Concerns of Beta Lactam Contamination: USFDA Warning Letter to Centrient

Failure to ensure test procedures were appropriately validated and established procedures were followed. For example, recovery studies were not adequate to demonstrate that the method for betalactam environmental monitoring can recover beta-lactam residue by swab sampling. Established procedure for swab collection was not followed.

Firm response indicates there is no impact to product quality. However, response is inadequate because justification is based on testing performed by a method used to detect beta-lactams in the buildings where non-beta-lactam drugs are manufactured that was not appropriately validated and was not followed. Additionally, firms method for detecting penicillin in environmental monitoring of beta-lactams in the non-beta-lactam buildings is not sufficiently sensitive to detect very low levels of contamination. For additional information, see FDA’s published analytical method that has a limit of detection (LOD) of 0.2 ppb at https://pubmed.ncbi.nlm.nih.gov/29766324/.

Because of the extremely low threshold dose at which an allergic response could occur, beta-lactam facilities need to be complete and comprehensively separated from non-beta-lactam facilities. For additional information, see FDA’s guidance document Non-Penicillin Beta-Lactam Drugs: A CGMP Framework for Preventing Cross-Contamination.

Firm to provide:

• A comprehensive assessment of firms laboratory practices, procedures, methods, documentation, and analyst competencies. Based on this review, provide a detailed plan to remediate and evaluate the effectiveness of your laboratory system.
• A comprehensive assessment of firms containment controls to prevent beta-lactam cross-contamination including, but not limited to, whether firm perform any sampling and testing of the air exhaust of the beta-lactam manufacturing buildings and common areas (e.g., cafeteria) and associated test results for the last 2 years.
• A commitment to either validate and implement FDA’s analytical method for the analysis of beta-lactam contamination in firms environment and in non-beta-lactam drug products to achieve an LOD of 0.2 ppb or validate and implement an analytical method with an LOD that is equivalent or better than 0.2 ppb.

FDA Warning letter observed:

• Centrient failed to ensure test procedures were appropriately validated and established procedures were followed. 
• Recovery studies were not adequate to demonstrate that the method for beta lactam environmental monitoring can recover beta-lactam residue by swab sampling. Established procedure for swab collection was not followed.

FDA did not accept the Firms claim that there is no impact to product quality. The FDA contended that the method for detecting penicillin in non-beta-lactam buildings is not sufficiently sensitive. The Warning letter also highlighted that because of the extremely low threshold at which allergic responses can occur FDA expects beta-lactam facilities to be completely and comprehensively separate from non-beta-lactam facilities.

FDA asked Centrient to provide a comprehensive assessment of its laboratory practices, procedures, methods and analyst competencies and a detailed remediation plan. Firm should also perform a comprehensive assessment of the containment control systems to prevent beta lactam cross contamination including from air exhaust of beta-lactam manufacturing buildings and common shared areas like the cafeteria. The test method for analysis of beta-lactam contamination in environment and non-beta-lactam products should be validated and shown to achieve a Limit of Detection (LOD) equal to or better than 0.2ppb.

• FDA guidance Non-Penicillin Beta-Lactam Drugs: A CGMP Framework for Preventing Cross-Contamination details the importance of manufacturing controls to prevent cross contamination of drug products and active pharmaceutical ingredients (APIs) with non-penicillin beta-lactam drugs. FDA expects manufacturers of sensitizing non-penicillin beta-lactam based products to treat them as similar to penicillin and have separate production facilities.
• It is difficult to determine the sensitizing potential of beta-lactam compounds and not possible to define an acceptable level of beta lactam contamination on non beta lactam drugs. There should be a comprehensive cross contamination prevention strategy comprising containment control systems and procedures, facility & engineering controls and procedural controls, risk assessment for potential contamination, environmental monitoring for beta lactam contamination of air and shared common areas, and other drug products with sufficiently sensitive methods.
• In manufacturing sites which has both beta-lactam and non-beta-lactam manufacturing operations
• manufacturers should assess and establish stringent controls (including appropriate facility design provisions assuring separation) to prevent cross-contamination

