USFDA 483 to Dr.Reddys (DRL) : Cleaning Deficiencies, Building Maintenance Issues

Observation 1

Deficient cleaning practices, presence of actives from previously manufactured products on swab samples from floor & equipment surface and in tablet samples.

• Observed spillage, residues, colour on the floor underneath equipment which were identified as from previously and recently manufactured products by production operators and IPQA employees. Analysis of the samples showed presence of (active) peaks in HPLC /LC-MS / MS chromatograms
• Surface swabs from equipment product contact and non contact areas showed presence of (active) peaks. Analysis of drug product samples (Tablets) also showed presence of (other active) peaks in HPLC chromatograms. There is also potential for the carry over material (from previous products) to react with drug product components and form unknown impurities during products shelf life.
• Equipment (In manufacturing area) were not cleaned underneath the mounted platform since installation and there is potential for material deposit and microbial growth in these areas. Layers of residues, wet areas were observed underneath the mounted platform. The material can deposit on machine components over several years due to positive pressure in the manufacturing area. Swab samples from underneath the platform also showed fungal growth
• Cracks were observed during inspection of manufacturing module and there is chance of tiny particle from the cracks to be introduced into the products manufactured.

Observation 2

• Visual inspection and checks on equipment and manufacturing area after preventive maintenance (PM) and equipment cleaning were inadequate. Observed broken pieces of sealant, residues of previous product on equipment. There is no evaluation for uneven surface and dent marks on equipment, presence of residues, potential leakage after preventive maintenance. Area clearance checks after cleaning or preventive maintenance are inadequate. Observed accumulated residues and wetness beneath equipment, mounted platform.

Observation 9

• Inadequate building maintenance – cracks on wall surfaces, erosion of coving in Production core areas, broken sealants on equipment, electrical panel mounting – makes it hard to clean, allows for entrapment of water, residue build up and microbial growth. Production personnel did not raise maintenance notification even after observing the impacted surfaces. Engineering team observed the same during routine facility inspection, yet documented facility is suitable to use.

Observation 1

Deficient cleaning practices, presence of actives from previously manufactured products on swab samples from floor & equipment surface and in tablet samples.

• Observed spillage, residues, colour on the floor underneath equipment which were identified as from previously and recently manufactured products by production operators and IPQA employees. Analysis of the samples showed presence of (active) peaks in HPLC /LC-MS / MS chromatograms
• Surface swabs from equipment product contact and non contact areas showed presence of (active) peaks. Analysis of drug product samples (Tablets) also showed presence of (other active) peaks in HPLC chromatograms. There is also potential for the carry over material (from previous products) to react with drug product components and form unknown impurities during products shelf life.
• Equipment (In manufacturing area) were not cleaned underneath the mounted platform since installation and there is potential for material deposit and microbial growth in these areas. Layers of residues, wet areas were observed underneath the mounted platform. The material can deposit on machine components over several years due to positive pressure in the manufacturing area. Swab samples from underneath the platform also showed fungal growth
• Cracks were observed during inspection of manufacturing module and there is chance of tiny particle from the cracks to be introduced into the products manufactured.

Observation 2

• Visual inspection and checks on equipment and manufacturing area after preventive maintenance (PM) and equipment cleaning were inadequate. Observed broken pieces of sealant, residues of previous product on equipment. There is no evaluation for uneven surface and dent marks on equipment, presence of residues, potential leakage after preventive maintenance. Area clearance checks after cleaning or preventive maintenance are inadequate. Observed accumulated residues and wetness beneath equipment, mounted platform.

Observation 9

• Inadequate building maintenance – cracks on wall surfaces, erosion of coving in Production core areas, broken sealants on equipment, electrical panel mounting – makes it hard to clean, allows for entrapment of water, residue build up and microbial growth. Production personnel did not raise maintenance notification even after observing the impacted surfaces. Engineering team observed the same during routine facility inspection, yet documented facility is suitable to use.

