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    DRL Fda 483 10 23

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    DRL Fda 483 10 23

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    abhijit_gothoskar6039
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    483 letter

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    DRL-FDA-483-10-23

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    483 letter

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    38 views25 pages

    DRL Fda 483 10 23

    Uploaded by

    abhijit_gothoskar6039
    483 letter

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    DEPARTMENT OF HEALTH AND HUMANSERVICES 12420 Parklawn Drive, Room 2032 Rockville, MD 2085 0/21/2023* Dr. Ranjana B Pathak, Global Head of Quality Dr. Reddy's Laboratories Surveys 41, 42 Part, 45 Part & 46 Part, _ Bachupally Medchal-Malkajgiri, Telangana, 500090 | rug Manufacturer India This document lists observations made by the FDA representatives) during the inspection of your facility. They are inspectional jobservations, and donot represont a final Agency determination regarding your compliance. Ifyou have an objection regarding an ‘observation, or have implemented, or plan 1o implement, corrective action in response to an observation, you may discuss the objection or ‘ction with the FDA representative(s} during the inspection or submit this information to FDA atthe address above, Ifyou have any questions, please contact FDA at the phone number and adress above. DURING AN INSPECTION OF YOUR FIRM WE OBSERVED: OBSERVATION 1 Equipment and utensils are not cleaned and maintained at appropriate intervals to prevent contamination that would alter the safety, identity, strength, quality or purity of the drug product, Specifically, major production equipment used to manufacture oral solid dosage drug products is not appropriately cleaned and maintained to prevent contamination. For example: A. On BEBE, we observed pale yellow to light yellowish color powdery materials along with white to off-white color powder on the product contact areas inside the firm’s Rapid Mixture Granulator (RMG) EEE Along with colored powdery materials inside the RMG, we observed pale yellow to yellowish color liquid spillage and dried powder of off-white and: yellowish color on the floor underneath RMG [REE while this equipment and the area’ Was in “TO BE CLEANED” status. Production Operators and IPQA employees identified the pale yellow to yellowish color powdery materials pertaining to the previously nanuicired dng 7 rs aa ME 216 white color powdery material pertaining to the recently manufactured product| The sequence of manufacturing these drug products included Common Blend (CB) for MC a SEE REVERSE | Saleem 4 Akhtar, Investigator 10/27/2023 OF THIS PAGE | Pratik S Upadhyay, Investigator ~ Dedicated | geese Drug Cadre Fee. XSPECTIONAL OBSERVATIONS ae PACES ‘SEE REVERSE OF THIS PAGE | Pratik 8 Upadhyay, Investigator - Dedicated DEPARTMENT OF HEALTH AND HUMAN SERVICES fe, Room 2032 De_Ranjana_B Pathak, Head of Quality eys 41, 42 Part, 45 Part & 46 Part, Dr. Reddy's Laboratories Ltd Medchal-Malkajgiri, Telangana, 500090 Drug Manufacturer seb (RMG ) (RMG. ). On BBE, the firm collected samples (pale yellow to yellowish and white to-off-white color powdery materials) from inside the lid of RMG and underneath floor of RMG. The qualitative analyses of these samples by HPLC revealed the presence of EN peak in sample injections at the same retention time to that of standard injections indicating potential mix-up and conyover 0 TE :ctive ; YS ors product B. — the firm collected additional samples from the interior surface of RMG (J lid and underneath floor and analyzed those samples by LC-MS/MS method in the firm's QC laboratory. The analyses of samples revealed the similar peak response for EEE and actives in the samples