USFDA 483 to Pharmathen Flags Deficient Aseptic Operations

USFDA Inspection of Pharmathen’s Rodopi facility in Greece (FEI 3009961173) resulted in issuance of Form 483 with nine observations. The facility was inspected by USFDA investigators  Khoa Nathan V Tran and Justin Boyd in November 2025.

The Form 483 highlighted critical cGMP deviations across Microbial contamination controls in sterile facilities, Validation of aseptic processes, Data integrity and document control issues. Failure investigations were also found deficient to identify specific root causes and establish appropriate corrective and preventive actions.

GIven the serious nature of observations, drug production was put on hold at the Pharmathen facility as per news reports. Cipla, a major generic player who was partnering with Pharmathen for the cancer drug Lanreotide is reportedly exploring alternate sites for technology transfer and manufacture of the drug.

Microbial contamination controls deficient

Aseptic Techniques and practices

During set up, assembly and installation & aseptic operations and interventions operators were seen reaching over sterile surfaces and open vials, with head inside the filling barrier, hands reaching over product contact surfaces. When forceps used in the Grade A barriers when moved out to Grade B areas, they were not disinfected before placing back. Operators performing aseptic operations wore goggles with hole on top of frame.

Covers removed from sterilised equipment were thrown on the floor which were collected by an operator and stored in a cabinet. These covers were reused, but there was no procedure governing the reuse or how many times the covers can be reused.

Facility design, Maintenance

Aseptic filling rooms were at negative pressure to adjacent Grade B corridors. Investigations of persistent mold contamination in aseptic manufacturing areas identified potential ingress of contaminants from the technical space due to negative pressure differential. Devices for monitoring differential pressure, temperature and humidity only displayed real time data and no historical data or alarms data. During any excursions in differential pressures alarms go off, but stops after returning to normal. But if operators are not present during the time, this will not get recorded or investigated.

A HEPA membrane distributor above the stoppering and filling area was missing and there was no investigation of its impact on the airflow in the area.

Facility corridor leading to aseptic manufacturing suites used for material transfer and movement of personnel had ceiling leaks, discoloured ceiling tiles, blackish mold like substance on walls, ceiling, and fans of cold room storing raw materials and finished goods. Analysis of the blackish substance showed microbial growth. The HEPA filters and diffusers in the Grade D gowning room leading to sterile manufacturing suites were covered with blackish substance which also showed microbial growth on testing.

Insects, flies and wasps were also observed in the facility corridor.

Deficient Environmental monitoring

For microbial monitoring in Grade A areas, inhouse procedure was not followed and settle plates were not positioned at highest risk locations. The plates were routinely positioned away from critical areas where assembly, filling operations and interventions occur.

Risk assessment for settle plate placement did not include an evaluation of routine operator behaviour. Also the EM programme did not include sampling of product contact surfaces like stopper bowl, stopper track, forceps etc.

Environmental monitoring for non-viable particles also did not follow SOPs, no monitoring was being performed when product contact equipment surfaces were exposed and during assembly in the filling line. Also non-viable monitoring sampling funnel was facing away from vial filling equipment. The plates used for environmental monitoring in Grade A and Grade B areas did not include any neutralisers though spray disinfectants are used in these areas routinely. It was also observed microbiologist performing contact plate sampling was not ensuring firm contact.

Identification of recovered microorganisms

There was no identification data for microorganisms recovered from pre-sterilisation bioburden studies to determine whether there are organisms with endotoxin risk or resistant to sterilisation process.

Vial filling for terminally sterilised product is performed in Grade C clean room. There has been no identification of recovered microorganisms from the environmental monitoring programme to evaluate risk of resistance of specific strains to terminal sterilisation or risk of endotoxin formation.

Test methods and Validation

Laboratory test procedures and practices were found deficient. In sterility testing, product was seen adhering on the side of the media bottles and not submerged in the media. Also the sterility testing method using the inoculation technique was not validated to ensure sample is effectively distributed in the media.

