Observation 1

Failure to thoroughly investigate discrepancies – Out of Specifications (OOS), Deviations.

• Bulk drug product OOS for assay retested and released with root cause as sample preparation error, without adequate hypothesis & scientific basis. Several similar OOS during the period of 2019 – 2022 attributing sample preparation error as root cause, but no adequate CAPA to prevent recurrence. The Firms response to FDA on the deficiencies observed is not comprehensive, only narrowly addressed the OOS events noted by FDA Investigators, and CAPAs were inadequate.
• Inadequate investigation into several instances of humidity excursions in manufacturing area, stability chambers. Humidity data between Dec 2022-Jan 2023 could not be reviewed, as data was not backed up and deleted every month. High levels of humidity can make capsules liable for microbial contamination. Firms response to FDA did not address the potential for microbial contamination, measures taken to maintain dehumidifier and overall conditions at the facility. 

Observation 1

Failure to thoroughly investigate discrepancies – Out of Specifications (OOS), Deviations.

• Bulk drug product OOS for assay retested and released with root cause as sample preparation error, without adequate hypothesis & scientific basis. Several similar OOS during the period of 2019 – 2022 attributing sample preparation error as root cause, but no adequate CAPA to prevent recurrence. The Firms response to FDA on the deficiencies observed is not comprehensive, only narrowly addressed the OOS events noted by FDA Investigators, and CAPAs were inadequate.
• Inadequate investigation into several instances of humidity excursions in manufacturing area, stability chambers. Humidity data between Dec 2022-Jan 2023 could not be reviewed, as data was not backed up and deleted every month. High levels of humidity can make capsules liable for microbial contamination. Firms response to FDA did not address the potential for microbial contamination, measures taken to maintain dehumidifier and overall conditions at the facility. 

OOS Investigations

Repeat incidents of OOS with no clear root cause and repeatedly assigning the cause as sample preparation error (similarly laboratory error, analyst error, glassware contamination and so on), indicate issues in analysis laboratory (QC) and analytical controls.

• Poor awareness and analytical skills of analysts
• Poorly written test methods (lacking step by step instructions for performing the test with all precautions, factors which can cause a wrong result)
• Poorly developed and established test methods which are not adequately validated / challenged during method validation – robustness studies 

It also shows poor investigation lacking focus to get to the root cause. The OOS incident(s) could be due to manufacturing issues as well – poor mixing, blending, granulation, storage.. but this can be missed when investigations are closed attributing laboratory errors as cause for OOS without a manufacturing investigation.

The OOS investigation should follow the – Phase 1 (Laboratory Investigation) and Phase 2 (Full scale Investigation) process as detailed in the USFDA / MHRA guidelines for handling of OOS. The Phase 1A looks at Obvious errors and Phase 1B – Laboratory investigation evaluate possible laboratory error – sample handling, sample preparation, test method, analyst awareness, instrument malfunction and so on, with a well defined checklist. And during Phase 1B evaluation if possible laboratory errors are identified, this shall be verified through hypothesis testing – testing performed to help confirm or discount a possible root cause:- for example it may include further testing regarding sample filtration, sonication /extraction; and potential equipment failures etc. Based on Phase 1B investigation and hypothesis testing, sample shall be retested and batch disposition decision concluded. However the hypothesis should be scientifically justified and supported by the facts of the initial analysis and observations made in Phase 1B investigation checklist. For example, a proposed sample preparation error of insufficient sonication / extraction is not convincing if there were several samples tested / sonicated together but only one or two samples were OOS. The root cause is not conclusive. When the root cause is not conclusive, the OOS investigation should also be extended to Phase II, manufacturing investigation. Manufacturing investigation should evaluate manufacturing steps and adequacy, equipment and facilities, materials, operator error, deviations, history of failure. The investigation should conclusively show that the OOS could not have been caused due to manufacturing related issues. Identifying scientifically sound probable root cause helps in implementing appropriate corrective and preventive actions (CAPAs) – e.g. redefining the sonication / sample extraction process – time, temperature; glassware cleaning methods, sample handling, training the analyst for improving the analyst skills, and prevent recurrence of similar OOS. Firms should track and review trend of the OOS for recurring events; recurring OOS events show the actual root cause was not identified and whatever CAPA were documented are ineffective. This should trigger a reopening of the previous OOS events and investigation, a deep dive into the OOS incidents to establish the actual root cause.

 The test methods and procedures should be appropriately validated and all possible variables evaluated during method validation. The test methods shall document the precautions and do’s and don’ts with possible impact. Preforming only basic rudimentary method validation for documentation and regulatory filing purpose is a sure recipe for later issues during routine quality control testing.

Firms should also establish adequate Quality and Executive Management oversight. The Quality Assurance (QA) function shall review the OOS trends, identify recurring OOS and flag for revaluation. There shall be periodic management review (typically once a month) where the executive management review the performance of the Quality Management system (QMS) along with site operations team and the Quality Unit. The management review meeting shall review trends of deviations, OOS, other discrepancies and failures, recurrence of the Quality events, CAPA implementation and effectiveness. Procedure for Management review meetings with defined agenda shall be documented.  

