance and (b)(4) printouts did not match your Laboratory Information Management System (LIMS) records

3.Your department failed to exercise appropriate controls over computerized systems. For example:

1. Your electronic batch records allowed changes to be made to manual entries prior to saving. Our inspector observed a production employee manually alter the reported time that an operation was performed. QA did not review audit trails as part of their batch record review to identify discrepancies and compare the reported date and time against that which was originally logged.
2. Analysts manually reprocessed chromatograms by adding integration events that were not approved by QC management. In addition, you lacked appropriate procedures describing when the analyst can manually input integration events, how these events should be used, or how they should be reviewed.
3. Destroyed KF raw data paper printouts associated with drug products were discovered by our inspection team in a trash bag. The KF instrument used for water content testing and assay testing is capable of storing electronic data; however, this capacity was not utilized, and you did not save this data electronically.
4. Your 2018 Process Equipment Assessment Report identified numerous gaps and deficiencies for electronic manufacturing equipment needing upgrades in access controls, audit trails, saving electronic data and preventing clock alterations. You had not documented closures of these corrective action and preventive action (CAPA) measures to support data integrity in your computerized systems. Your QA department had not performed a similar assessment in your QC laboratories.

4.You failed to have adequate oversight of laboratory investigations and to implement a systemic CAPA to address the high number of aborted chromatographic sequences. For example:

1. You invalidated multiple out-of-specification (OOS) results for (b)(4)USP without adequate scientific justification. You then prepared new samples and reported passing results. You concluded the OOS results may be due to (b)(4)contamination during initial sample preparation. However, the laboratory investigation, which was approved by QA, did not discuss why other samples in the same analysis of lots, from the same material, prepared by the same analyst, under the same test conditions, were not affected by such contamination.
2. You aborted hundreds of chromatographic sequences in your QC laboratories between January 2020 to November 2022. Each of the incidents were investigated by the quality control laboratory; however, you lacked adequate trending and CAPA systems to evaluate and identify recurring issues that should be targeted for laboratory improvements.

5. 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)).

1. Your laboratory records lacked complete and accurate data to support the analysis performed. Colony forming units (CFU) were not counted accurately in the laboratory’s environmental monitoring (EM) data. Our investigators observed colony counts shortly after being read by your analyst for environmental and personnel monitoring that did not match your official records.
2. Laboratory raw data was missing and could not be provided during the inspection. For example, analysts did not consistently include (b)(4)printout raw data in laboratory records. Paper printouts for the (b)(4)determinations and pH printouts could not be reconciled for (b)(4) injection, (b)(4) mg, process validation batch (b)(4).

Because the (b)(4) instrument lacked audit trail capabilities, unreported raw data could not be detected during the QA review process.

Failing to maintain complete records of the data and testing conditions associated with all tests significantly compromises the reliability of data and your QA’s ability to perform its obligation to assure quality through conformance with CGMP.

6. Your firm failed to establish and follow required laboratory control mechanisms (21 CFR 211.160(a)).

Your firm failed to have appropriate procedures for the integration of chromatographic peaks and for the review of chromatographic data.

Our inspection team identified examples of your analysts entering manual integration events that yielded passing results without adequate procedural controls or justification.

In addition, your chromatographic data integration procedure is inadequate because it does not identify when it is appropriate for an analyst to input manual integration events. Your procedure lacked a requirement for supervisory approval and other controls such as data review and justification to consistently document when and why an analyst manually performs integration events.

7. Your firm failed to establish adequate written procedures for production and process control designed to assure that the drug products you manufacture have the identity, strength, quality, and purity they purport or are represented to possess (21 CFR 211.100(a)).

Your firm failed to adequately validate the manufacturing process for (b)(4) injection (b)(4) mg. Specifically, your process validation lacked an evaluation of inter-batch and intra-batch variability observed for (b)(4) impurities and (b)(4).

A fourth process validation batch for (b)(4) injection (b)(4) mg was initiated to evaluate related substances from different positions within the (b)(4) due to the incomplete impurity testing. This fourth process validation batch yielded a high OOS result for the (b)(4) impurity. This OOS and failure of the fourth process validation batch was not referenced or discussed in the validation summary report or addendum. A fifth process validation batch was manufactured and included in the addendum report. You subsequently rejected a commercial batch for the U.S. market, (b)(4), due to a high OOS result for the (b)(4) impurity.

8. Your firm failed to establish the accuracy, sensitivity, specificity, and reproducibility of its test methods (21 CFR 211.165(e)).

Your QA department did not ensure raw materials used in the manufacture of drug products were appropriately tested. Your firm failed to perform method validation (or verification, as appropriate) of test methods to ensure that they were suitable for their intended use. You provided a list of multiple in-house methods and compendial methods which have not been validated or verified, including for raw materials such as (b)(4).

Method validation and verification is necessary to support reliable determination of identity, strength, quality, purity, and potency of drugs. Without evaluating the validity of methods, you lack the basic assurance that your laboratory data accurately reflects drug product quality.

Repeat Observations at Facility

In previous inspections, including this inspection FDA cited similar CGMP observations. Repeated failures demonstrate that executive management oversight and control over the manufacture of drugs is inadequate.

