USFDA 483 / Torrent, Indrad, India / FEI 3005029956 / Inspection 8-16 April 2019 / FDA Inspectors – Lata Mathew (USFDA investigator), Jogy George (USFDA Investigator), Zhao Wang (USFDA) / Observation 2

There are no written procedures for production and process controls designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess.

Failed process validation protocol requirements and quality attributes were deemed acceptable and counted towards successful manufacturing process validation.

Observation A.

Process validation (PV) for Losartan  Potassium USP 50mg and 100mg tablets* for qualifying an alternate API code (vendor) is deficient. [*This observation was also cited in the Warning letter (MARCS-CMS 585255 — dated October 08, 2019). The warning letter mentions, a new interim protocol  was developed to justify use of alternate API and circumvent original protocol, even though there was data demonstrating process was not capable of producing quality material using the new alternate API).

First batch of the 3 process validation batches failed for dissolution, assay and other parameter (OOS investigations – OOS/IN/F/FP/16/257, 137 & 263 were initiated on the first process validation batch). Due to the failure of first batch, an additional PV batch (#4) was added to the validation campaign. However the 4th batch failed for F2 dissolution similarity factor (OOS/IN/FP/17/139 & 143). The first and fourth batches were rejected and destroyed leaving only 2 successful process validation batches. The Quality unit rejected these 2 remaining batches as well. Despite the PV batch failures and rejections, the process validation for the alternate API vendor was deemed successful as per interim validation report #PVR/BTL.508.01-33E/18, approved on January, 17, 2018.

 Observation B.

Process validation initiated to qualify alternate API supplier was deficient; Three process validation batches were rejected and destroyed based on OOS investigation. However manufacturing process utilizing alternate API supplier was still considered valid and acceptable by Quality unit. The process validation report #PVR/BTL.510.01_40E/18 approved on January 05,2018 stated that during further review, the route of synthesis for old API code and new API code are only marginally different and would not impact quality of finished product; due to change in API there is no impact on manufacturing process and no impact of API quality on finished goods.

Observation C.

Process validation for Lamotregine ER tablets 200mg is deficient.

Pre-validation risk assessment to determine the number of batches required to demonstrate process validation is not scientifically sound. For example, risk assessment in the process validation protocol (PB/BTL.524.01-5E/17/01-01, approved on November 04, 2017) considered functional coating to be minor risk factor although there are documented critical parameters that could impact dissolution of the product. This approach led to determination that only 2 batches are required to demonstrate process validation. For the PV batch #BFR5D002, a deviation ( D/I/F/2017/0477) was initiated for film coating process. The differences between the two process validation batches were noted in the deviation, but the  impact of the differences were not thoroughly understood at the time of batch execution. The impacted batch BFR5D002 failed for dissolution in stability at the 3M and 6M timepoints  and consequently the batch was recalled from the market. A thorough retrospective evaluation of the manufacturing process was not conducted after the stability failures, no consideration was given to establish process robustness with additional PV batches.

It was also discovered that the firm has no procedural requirement during tablet coating process to calibrate and assure that the volumetric is uniformly maintained during entire coating process.

Observation D.

Bulk holdtime study design is deficient. In several quoted example products, with relatively low active content, the sample quantities used to establish hold times do not represent the actual batch sizes of the product.

Observations A, B, C

When Process validation is initiated for qualifying alternate vendors for APIs and batch (es) fail, and there is no convincing / conclusive evidence that API from alternate source is the cause for the PV failure, the manufacturing process and/or laboratory process could have been the reason for the OOS results and batch failure. But this need to be adequately investigated, and causes established. Due to Supply Chain pressures or other pressing factors, the QMS requirements should not be short circuited. If Process validation (PV) protocols and reports are used to conveniently redefine the PV requirements and criteria – number of batches to be taken, process validations considered completed even when there are PV batch failures, this gives an impression of lack of standard procedure and practice for process validation.  Organisations should establish robust OOS investigation procedures which help zero down on probable root causes; And consistent approach to different GMP activities (like Process Validation).

