In October, FDA posted three notable Form 483s to sites of Aurobindo, Lupin Limited, and Cipla Limited, all of which are located in India.  Aurobindo’s 14-page 483 featuring seven observations is topped by Cipla’s 38-page 483 with 11 observations. Not to be overlooked is FDA’s continued enforcement of Lupin which we provide more information on below.

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483s Issued

DRUG FIRM: Aurobindo Pharma Limited

Aurobindo Pharma Limited received a 14-page form 483 at the close of inspection on September 27, 2019. The site in Telangana, India, manufactures finished pharmaceuticals.

The 483 includes seven observations. A story on LiveMint reports data integrity observations, inadequate process validation, and inadequate cleaning of equipment. The firm has had its share of problems in complying with FDA GMPs and received a warning letter in June 2019 based on an inspection at an API facility located in Srikakulam District, AP, India. This warning letter identified, among other items, failure to submit the necessary supplements to FDA to support identification of impurities above the levels in USP and ICHQ3A(R2). And FDA also notes that two other API and intermediate facilities were inspected and cited for similar problems, and state that “These repeated failures at multiple sites demonstrate that management oversight and control over the manufacture of drugs are inadequate.”

Observations include but are not limited to the following:

  • The firm’s management and investigations of OOS events and customer product complaints are inadequate. FDA provides 6 ½ pages of examples that include: invalidation of an extraordinary percent (43-100%) of OOS events for raw materials, in-process steams, process validation, finished product testing and stability.  
  • Batch records have been issued and executed but were not on the list of lots provided to FDA, as confirmed by the VP of Quality. Examination of the audit trail in the Data Storage and Retrieval System served to identify the ‘other’ batches. An uncontrolled Excel Sheet is used to log events of batch record issuance.  
  • Process validation is inadequate. Examples of lot failure include the first attempted commercial validation batches and commercial lots after validation failed intermittently. Further, sample quantities taken to support hold times are not representative of the bulk batch size.
  • Review of audit trails for the Auto-titrators / Karl-Fischer titrators showed repeated events of ‘determination stopped’, ‘determination reprocessed’, ‘determination interrupted’ and ‘determination error’ during test runs. The Quality Unit did not periodically review the audit trails and determine what caused the problems. 
  • Responsibilities of the Quality Unit are not followed. This observation focused on apparently misleading statements made by staff to investigators and documents provided during the inspection. Further, a variety of executed product samples and executed batch records were found stored in ways they should not have been.  
  • Residue was found on product contact surfaces of equipment marked as ‘clean’.

DRUG FIRM: Lupin Limited

Lupin Limited received a three-page form 483 at the close of an inspection on September 20, 2019. This site in India manufactures APIs. Another Lupin site received a warning letter just ten days prior on September 10, 2019. (Note: read here for a thorough review of Lupin’s repeat deficiencies.)

Observations from this inspection include but are not limited to:

  • Investigations into metal particle contamination are not adequate. Further, the site does not have a metal detector so it would be difficult to determine whether the APIs made and distributed are free of metal particles.
  • Changes were made to batch records without approval by the Quality Unit. 
  • Storage of clean utensils occurs in locations that may contribute to contamination.

DRUG FIRM: Cipla Limited

Cipla Limited (Goa, India) received a 38-page Form 483 with 11 observations that was issued at the close of the 11-day inspection on September 27, 2019. This is among the most lengthy Form 483s in recent years, and we would expect a warning letter to be issued in the future as a result. An inspection with this many observations rarely ends well for the recipient. Thomas Arista was one of the three FDA investigators for this inspection.

