Natco Pharma USFDA 483:Cleaning deficiencies, Data Integrity

Observation 1:

Deficiencies in cleaning and maintenance of non-dedicated equipment and risk of cross contamination

1. Observed thick residues in parts of equipment not cleaned for several years since installation, swab sample results from different parts of equipment showed active ingredients of different products upto 800 times acceptance limit, several unknown peaks in chromatograms indicating potential for cross contamination. The equipment was in “CLEANED” status.
2. New cleaning equipment was installed, but there was no risk / impact assessment based on condition of equipment that was opened  after11.4 years. Impact assessment stated “To improve cleaning efficiency hence no impact” while there was no cleaning mechanism in the first place for 11.4 years.
3. Swab sample analysis procedures are deficient – test procedures (STP) do not address preparation of swab blank solution in the absence of which analysts were testing swab diluent which do not involve treatment with swab stick. The test procedures were not detailing type of swab sticks to be used and due to this QC analysts were not aware if they prepared swab solution correctly and reliability of test results. Swab sample solution stability is not always established. Adequate correct (qualified) swab sticks for swab sampling were not maintained. Quality control is not aware of final swab sample limits and relies on QA for calculation of final swab sample test results and investigation of any quality events. But as per procedure QC is responsible for evaluating whether swab sample test results have met the specifications or not. There is no oversight of QA over accuracy of test result calculated by them.
4. Inadequate maintenance of equipment – scratches, dents, missing pieces on surface of equipment, coloured residue on gaskets.

Observation 2:

• Lack of Quality oversight over control of GMP documents and data integrity – Employees of QC/Microbiology, Production, Engineering and Maintenance were not following Good Documentation Practices (GDP) procedure and destroyed GMP documents by tearing them and disposing to scrap yard. Torn pieces of raw data sheets, balance print outs, batch record sheets, data recorded in uncontrolled white paper, tissue papers, note book pages, gloves were observed in scrap yard. When some torn pieces of documents were put together, unit Quality management confirmed the torn pieces belonged to original record.
• There were Incidents logged for missing pages in batch records, QC testing documents, missing equipment logbooks., but Investigations of the events were inadequate, lacked integrity, failed to establish root cause. For example 1) additional sheets were issued for missing pages in batch record, and these pages were updated several days later including From and To Time records; 2) In QC, raw data sheets and balance print outs for sample and standard were missing for test on tablets, but still analysis was proceeded and results calculated and reported; 3) Incident of missing equipment usage log book. Investigations did not extend to potential destruction of data by employees. Training was provided to employees as CAPA, with employees scoring 100% in training assessment. But questionnaire-based training assessment sheets or other justifications for giving 100% marks were either not available or the questionnaire were with questions not relevant to the incidents. 

Observation 1

Deficient cleaning, cleaning verification continue to be one of most often cited observations in regulatory audits. As discussed in multiple posts by Qvents, most manufacturing equipment have difficult to clean, not easily accessible parts. Many a time it is not so obvious / user department personnel are not aware that there can be accumulation of product dust and residues in such parts and can cause cross contamination during operation/ cleaning of the equipment. For example (but not limited to) air supply and ventilation ducts of FBE (fluidised bed equipment), Tablet coating machine, discharge lines/chutes of equipment, material transfer lines. It is critical that a Cross Functional Team (CFT) is involved during development of cleaning procedures – with personnel from Production, Engineering, QA, QC. The CFT should debate and do a risk assessment of where all product residue can carry during production / cleaning and develop cleaning procedures addressing each part of the equipment. One may need to involve the equipment supplier as well in this assessment. Equipment cleaning procedures shall elaborate the cleaning for each part, with specific cleaning verification checkpoints for each section / part of equipment. In cleaning verification and cleaning validation each of these parts shall be addressed.

