Importance of Corrective action and Preventive action (CAPA) FDA Warning Letter on GMP Violations

With this FDA warning letter you can learn about Importance of Corrective action and Preventive action (CAPA) and also know about how REGULATORY inspectors will call back to the firm on CAPA effectiveness and how could firm investigation system effective on respective deviations.

With this warning letter you can understand few of GMP Violations which are highlighted. 

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Porton Biopharma, Limited (formerly known as Public Health England), at Manor Farm Road, Porton Down, Salisbury, from March 7 to 18, 2016.

This warning letter summarizes significant violations of current good manufacturing practice (CGMP) for finished pharmaceuticals, 21 CFR parts 210 and 211, and significant deviations from CGMP for active pharmaceutical ingredients (API).

In a previous inspection of your facility from January 12 to 23, 2015, FDA cited similar CGMP violations. You proposed specific remediation for these violations in your February 12, 2015, response and during a regulatory meeting with FDA on November 24, 2015. These repeated failures demonstrate that management oversight and control over the manufacture of drugs at your facility is inadequate, and that your previous corrective actions did not address persistent contamination hazards and drug quality issues.

Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your drugs are adulterated within the meaning of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 351(a)(2)(B).

We reviewed your April 8, 2016, and September 16, 2016, responses in detail and acknowledge receipt of your subsequent correspondence.  

During our inspection, our investigators observed specific violations and deviations including, but not limited to, the following.

Finished Product Violations

1.     You’re firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed (21 CFR 211.192).

Your quality control unit identified particulate matter in several batches of Erwinaze® lyophilized powder for injection that exceeded established action limits. 

You did not adequately investigate these particulate matter failures. For example, your investigation into visible particulate matter detected in 237 units of batch CAMR171 (nonconformance investigation CN16305, initiated on April 22, 2015) identified the stopper supplier’s manufacturing process as the likely source of metal particles. However, the only correction implemented at that time was to update your standard operating procedure, Inspection, Counting and Packaging of Erwinaze® by adding foreign material as a subcategory in your reject criteria for finished drug product. Your firm’s corrective action and preventive action (CAPA) plan was inadequate. You did not investigate how you manage incoming stoppers or your supplier’s stopper manufacturing process until after the inspection, as described in your response to the Form FDA 483.

Your firm initiated nonconformance investigations for Erwinaze® finished drug product batches CAMR174, CAMR175, and CAMR176, and again identified the particulate matter as mostly (b)(4) metal particles, likely originating from the stopper manufacturing process. However, these investigations were incomplete and it was not until the inspection on March 7, 2016, that two additional CAPAs were initiated to investigate the root cause of the particulate matter in CAMR176.

Your firm also detected fibers in the lyophilized product of five finished units of lot CAMR171. The fibers were later identified as cardboard or paper. Your firm did not adequately investigate the potential sources of this unusual extrinsic contamination in your sterile drug product. 

In addition, in October 2016, your firm submitted additional batch records for batch CAMR178, documenting that this batch contained visible particulate matter of (b)(4) origin. In December 2016, your firm submitted batch records for batch CAMR179, documenting that the batch contained visible particulate matter including that of proteinaceous nature. Your investigations indicated that these additional instances of contamination are likely from another source besides the stoppers and call into question your ability to prevent contamination.

Your response to the Form FDA 483, dated September 16, 2016, states that your stopper supplier has been upgrading their equipment and facilities to reduce particulate matter on their stoppers, and that you have increased quality control sampling of stoppers to (b)(4) percent.  

We also recognize your efforts to evaluate use of an alternate supplier for stoppers. However, based on your written response, you have not yet completed qualification to enable your use of stoppers from an alternate supplier. We encourage you to consider additional CAPA to mitigate risk until you have fully qualified an alternate supplier of stoppers. 

Your firm has failed to implement prompt and sufficient corrective and preventive actions to resolve the hazard posed by foreign contaminants in your injectable products. The continuing presence of various types of visible particles in Erwinaze® batches is evidence of an insufficient assessment of all potential manufacturing failure modes and an overreliance on finished product visual inspection.  

Additionally, your firm does not have appropriately strict action limits for certain individual defect categories, including but not limited to particles that are extrinsic to the process (e.g. fiber or cardboard).

2.    Your firm failed to establish and follow appropriate written procedures, designed to prevent microbiological contamination in drug products purporting to be sterile (21 CFR 211.113(b).    

During our January 2015 inspection, our investigators observed several deficiencies related to your aseptic manufacturing operation, including the following:

·         a restricted access barrier system (RABS) (b)(4) which had fallen off the enclosure system;

·         a lack of environmental monitoring within the RABS;

·         no use of sporicidal disinfectant on surfaces inside aseptic filling room (b)(4), although your environmental monitoring detected spore-forming organisms there; and

·         a lack of traceability for media-filled vials.

We discussed these deficient manufacturing practices during a regulatory meeting with your firm on November 24, 2015.

During our March 2016 inspection, our investigators observed the following additional aseptic manufacturing issues:

·         a floor exhaust vent, shown in smoke studies to remove air entering the filling room, blocked by ancillary equipment during media fill process simulations

·         inadequate validation of the (b)(4) sterilization cycle used on equipment to be transferred into aseptic filling room (b)(4)

·          

It is critical that your firm implement proper ongoing control over your aseptic processing operation to prevent microbial contamination of your injectable products. 

We note that your firm did not conduct drug product batch manufacturing during our recent inspections. We will need to observe your manufacturing operation during the next inspection to determine whether corrective actions have been fully implemented.

Drug Substance Deviations

1.    Failure to establish and follow change controls to evaluate all changes that could affect the production and control of intermediates or API.

Your firm failed to conduct adequate change controls prior to the use of each working cell bank. For example, your firm has used working cell banks (b)(4) for the production of drug substance and drug product batches of Erwinaze®.Your firm previously used only working cell banks (b)(4) for production of Erwinaze® drug substance and drug product batches. You failed to ensure sufficient change control oversight to assure the (b)(4) new working cell banks were acceptable for use in the commercial operation.  

You manufacture Erwinaze® under contract on behalf of Jazz Pharmaceuticals, which holds the Biologics License Application for Erwinaze®. The process changes discussed above were not approved by FDA before you manufactured, or your customer, Jazz, distributed, Erwinaze®. Specifically, working cell banks (b)(4) were used in commercial production prior to approval. These working cell banks were not reviewed and approved by the Agency for their suitability for Erwinaze® manufacture, even though the changes in the source material or cell line have a substantial potential to adversely affect the identity, strength, quality, purity or potency of Erwinaze®.

Warning letter issued to Porton Biopharma, Limited

Manor Farm Road      

Porton Down

Salisbury, SP4 OJG, United Kingdom

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