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Warning letters, 483s, Recalls, Import Alerts, Audit observations

Updated on August 7, 2023

The Warning letter cite Failure of Quality unit in ensuring cGMP compliance, Inadequate control over paper and electronic records – blank analytical worksheets and other cGMP documents, multiple cGMP documents with same control number, shredding of cGMP documents after terming them as “discard waste papers”; Failure to appropriately test materials;  Inadequate cleaning of equipment with material encrusted and peeling off from “Cleaned” equipment. The June 2023 Warning letter was issued to Centaur after USFDA inspection observed significant deviations at the API facility at Ambernath near Mumbai (FEI 3003973520 ) in November 2022 and inadequate response by Centaur. 

USFDA Warning letter

1. Failure of Quality unit to exercise its responsibility in ensuring cGMP compliance

A. Inadequate document control over paper and electronic records

  • Documents with uncontrolled access in laboratory drawers – Preprinted blank forms, Analytical worksheets, incident report forms, non-conformance reports, batch release copies, a filled in analytical work sheet and another blank Analytical work sheet with same version number.
  • Analytical worksheets, laboratory incident forms, training records in shredded documents described in Shredder log book as “Discard Waste papers”

B. Quality Unit failure to ensure that materials are appropriately tested and result reported

  • HPLC system processed unlabelled vials of solution, No evidence to show the vials contained solutions mentioned in the HPLC sequence

Firm’s response (to deviations) is inadequate as it has not identified the scope and extent of its practices of discarding and shredding cGMP documents, issue of multiple documents with same document number, unlabelled vials in HPLC and the Firms cGMP training programme is inadequate.

Firm is asked to perform a comprehensive assessment and review of documentation system throughout the manufacturing and laboratory operations, material system (qualification, analysis, release), laboratory practices and analyst competencies, training programme effectiveness for QC and laboratory operations, provide a remediation plan which ensure adequate resources and authority to Quality Unit.

Observation 2:

Failure to clean equipment and utensils to prevent contamination and carry over:

  • In equipment labelled “Clean” observed residues, encrusted material, peelings in discharge point.
  • Inadequacy of response (to FDA), did not evaluate the potential risk of the peeling on all APIs the Firm manufacture.

Firm is asked to perform comprehensive, independent, retrospective assessment of cleaning effectiveness, cleaning program.

1. Document control, laboratory control and labelling of samples

Control of cGMP documents – issuance, retrieval, reconciliation, archival and retention and retirement (destruction after completion of retention period) is of paramount importance. It will not be an overstatement to say the reliability and integrity of the Quality system and Firm is as good as its document control system. When there are uncontrolled blank forms, analytical worksheets, other cGMP document in a site, it directly cast doubts on integrity of all activities performed – manufacturing process and controls of batches, handling of quality events, analytical reports, training records so on and so forth. Various citing of finding GMP documents in scrap / shredded documents during audits, reinforce the point that if an auditor picks up such a piece of document from anywhere in the site and challenge the document control and integrity, Quality unit and the Firm should be able to trace and explain the shredded / scrapped piece of document and why it was scrapped. There should be strong internal review and checks to identify any violations. Observation of multiple documents with same version number, shredding of documents without traceability are clear pointers. Executive Management and leadership should ensure appropriate Quality culture and oversight over operations and compliance and  adequate resources and authority to Quality Unit to ensure compliance.

