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Warning letters, 483s, Recalls, Import Alerts, Audit observations
Warning letters, 483s, Recalls, Import Alerts, Audit observations
USFDA inspected Granules India’s Finished Dosage and PFI facility (FEI 3004097901) at Gagillapur Village, Hyderabad in September 2024. The USFDA 483 issued to Granules India highlighted significant lapses in Cleaning and maintenance practices, Document control and Data integrity, Compliance to procedures, Recovery and reuse of materials, and Handling of out-of-specifications. The facility was audited by USFDA investigators Pratik S. Upadhyay and Joseph A. Piechocki.
The FDA investigators observed the Air Purification Unit (APU) filters were severely damaged and torn in several sections and contaminated with white to off white residues with water droplets and blackish material indicating microbial growth. Powdery residues were also observed encrusted in the HEPA filter chambers, and extruding from corners of the HEPA filters indicating the integrity of the filters is compromised. They filters have not been appropriately cleaned since their installation. Significantly FDA noted that the Engineering personnel did not have an understanding of the purpose of the HEPA Filters, the filters should block particulates and there should be no powdery material in surrounding areas of HEPA filters. Engineering simply replaced filters as per frequency and there was no Quality unit oversight and evaluation of the conditions during the replacement. There was no logging of deviations or investigation to determine the impact of potential cross contamination due to residues and powdery material in the filter chambers. Analysis of the swab samples from the chambers of the HEPA filters revealed presence of drug substance from previously manufactured products and unknown peaks with area response several times that of the known active peaks. This could be degradants of the actives and drug products. Swab samples from the APU showed several TNTC (too numerous to count) fungal, bacterial and Total Viable Particulate Count colonies which has potential to contaminate the products manufactured in the equipment.
Deficiencies were also observed in handling of the deviation observed during the audit. The Firm filed FAR for few of the products, but not all products manufactured in the module. No FAR was filed or impact evaluated for possible microbial contamination of products.
FDA Investigators also observed the service floor area poorly maintained with significant white residue and dust in the area and over the equipment, equipment cleaning skid and ducts in the area, corrosion, pools of stagnant water with potential for microbial growth. Bird droppings and feathers were observed as the walls to the area were not secured to prevent bird and dust entry. A water tank storing water used for cleaning was rusted with brownish stains and the tank has never been cleaned since installation. Overall the observations leave an impression of poor facility maintenance and Quality oversight.
Concerns were also raised over cleaning of manufacturing equipment with observation of significant quantity of powder on walls of equipment after Type B cleaning and visible powder on the punches of compression equipment after Type A cleaning.
Learnings :FDA inspectors have been focussing on the cleaning and maintenance of air supply ducts of manufacturing equipment like FBEs for several years as this poses an immediate risk of cross contamination. Maintenance programme for APUs should ensure the prefilters and filters in the APU are maintained, cleaned, and verified, HEPA filters replaced at defined frequencies based on site conditions and dust load. Observation of dust, moisture etc in the duct and HEPA chambers should alert the personnel involved in the cleaning and maintenance to potential risks to the product. The Engineering personnel involved in maintenance of AHUs should receive adequate cGMP training, should understand the purpose of the system in totality, not just the mechanical functioning of the unit. They should be aware of implications of failure of filter integrity, dust ingress and trained to raise alarms when discrepancies are observed. As FDA auditors observed, Quality Unit should have an oversight of the Cleaning and Maintenance of critical equipment with a procedure for verification of equipment during and after maintenance.
The prefilters and filters of the APU act as primary barrier to dust and particulate ingress with HEPA filters providing the final filtration and prevent fine dust and microbial contamination of the equipment and product contact areas. Swab analysis of the prefilters for microbial contamination may not be very meaningful. However any observation of other product actives in the swab analysis from the APU and the HEPA chambers will be concerning. Design and orientation of the APU inlet dampers should take care that any residues from exhausts of clean rooms / equipment are not being sucked in by the APUs. Where there is potential for high particulate load in exhaust, one may need to have filters to prevent release of product particulates to environment.