Aseptic Processes, Process controls and Validation

Smoke studies

Smoke studies for the aseptic manufacturing areas did not demonstrate the HEPA filtered air was reaching the critical areas. In the filling machine area, smoke was observed to be flowing outward near the top, and static smoke study video showed turbulent air above filling machine. Also, the camera angle in the video recording of the smoke studies and placement of smoke generators did not allow adequate evaluation of airflow direction during aseptic operations.

During aseptic filling of the batch, a LAF was observed to be placed behind the operator performing interventions at the filling machine, with exit air grate directed towards the operator’s back and air flowing past the operator towards filling area. No such LAF placement was configured in the smoke studies. Also, several activities in the vial filling line were not evaluated during smoke studies.

Media Fills

Media fill studies did not simulate routine aseptic operations. Intervention frequencies during media fill did not reflect routine production. There was no data or scientific justification for the interventions in the media fill studies – during routine operations all interventions performed are not documented. Also number of vials removed during media fill interventions is not representative of routine production as number of vials removed in routine operation are not documented. Also all integral vials were not incubated in media fill studies; vials with scratches, lower fill volume were rejected.

Visual inspection Procedure, Visual Inspection failures

Changes were made to visual inspection process (for increasing inspection time and requirement of magnification) without any change control, training of visual inspectors or SOP updation. Changes were only communicated verbally to visual inspectors.

After implementation of the extensive visual inspection, deviations were logged for presence of foreign particles exceeding rejection rate limits in batches where there have been no such deviations logged prior to these changes. However, there was no investigation of impact on the within expiry batches manufactured before changes in visual inspection process. Also, these deviation investigations failed to categorize types of visible particles, identify the particles and their sources; and no effective preventive actions are implemented.

As per a visual Inspection summary report for identification of particles in two products, most common particles were identified as API. However, there was no root cause identified as to how these particles are forming, except stating that the residues originate from the product during the complex bulk manufacturing process. Also, there was no evaluation of whether this impact the cleaning or manufacturing process as the manufacturing equipment are not product dedicated.  The summary report also identified blue cellulose fibres, acrylic yarn fibres, but there was no identification of source of these particles in the aseptic manufacturing area.

Several deficiencies were also observed in the Visual Inspection program

• Visual Inspection program was deficient in that there was no alternative destructive testing included in the process and this is a repeat observation from a 2022 FDA inspection.
• The size and specific type of particles were unknown for the visual inspection qualification challenge kits. Documentation of results for the 100% visual inspection of batches was also found deficient.
• No AQL (Acceptable Quality Level) evaluations were performed unless a limit for specific defect category is exceeded in visual inspection. Also, AQL was allowed to be performed by same personnel who were involved in visual inspection.

Data Integrity, Document control issues

Several lapses were found in documenting laboratory test records, sampling documentation at the time of performance contemporaneously.

Laboratory controls

In the Microbiology investigators observed ongoing sterility tests and testing of environmental monitoring samples from Grade A and Grade B areas with no documentation. Sampling records were not made at the time of sampling and analysts were filling sampling information paperwork during plate reading. Several sampling records were found to be incomplete / only partially complete.

Document control, Incomplete GMP documents

A binder of non-viable particle monitoring records of sampling locations in sterile manufacturing suite was observed with numerous incomplete, unsigned, unreviewed particle monitoring sheets and particle counter print outs. Sticky notes were placed on records identifying which personnel need to complete and sign the documents.

The IQVIA software used for printing of production and laboratory GMP documents could print multiple copies of same document with same serial number. There was no audit trail for this printing, and no reconciliation between GMP documents printed and documents returned to QA.

Control of electronic records

There was no procedure governing review of raw electronic data from computerized systems used in GMP operations, defining responsibilities, requirements, review of original electronic data.