• Physical separation of beta lactam production areas
• Separate air handling units (AHUs) for beta-lactam and non-beta-lactam production areas; pressure cascading in buildings with pressure differentials between different areas and air locks; design control of waste flows (like exhausts, vacuum systems) to ensure there is no contaminants being carried from one building to other; design of effluent flows and movement (liquid, solid), destruction (deactivation) of beta-lactam structural element in wastes
• Dedication of facilities, equipment; use of closed systems (Like isolators, barriers, glove boxes) for handling beta lactams.
• Control on material flow (such as but not limited to : no return of materials from beta-lactam areas to common or non-beta-lactam areas)
• Control on personal flow, gowning and degowning, decontamination of gowning, laundry handling and controls, monitoring of laundry for residues, control on use of common facilities and areas (Cafeteria, Health centre, lockers)
• Monitoring – Environment (non-beta-lactam production areas), other common areas, personnel, products (Testing and evaluation). The methods should have high sensitivity (typically Limit of detection should be less than 0.2ppb and results expected as “not detected”).
• Quality risk assessment of all design controls, procedural controls.

• The analytical method used for detecting beta lactams in environment (in non-beta-lactam buildings) should be sufficiently sensitive to detect very low levels of contamination. The methods shall be validated and the limit of detection, quantitation (LOD & LOQ) should be established. FDA expectation is that the limit of detection is 0.2ppb or lower in line with FDAs published analytical method. This should apply to all residue evaluation methods employed in different areas – cleaning validation, area monitoring, laundry monitoring.
• The sampling methods should have sufficient recovery (typically 80-120%) for the beta-lactam residues. Where necessary appropriate recovery factors shall be used in the test methods for calculation of residue levels.
• Firm should follow the established, validated procedures for sampling, analysis for beta-lactam in non-beta-lactam buildings for the environmental monitoring programme.

When an FDA inspection cites critical deficiencies, evaluation and assessment of the observations cited, their impact on batches manufactured & distributed and remediation actions should be comprehensive. It shall be performed against a protocol with defined scope and conclusions drawn should be scientifically sound. The CAPA plan shall address:

• Evaluating the sensitivity of the current method for testing of environmental monitoring for beta-lactam residues. If the method is sensitive validate the method, establish the limit of detection (LOD<0.2ppb).
• If current method is not adequately sensitive, adopt the alternate methods, like the USFDA published method for monitoring beta-lactam contamination in drugs and manufacturing surfaces. Method suitability and verification shall be performed. Adequacy of the sampling method shall be established with respect to recovery of the residues (e.g. swab recovery)
• Compilation of all the test results of the beta lactam environmental monitoring programme in non-beta-lactam production areas; AHU vents, vacuum system exhausts; common areas (Cafeteria); personnel; gowns, equipment and facility surface. Assessment of the test results considering the sensitivity of the testing method and validity of sampling method. Assess the reliability and adequacy of this data to make conclusions on level of beta-lactam contamination at the facility.
• Comprehensive Quality risk assessment of the beta-lactam contamination control systems against the requirement of Complete and Comprehensive separation of betalactam and non betalactam facilities recommended in the FDA guidance
  • design (facility) controls,
  • procedures for beta lactams containment and monitoring.

Identify gaps and take remediation measures as necessary.

• Initiate a beta lactam environmental monitoring programme using appropriately validated and sensitive methods. This will provide new baseline, and guide in concluding whether there were actually unacceptable levels of cross contamination, and further measures to be taken.
• Perform an assessment of other products for beta lactam contamination. Establish the method, perform method verification, test representative batches of other products. The selection of batches should be well defined – For e,g. an assessment matrix may be defined:

• • batches of products manufactured in non beta lactam buildings when beta lactam production was going on,
  • other risk based exclusion criteria – type of beta lactam product manufactured (liquid, solid), facility used and controls (availability of closed systems),
  • also provide for extensive testing of batches based on results from initial selection of batches.

• Based on the conclusions on level of beta-lactam contamination at the facility and testing and results of potentially impacted products and batches initiate remediation action including product recall.

• When FDAs flags laboratory practices, procedures, methods, documentation, and analyst competencies the CAPA plans shall address this comprehensively. Perform an assessment of the laboratory control systems and procedures against a well defined protocol and checklist covering:
  • availability of procedures for specifications and acceptance criteria, test methods, method validations, calibration, qualification, certification of standards; status of validation of all the different test methods, sampling methods; sensitivity of the methods and their suitability for the purpose; competency of analyst (training, understanding).

Based on the assessment develop a plan for improving laboratory systems and procedures, competency of analysts, hiring experienced and competent personnel, training  and coaching of the analysts.