and standard injections confirming the presence of these actives in samples collected from the product contact areas of RMG lid and non-product contact areas of | undemeath floor of RMG while this area and equipment was used in the campaign manufacturing of During the inspection, QC Unit of the firm analyzed and EMI £0: Related Substances by HPLC test methods of [IEEE and ME finished drug products. The analyses revealed the presence of [III and BEE «cscs inthe test sap les EEE 1 presence of BEBE cciive in test sample of MINIM. The details of sampling locations, products analyzed, and test results obtained are tabulated below: 10/27/21 eem A Akhtar, Investigator Drug Cadre FORTDAWa em Tenn aoe INSPECTIONAL OBSERVATIONS, PAGE 212 FACES DEPARTMENT OF HEALTHAND HUMAN SERVICES 12420 Parklawn Drive, Room 2032 Rockville, MD 20857 Dr. Ranjana B Pathak, Global Head of Quality Dr. Reddy's Laboratories Ltd, Surveys 41, 42 Part, 45 Part & 46 Part, : Bachupally Medchal-Malkagiri, Telan India aria, 500090 Drug Manufacturer Location Product [LC-MS/MS Related Substances by [HPLC aS a PPM) interior of fd Binder addition granules iner-18 (Middle) [ER tablets ME Conta iner-36 (End) _ ER tablets NA: Not Applicable ND: Not detected (PPM) = port - Cl Floorbereth TT = IRMG - C3 leranules * Floor beneath = = = RMG-C4 [granules | ae INA -_ = tablets Co: a Na INA = = iner-1 (Initial) ER tablets a Con (NA INA = =: = = Zz S| [NA ‘There is a potential that the obtained carryover materials may react with the product components and form unknown impurity which may increase over the period of the product’s shelf life. There is no mechanism established by the firm to identify those impurities for all the batches manufactured using RMGs across the firm and that the firm has limited number of batches SEEREVERSE | Saleen a Akhtar, Investigator 10/27/202 OF THIS PAGE | Pratik s Upadhyay, Investigator - Dedicated FORD, 9 08) ws rome ‘DEPARTMENT OF HEALTH AND HUMAN SERVICES 12420 Parklawn Drive, Room 2032 10/19/2023-10/27/2023+ Rockville, MD 20857 ey eee 3002949099 Dr. Ranjana 5 Pathak, Global Head of Quality Dr. Reddy's Laboratories Ltd. Surveys 41, 42 Part, 45 Part 6 46 Part, Bachupal ly Medchal-Malkajgiri, 7% India angana, 500090 Drug Manu£ charged on stability annually depending on pack sizes. As a result of finding powdery materials of [/ ond EEE actives in [| drug product, the firm reported Field Alert for [EE |, Batch Number: EEE, Expiry date: C. The [EEE non-dedicated Rapid Mixture Granulators (RMGs) used in the manufacturing of] finished drug products at the firm have not been cleaned and verified for cleanliness underneath| the mounted platform areas since their installation several years ago. There is a potential for deposition of powder} materials and microbial growth in these areas in all RMGs across the| facility. [Serial. ]Equipment name Equipment |PQ Date INo. number i Rapid Mixer Granulator Il L — | 2, Rapid mixing granulator [lL — | 3. Rapid mixing granulator if L — la. Saizoner Mixer Granulator Iii | NT [ 5 [Saizoner Mixer Granulator AL | | 6. [Rapid mixing granulator 7, [Rapid Mixer Granulator [i L Rapid mixing granulator Ill L | 9. Rapid Mixer Granulator-fiil a — SEEREVERSE | Saleem A Akhtar, Investigator 10/27/2023, OF THIS PAGE | Pratik S Upadhyay, Investigator ~ Dedicated | Drug Cadre 7 ony 4.8390 mean oon INSPECTIONAL OBSERVATIONS race ta as 12420 Parklawn Drive, Room 2032 Rockville, MD 20857 [meno a 6 3002949099 DEPARTMENT OF HEALTHAND HUMAN SERVICES FOOD AND DRUG ADMINISTRATION 7 1-20/27/2023* Dr. Ranjana B ak, Global Head of Quality Dr. Reddy's Laboratories Ltd, Surveys 41, 42 Part, Bachupally Part & 46 Part, Medchal-Malkajgiri, Telangana, 500090 India g Manufacturer 10. Rapid mixing granulator [ll Hl. [Rapid mixing granulator [ll L 12, Rapid mixing granulator Ill L 13, Rapid Mixer Granulator [lf L 14, [Rapid Mixer Granulato 15. [Rapid Mixer