Quality unit should have overall oversight on the cGMP practices in the site. Critical observations during audit prompt the auditors to delve deeper to assess extent of deviations and inspection turn into investigation. Poor site upkeep, maintenance of service areas and surroundings all leave an impression of inadequate Quality and Management oversight. When deficiencies are observed, the investigation should cover a thorough impact evaluation and risk assessment of cross contamination, microbial contamination covering all similar equipment and systems and documentation. Actions taken and where no action is required both should be adequately documented and justified.
Multiple lapses and inconsistencies were observed in handling OOS and OOT incidents. During a process validation campaign, the first validation batch failed for certain in-process parameters and was rejected. Process validation was reinitiated, but a similar failure was observed in the third validation batch, yet the process validation was concluded, and the batches were released to the market. Deficiencies were also noted in the in-process specifications and controls, allowing a batch failed at intermediate stages to proceed to compression, rendering the in-process specifications meaningless.
An OOT of a drug product batch for an impurity was attributed to impurity from a specific API source. Additional control measures were implemented to test the API from the source using a finished product method and to use the API only if the impurity was within defined limits. However, this principle was not applied to the OOT batches which triggered the action; which were still released to the market.
Investigations were also found to be lacking in multiple OOS/ OOT incidents. A cleaning sample failures did not trigger investigations of the cleaning process or its impact on previous batches. A stability OOS for an impurity was attributed to glassware contamination without adequate justification
Learnings :
When unexpected events occur during Quality processes like process validation this require a thorough investigation. Inprocess specifications shall be defined considering both process capability as well as process requirement with sufficient justifications. When a deviation or failure occurs in a process validation campaign, the reasons for the failure, its impact on product quality, and the need for revising specifications or tweaking processes should be thoroughly investigated. It will be inappropriate to define a specification and then not respecting the specification. Some of the inprocess parameters may be monitored for information for which limits may be applied in future after sufficient data is generated over several batches for improved controls. However for certain attributes (for e.g. Blend Uniformity or Assay at intermediate granulation stage) it will be inappropriate to define specifications which allow moving to next stage even when the criteria are not met. This could indicate lack of depth in the Quality system processes, process development studies.
Handling of deviations, OOS, and OOT incidents should ensure thorough well-documented investigations and impact evaluation and remediation actions should be consistent. As a result of the incident if additional control measures are implemented, it should apply to all batches. if a tighter limit is being applied for future batches, while the current batches are being released with a more relaxed limit, the rationale should be well documented.
A failure in a cleaning sample should prompt a thorough evaluation of the cleaning process’s adequacy. A Cleaning process is validated by following a defined series of cleaning steps, multiple samples are evaluated from different locations which confirm if the cleaning process is performed adequately the equipment will be free of previous residues. A failure of a cleaning sample could be due to a one time deficiency in applying a defined cleaning process, operator error etc. or it could be that the cleaning process is not adequate to ensure cleanliness of the equipment consistently. If a cleaning process is found inadequate, it should be revised, revalidated, and the impact on all batches manufactured should be assessed.
Attributing root causes like glassware contamination for OOS ,OOT incidents are inconclusive failure investigations and need to be supported with thorough evaluation and rationale to rule out other possible causes. Investigations should assess product robustness, process robustness, analytical method robustness and other possible factors and CAPAs should address the identified root causes. Or it could be seen as an easy way out to close an OOS/OOT incident.
The inspection revealed significant lapses in data integrity and document control. The quality unit lacked proper oversight over GMP documentation, with employees recording data on uncontrolled white paper and disposing of GMP documents and records like analytical instrument printouts and other raw data documents. Discarded GMP documents, including torn and intact balance printouts, Karl Fisher printouts, pH meter printouts, and handwritten documentation in blue and green ink used by QA, were found in a scrap truck and scrap bags being moved out of the QC lab. The quality unit confirmed that these torn pieces of documents were original records, raw data, and metadata pertaining to QC and manufacturing units, which should not have been destroyed.
