Warning letter (2019) / Cadila, India / Critical deviation Residues in Cleaned Equipment

Observation 1 (Warning letter)

The issue was cited in the USFDA 483 as Observation 1.

Failure to clean, maintain, sanitise, sterilise equipment to prevent contamination

During inspection, Investigators observed residues on equipment marked as cleaned. The residues were observed on the back of (..masked) after product change over cleaning and the Firm lacked provisions for inspecting or cleaning the area behind. Further Firm’s review observed residues in other non dedicated equipment also & swab samples and visible residue samples from the equipment product contact surfaces recovered multiple active ingredients. Several examples are quoted

Firm further tested the reserve samples of several batches of drug products and observed contamination with other active ingredients. Firm recalled numerous batches of drug products.

In the responses to FDA, Firm’s review concluded the contamination do not represent a risk to patient, contamination into next product can be nearly uniform. But FDA in the Warning letter noted that this statement by the Firm is not scientifically sound and the response is insufficient;  cross contamination cannot be assumed to be uniformly distributed.

Warning letter also states, the response failed to explain when cross contamination would have started and why it is not detected. Firm stated in the response that testing for cross contamination in the drug products give assurance of detection of contaminants. But FDA in the Waning letter elaborates that testing of cross contamination in the product cannot give assurance of detection of carry over of contaminants and reserve sample testing alone is insufficient to mitigate associate risks; Extent of cross contamination observed suggests lack of assurance of product quality and safety.

Agency asked Cadila:

• CAPA plan which will include prompt detection of equipment / facility issues, timely preventive maintenance, repairs and upgrades of equipment, improved management reviews
• Comprehensive independent assessment of past cleaning effectiveness and number of batches that could be impacted due to cross contamination and scope of recall.
• CAPA plan detailing vulnerabilities in the Cleaning lifecycle management, improvements in Cleaning program, cleaning effectiveness and ongoing cleaning verifications
• Improvements in Cleaning validation program addressing all worst cases – drugs with higher toxicities, potencies, lower solubilities, difficult to clean drugs, difficult to clean areas, maximum holdtimes before cleaning (dirty hold time).

(Further the Warning letter was closed out in November 2022 by FDA and issued a Closeout letter to Cadila)

This Warning letter highlights how critical it is for Pharma operations team to fully understand their manufacturing equipment, areas and parts of equipment where product residues can accumulate during operations and miss the same during cleaning and cleaning verification. For e.g equipment like Fluidised Bed Driers / Equipment (FBD / FBE), Coating machines etc with air inlet and exhaust ducts, vents, valves all have potential for product residues to carry and accumulate in the ducts. Similarly other equipment can have pockets which are not easily cleanable / reachable.

When developing cleaning programs and procedures for equipment, it is important for a cross functional team (of Production/Manufacturing, Engineering & Maintenance, Quality control, Quality Assurance) to sit together with complete engineering drawings and operations manual of each equipment and discuss – which all areas product residues can travel and accumulate during equipment operation, how well these areas can be reached for cleaning, what are appropriate tools for cleaning, which areas are difficult to clean and hold maximum risk of contamination carry over, which areas should be sampled and how the areas can be accessed for sampling, sampling methods (Swab / Rinse). Some parts and components of the equipment may require to be completely dismantled / opened up and cleaned, reassembled and this will involve production, engineering, QA, QC teams with their defined roles and tasks.

This assessment is best done with a checklist covering each part of the equipment:

• Whether product can travel / remain / come in contact with each different equipment part (If not why)
• How the part can be cleaned, what cleaning tools will be used (e.g. water jets, scrubbers, CIP systems)
• How the part will be accessed and verified for cleaning effectiveness
• How the part will be sampled for cleanliness verification. What method will be used. Which all areas will be sampled

Based on this assessment develop the equipment cleaning procedures and cleaning verification checklists.

Perform a risk assessment for each of the equipment /equipment part for residue to remain, escape detection leading to cross contamination. Identify any additional measures required and include the same in the equipment cleaning procedure.

Instead, a routine approach of say, Production team defining cleaning procedure for the equipment, QA reviews and approves; QA / QC follows the SOP for sampling and verification & a rudimentary risk assessment concluding there is no risk of contamination from equipment as there is a cleaning and verification process is in place will not identify all worst cases and areas of cross contamination. 

Cleaning, Cleaning effectiveness and prevention of cross contamination is the most critical aspect of operational cGMP and assuring product quality and safety. Pharma manufacturing sites may well do a comprehensive assessment of their individual equipment cleaning procedures, to see whether all vulnerabilities in cleaning and cleaning verification are identified. If additional measures need to be implemented (procedure improvement, new cleaning tools or CIP systems) identify the same and implement. Support the cleaning procedure with a detailed cleaning and cleaning verification checklist and risk assessment.

And if during the assessment, areas of concerns are identified, perform a comprehensive impact evaluation. If contamination possibility is suspected do perform the reserve sample assessment. But this alone will not be sufficient justification for concluding that the product quality is not impacted. There should be an assessment with sound scientific rationale of what maximum contamination can happen, will this contaminant be uniformly distributed and if so why, how well this will be detected if present, what is risk to product quality, safety at maximum possible contaminant level. Based on this if a conclusion is made that the products are not impacted, document the same. The reserve sample testing data will be an additional support for this assessment. And if the assessment shows there are potential risks, initiate actions like recall for all impacted batches to mitigate risks. Also apply sound rationale while assessing scope of impacted batches – all batches within valid expiry will need to be assessed.