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.

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.

• Companies and sites which have Beta lactam manufacturing operations should have adequate containment controls systems & practices, defined procedures for containment and prevention of beta lactam cross contamination to environment, non betalactam buildings and products, risk assessment of containment control systems, documentation. This is more critical when the site has both betalactam and non betalactam production facilities. FDA requirement is a complete and comprehensive separation of the manufacturing operations of beta lactam drugs from manufacturing operations of other drugs.
• 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 betalactam drugs. No safe level of penicillin contamination has been determined to be a tolerable risk. Hence when there are both betalactam and non betalactam manufacturing operations in the same manufacturing site or premises (even if in different buildings) , there should be a comprehensive cross contamination prevention strategy implemented to ensure there is no possibility of beta lactam contamination of non betalactam drugs. This should be well defined, implemented, documented (containment control systems – facility and procedural controls, risk assessment) and also supplemented by environmental monitoring and testing of products with sensitive methods. The 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 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; and expectation of results is below detection levels. The strategy shall include all or several of design controls, procedural controls and monitoring of betalactam contamination as discussed in the FDA guidance: Non-Penicillin Beta-Lactam Drugs: A CGMP Framework for Preventing Cross-Contamination at https://www.fda.gov/media/79971/download:
  • Physical separation of betalactam production areas
  • Separate air handling units (AHUs) for betalactam and non betalalactam 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 betalactam 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 betalactam areas)
  • Control on personal flow, gowning-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 betalactam 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.

• All analytical methods for betalactam residue evaluation (as a matter of fact any residue evaluation methods used in different areas -like cleaning validation, area monitoring, laundry monitoring so on and so forth ) should be validated and the methods should have defined sensitivity. All residue monitoring programmes (environment, buildings, products) programmes should have defined acceptance criteria with sound rationale for residue levels. The methods for sampling should also have sufficient recovery (typically 80-120%) and recovery should be verified. Where necessary appropriate recovery factors shall be used in the test methods and calculation of residues.
• Firms should have general policy or procedure for method validation, setting acceptance criteria, sampling and testing methods, validation of sampling & testing methods, for reviewing and approving 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 has cited Critical deficiencies, evaluation and assessment of the observations cited, their impact on batches manufactured & distributed, remedial actions should be comprehensive,  There should be a well defined protocol for evaluation and assessment with well defined scope and conclusions should be scientifically sound. The conclusions, rationale and response should not give an impression to agency that the Firm is not serious, is trying to shortcut the  evaluation (For example, a response like Method used for testing to show there is no impact on product quality (and therefore firms practices are adequate) without appropriately validation of method and assessment lacks sound rationale)

• 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, adoption of the USFDA method (given in reference) for testing of environment and products., Verifying the suitability of the method, validation or verification of the method including swab recovery.
• Compilation of all the test results of the beta lactam environmental monitoring programme  in non betalactam production areas; AHU vents, vacuum system exhausts of of betalactam production areas; common areas (Cafeteria); personnel; gowns and so on – covering 2 years (current method). Assessment of the test results, reviewing the sensitivity of the testing method, sampling method. Make conclusions on the data and further actions.
• Comprehensive assessment of the Betalactam contamination control systems against the requirement of Complete and Comprehensive separation of betalactam and non betalactam facilities –  design (facility) controls, procedures for beta lactams containment and monitoring. Document the evaluation. Perform a quality risk assessment and if additional measures are identified plan and execute the additional actions as per defined timelines.
• Initiate a beta lactam environmental monitoring programme with increased frequency using appropriately validated and sensitivite method. This will provide new baseline, and guide in concluding whether there was 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. define a matrix  – batches of products manufactured in non beta lactam buildings when beta lactam production was going on, other exclusion criteria – type of beta lactam product manufactured (liquid, solid), facility used and controls (availability of closed systems and so on), number of batches to be tested etc. Also provide for extensive testing of batches based on results from initial selection of batches.
• Perform a comprehensive impact assessment and document the same based on the outcome of the actions and assessment (evaluation of previous test results, assessment of containment control systems, test results from newly initiated environmental monitoring programme, test result on products). Accordingly initiate further market actions such as recall of products in distribution, if there is risk of contamination identified.
• FDAs has flagged firms laboratory practices, procedures, methods, documentation, and analyst competencies. Perform a comprehensive assessment of the laboratory control systems and procedures against a well defined protocol and checklist covering aspects such as:
  
  • 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), and so on.
  • 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.