  • All of all cGMP documents should be controlled – analytical worksheets, checklists, batch records, training sheets, protocols, labels and so on…This is a basic requirement of cGMP (Refer ICH Q7A, Section 6 for all regulatory requirements and expectations for document control). QA an independent function and custodian of Quality Management system shall be responsible for control of cGMP documents
  • Every document for recording activities (operational data, raw data), shall be issued with a Issuance Number / Version number logging the issuance on a register and record the retrieval, while the filled in document is retrieved / returned to QA. Forms shall be issued for specific activities / events and shall be traceable from the log book- e.g. – for a specific batch analysis, for specific deviation logging, specific training programme and so on. These version numbers / issuance numbers cannot be duplicated, as it defeats the purpose of the issue control. If a duplicate copy is required, it should have a different issuance number. There shall be periodic reconciliation (weekly, monthly as appropriate with respect to type of document and number of the documents that get issued) of all Forms – QMS system documents like Change control, Deviation, Training etc, Forms and documents for recording operational data like Analytical work sheets, Batch records, Review checklists and so on.
  • There shall be a system to retrieve unused Forms not used within a predefined period, to prevent misuse and for better control on reconciliation of documents – For e.g. – Batch records / Analytical work sheets within fifteen days from issuance; Checklists like Preventive Maintenance checklists within one week.
  • Persons assigned for the Job of document issuance and control shall be trained well both in the procedure and process as well as the intent of the control. It is not uncommon to assign the task to the most junior members / freshers as this activity is considered rudimentary and nontechnical. But the persons should be well trained and made aware of the criticality of the role – they are the backbone of the Quality Assurance system and its reliability.
  • Considering the large amount of documents and Forms a Pharma Unit typically manage, consider digitising the entire document management and control process – like a DMS system (document management system) for control of issuance, retravel, archival, retention tracking.
  • As an extended step, exercise additional controls – for e.g. Control all Xerox /Copier Machines and Printers in the site. Only specific functions (e.g. QA  and designated QA persons) may have access to Xerox Machines and Printers to prevent misuse, manipulation and unauthorised creation of documents. Centralise the printers in functions like QC laboratories where large number of documents gets printed with control on what can be printed from each system (e.g. allow only prints from analytical instruments and systems, disable or control access to functions like Microsoft Word / Excel).
  • Shredding of cGMP documents shall be a controlled activity  – authorisation by Quality unit, logging the details of each document shredded in a Logbook for shredder with full traceability of What (document is being shredded), Why (it is being shredded), When, by Whom. QA being custodian of the Quality system, shredders and all shredding activity of cGMP documents shall be handled by / under direct supervision of QA,
  • Institute regular internal audits and surprise checks in each department / function to verify the document control practices.
  • Labelling of working solutions in laboratory to maintain identification and traceability is another fundamental aspect of cGMP, applicable not only in chromatography, but all analysis. In chromatographic analysis (and other similar analysis) which involve creation of sequence and auto injection of samples, sequences created shall be verified by a second person / supervisor and authorised before executing the sequence. This verification shall be with a checklist which verifies different aspects including proper sequencing of injections (blanks, system suitability, samples, bracketing and also proper identification and labelling of sample vials). For ensuring consistent practices, the labelling convention for different working solutions and sample solutions shall be defined in a procedure ( for e.g. Blank – B, Standard -ST1, ST2…Sample solutions as SM1, SM2…) and the sequence shall capture the vial identity.
  • And foremost instil a Quality Culture. Make people aware of the criticality of cGMP compliance, data integrity, implication of non compliance and data integrity on patient safety and the corporate through trainings and workshops. Take measures to encourage compliance and integrity – R&R mechanism (Reward and recognition), a zero tolerance and consistent approach to compliance and integrity violations.  Executive management shall empower the Quality unit to enforce compliance, provide adequate resources for surveillance and tracking (like regular Inprocess Quality Assurance (IPQA) checks of processes and activities, surprise inspections, escalation of critical deviations), trained and competent personnel. Executive Management should be part of periodic Quality review meeting where all deviations, failure investigations, CAPAs and progress shall be reviewed.

2. Failure to clean equipment

Almost all manufacturing equipment have difficult to clean, difficult to reach areas for cleaning (material transfer and discharge lines and ports, chutes, air supply ducts and ventilation ducts in equipment like Fluidised Bed Driers, Multimill blades and so on). Equipment cleaning procedures shall be developed by discussion within a cross functional team (CFT) involving Manufacturing, Engineering, QA, QC and even Equipment vendor, to understand all product contact parts and possible areas where product residue accumulation can happen. Product change over cleaning may require complete dismantling of equipment for reaching all hard to clean areas. Cleaning procedure /Cleaning verification checklist should detail every component and contact surface. Perform a risk assessment of potential cross contamination from each equipment by the CFT, identify all potential areas where product dust/residue can reach, address the same in cleaning procedure and cleaning verification. Inputs from Engineering department will be critical to identify all areas product residue / dust can travel during manufacturing and cleaning operation. Accordingly develop/ enhance cleaning procedures and cleaning verification checklists.

Cleaning, Cleaning verification and Cleaning validation is of highest concern with non dedicated equipment and accessories. The CFT can also review where the equipment cleaning and assurance of cleanliness is most difficult and scope for dedication of such equipment, accessories for specific products (For e.g. Sifter screens, Discharge chutes in Equipment like Sifters, ANFD). A control procedure with verification checks also need to be established to ensure these dedicated  equipment / accessories are used only for the specific products. This can also help ease out the rigour of cleaning / verification requirements and significantly reduce product change over times.

Establish Cleaning  / Cleaning verification and Cleaning validation programmes considering worst cases – product with highest toxicities / potency, most difficult to clean, lowest solubility. Establish the Maximum carry over limits (MACO) for each product. Cleaning procedure adopted shall be able to clean the drugs with highest toxicity / potency and most difficult to clean to below the allowable limits for carry over into the next worst case product (typically smallest batch of the next product. Establish appropriate sampling procedures (rinse and swab sampling) from worst case sampling locations -hard to clean, hard to reach in each equipment, identify the same with equipment drawings and document the rationale. (Refer the APIC guidelines for Cleaning Validation & other guidelines on Cleaning Validation by EMA, WHO, USFDA).

Establish maximum hold times for equipment before cleaning (dirty hold time); As a practice ensure cleaning as soon as possible after a batch operation is completed in an equipment. More time equipment are left unclean, more difficult it is to clean, degradants develop which may not get detected in the cleaning sample analysis. 

