Warning letter / DuPont Nutrition USA Inc. / MARCS-CMS 627211/ 627211/ DECEMBER 02, 2022/ Observation 5

Failure to have adequate laboratory control records that include complete and accurate data from tests performed to ensure conformance with specifications and standards; Failure to record activities at the time of performance.

Laboratory personnel backdated the approval section of an in-house microbiological media preparation worksheet after the media had been used. Microbiology laboratory personnel were observed using unreleased microbiological growth media plates during drug testing.

Personnel improperly retested pH, conductivity, loss on drying, and particle size samples. Failing results changed to passing based on retest results. Unable to provide adequate investigations or justification associated with the retests.

Sample testing records are incomplete because they do not include information about sample weight, and a reference to reagents and instruments used. Without complete, timely, and accurate testing records, you cannot adequately evaluate the quality of your excipient, make appropriate batch release decisions, or fully understand the potential impact of poor manufacturing practices on the quality of your excipient.

Response (for 483s) is inadequate. For example:

Firm acknowledged the testing record was backdated. However, investigation lacked a comprehensive assessment into the extent of the data integrity breach. Firm did not investigate to determine if similar events occurred elsewhere in the facility.

Firm stated that no other incidents were found for the usage of unapproved media in the microbiology laboratory. Firm did not provide supporting evidence of this review, and did not describe the time period of evaluation. It is not clear whether the firm expanded evaluation to the analytical laboratory.

Firm committed to establish and validate automatic data transfer to (archives / data centre / servers), and firm acknowledged that not all instruments will be able to transfer data. However, firm did not provide a CAPA plan with interim controls to prevent data and file deletion or modification until data (archive / back up facility and instruments) is updated or how firm will manage instruments that cannot transfer data.

Firm did not provide an investigation or documented evaluation into changes in results without justification and their impact on distributed excipient.

Firm stated sample weights for sample preparation were documented on paper for the compendial method, but did not provide supporting evidence.

 In response to the warning letter, to provide:

A comprehensive, independent assessment of firm’s laboratory practices, procedures, methods, equipment, documentation, and analyst competencies. Based on this review, to provide a detailed plan to remediate and evaluate the effectiveness of laboratory system, including specific measures being taken to ensure all laboratory data is contemporaneously recorded and errors are immediately documented and properly investigated.

A complete assessment of documentation systems used throughout manufacturing and laboratory operations to determine where documentation practices are insufficient. Include a detailed CAPA plan that comprehensively remediates firm’s documentation practices to ensure firm retain attributable, legible, complete, original, accurate, contemporaneous records throughout its operation.

 Data Integrity Remediation

Firms quality system does not adequately ensure the accuracy and integrity of data to support the safety, effectiveness, and quality of the excipient.

(FDA) strongly recommend that firm hire a qualified third-party auditor/consultant with experience in detecting data integrity problems to assist the firm with coming into compliance with CGMP requirements.

In response to the warning letter, firm to provide the following:

A comprehensive investigation into the extent of the inaccuracies in data records and reporting including results of the data review for excipient distributed in the United States. Include a detailed description of the scope and root causes of your data integrity lapses.

A current risk assessment of the potential effects of the observed failures on the quality of excipient. Assessment should include analyses of the risks to patients caused by the release of excipient affected by a lapse of data integrity and analyses of the risks posed by ongoing operations.

A management strategy for firm that includes the details of global corrective action and preventive action plan. The detailed corrective action plan should describe how the firm intend to ensure the reliability and completeness of all data generated by firm including microbiological and analytical data, manufacturing records, and all data submitted to FDA.

 Test Results Out-of-Specification

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

 CGMP Consultant Recommended

Based upon the nature of the deviations we identified at the firm, (FDA) strongly recommend engaging a consultant qualified to evaluate firms’ operations and to assist the firm in meeting excipient CGMP requirements. We also recommend that the qualified consultant perform a comprehensive audit of your entire operation for CGMP compliance and that the consultant evaluate the completion and efficacy of corrective actions and preventive actions before firm pursue resolution of compliance status with FDA.

Use of a consultant does not relieve firm’s obligation to comply with CGMP. Firm’s executive management remains responsible for resolving all deficiencies and systemic flaws to ensure ongoing CGMP compliance. 

Organisations operating in the Pharma space should have good knowledge and awareness of GMP requirements and expectations. Lack of awareness of GMP practices lead to casual handling of discrepancies and abnormal events (like test a sample once again, if a failing result happens, without handling it through an OOS event and investigation), lack of completeness in documentation to ensure complete traceability, overlooking systems and procedures and steps (like going ahead with microbial testing, even when a formal release of microbiological growth media plates  is not completed). Organisations should have adequate procedures with checks and balances for handing events like OOS, completeness of documentation (for e.g. print outs from equipment such as weighing balances, pH meters, conductivity meters), document review with checklists, equipment and instruments with electronic data controls (like audit trails, data back up). When a regulatory inspection like USFDA inspection cites major deviations, the responses should be well conceived, comprehensive, addressing all pertinent issues. 