Also refer the posts:

• Warning letter / DuPont Nutrition USA Inc. / MARCS-CMS 627211/ 627211/ DECEMBER 02, 2022/ Observation 2 
• USFDA 483 / IPCA Laboratories, Silvassa, India / FEI 3005977675/ USFDA Investigators: Rajiv Srivastava, Kellia Hicks  / Inspection dates April 18-26, 2023 / Observation 1 – Deficiencies in failure investigations (OOS, Complaints) 

  Humidity excursion deviations.

Humidity excursions in manufacturing areas can affect product quality; impact may show immediately (in batch release testing) or could manifest later during the shelf life of the product. Humidity excursions in manufacturing areas could be due to one or several causes – for e.g. (but not limited to) – issues with dehumidification system, compressor, fan, leaks in refrigerant coils, clogging of condensate lines, water drainage from system; it could also be due to other factors in manufacturing area – operator practices, frequent opening and closing of doors, leaving doors open, specific processes. Repeat excursions should trigger a full scale investigation involving a cross functional team (CFT) – Manufacturing, Engineering, QA, as the root causes could be system related, practice related, process related or a combination of several factors. Use an appropriate investigation tool – a brain storming session with Ishikawa (fishbone) analysis could be a useful tool to evaluate various factors – Men / Machine / Method / Material / Mother nature. Review the cleaning and maintenance practices of the dehumidifier system. If the corrective action identified to address the root cause need a lead time – for e.g. defect with the dehumidifier requiring major overhaul or replacement, establish interim control measures. For example – Limiting operations so that the HVAC / dehumidification systems can support the most critical areas in manufacturing and packing; temporary solutions like potable dehumidifier. Perform a risk assessment of the impact of humidity on products, identify products which require less stringent humidity controls. A temporary relaxation of limits (planned deviation or temporary change) for humidity specifications may be applied, production plan tweaked to take up products which have less humidity impact till the issue is resolved. Deviations can be handled in different ways minimising impact on production and ensuring quality & safety of products, but the key point is that deviations from prescribed conditions / specifications and processes should be identified, acknowledged and investigated promptly.

Nowadays stability chambers come with various features to alert the users in case of excursions, prevent excursions – e.g – Mobile alarm systems, standby compressors in case primary control fails, compliant software for stability chamber data management with access controls, back up, audit trails. Ensure the stability chambers have the  required controls and features / upgrade the systems. In spite of such controls, if excursions still happen, investigate the root cause–  are the alarms active and working, are the standby system in place and working, is the preventive maintenance programme cover alarm functioning, verification of standby systems. is there a process in place for people to respond to alarms in time and act if excursion happen in silent hours (when regular QC, QA and other operational staff are not present say in night time / holidays). Accordingly implement corrective actions to address the gaps.

The stability chamber temperature and humidity records, and alarm data, backup status shall be verified daily. This ensure that even if excursions happen, or a data loss happen due to any hardware/software malfunction, this could be for a maximum of 12-24 hours by when the issue is noted, and acted upon. It is a good practice to take print of the stability chamber data daily, review and archive (either as paper copies or electronic copy). 

It will be prudent for Firms to review their historical OOS events, invalidated OOS events, recurring OOS events, root cause(s), CAPAs implemented and their effectiveness and take measures to address lapses if any.

1. Review all past invalidated OOS incidents with laboratory error as root cause. Evaluate whether the root cause(s) is conclusively established, CAPAs are implemented, effectiveness of CAPAs implemented, are the OOS recurring and reason for recurrence. Review whether manufacturing investigations are performed for all invalidated OOS with laboratory error as root cause.
2. Where gaps are identified reopen the OOS incidents for an assessment against a protocol. Assess what other causes could have caused the OOS, perform hypothesis testing where required and conclude the root cause(s). If the investigation shows the past CAPA were inadequate, take additional measures; If investigation shows the OOS could be valid, take remediation actions (recall, stop distribution, customer intimations etc.). 
3. Where root cause is concluded as method issues, analyst errors, review for similar situations in other methods. For example, if the optimal sonication time for assay for a product with a particular matrix and active (API) needed to be revised because of an OOS event, evaluate whether there are other similar products and extend the CAPAs to these products as well; Or if a product with specific active (API) tend to give more impurities due to temperature or sample preparation delay, evaluate other products and methods involving same active.
4. Review the methods and method validation data – especially robustness studies. Whether all possible variables are evaluated  in robustness studies, optimum ranges for parameters established. If not, take up the same with a defined timeline for closure. Review the test methods documented for clarity of instructions, precautions to be taken to avoid errors – e.g – shaking /sonication time, temperature, special requirement like amber coloured glasses, type of filters and so on. Extend the action to other similar methods. For these evaluations, use a matrix approach for matrixing similar products, similar methods.
5. Review and revise the OOS Handling and Investigation procedures as elaborated in the previous section in line with the OOS guidance of USFDA / MHRA. Train the personnel. Take workshops / case studies with specific cases from the Firm, examples from different published USFDA 483s / Warning letters. 

When humidity excursions happen in manufacturing area or in stability chambers, perform a comprehensive investigation to establish root cause and CAPAs. Review and enhance control features in stability chambers. Assess batches that could be affected by the humidity excursions in manufacturing area, and consequent impact on microbial quality. Reserve samples of affected batches within valid expiry shall be retested for microbial counts and where failures are observed, initiate remediation action. Review potential for humidity control failures in other manufacturing lines and areas, document the same and extend the corrective actions identified (procedural controls, preventive maintenance checks, cleaning and others) to these areas as well.