PHARMACIA UPJOHN FACILITY RECEIVES SECOND FDA FORM 483 IN ALMOST FIVE YEARS

IS A WARNING LETTER FORTHCOMING?

A Pharmacia Upjohn subsidiary of Pfizer (Kalamazoo, MI) received a FDA Form 483 following an inspection from June 23 through July 9, 2015. This eight Observation 483 covered both non-sterile and aseptic issues. This audit used the Agency’s recently introduced team-based inspection approach and included Thomas Cosgrove, CDER’s Manufacturing Quality Director.

Of particular note were the following microbiologically related issues.

PRODUCTION SYSTEM

OBSERVATION #6

Procedures designed to prevent microbiological contamination of drug products purporting to be sterile are not written and followed.

Specifically,

The rationale for the selection of representative processes for demonstration during media fill simulations within SOP 10554, Media Fill Program, does not include an assessment of the risks associated with various filling line speeds to capture worst case scenarios for aseptic processing lines(b)(4). In addition, filling line speed during media fills are not specified or recorded for evaluation at the time of fill. For example:

Media Fill lot W417J was filled on line (b)(4) simulating (b)(4) mL (b)(4) vials. The line speed limits in the batch record are (b)(4) containers per minute (cpm) with no specified setting stated or recorded.  Data pulled from the automated line historian indicates the line was running at approximately (b)(4) (cpm) for most of the batch.  Media Fill lot W411JF was filled on line (b)(4) simulating (b)(4) mL (b)(4) vials. The line speeds limits in the batch record are (b)(4) cpm with no specified setting stated or recorded.  Line speed data for this lot was not available from the historian.

COMMENT:

21 CFR 211.113(b) states that procedures designed to prevent microbiological contamination of drug products purporting to be sterile are written and followed. When media fills are performed, one of the criteria that must be included is the line speed.  Line speeds are important since the speed of the line impacts the time the vial is being filled and remains open prior to having the stopper seated. Please also view two Ben Venue Form FDA  483s which were issued for not considering line fill time nor size of lot following the development of a media fill volume.  

1. The program for managing aseptic processing personnel participation in media fills does not ensure that a person’s participation is representative of their routine responsibilities.  For example, a “technician” is responsible for the majority of critical filling line setup tasks and typically performs the majority of the major interventions required during routine processing.  However, technicians (b)(4) did not participate in setup activities or perform major interventions in any media fills since (b)(4). For example, (b)(4) media fill participation history consisted primarily of manipulating vials with forceps.

COMMENT: 

CDER has periodically cited firms for their media fill management and, in particular, their performance of setup tasks the various subsequent interventions. The FDA does not insist that each employee perform all of the setup and intervention tasks, but that those individuals performing the various tasks during the aseptic fill also participated in the same tasks during the media fills (see Benue Venue 2011 Form FDA 483s). 

OBSERVATION #8

Drug products not required to be sterile are not examined to prevent objectionable microbiological contamination.

Specifically,

API products such as Phenytoin Sodium, Toceranib Phosphate, Triazolam are not examined to ensure they are free from objectionable microbiological contamination.

COMMENT:

21 CFR 211.113(a) states that “products that are not sterile should assure that they are free from objectionable microbiological contamination”.  In addition USP <61>, <62>, <1111> and <1115> all discuss various aspects of the management of non-sterile products. What cannot be determined from the Observation is whether these non-sterile products were ever tested for specified or objectionable microorganisms.