Type of swab sticks to be used, stability of swab solutions, performance of a swab blank analysis (to identify the matrix peaks and avoid false alarms) are essential aspects to be addressed while defining testing procedures for cleaning samples. While establishing and validating a test procedure for cleaning sample analysis ensure at a minimum the following are addressed:

• Specificity
• Linearity & Range
• Accuracy (% recovery)
• Limit of Quantitation (LOQ) and Limit of Detection (LOD)
• Robustness (solution stability)
• Swab recovery / Rinse recovery (from each type of equipment surfaces – stainless steel, glass, others)
• Define adequate system suitability criteria (Resolution, Repeatability (%RSD)… Include a swab blank evaluation using a swab blank solution, to help identify artefact peaks (to help discard them during analysis of cleaning samples).

(Refer APIC Guidance on aspects Of Cleaning Validation in Active Pharmaceutical Ingredient Plants; Section 8.2 Validation Requirements)

While documenting the test procedure ensure all precautions like solution stability, type of swab sticks to be used, other do’s and don’ts of the test procedure are documented. Procedurise the same into a general SOP and checklist for e.g.; Procedure for establishing and validating cleaning test procedures.  It is always a prudent strategy to validate same swab stick for different products, unless it is not an option due to specific sample characteristics. This will avoid the issue of having to maintain inventory of different type of swab stick stationary. It is possible some of the test procedures where developed several years back with different swab sticks. Even in such cases it is more convenient to revalidate (with minimum set of parameters – matrix interference, swab recovery) the test procedures with more commonly used swab sticks, to avoid inadvertent mistakes at analyst level during sampling and analysis.

QC being the agency for testing of the samples (and in turn responsible for logging incidents / deviations / OOS in case of discrepancies or non-complying results), it is imperative that QC / Laboratory is aware of the cleaning / swab test limits. QC shall provide the results with comments whether the samples are complying or not to QA, who shall review the data and decide clearance of equipment for next product. In case of any discrepancies or test result not complying to limits, QC shall initiate logging of a Quality event and along with QA and other relevant functions initiate an investigation. 

Condition of manufacturing equipment with severe scratches, visible dents, chipping does raise auditor concerns, especially if there is no documentation and risk assessment of such issues. This raises concerns about Firm’s equipment upkeep and maintenance procedures, cleanability of the equipment, competency and skills of personnel involved in operations. The issues causing such situations (scratches, dents etc) should be comprehensively understood and addressed – providing appropriate tools for the personnel for material discharge and cleaning; training personnel on GMP and acceptable and non-acceptable shop floor practices (for e.g. many times dents and scratches are developed due to hitting the equipment body for dislodging sticky material, scratching the  material from equipment and others. And still events could occur causing dents/scratches on equipment. But rather than waiting for such issues to be picked up during regulatory audits, log the incident as a Quality event and investigate, perform impact assessment. Capture the event in the equipment history card for easy traceability of the event and its investigation during audits. Put effort to identify the root cause(s) for the events and establish CAPA – improve cleaning procedure, appropriate tools for material discharge, training. This gives the auditors the confidence that when events happen, there is a system to document, evaluate, investigate and identify solutions.

Observation 2 – Quality oversight over control of GMP documents, Data Integrity.

Recording of raw data on uncontrolled sheets, tearing of GMP records, updating of records non contemporaneously, control of GMP documents and raw data sheets are fundamental to GMP. The ICH Q7A (Section 6), USFDA Guidance on Data Integrity, EMA Guidance on GMP and Questions and Answers on Data Integrity and similar guidelines from different agencies clearly establish the tenets for control of cGMP documents and Data Integrity – Parent procedures for all cGMP documents, Identification and Traceability, Authenticity, Version & Revision control, Retention, control of disposal of cGMP documents.

Still one of the most often cited deficiency in audits is on document control and data integrity – shows how important it is for Companies to establish and nurture a quality culture based on the pillars of integrity, compliance, transparency, accountability.

It is fundamental that Companies establish robust procedures for control of documents and data in line with regulatory requirements which is straight forward and not so complex.

