Welcome to the second of the 3 part exclusive unwrapping of the observations reported from the US FDA’s inspection of Lupin Pharmaceutical’s facilities. If you have directly jumped to this page, we would request you to read through the Introduction post and the first part of this series before you proceed ahead before you proceed ahead. Though this is not mandatory, a good read is a good read only if read from front to last and not from the middle to the last.
Part 2 –Covering the FDA’s inspection of the Goa facility which has operations in both Manufacture and Packing. The facility does not have the permissions for API manufacturing.
Specifically related to the Goa plant, we were able to locate one recall that was performed in relation to the product manufactured at the Goa facility.
The US FDA revealed that (January 18, 2016), that Amerisource Health Services’ (ABC) initiated a recall of certain lots of Levofloxacin Tablets, USP, 500 mg packaged in 100-count (10 x 10) blister cards per carton (Levo 500mg Tabs).
The recall affects 3,888 cartons due to “Failed Dissolution Specifications: Unexplained low out of specification results for dissolution”. The Final Printed Labelling (FPL), indicates that Levo 500mg Tabs that are repackaged into the blister cards by ABC are manufactured by Lupin Pharmaceuticals, Inc. (Lupin) in Goa, India.
This section covers only the initial inspection. You will find the section covering the re-inspection below here.
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Initial Inspection Observation 1
What we understand:
Drug products batch used as a raw material in the production of the final finished product batch did not meet the quality control requirements and had not been rejected by the quality control team. Rather the impure product was used in the production of the final products. However, some of the batches of the impure final product were not distributed for sales by the company.
Initial Inspection Observation 2
What we understand:
The purpose of these reserve samples is to ensure that the results upon which FDA bases approval of New Drug Applications (NDA) and Abbreviated New Drug Applications (ANDAs) are reliable.
For an ANDA, reserve samples of both the test article (the test article means the drug product for which the applicant is seeking approval) and the reference standard should be retained at the study site for a period of 5 years.
The Quality Control unit at Lupin did not provide any evidence of visually examination performed as evidence of deterioration in the reserve samples. This also meant lack of adherence to the SOP which clearly states this as a general procedure.
Initial Inspection Observation 3
What we understand:
This is in relation to an oral (liquid/solution) product manufactured by the company which had some unexplained discrepancies.
The inspection revealed that over 40 complaints were received regarding the discrepancy in the product but the Quality Control Unit did not investigate whether the issue was due to mishandling of the product during shipping or the result of packaging quality issues. The issue was (though not revealed) relates to some leakages from the bottle.
Not only did the firm fail to recall the products already distributed, there was lack of action over identifying the root cause or performing investigational testing (imitate a scenario to demonstrate that it was the patients fault or the company’s fault).
Though some investigations were carried as part of the OOS, the QCU initiated various extensions over the investigations with a closure date of greater than 6 months or more.
Initial Inspection Observation 4
What we understand:
When a particular data changes hands/ sources, a test for its completeness and accuracy is required to be performed. Ex: If a report is downloaded/ uploaded to a different source, this uploaded report should be cross verified to ensure that the complete report has been uploaded and that all data that has been uploaded is accurate and matches the source report. The inspection revealed that there are no such checks performed.
In addition to the data, the SACDA (Supervisory Control and Data Acquisition) software/hardware is not checked frequently for the accuracy of its output.
Initial Inspection Observation 5
What we understand:
The main rationale for requiring clean equipment is to prevent contamination or adulteration of drug products. Historically, FDA investigators have looked for gross insanitation due to inadequate cleaning and maintenance of equipment and/or poor dust control systems (A common problem associated with detergent use is its composition. Many detergent suppliers will not provide specific composition, which makes it difficult for the user to evaluate residues.)
The company does not use dedicated mops for the specific areas of the facili
ty. Using of non-dedicated mops leads to transmission of contamination from a general area to a more secured area leading to bacterial effect on the production floor of the facility. Also accounting into the fact that materials and personnel of the building enter/ exit non-dedicated processing areas, this only enhances the risk of contamination.
FDA has noticed that historical in one such case (not related to Lupin’s facility), some shipments of the pesticide contaminated bulk pharmaceutical which were supplied to a second facility at a different location for finishing. This resulted in the contamination of the bags used in that facility’s fluid bed dryers with pesticide contamination. This in turn led to cross contamination of lots produced at that site, a site where no pesticides were normally produced.
Initial Inspection Observation 6
What we understand:
Though written procedures for cleaning and maintenance of equipment and utensils used in the manufacture, processing, packing or holding of a drug product was present, the procedures were not followed by the cleaning and maintenance staff.
Also on verifying this procedure, the inspection revealed that there was no comparison performed on the planned versus the actual cleaning and maintenance performed.
The FDA does not mention the frequency at which the equipment needs to be cleaned and maintained. However, the FDA has been liberal on this front and let companies decide the frequency. Though this is not a major issue, non-adherence to the SOP is a high risk observation.
Initial Inspection Observation 7
What we understand:
This is more on the lines of Observation 7 i.e. absence of records for cleaning and maintenance of non-dedicated equipment used in the manufacturing of different products.