Granulator Il L 16. [Rapid Mixer Granulator [ll 17. Rapid Mixer Granulator [ll 18, Rapid Mixer Granulator [il [9 Rapid Mixer Granulator lll On IEEE \.c observed thick deposition and layers of off-white, pale yellowish to yellowish and black to brownish powdery materials underneath the mounted platform of RMG Jz This RMG mounted platform has about 1.5 feet opening from all four (4) sides through which powdery residues of drug products manufactured in this room [ME may have deposited throughout the machine components of this RMG over the period of several years due to positive air pressure inside the room. Along with the powdery materials, we observed the sut underneath RMG platform had pale yellow to dark brown color liquid and wet surface acros: areas which is indicative of potential microbial growth in those areas of RMG. The swab s were collected from these areas which revealed the presence of [J growth on mounted aa surface underneath RMG 1D: J SEEREVERSE | Salcen A Akhtar, Investigator 10/27/2023, OF THIS PAGE | Pratik S Upadhyay, Investigator ~ Dedicated Drug Cadre Foun. 09, srs (CTIONAL OBSERVATION: DEPARTMENT OF HEALTHAND HUMAN SERVICES 12420 Parklawn Drive, Rockville, MD 20857 Room 2032 /19/202 3002949099 0/27/2023* Dr. Ranjana B Pathak, Global Head of Quality Dr. Reddy's Laboratories Ltd. Surveys 41, 42 Part, 45 Part & 46 Par 7 Bachupally _ Medchal-Nalkajgiri, Telangana, 500090 Drug Manufacturer India a ‘Location Details ITAMC TYMC [Colony Characteris (CFU/Swab) |(CFC/Swab) |match [Gear box upper shaft |Gear box end base Left side Motor and gear box middle (Gear box base right side IRMG bow! bottom outside \(close to product discharge) are sold into the US market. D. On SEE during the inspection of | Fluid Bed Dryer (equipment There arc IIE drug products manufactured in [EE area of which about [IIE manufacturing area, |) was observed with two cracks on the view glass. Both cracks impacted the view glass surface from one end to the other. This view glass is a 'BD Bowl attached to SEE REVERSE com A Akhtar, Investi 10/27/2023 OF THIS PAGE 8 Upadhyay, Inves' Dedicated ‘ade x DEPARTMENT OF HEALTH AND HUMAN SERVICES FOOD AND DRUG ADWINSTRATION 12420 Parklawn Drive, Room 2032 10/19/2023~10/27/2023* Rockville, MD 20857 Dr. Ranjana B Pathak, Global Head of Quality aS [erence Dr. Reddy's Laboratories Ltd. Surveys 41, 42 Part, 4§ Part 6 46 Part, | Bachupaliy. Drug Manufacturer Medchal-Malkajgiri, Telangana, 500090 India product contact surface. There is a reasonable chance that the tiny pieces from the racked view glass can potentially be introduced into the product. Equipment use logbook indicated the firm performed product changeover cleaning on this equipment on fter manufacturing a US batch of| eee OBSERVATION 2 The responsibilities and procedures applicable to the quality control unit are not fully followed. Specifically, There is a lack of adequate evaluation of equipment conditions upon preventative maintenance, equipment cleaning, and line clearance. For example A. On HBB, we observed the firm’s production operators and IPQA officers conducted inadequate visual inspection of RMG [EEE upon major cleaning (Type B). This RMG contained powdery residues of previously manufactured colored products on RMG lid and discharge port (product contact areas). As a result of this, colored residues of previously manufactured drug products were observed inside RMG while the firm manufactured In addition to equipment clearance, we observed concerns pertaining to area clearance. There were pale yellow to yellowish color powdery residues of| previously manufactured drug product underneath produet discharge port and mounted platform of RMG EEE (Refer to OBSERVATION 1A to C). B. The firm performed quarterly preventative maintenance (PM) of RMG EE on EE |, we observed broken silicon sealant along with missing pieces of sealant ‘on many areas of RMG