Investigation deficiencies

Investigation of discrepancies and batch failures were found deficient and not thorough:

Media fill / Sterility failures

Investigation of Media fill failures and sterility failures identified several human source microorganisms: Staphylococcus, Microсоссиs, Косuria, Acinetobacter, Bacillus species, Corynebacterium jeikeium.  But the investigations failed to identify specific root cause(s). Root cause was attributed to poor aseptic behaviour, inadequate aseptic techniques, but did not identify specific instances, The preventive actions taken failed to ensure aseptic behaviour and were not effective,

An investigation of media fill failures did not identify critical equipment and procedural deficiencies that contributed to the failure – system design gaps which did not ensure drainage, stagnant areas which allowed proliferation of several gram negative bacteria: Burkholderia cepacian, Ralstonia insidiosa, Ralstonia pickettii, Sphingomonas paucimobilis, Delftia lacustris, Delftia acidovorans, Comamonas testosterone.

Firm did not have a procedure specifying when microorganisms in systems must be identified, there was no identification performed following a media fill failure to ensure the microorganisms did not stem from the system.

Also there was no investigation of integrity test failures as defined in the inhouse procedures.

Out of specification (OOS) investigation of injection products for assay did not have any Phase II manufacturing investigation. OOS result for a batch was invalidated after testing new samples and root cause was attributed to sample preparation errors with no scientific rationale.

Learnings, Remediation Actions

Criticality of aseptic operations and facilities is among the highest in pharmaceutical manufacturing due to risk of microbial contamination and particulates. Deficiencies in aseptic manufacturing facilities, operations and controls require comprehensive remediation actions

• Listing of each aseptic manufacturing line and evaluation of facility deficiencies, airflow visualisation studies, pressure differentials, devices for monitoring of manufacturing conditions, facility maintenance issues.
• Listing of all operator interventions and actions during aseptic operations.
• Comprehensive assessment of microbial contamination risk of all products manufactured and within expiry due to facility deficiencies and operator practices, with well documented rationale. Initiation of recall products with product integrity and sterility risk.
• Corrective actions for facility design issues and facility maintenance issues.
• Requalification of the facilities as per regulatory and GMP requirements (USFDA guidance: Sterile Drug Products Produced by Aseptic Processing — Current Good Manufacturing Practice)
• Evaluation of all media fill studies, identification of gaps between actual batch operations and media fill studies.
• Review of all manufacturing documentation, batch records to address gaps in documentation. Fresh media fill studies with well-defined protocols to simulate commercial operations and interventions.
• Review of all personnel involved in aseptic operations, understanding and competency for performing aseptic operations. Retrain and requalify operators in aseptic behaviour.
• Comprehensive review of the environmental monitoring program to address gaps in sampling for microbial monitoring in aseptic areas, sterile surfaces and product contact surfaces, monitoring of non-viable particles.
• Review all OOS investigations (validated and invalidated) for identification of root cause(s), appropriate corrective and preventive actions. Reopen the OOS investigations where gaps are observed to identify probable root causes and establish corrective actions.
• Review the Visual inspection programme and procedures. Update SOPs to address gaps from practices, destructive testing, AQL testing programme. Ensure AQL are performed by operators not involved in the visual inspection of the batch.
• Comprehensive review of all test methods and method validations for technical correctness, clarity of instructions. Address the gaps, perform revalidation where required and retrain analysts.
• Comprehensive review of GMP operational documents and documentation practices for contemporaneous documentation and alignment with ALCOA principles. Identify root causes for deficiencies (for example operational constraints, system deficiencies, adequacy and competence of personnel) and address the issues.
• Comprehensive assessment of computerised systems used in GMP operations and evaluate for electronic data control and compliance. Establish procedures for review of raw electronic data, audit trails.

Remediation requires a holistic programme encompassing facility upgrades, operator requalification, robust validation, strengthened investigations, and a cultural shift towards quality and transparency.

Pharmathen Greece, USFDA 483 (November 2025)