Initial Inspection Observation 8
What we understand:
The Quality Control Unit does not select adequate samples from the finished product for conducting the uniformity testing. The company does not have a procedure in place to monitor and validate the process that maybe responsible for the variability.
The test results are used to monitor the manufacturing process output that is most responsible for causing finished product variability. The test results can be used to develop a single control procedure to ensure adequate powder mix and uniform content in finished products. This can be a result to check the contents of the finished product, the compression strength or the quantity of filling in each batch of tablets etc.
Initial Inspection Observation 9
What we understand:
Raw materials stored in the warehouse were not stored as per their assigned locations leading to mix-ups. To explain this, consider going to a garment shop and not being able to find the right size in the right section of the store (also the sections of the stores are unmarked).
Leaving products in unmarked areas or leaving products in unassigned areas may lead to selection of a wrong product to be used in the manufacturing process.
Being unable to identify the right product or taking the wrong product from an incorrectly assigned storage area is a big risk which can hamper the entire inventory system of the company.
This section covers the re-inspection performed after a period of over 7 months from the initial inspection at the Goa facility. This re-inspection was a more detailed one that the initial inspection performed. Every observation reported by the inspection team provided detailed specifics in relation to the observations.
Re-inspection Observation 1
What we understand:
The company retested drug product samples during the process validation stage to meet the validation parameters acceptance criteria. While 2 of the 3 process validation batches failed, the company failed to perform a root cause analysis to identify the exact reason for failure. Rather, the company used the 1 batches that met the validation parameters criteria and thereby released the lots.
This shows a lack of ethical standards maintained by the company towards stopping the production and investigating the root cause rather than releasing the lots for further processes.
Re-inspection Observation 2
What we understand:
The company failed to adhere to its own SOP. The inspection revealed that parts of the previous product/batch were not removed via vacuum but rather they were sprayed with water leading to a large pool of water covering the production floor. This was in contrast to the SOP which mentioned that they first need to be vacuumed for dust and then sprayed with water.
Brushes to be used for scrubbing were not used and rather were only wet wiped. This was inconsistent with the established cleaning protocol.
The established process of cleaning the ceiling and
wall between different batches using a mop dipped in portable water followed by cleaning with a mop dipped in disinfectant solution and then with a dried with a different mop was not performed. Rather the site was present with dust accumulated on ceiling surfaces.
Also the cleaning checklist was not being reviewed by the Management of the Quality Assurance team on a regular basis.
Re-inspection Observation 3
What we understand:
Not only were the buildings of the facility unclean as mentioned in Observation 2, the procedures failed to describe the specific method and points of cleaning of the equipment’s used in both the manufacturing and non-manufacturing processes.
Due to this it is unclear if the cleaning procedures would actually make a positive or a negative impact on the operational procedures of the facility.
Re-inspection Observation 4
What we understand:
Every manufacturing process results in a certain variability in the characteristics of the materials used in the preparation of the final drugs and the drug products. In this case, the company does not have procedures that can assist with monitoring the output and validating the performance of the manufacturing processes which cause the variability.
2/3 batches failed the validation process. However, the Quality Assurance team released all the 3 batches for the further processing. These batches were released and distributed in the US as well.
Re-inspection Observation 5
What we understand:
The Entry Exit and Gowning Procedure established were not being followed to the core. It was noted that an operator was not wearing the snood (a type of headgear designed to hold the hair in a cloth or yarn bag but covers the entire face except the eyes) thereby exposing his nose. This was noticed on multiple occasions leading violation of procedures designed to prevent objectionable micro-organisms in the drug products.
Re-inspection Observation 6
What we understand:
Vibrations created by machines affected the storage area where the drugs are segregated and stored. Vibrations may lead to mixing up of capsules of different features.
No review of the logbook by the Management or the Quality Assurance team leading to non-compliance of good documentation practices.
It was also noted that in the record log of the RLAF Usage and Cleaning Record did not contain the details of the person who had completed the task. Rather a scribbled signature was markets in the “Done by” column thereby resulting in non-identification of the person responsible for it.
Re-inspection Observation 7
What we understand:
The packing and holding areas of the facility were not free of filth and other infectious materials. The floor plates of the areas were missing. This room was also accessible by the production employees who did not wear shoe coverings which would lead to movement of the filth and infectious materials onto the production floor.
Re-inspection Observation 8
What we understand:
This observation is a continuation of Observation 7 but more related to the structure of the facility. It was noted that the doors of the raw material warehouse had gaps underneath the doors (almost half an inch). This exposed lights and also becomes a passage way for rodents to move within the facility.
Re-inspection Observation 9
What we understand:
A hygiene observation, there was no trash container/holder bin at the trash collection site.
With this we end the second part of our 3 series posts. You can read the final part of the series here or go back to our Introduction post
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We hope you have a good learning experience from these posts. We welcome your feedback and comments.
Disclosure: Capital Mind had earlier recommended Lupin as part of a momentum portfolios, but at the moment it is not a stock in any recommended portfolio. The authors at Capital Mind do not own it in their personal/family accounts, and the company does not own any position in the company’s stock. There is no business relationship between the companies mentioned and Capital Mind.
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