• Comprehensive procedure for microbiology media preparations, microbiology analysis, templates and formats for documenting the activity, review of the analytical documentation before release of the test results by analytical document reviewers and release and handling of media plates, microbial analytical results should be in place. Similarly procedures, documentation formats, review system to be in place for chemical analysis and laboratory.
• Comprehensive procedure for handling of OOS results complying to USFDA / MHRA guidelines. OOS results should undergo a systematic investigation (Phase 1A investigation to identify any obvious laboratory error, Phase 1B extended laboratory investigation). If no conclusive and clear reasons for laboratory error is identified (either no reasons or only probable reasons are identified), investigations should extend to manufacturing process, materials – detailed investigation. Any retest for the material and invalidation of original (initial) result should be scientifically justified.
• Analytical documentation should be complete. The formats for documenting analytical work should have adequate provision for recording all pertinent data – sample /standard weights, details of standards used, reagents used, instruments used, calibration status of instruments, traceability to analyst who performed the analysis, who reviewed the analysis. Provisions should be provided wherever possible to have secure print outs or secure electronic data (like chromatograms) of pertinent data. Such systems should be secure with no possibility for generation of uncontrolled duplicate data, changing date / time / user name etc.
• Instruments which generate electronic data and computers connected to instruments should be complying to computer system and electronic data control requirements as per 21 CFR Part 11 guidance. Systems should be qualified, should have user access controls, should be secure with no scope for change of date or time at the user level, user roles and privileges should be defined, data should be secure and should not be deleted, data back up / archival procedures should be in place for electronic data, audit trails should be available. As this is also a cited observation by FDA, when working out a CAPA plan immediate interim measures to have the situation in control as well as long-term CAPA actions for eliminating the source of causes should be covered. Interim controls could be implementing doer – checker procedure for critical activities, arranging print outs which will be archived along with other batch documentation etc. CAPA plan to address all the requirements as mentioning in the paragraph.
• The lapses observed by FDA are basic GMP requirements. When such lapses including potential data integrity is observed, the evaluation, investigation and impact assessment need to be comprehensive. When there are observation of data integrity (backdating) in one area in microbiology testing, firms should investigate and evaluate possibility of such occurrences in other areas of microbiology testing, chemical lab testing. For e.g – review the analytical documentation of all batches (within expiry) in microbiology, chemical laboratory, documentation in manufacturing area. A plan to be developed for the evaluation based on criticality of product / test parameter and based on the review and observations, the scope may be expanded or reduced. The evaluation, rationale applied should all be documented. This should be detailed in the response on inspectional observations to FDA. The scope and time frame for investigation (to review all previous batches) should be well defined in the investigation document /protocols. Typically this will include all batches within expiry; additional filters may be applied with scientific justification for narrowing down the scope and number of batches to be reviewed. (e.g  – changes in the documentation templates or key people movement etc, this may be helpful in proposing cut offs for depth of investigation).
• Similarly, when it is observed that certain OOS were invalidated without sufficient investigations, all previous OOS results should be evaluated for similar occurrence. The timeframe and scope of such evaluations should be rationalized – for e.g. review of all OOS of batches within valid expiry. Based on the evaluation, if it is identified that there are other OOS which are invalidated / retested and released without sufficient rationale, whether the product quality is impacted should be evaluated, the rationale for conclusions should be documented. Consideration can be given to supporting systems and controls while evaluating the impact / potential failures  – for e.g. if there is an OOS result of pH testing on final product which was invalidated based on retest result, one can look at whether there are in process controls – online pH monitoring of the batch during manufacture, number of water washes to remove acidity / basicity in the process etc. 
• In response to agency when claims are made like no other similar incidents (backdating, incomplete documentation etc) were found for the usage of unapproved media in the microbiology laboratory, this should be properly justified. The evaluations performed to arrive at the conclusion no other similar incidents should be documented and logical.

Microbiology lab – backdating, use of unapproved media plates: Review historical data of all batches with valid expiry for similar observations. Perform the evaluation against a checklist covering for e.g. – date of testing, media plate preparation date, media plate evaluation date, sample analysis date, whether testing and release of plates is documented and other pertinent aspects. Perform an impact evaluation of using unapproved media plates for microbial testing against a defined protocol. This impact evaluation may consider different aspects such as:

• • What is possibility of generation of wrong microbial results (passing an actually failing batch)

• • What Manufacturing controls are in place for preventing microbial contamination (clean room, manufacturing process with chemicals / reagents, process parameters like temperature).

• • Characteristic of Avicel and possibility of microbial growth.

• • Retest of representative batches against a scientifically sound plan – e.g. if there are more than one product batch tested with each lot of media plates, test one of the product batches for each lot of media plate). In protocol define testing of additional batches / all batches based on test result.

Establish enhanced procedure for control of microbiological testing, review of results and release of test results as explained in previous section (What companies should do…).

OOS Handling and procedural deficiencies, Retest of OOS batches without adequate scientific rationale and investigation: Investigate all previous invalidated OOS results against a defined protocol. 

• • Scope and time frame – all batches within valid expiry.