Qvents has discussed the regulatory requirements for Document and data control and Data Integrity and actions companies should take in several posts; To cite a few:

• USFDA 483 / Sun Pharma, Mohali, India……. Backdating, Non contemporaneous documentation
• USFDA 483 / Intas, Matoda, India / FEI 3004011473 / Inspection 22 Nov – 12 Dec 2022 / FDA Inspectors -Jose E Melendez, Justin A Boyd, Pratik S Upadhyay / Observation 3
• Warning letter / Centaur / July 2023 / Failure of Quality Unit, Uncontrolled cGMP documents, Equipment Cleaning issues
• USFDA 483 / UCB, Belgium / FEI 3003909356/ USFDA Investigators: Hamet M.Toure, Alice S.Tsao / Inspection dates April 17 -21, 2023 / Observation 1 – Deficiencies in Document control

Apart from establishing robust systems and procedures for document controls, there should be a strong focus and efforts on establishing a Quality culture and nurturing and sustaining it. This shall be driven by the top management with right messaging, leadership by example, involvement in shop floor activities and engaging with employees, Gemba walks, regular reviews.  A culture of Quality, Compliance and Integrity should be sustained through continuous measures:

• Quality oversight / Management oversight: In depth reviews and regular audits in multiple layers – internal audits within the site, corporate quality audits (by teams external to site), audits by third party agencies
• Employee involvement / Ownership: Regular small group workshops conducted in each department, where teams of 10-15 members debate activities and potential areas of concern. Identify issues and rectify the same with support of managers and management.
• Build Awareness & Employee sensitivity: Sensitising personnel regularly through training programmes, seminars / case studies with topics from within the company (Quality events)  / outside the company (like published USFDA 483s, Warning letters to debate different type of observations), impact of the observations and gaps. Debate whether there is scope for similar observations in their areas. Educate employees on the finer aspects of Data Integrity and compliance, acceptable behaviour. Sometimes what we consider very obvious is not so obvious to all. For example, contemporaneous documentation. if replacement sheets / additional sheets are issued for a batch record or analytical record it shall be only for recording data as it happens, say when the issued pages or documents got damaged, torn. It is not for documenting activities that occurred in past if some pages are missing or lost.  If pages are missing or lost, it shall be handled as a Quality event, evaluate the impact of the missing information and accordingly decide on the matter at hand (batch release, approval of a test result and so on).
• R&R (Reward & Recognition) Systems: Establish appropriate reward and recognition (R&R) systems which reward Quality, compliance, persons who highlight areas of concern. And ofcourse weed out the bad elements – habitual offenders from the system – reassign / reallocate and where required remove.

A McKinsey presentation Building Quality Culture and Capabilities in an IPA conference 2019 highlights five pillars of Quality culture Quality as top priority, Open dialogue (transparency), Employee Ownership, Leadership (Lead by example), True resolution of problems which very much resonate with the points discussed above.

The true resolution of issues when Quality events happen (Deviations, failures, discrepancies) is a critical element of Quality culture as well as Integrity. Inculcate a culture when deviations / failures happen, they are investigated in sufficient detail with adequate time, root cause is established and CAPAs identified before the issue is concluded and closed. Empower the team members and the Quality unit to take appropriate decisions so that issues are resolved rather than events are just managed.

Training as a CAPA for Quality events can only be part of the actions. The focus in investigation shall be the primary event, what caused the event and what are corrective action for the same. (For e.g. what caused the pages to go missing in a BMR; was it that no proper storage space in operational areas for issued documents, uncontrolled access to documents; or personnel removed the pages for hiding some activity gone wrong). And when training is identified as one of the CAPA, the process of training assessment shall be scientifically sound. If training assessment is performed through an interview with employee, summary of the interview shall be documented. If a questionnaire-based assessment is performed, ensure the questions are relevant to the event, rather than picking up some related questionnaire.