Some of the observations identified include but are certainly not limited to:

  • Failure to clean, and residues were visible on the inside surface of air exhaust ducts of equipment that is shared among products. The 483 provides 11 ½ pages of examples. Hopefully, the firm received the ‘message’ that this is a problem. 
  • Equipment for control over air pressure, micro-organisms and dust is not provided when appropriate. For example, in the aseptic processing area, the environmental classification of area immediately outside the open RABS is Class 10,000 rather than Class 1,000. Further, there is no non-viable particle data to support Class 1,000 classifications.
  • Controls over aseptic processing areas are not adequate including adequate smoke studies. The 483 includes approximately 3 ½ pages of areas where uni-directional airflow patterns could not be determined or observed.
  • The CCTV system used to monitor the aseptic manufacturing area was deemed inadequate. 
  • A list of areas where environmental microbial contamination was identified is provided; the FDA indicates that actions taken to prevent microbial contamination are inadequate. Again here, the FDA provides an exhaustive list of problematic practices.
  • Equipment cleaning is not appropriately validated.
  • In-process testing does not include a description of sampling plans.
  • Equipment IQ/OQ/PQ is not supported by adequate procedures.
  • Investigations are not adequate.

COMPOUNDING/OUTSOURCING FACILITIES

Columbia River Pharmacy, LLC

Columbia River Pharmacy, LLC (Richland, WA) received a form 483 at the close of inspection on August 16, 2019.

East Marietta Drug Company

East Marietta Drug Company (Marietta, GA) received a form 483 at the close of inspection on August 23, 2019.

Exela Pharma Sciences, LLC

Exela Pharma Sciences, LLC (Lenoir, NC) received a form 483 at the close of inspection issued on July 18, 2019.

Infusions Options, Inc

Infusions Options, Inc (Brooklyn, NY) received an amended form 483 issued July 8, 2019.

InfuScience, a subsidiary of Bioscrip

InfuScience, a subsidiary of Bioscrip, (Mt. Pleasant, SC) received a form 483 at the close of inspection on July 30, 2019. 

Joe Wise Pharmacy, Inc

Joe Wise Pharmacy, Inc (Littleton, CO) received a form 483 at the close of inspection on June 29, 2019.

Pacifico National Inc

Pacifico National Inc (Melbourne, FL) received a form 483 at the close of inspection on June 20, 2019.

Pavilion Compounding Pharmacy

Pavilion Compounding Pharmacy (Atlanta, GA) received a form 483 at the close of inspection on February 8, 2019.

RAM Pharma, Inc

RAM Pharma, Inc (Idaho Falls, ID) received a form 483 issued at the close of inspection on August 1, 2019.

Shertech Pharmacy

Shertech Pharmacy (Easley, SC) received a form 483 at the close of inspection on July 18, 2019.

Southern California Compounding Pharmacy LLC

Southern California Compounding Pharmacy LLC (San Diego, CA) received a form 483 at the close of inspection on August 1, 2019.

Stonegate Pharmacy LP

Stonegate Pharmacy LP (Austin, TX) received a form 483 at the close of inspection on August 8, 2019.

Synthetopes, Inc

Synthetopes, Inc (Conway, SC) received a form 483 based on the outcome of an inspection ending May 16, 2019.

Vitalab Pharmacy, Incorporated

Vitalab Pharmacy, Incorporated (Phoenix, AZ) received a form 483 at the close of inspection on August 2, 2019.

Most Purchased Individual 483s

483 Ajanta Pharma Aurangabad Jun 2019
483 Alliance Medical Products Irvine Feb 2019
483 Baxter Healthcare Jayuya Dec 2018
483 Cipla Vasco Da Gama Sep 2018
483 Fresenius Kabi Oncology Nadia May 2017
483 Hill Dermaceuticals Sanford May 2018
483 Linhai Tianyu Pharmaceutical Taizhou Apr 2019
483 Livzon Group (Ningxia) Pharmaceutical Shizuishan Oct 2018
483 Livzon Group Fuzhou Fuxing Pharmaceutical Fuzhou Aug 2018
483 Luen Fook Medicine Sdn. Bhd. Masai Dec 2018
483 Medtronic Puerto Rico Operations Humacao Mar 2017
483 Mylan Labs Limited (Unit 8) Vizianagaram Dec 2018
483 Mylan Labs Limited (Unit 8) Vizianagaram Jun 2019
483 Sun Pharmaceutical Industries S A S Nagar Sep 2018

[NOTE: With a 483 Observation Report, you can quickly determine if there’s a citation trend you should be aware of. Learn more here!]