Ineffective Quality System

Significant findings in this letter demonstrate that your firm does not operate an effective quality system in accord with CGMP. In addition to the lack of effective production and laboratory operations oversight, we found your quality unit is not enabled to exercise proper authority and/or has insufficiently implemented its responsibilities. Executive management should immediately and comprehensively assess your company’s global manufacturing operations to ensure that your systems, processes, and products conform to FDA requirements.

Test Results Out-of-Specification

A possible laboratory error is insufficient to close an investigation at Phase 1. Whenever an investigation lacks conclusive evidence of laboratory error, a thorough investigation of potential manufacturing causes must be performed.

Process Validation

Process validation evaluates the soundness of design and state of control of a process throughout its lifecycle. Each significant stage of a manufacturing process must be designed appropriately and assure the quality of raw material inputs, in-process materials, and finished drugs. Process qualification studies determine whether an initial state of control has been established. Successful process qualification studies are necessary before commercial distribution. Thereafter, ongoing vigilant oversight of process performance and product quality is necessary to ensure you maintain a stable manufacturing operation throughout the product lifecycle.

Conclusion

The violations cited in this letter are not intended to be an all-inclusive list of violations that exist at your facility in connection with your products. You are responsible for investigating and determining the causes of any violations and for preventing their recurrence or the occurrence of other violations.

FDA placed your firm on Import Alert 66-40 on June 1, 2023.

Correct any violations promptly. FDA may withhold approval of new applications or supplements listing your firm as a drug manufacturer until any violations are completely addressed and we confirm your compliance with CGMP. We may re-inspect to verify that you have completed corrective actions to any violations.

A detailed warning letter can be accessed through link Intas Pharmaceuticals Limited – 652067 – 07/28/2023 | FDA

Warning Letter 320-23-19

July 25, 2023

This warning letter summarizes significant violations of Current Good Manufacturing Practice (CGMP) regulations for finished pharmaceuticals. See Title 21 Code of Federal Regulations (CFR), parts 210 and 211.

During our inspection, our investigator observed specific violations including, but not limited to, the following.

1. Your firm failed to clean, maintain, and, as appropriate for the nature of the drug, sanitize and/or sterilize equipment and utensils at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements (21 CFR 211.67(a)).

Your cleaning and maintenance procedures for non-dedicated (b)(4) equipment (b)(4), including your (b)(4) and (b)(4), are inadequate. Our inspection identified residues of what appeared to be different products on direct and indirect product contact surfaces, including those located inside (b)(4) systems, (b)(4) units (b)(4), and (b)(4). Your firm acknowledged that sections of the (b)(4), (b)(4), and (b)(4) have not been cleaned or examined for cleanliness since they were installed over 14 years ago. During the inspection, your analytical testing confirmed these residues contained multiple active ingredients. Furthermore, during the inspection, you collected residue samples at the end of placebo batches and subsequent cleaning, which also demonstrated active ingredient cross-contamination on surfaces.

(b)(4) over dirty surfaces can facilitate contamination of the drug being processed in an (b)(4). Robust design, cleaning, and maintenance of this and other equipment is critical to prevent cross-contamination.

The inspection also noted missing or faulty (b)(4) in (b)(4), as well as material back flow, which resulted in equipment contamination. For example, you stated the manually operated (b)(4) inside (b)(4) number CP/PT/(b)(4)-01 in (b)(4) Area (b)(4) is always in the open position. You also indicated the buildup of powder inside the (b)(4) and (b)(4) of this equipment was caused by the back flow of materials during equipment (b)(4).

As a result of these inspectional findings, you communicated with your client, Breckenridge Pharmaceutical, Inc., who initiated a recall of numerous batches of alprazolam tablets and clobazam tablets manufactured in your (b)(4). We also acknowledge the recall initiated by (b)(4) of (b)(4) tablets you manufactured.

2. Your firm failed to establish an adequate quality 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 (d)).

Your quality unit (QU) failed to adequately implement the facility’s quality function and ensure quality oversight. For example:

1. Inadequate cleaning procedures

Your procedure to clean (b)(4) lacked sufficient requirements to clean (b)(4) and (b)(4), which had not been cleaned since they were installed more than 14 years ago. Also, your procedure for visually ensuring cleanliness of equipment failed to identify visible contamination.

1. Inadequate Investigations

Your QU failed to adequately investigate extraneous peaks observed in long-term stability samples tested for dissolution by high-performance liquid chromatography (HPLC). Your investigation dated January 24, 2020, identified varying intensities in the peak response, and noted the peak eluted in some tablets, but not in others from the same batch. You determined the root cause to be interference from excipients used during manufacturing and concluded the peaks do not impact product quality. However, you provided no scientific explanation for this conclusion.

Conclusion

The violations cited in this letter are not intended to be an all-inclusive list of violations that exist at your facility. You are responsible for investigating and determining the causes of any violations and for preventing their recurrence or the occurrence of other violations.

A detailed warning letter can be accessed through link Centaur Pharmaceuticals Private Ltd. – 655231 – 07/25/2023 | FDA