1. Document control, laboratory control and labelling of samples

Lack of control of cGMP documents touches the core of compliance and integrity. When Firms find issues in this area (through internal or external audits) the remediation approach should be holistic and comprehensive.

  • Initiate comprehensive assessment of possible lapses across the site covering all cGMP functions – operations,  laboratory controls, materials, training, engineering, quality assurance. Assess what are the working documents each function handles and their control,  who are the people involved in the document control – issuance, retrieval, archival, usage. Make an assessment of lapses for each individual and document with rationale. Take actions to enhance document control in each function, actions on individuals – reassignment, retraining, removal (zero tolerance) for enhancing the document control system.
  • Implement all control measures as discussed in above section. For actions which require time (such as digitisation of document control system, implementation of DMS etc) work out time bound action plans.
  • Work out a retest / reanalysis programme for all the products under distribution, stability samples on current date. A priority matrix may be worked out with the most vulnerable products and samples getting higher priority – e.g. those products which have higher incidents of OOS, Deviations –  and document the rationale. In case of failures during retest, take prompt remediation measures – like product recall. Take up revalidation of all analytical methods. Make an assessment of validation status of all products, assess against the data from the retest programme, where revalidation is necessary work out a plan for the same.
  • For comprehensive remediation of lapses in laboratory control, take up brain storming sessions involving all laboratory personnel to identify lapses and gaps in laboratory compliance, labelling and traceability across all analytical activities. Identify and address the gaps by defining control procedures and verification checks.
  • Develop a comprehensive internal audit and assessment programme, possibly with third party cGMP expert across laboratory operations and compliance & document control procedure and practices in all functions. 

2. Failure to clean equipment:

Peeling residues, encrusted material on equipment and accessories which are with a status “Cleaned” raise serious contamination / cross contamination concerns and straight away raise a cause for Product recall. When Firms face such situations, a comprehensive, in-depth systematic evaluation of the contamination issue and risk assessment can help limit the batches to be recalled to those most at risk. For e.g.

  • Develop a protocol for assessment of potential for contamination from each equipment due to lapses in Cleaning processes
    • Classify the equipment:
      • Dedicated / Non dedicated;
    • Equipment which are :
      • Easy to Clean and has least risk of contamination (Glass Lined reactors, Nutsche Filers, Blenders…)
      • Hard to clean has highest risk of contamination (e.g. Multimill, ANFD…)
      • Medium risk (Centrifuges, Driers…)
  • Develop a rationale for assessment of Potential contamination of Products (For e.g:)
    • Batch (es) which are run immediately after a product change over and which involve the equipment Hard to clean / Medium risk – Highest risk batches (candidates for recall)
    • Batches run subsequently in the campaign and involve equipment Hard to clean / Medium risk equipment– Lower risk batches (may be considered for recall, based on evaluation results)
    • Batches run only involving equipment with Medium risk after a product change over cleaning – Lower risk batches (may be considered for recall, based on evaluation results)
    • Batches run in only equipment which are Easy to clean (Least risk batches of contamination, need not be considered for recall unless evaluation of Lower risk category indicates contamination potential).
    • Batches with only dedicated equipment shall be considered as of Least risk
  • Collect the residues, peelings, encrusted material observed in the “Cleaned” equipment. Work out an analysis plan for identifying the content in the collected material considering for e.g. product, intermediate involved in the equipment, document the rationale.
  • Based on the contaminants identified in the material collected, develop methods for analysis of batches at risk for presence of contaminants. Validate the methods.
  • Develop an analysis plan of all the reserve samples of all batches manufactured and within expiry, for example:
    • All batches of Highest risk (These are analysed to get an understanding of extent of contamination)
    • All batches of Lower risk (Evaluation with objective to see whether contaminants are getting carried onto lower risk batches as well).
    • Least risk batches (To be analysed only if Lower risk batches show contamination carry over)
  • Develop a Product Recall plan based on risk assessment and results of sample evaluation
    • Highest risk batches – Immediate recall (do not wait for result as the contamination cannot be expected to be uniform and testing may or may not indicate presence of contaminants)
    • Lower risk batches (Consider recall, if Highest risk batches and /or lower risk batches evaluation show presence of contaminants. If both Higher risk batches and Lower risk batches do not show any contaminants in analysis, no further recall actions)
    • Least risk batches (Consider recall if Lower risk batches / Least risk batches show contaminants in analysis; If not, no further recall action)
  • Entire activity of assessment and recall /remediation action shall be accorded highest priority and completed in a time bound manner. Document the outcome with scientific rationale.
  • Enhance Cleaning / Cleaning verification and Cleaning Validation programmes comprehensively considering all the aspects as discussed above – worst case residues, hardest to clean, lowest solubility, sampling locations and maximum hold times before cleaning.
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