EEE. The firm’s PM is deficient in that there is no evaluation of uneven, and dent marks on equipment surfaces along with the presence of powdery residues and ] emoreraanine — SEEREVERSE | Saleem A Akhtar, Investigator | 10/27/2023 OF THIS PAGE | Pratik 5 Upadhyay, Investigator ~ Dedicated | brug Cadre | FORA 0H rcs ceete INSPECTIONAL OBSERVATIONS PAGE 2S PAGES DEPARTMENT OF HEALTH AND HUMAN SERVICES 10/19/2023-10/21/20 3002949099 12420 Parklawn Drive, Room 2032 Rockville, MD 2085 Dr. Ranjana B Pathak, Global Head of Quality Dr. Reddy's Laboratories Ltd Surveys 41, 42 Part, 45 Part & 46 Part, Bachupally Medchal-Malkajgiri, Telangana, 500090 Drug Manufacturer India potential leakage leading to wet surfaces underneath equ'pment in the surrounding areas of gear box (Refer to OBSERVATIONS IA to C and 9B). OBSERVATION 3 . Determinations of conformance to appropriate written specifications for acceptance are deficient for drug products, Specifically, determination of conformance to written specifications are deficient for TAMC (Total Aerobic Microbial Count) test and TYMC (Total Yeast and Mold Count) test conducted for purified water and drug products. On BEBE, the colony counter (equipment [IEEE in micro lab was observed missing the colony counts when the analyst was reading the plates and reviewer was verifying the counted colonies for water samples collected on [EEE For example: A. The colony counter did not count every colony for multiple samples including LIMS sample # f= (location: Return to Tank [J KL, Location 1D: [EEE when micro lab analyst PI yressed the media plate placed on the colony counter (ED with his pen. B. The colony counter did not count every colony for multiple sas including LIMS sample # HEE (0cation: EE MEE, 1 ocation 1: when micro lab reviewer Ii performed the verification of the colonies counted by analyst J. During the verification [i pressed the media plate placed on the colony counter (EEE with his pen. For this sample, the colony counter failed to count the colony even when the reviewer pressed the plate with such a force that the tip of her pen broke. SEEREVERSE | Salcen A Akhtar, Investigator 10/27/2023 OF THIS PAGE | Pratik dhyay, Investigator ~ Dedicated Drug ¢ vomNerD4 3908) pau toot INSPECTIONAL OBSERVATIONS TAGE a PACES DEPARTMENT OF HEALTH AND HUMAN SERVICES - FOOD AND DRUG ADNANISTRATION _ 12420 Parklawn Drive, Room 2032 Rockville, MD 20857 A pean 3002949099 0/27/2023* Dr. Ranjana B Pathak, Global Head of Quality Dr. Reddy's Laboratories Ltd. Surveys 41, 42 Part, 45 Part & 46 Part, Bachupally Medchal-Nalkajgiri, Telangana, 500090 Drv India Manufact: This colony counter (MIRED has been in use since it was qualified on [EINE In addition to} routine environmental monitoring samples, this equipment has been used for the last [ll MII to test [Mf batches (I commercial release and If stability batches) of drug products for the US| market. C. Discrepancies were observed in number total colony counted by the analyst and the reviewer pertaining to many media plates that were read on IEEE. Following are few examples: Sample Colony Counts | Colony Counts LIMS# _| by Analyst ro lab for about [if and ff years respectively. The analyst and reviewer are working in the n OBSERVATION 4 SEEREVERSE | Saleen A Akhtar, Investigator 10/27/2023 OF THIS PAGE | Pratik S Upadhyay, Investigator - Dedicated Drug Cadre x! Fon roa (008) renee cect INSPECTIONAL OBSERVATIONS ace 9of29 PACs DEPARTMENT OF HEALTHAND HUMAN SERVICES 1000 AND DRUG ADMINISTRATION 12420 Parklawn Drive, Room 2032 0/27/2023% Rockville, MD 20857 [Rio !