• • Perform manufacturing investigation to see possibility of failure of batches for pH, conductivity, loss on drying, and particle size due to manufacturing process related issues. What aspects in manufacturing process can cause failure, whether these factors were in control during manufacture, any deviations were logged during manufacture of batches, any history of valid OOS for the parameters and root causes for the same & possibility of similar factors causing OOS in invalid OOS batches.  Review alternate controls during manufacturing to ensure product quality – such as in process tests, intermediate tests, online parameters.

• • Review any history of complaints for the parameters pH, conductivity, loss on drying, and particle size samples. Time period could be manufacturing date of the oldest batch within expiry + 2 years (for historical review).

• • Based on the above investigation identify batches if any which may have a valid OOS result. Perform retest of such OOS batches in replicates (predefined) for statistical significance.

• • Perform a risk evaluation of potential failure of batches for pH, conductivity, loss on drying, and particle size samples. (Product performance, patient safety).

• • Based on the investigation and risk identification take further actions such as intimation to customers, product recall.

• • From the investigation also identify the root causes for laboratory error (wherever the OOS is concluded as due to laboratory error) and establish corrective actions for the same. The actions shall include – training and coaching of the laboratory personnel for competency improvement, mentoring, hire experienced staff and coaches where necessary, evaluation of competency and retraining, reassignment of tasks of personnel, laboratory controls such as environment control, improved laboratory instrumentation.  

Establish enhanced procedure for investigation of OOS results, in line with the USFDA guidance (Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production) covering laboratory investigation, manufacturing investigation and impact assessment as explained in above section (What companies should do…).

Data Integrity issues: Investigate other areas for potential data integrity issues – other areas in microbiology laboratory, chemical laboratory, manufacturing. Define a protocol for the investigation, covering

• • Critical documentation and activities for potential data integrity (DI). Define rationale for scope of evaluation of documents and activities  – e.g. criticality of the document (batch analysis reports, manufacturing batch records, calibration records, standard certification and so on). A risk evaluation template following a Failure Mode Effective Analysis (FMEA) may be used for identifying the critical areas to be investigated for DI. Map and list all analytical and manufacturing activities and documentation and a risk score assigned for each, evaluating the risk potential for DI issue with respect to Possibility, Detectability, Severity. Review all activities and documents above a threshold risk score for any DI issues.

• • Based on this investigation take necessary actions to mitigate impact of critical DI issues:

• • • Impact on quality of product / batches, impact evaluation and actions (customer intimation, product recall)

• • • Impact on regulatory documentation (documents submitted to authorities) and updating of the data.

• • Implement appropriate corrective actions to prevent future DI issues which will include:

• • • Providing instrumental / computer system controls such as implementation of electronic documentation and data control (Laboratory Information Management system – LIMS, IT enablement of Quality Management systems).

• • • Upgradation of computer systems for 21 CFR compliance and qualification and validation of the systems

• • • Establishing structure and systems for enhancement of Quality oversight – review of activities and documents – such as document reviewers, in process quality assurance checks and personnel (IPQA) and control points, increased frequency of internal audits, periodic audits using 3^rd party auditors, corporate quality management.

• • • Interim and immediate measures such as  – Printers for balance, standard templates for documentation of activities in laboratories and manufacturing to record all details with date and time (refer details discussed under section – (What companies should do…).

• • • Trainings and coaching for personnel on cGMP, data integrity, good documentation practices (GDPs). Establish a Quality culture enhancement program with regular workshops, case studies with involvement of qualified third party consultants / trainers.

• • • Establish a Data integrity policy and procedure including Dos and Don’ts, Reward and Recognition (RRs) specifically linked to DI issues. Review DI issues in management reviews with involvement of senior leadership; establish procedure for management review meetings and document the meeting deliberations, outcome and follow up actions.

Completeness of Documentation: Review all documentation systems, procedures, formats, templates for completeness of information (analytical raw data sheets/work books, batch records, log books, other data sheets (calibration, validation, standard certification, recording and investigation of quality events and so on). Upgrade the documentation systems and templates.

Perform an assessment of all computerized systems for compliance with respect to 21 CFR part 11 requirements. Based on the assessment work out long term and short term actions. Refer discussion in above section – (What companies should do…).

As suggested by FDA engage experienced and reputed 3^rd party cGMP / Data Integrity (DI) consultant for assessment, review and audit of the system, help in developing systems, procedures and controls and assess all the investigations, corrective and preventive actions, remediation measures. The assessment should cover all aspects of firms manufacturing and controls, laboratory practices, procedures, methods, equipment, documentation, analyst competencies. 

A detailed management strategy shall be worked out with the involvement of the 3^rd party consultant which will cover:

• • Enhancement of Quality Management system – procedures, documentation
  • Enhancement of computer systems and controls
  • Enhancement of laboratory systems and controls including competency of personnel.
  • Enhancement of Quality oversight
  • Enhancement of Quality culture through training, coaching, mentoring and monitoring
  • Management review Quality operations, compliance and data integrity involving senior management

Large organizations with multiple manufacturing sites should also evaluate other sites for similar situations and take remedial actions (Global CAPA). A proposal for the same also to be part of the CAPA and response.