• Educate the team (Production, Engineering, IPQA, QA, QC) on the criticalities of cleaning, impact of contamination on patients, product Quality, regulatory impact.
• Make Cleaning and Cleaning verification systems robust – cover each nook and corner of the manufacturing area and equipment specifically in the checklists – e.g. areas below equipment, underneath mounted platforms, difficult to reach / hidden areas (air ducts, exhausts), transfer lines and transfer chutes and so on.
• Effective building maintenance procedures – Facilities and buildings maintenance checklists for periodic checks to cover issues like cracks / damages on walls, floors, ceilings, equipment mountings (ducts, exhausts, transfer lines), doors, utility lines and so on. Define frequency for checks based on criticality and risk to product -for e.g – core manufacturing areas at a higher frequency (say once a month) and other areas at a lower frequency. The building checks shall be by a CFT (cross functional team) with team members from Production, Engineering and QA.
• In the manufacturing areas, assess all potential areas of product dust, moisture accumulation. Avoid gaps between equipment / equipment mounting and the floor, walls in the manufacturing areas. Close such gaps, make the mountings, joints flush with floor, walls.   
• Regulatory expectations and requirements of cleaning and maintenance of equipment are defined in detail in USFDA 21 CFR, ICH Q7A and other guidelines – e.g. (but not limited to) CFR 211.42,56,58,63,65,67,182; ICH Q7A Section 4, 5.2, 6.2. The cleaning and maintenance procedures and checks shall be designed to cover all the requirements elaborated in the regulations and guidance’s and ensure effective compliance.

Observation of residues in equipment, products and microbial growth in manufacturing area and deficient cleaning practices are critical findings. When such issues are identified, corrective and preventive actions (CAPAs) should address comprehensive improvements in systems – enhancing the cleaning procedures, practices, fix accountability for the lapses, redeploy – replace – retrain personnel. Equally important is assessing the impact on products in the market and take market actions to stop further availability of the impacted products to patients (e.g. recall).

For a comprehensive impact assessment and evaluation of extent to which products are impacted make a protocol based assessment; For e.g.:

• Make a complete list of all product change over cleanings covering all products till be earliest batch with valid shelf life.
• Categorise the batches as High risk (first batch immediately after a product change over cleaning), Moderate risk (second-third batch after change over cleaning), Low risk (subsequent batches).
• List the potential carry over contaminants based on cleaning and batch charging history – for e.g. Actives from product immediately preceding each change over cleaning and previous one or two products could the most potential contaminants in a batch manufactured immediately after a product change over cleaning. Document the rationale; consider cleanability of the residues when rationalising the list and make a matrix.
• Make a plan for analysis of High risk and Moderate risk batches for previous product residues. Establish and validate the method for testing the batches for presence of previous residues
• High risk batches shall be considered for recall without waiting for analysis and results as the contamination cannot be assumed to be uniformly distributed and detectable in analysis of samples. However if analysis of both High risk and Moderate risk batches do not show presence of previous residues, it may be justified that the risk of contamination is negligible for moderate and low risk batches. But if residues are observed in High / Moderate risk batches, even moderate risk batches will need to be considered for recall; and analysis of Low risk batches also to be taken up followed by market action if warranted.

For incidents like microbial growth underneath equipment, mounting platform etc, perform a risk assessment for evaluating extent of impact. Review the environmental monitoring trend data, pressure cascading, differential pressure recording data. If the data support that there has been no significant changes, incidents, increase in the microbial counts and trends it could be rationalised that risk for impact on product is low. But if the environmental trend data are erratic, inconsistent with occasional spikes etc., impact on product quality and risk to patients need to be further evaluated; reserve samples analysed for any microbial excursions and accordingly and further actions (like recall) shall be taken.

CAPAs shall address comprehensive enhancement of procedures for cleaning, cleaning verification, checklists as described in previous section and training of teams. Operating personnel shall have adequate understanding of the procedures and their responsibilities. They should also have authority and should be empowered to initiate actions when deficiencies are observed – like raising maintenance notification, documenting an incident or deviation. CAPAs shall also address redeployment, replacement of personnel lacking GMP compliance, skills and aptitude.