Sichuan Deebio – 483, OAI and Warning letter.

The USFDA inspection revealed critical data integrity (DI) deviations – Microbiology plates discarded in waste bin without recording results and QC team leader not telling truth about recording the results; missing test data; samples getting tested repeatedly till desired results are achieved. The Firm’s failure investigations, complaint investigations were inadequate and deficiencies observed during customer audits were not officially documented through the Quality Management system. Production and Process controls were found to be lacking. Multiple API lots were serially blended to make one finished lot of API, but the process was not in control and failed to establishing blend uniformity. Equipment cleaning, cleaning records and cleaning validation was also found to be inadequate. Serious deficiencies were observed in impurity evaluation, control and investigation of failures. Investigation into additional peaks in chromatographic analysis did not identify the source for the peaks and corrective actions. QC specifications and test methods were inadequate with failure to evaluate impurity profile of drug substance and test API for impurities. The FDA 483 also cited lack of Transport validation studies to assure the APIs stayed within the defined storage condition during transit.

In the Warning letter that followed FDA raised concerns about validity and integrity of laboratory data and failure of Quality Unit (QU) to investigate and resolve deviations and complaints, ensure control of documents and electronic records. FDA found the Firm’s response to the FDA 483 inadequate as it fails to provide sufficient retrospective review of all documentation practices, investigations and data retention deficiencies. FDA asked the Firm to provide:

• Complete assessment of documentation systems, procedures across operations
• Investigate extent of inaccuracies in data records and risk to patients due to failures and lapses of data integrity
• Provide a Complete remediation plan for the lapses in documentation practices & Management strategy to ensure reliability and completeness of all data & provide the QU authority, resources and top management support to function effectively.

FDA 483 to Chinese API Manufacturer Sichuan Deebio cites Data Integrity issues (Qvents News).

Data Integrity: Basic DI issues like not recording the reading of microbiology plates, test data not available as print outs or electronic data, Testing of samples into compliance all underlines the importance of an independent Quality Unit (QU) with authority and resources. The QU need to routinely monitor activities, flag issues, document quality incidents and deviations, ensure investigations to establish root cause and implementation of CAPAs.  Ensure Contemporaneous documentation which is attributable and traceable, retention of all original records, control of computer systems and data, review of audit trails.

Impurities and Control: Control of Impurities in drug products and drug substances shall include process and degradation impurities (ICH Q3A, ICH Q3B, USP<476>, USP<1086>), residual solvents (ICH Q3C), genotoxic impurities (ICH M7), elemental impurities (ICH Q3D), nitrosamines (USP<1469>, USFDA Guidance on Nitrosamines). For OTC monograph products also, where FDA do not assess and approve products, same principles apply.  Many USP monographs for drug product and API and the OTC monographs may not specifically address limits for impurities. Nevertheless the drug products and APIs shall comply with requirements for impurities as elaborated in USP general chapters  <476> and <1086>. The USP <1086> is categorical that if an individual monograph does not include control of impurities, manufacturer is responsible for developing and validating analytical procedures and establishing acceptance criteria for impurities. Manufacturers should refer to current regulatory guidance and implement control strategies for impurities.

When additional peaks are observed in chromatograms investigations shall be comprehensive. Not only identify the peak, but assess possible reasons as well. It could be other solvent peaks due to contamination from equipment, storage tanks, transfer lines or hoses, previous product residues, laboratory contamination and so on. The investigation should assess probable causes, impact on product quality, actions to be taken to avoid recurrence. In the analysis review checklist for chromatographic analysis, include check point for additional peaks and evaluation so that such incidents are proactively acted upon.

Blending of batches and Validation: By definition a Batch is a specific quantity of material produced in a process or series of processes so that it is expected to be homogeneous within specified limits (ICH Q7A). Serial blending of API lots to make a finished API lot do not make a Batch. Each blended sublot (which is actually the specific quantity of material produced in a blending process) shall go for complete analysis against the specification and batch release review. Only individually tested and released batches of APIs shall be blended to make a commercial lot, and if this is complied, there is no case for a batch result to be failing (say for impurities) when sampled from top, middle, bottom. That is unless the API has intrinsic stability issues and handling and exposure during blending process can affect critical quality attributes, impurities. Blending process shall be validated, parameters that can be affected due to the blending process evaluated– impurities, microbial parameters, particle profile, physical properties  – to assure quality and homogeneity of the blended batch.

Cleaning Verification, Validation, Solvent residue carry over: Observation that equipment cleaning and testing methods did not assure ability to remove the residual solvents and detect the residues highlights an often-ignored area in Cleaning verification and validation. Typically cleaning verifications and validation focus on the previous product residue and seldom on the process solvents involved in previous product. A risk assessment of the cleaning process evaluating potential carry over residues including solvent residues can help avoid surprises. If there is a potential risk of carry over solvent impurities, perform an evaluation and implement control measures. Or if there are sufficient justifications that there is no risk of carry over of any additional solvent residues document the same with rationale (e.g. similar solvent matrix for previous product, previous product solvents are highly soluble in the cleaning solvent etc.).

Chromatography practices and control: Laboratories should have clear procedure for chromatographic peak integration and manual integration. Define conditions under which manual integration is allowed with authorisation and justification for manual integration (Refer: WHO TRS 1025 – Annex 4: Good Chromatography Practices). The Chromatographic system shall flag manual integration. Manual integrations along with justifications and authorisation of manual integration shall be reviewed before batch release. Again this point to importance of an independent review of laboratory documentation by QU (QA function).

Logging Deviations and Investigations: A mature Quality Management system shall ensure that when deviations or deficiencies are identified – whether it is through regulatory audits, internal audits, customer audits it is addressed through the official QMS – e.g. logging a deviation or an investigation, logging CAPA, implementation of CAPAs through a Change control system. This is also important trend and review quality incidents, assess effectiveness of corrective actions. It doesn’t give confidence to regulatory auditors when such gaps are addressed outside the formal QMS system and get exposed during audits. More often than not the lady luck doesn’t favour, and somewhere in the documentation trail the threads get picked up – it could be a change control document, qualification document for a new system, a training record for a revised procedure etc, etc.

Transport Validation: Transport validation assure that storage conditions are adequate to ensure safety and integrity of the drug during transportation of the drug product and drug substance. The transport validation should address different connected aspects – Defining storage conditions (Temperature and %RH), packing, stability studies, impact of short term excursions of defined storage conditions during transport, transport route verification, establishing transit times, assessment and qualification of storage areas, containers, transport vehicles. This is especially critical in the case of Temperature sensitive drug products and drug substances. WHO TRS 961 – Annex 9: Model Guidance for the Storage and Transport of Time and Temperature Sensitive Pharmaceutical Products (August 2011) and supplements gives a comprehensive set of procedures and steps for transport validation.

To sum up, well defined document and data controls across operations, processes to document deviations, investigations and establish root cause and corrective actions (CAPAs), systems to ensure reliability of all data and documentation, overseen and monitored by an independent Quality Unit with authority and adequate resources is the baseline for an effective Quality system and to ensure conformance to cGMP requirements, and quality and safety of Pharmaceutical products.