Learnings : Control over GMP documents and data integrity (DI) is fundamental to GMP to ensure the completeness, consistency, and accuracy of data. Effective quality oversight and a nurturing quality culture that rewards compliance and integrity and penalise noncompliance with firm actions are key to sustained GMP compliance. DI failure Investigations should be prompt, cover all activities of personnel involved in DI issues, including interviews with current and former employees, assessment of the nature of the testing and manufacturing data prone to DI deficiencies, and a comprehensive evaluation of such records and data. Personnel found to be involved in DI issues should be removed from positions and activities where they can influence cGMP data and investigations. Investigation should be able to establish the extent of DI issues and their impact on products. Remediation actions shall cover recalling potentially impacted products, notifying customers, evaluating the impact on drug applications/dossiers (approved and under approval) and updating the records.
Implementing systems and processes that facilitate minimal manual recording of data and require minimal paper printouts can significantly boost DI compliance. Systems and oversight should ensure that all pieces of printed GMP documents and records are filed and archived along with the original data. The destruction and discarding of GMP documents should be controlled with quality oversight – disposal of records and paper scrap from GMP areas like manufacturing and QC, usage of paper shredders.
Lapses were observed in the recovery and reuse of material from equipment. Material adhering to the walls of equipment was recovered and used within the campaign after a visual inspection for physical appearance. However, documentation of the recovery, verification, and reuse process was deficient, failing to identify when, who, how and in which unit operation the material was recovered and reused. There was no documented evaluation of the surrounding equipment or area during recovery to avoid cross-contamination. There was no evaluation of any other attributes of the recovered material, such as impurities and related substances to show the recovered material meets minimum inprocess checks. Material recovered from equipment before Type C cleaning for product change over is allowed to be carried over to next campaign. But there has been no study on the impact of using this carry over material on quality of subsequet campaign batches. A market complaint for black particle identified the root cause to be active ingredient adhering to walls of equipment turning colour and failure of inspection of material to identify particle in the material. But the investigation did not evaluate impact of the practice on other products and did not address the adequacy of visual inspection.
Learnings:
Recovery and reuse of material should be documented in detail in the batch records, including inspection and clearance of the area before recovery. It should identify the steps in which the material is added, the quantity, and the persons who performed the recovery, verification, and reuse. The reuse of recovered material should be validated during process validation. For example, in a process validation campaign of three batches, a fourth batch can be taken with use of recovered material, quality profile of all four batches compared. Also perform stability studies on all the four batches. During process validation, key quality attributes of the recovered material, including related substances and appearance, should be evaluated. Based on the data, define adequate in-process checks for the recovered material which shall be performed by the Quality Unit (QC) and material cleared for reuse.
Auditors also observed that operating personnel were not following SOPs and written procedures for in-process controls. For example, during tablet verification, both faces of the tablets were not being verified and counted. Tablet weight checks were performed with tablets collected and stored in the in-process sample container instead of checking samples from the compression machine each time. When in-process parameters were found outside the limits, a note was added to the printouts, and samples were reanalyzed without logging and investigating deviations as defined in the procedure.
Learnings: When serious discrepancies are observed during an audit, auditors start reviewing every activity minutely to assess extent of deviations in cGMP practices. Nevertheless, Firms should ensure defined procedures are followed by personnel all the time. Lapses in personnel following the defined procedures are indicative of inadequate control of the Quality Unit over GxP practices. Equally important is to ensure that the processes and procedures are defined in a manner easy to follow and avoid cumbersome paperwork. For instance, rather than logging a deviation for each in-process failure, it may be more practical to document these in the batch records and reviewed during batch release, while major deviations can be logged and investigated. Simple and easy-to-follow procedures help ensure compliance
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