• First and foremost is to ensure that OOS results are thoroughly investigated through Phase 1A, Phase 1B, Phase II investigation approach (Refer the discussions under Observation 1 – USFDA 483 / Torrent, Indrad). Root cause for the failure – laboratory error or production issues should be established and corrective actions taken.

a. If root cause is laboratory error established with scientific rationale, batch can be retested and initial OOS invalidated. And the process validation can be successfully demonstrated.

b. If the root cause is Production / process issues, the issues shall be addressed. Reinitiate the process validation (process qualification) with 3 fresh consecutive batches. Of course this has to be further followed up through the continuous process verification (CPV) systems. However if it is established that the failure of batch (es) in a PV campaign is not due to process performance reasons, but one time issues (e.g – an equipment failure or obvious human error in operation), then the process validation may be completed by taking the additional batch(es).

c. Where the laboratory error is not conclusively established and no process error is also established, the OOS as well as process validation remain open. In such situation it is incorrect to conclude the process validation (for e.g the batch failure or process validation failure is not due to the changes like API source change). Other options should be considered for completing process validation in such cases, for example: 

i. Perform an indepth assessment of the production process, perform a quality risk assessment considering what can go wrong in each step of operation which can lead to an OOS. If risk areas are identified, bring in additional controls – additional inprocess checks, operational controls and monitoring, environmental controls. If the assessment does not identify any potential risks, document the same with adequate rationale. Consideration to be given to process / product history, process controls in place. 

ii. Initiate a new process validation (qualification) with three batches. For this process validation activity, prepare a more elaborate and extensive process monitoring plan (Increased frequency of monitoring and recording different process parameters, additional in process samples during different unit operations to check assay, dissolution, uniformity, impurities as applicable). Establish the process validation (qualification) with the 3 batches. Based on the data from the exercise rationalize that the defined  process and product can give consistent quality of the product as established through extensive process monitoring data. Some of these additional monitoring can be made regular process control / monitoring parameters.  

Observation D 

The bulk hold time study should simulate the storage conditions – quantity per container, container closure system, storage conditions of the bulk stage material. It is not sufficient to perform study on small sample sizes (e.g-50gm, 100gm etc kept typically in poly bags) as this may not give a true picture of typical issues for example – segregation in granules or impact on tablets due to humidity /hygroscopicity etc. 

Hold time studies shall be performed in actual bulk storage containers. For example if the bulk granules are stored in polybags in 25kg HDPE drum; one of the drums can be used for holdtime studies. Design the holdtime study with scientific rationale, e.g – 

a. Hold the material for the desired time period (1 week, 2 weeks and so on), analyse the material at the end of the period and if complying perform next operation. (e.g compression of granules; coating / packing of bulk tablets). Perform the complete analysis. Also perform stability studies on the final material processed after the holdtime (after compression / packing). 

b. This will establish that, 1) the bulk intermediate can be stored for the holdtime period with no impact on quality of the product 2) stability of the product when the bulk stage material is processed after holding.

1. Enhance the procedure and practices for OOS handling and investigation. (Refer to discussion under USFDA 483, Torrent).
2. Enhance the Process Validation procedure and practices, elaborating handling and conclusions of process validation (qualification) under different scenarios.
3. Retrospectively review all the processes for status of successful process validation against a documented protocol and checklist – covering points such as but not limited to – number of PV batches taken, any discrepancies (OOS/deviations etc) during the PV batches and their resolution, performance of the product /process after the process validation (OOS, deviations, stability failures). Based on this review and assessment identify the products / processes where process validation (or process performance qualification) will be reinitiated, whether the PV will be performed prospectively or concurrently, define the timelines for completing the same. If the assessment shows the status of process validation acceptable with no additional actions, document the same with scientific rationale (e.g. – no failures during PB batches, no OOS / deviations in the batches after the process validation.
4. Review all manufacturing equipments / systems to verify any key components of are missed to be covered in calibrations. Document the assessment listing all systems. Cover the missing calibrations through an appropriate calibration procedure.
5. Enhance the bulk hold time study procedure detailing hold conditions simulating actual storage conditions and batch size. Initiate hold time studies for all the processes/products as per enhanced procedure and reestablish the bulk hold times.