*!S”*~ of I AP, Batch Number: SMM and standard injections. This unknown peak at around [EEE was absent in blank injections and system suitability injection. QC Supervisor of the firm deviated from section | of SOP No.: I by applying inhibit peak integration function. There was no investigation conducted to identify these unknown peaks which were not present historically during the validation of analytical method and qualification of working standards. Further, the firm provided no explanation for the presence of the unknown peak EE in standard solution injection but not in system suitability injection while the inhouse working SEE REVERSE | Saleem A Akhtar, Investigator 10/27/2023 OF THIS PAGE | Pratik S Upadhyay, Investigator ~ Dedicated | Drug Cadre x| oR Fo 90) nour ae INSPECTIONAL OBSERVATIONS Or oP DEPARTMENT OF HEALTH AND HUMAN SERVICES FOOD AND DRUG ADMINISTRATION ve, Room 2032 Rockville, MD 20857 3002549099 1ak, Global Head of Quality tories Ltd. Surveys 41, 42 Part, 45 Part & 46 Part, Bachupally Medchal-malkajgiri, Telangana, 500090 Drug Manufacturer standard used for preparing both standard solutions remained the same. OBSERVATION 5 ‘The use of instruments, apparatus and recording devices not meeting established specifications was observed, Specifically, major Laboratory equipment including but not limited to HPLCs, GCs, and UV Spectrophotometers that are actively used in commercial release and stability analysis were observed not ‘meeting the calibration specifications. In the last [III the firm initiated [J incident reports when laboratory equipment failed to meet routine calibration specifications. [IM of the I incidents are listed below [ Incident No Date Equipment name | Equipment Reported iD | } Results not spectrophotometer meeting, acceptance | criteria Ba iric %RSD not meeting the | acceptance ee | _feeriteria | SEEREVERSE | Saicen A akht OF THIS PAGE 1 estigator 10/27/2023 Pratik § Upadhyay, Investigator - Dedicated Drug Cadre 12 DEPARTMENT OF HEALTHAND HUMAN SERVICES FOOD AND DRUG ADMINISTRATION 0 Parklawn Drive, Room 2032 /1.9/2023~10/27/2023* Rockville, MD 20857 ERT 3002949099 jana B Pathak, Global Head of Quality dy's Laboratories Ltd Surveys 41, 42 Part, 4§ Part & 46 Part, Bachupally. Nedchal-Malkajgiri, Telangana, 500090 Drug Manufacturer India Deficiencies were observed in the incident investigation reports (EEE and MI) generated for laboratory equipment calibration and preventive maintenan: UV Spectrometer (equipment ID: [NEED and HPLC (equipment ID: JRE and the firm’s program. For example: A. Incident report IEEE was initiated on [IE when UV Spectrophotometer (1D failed to mect the limit of stray light during routine calibration that was being performed on MIMI Te soroance of sry light Mum was observed as MB agains the specification of not less IEEE This equipment has J mirrors |. During the investigation, the firm observed — mirrors ( appeared to have scratches that caused the OOS results for stary light. The firm replaced all three mirrors, repeated the calibration, and reported the conforming results. It was observed the firm performed preventiv: maintenance of the equipment EIEN replaced the [IJ mirror ( as well as I lamps (Tungston Halogen Lamp and Deuterium Lamp) during the preventive maintenance that was performed before the calibration This UV spectrophotometer is calibrated after [IEEE and previous successfull calibration’ for this equipment was performed EEE This cquipment was initially qualified and since then its mirrors were not changed, The QC Lab Head stated stray light can’ impact the absorbance of samples and standards, The absorbance value is used to calculate the potency of drug products that are tested by using this equipment. During the impact assessment, the firm did not test any retain samples to assess if the data generated from this equipment is reliable. The firm routinely uses this equipment in quantitative analysis. For example, this equipment was used to test for about Ii SEEREVERSE | Saleem A Akhtar, Investiga! OF THIS PAGE | Pratik S Upadhyay, Invest iga 10/27/2023 Drug Cadre x oma sp4 san onsen sce INSPRCTIONAL OBSERVATIONS TAGE 1

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