FDA ISSUES WARNING LETTER FOR CLINICAL SUPPLY MANUFACTURING FACILITIES — FEBRUARY 10, 2011

Formatech, Inc Receives Warning Letter at Facility Manufacturing Clinical Trial Materials

Comment:

Clinical Supply Manufacturing (CMO) facilities are not customarily audited when they produce Phase 1, Phase 2 or Phase 3 Clinical Trial materials.  A CMO would not typically receive its initial FDA audit until it requests its Pre-Approval Inspection (PAI) for a new drug.  However, because this firm primarily provides aseptic production facilities for the manufacture of parenteral products for clinical trial materials, it has a higher probability of inspection. The clinical supply manufacturing facility was audited between August 25 and October 15, 2010, and following the firm’s response of November 3, 2010, the FDA determined that “it (Formatech) lacks sufficient corrective actions.”  This follows three U.S. and three MHRA audits where the firm received minimal FDA-483s or foreign observations. 

Several interesting observations arise as a result of this Warning Letter.  They include:

1) Phase 1 Clinical Trial materials may be audited by the FDA — even though their Guidance for Industry, Phase 1 Clinical Trial Materials, July 2008 (see: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070273.pdf and following paragraph) indicates this remains unlikely. 

“FDA reviews the submitted IND to determine whether the Phase 1 investigational drug to be used in the clinical trial is sufficiently safe to permit the trial to proceed. This determination is based, in part on whether the investigational product has the identity, strength, quality, and purity, and purported effect described in the IND application. In certain circumstances, FDA also may choose to conduct an inspection (e.g., if there is insufficient information to assess the risks to subjects or if the subjects would be exposed to unreasonable and significant risk). Finally, FDA could decide to place a proposed or ongoing Phase 1 clinical trial on clinical hold or terminate the IND. FDA can also take any of these actions if there is evidence of inadequate QC procedures that would compromise the safety of an investigational product.”

2) Phase 1 Clinical Trial materials usually are audited by the EMA (MHRA) for Phase 1 studies conducted in Europe or the U.K. As noted from (1) above, this does not occur on an on-going  basis within the U.S.

3) Companies must remain in a state of compliance at all times.  Because a firm receives none or minimal citations or observations does not permit that organization to become less vigilant.  Various investigators may possess differing backgrounds and skill sets and observe different non-conformances during their respective audit.

4)  Hiring a microbiological consultant does not minimize the Client’s responsibility to their firm.  Various firms to include the Triad Group (see recent FDA-483, January and March 2011; see also Chiron Warning Letter; September 2004) have not employed appropriate personnel, primarily microbiologists, to assist them with their on-going microbiological issues.

“Under CGMP, if a sponsor or manufacturer initiates a contract with another party to perform part or all of the Phase 1 investigational drug manufacturing, the sponsor or manufacturer, and contractor are both responsible for assuring that the phase 1 investigational drug is manufactured in compliance with CGMP. This assurance is achieved, in part, by having effective quality control functions (see section V.B). We recommend that the manufacturer or sponsor assess the contractor to ensure that effective quality control functions are in place.” (From FDA Guidance for Industry, Phase 1)

Having read the background material, please review the initial observation 1(a).

1. Your firm has not thoroughly investigated the failure of a batch or any of its components to meet its specifications whether or not the batch has already been distributed [21 C.F.R. § 211.192]. For example,

a) Your firm has routinely failed to thoroughly investigate and identify root causes when environmental monitoring data exceeds the action limit. 

In your response, your firm states that you have hired a consultant to assess the environmental data and subsequently, repaired the facility. Your response, however, is inadequate because your firm failed to investigate adequacy of your disinfectant procedures, frequencies, and preparation as part of your investigation for environmental samples that exceeded action levels in the critical and supporting clean areas.  For example, your firm’s disinfection program included insufficient use of sporicidal agents. It is essential that environmental control is continually maintained throughout your aseptic processing facility. 

Comment

Aseptic processing facilities should align themselves with FDA’s Guidance for Industry, Sterile Drug Products Produced by Aseptic Processing, September 2004, USP<1072> Disinfectants and Antiseptics, USP<1116> Microbiological Evaluation of Clean Rooms and Other Controlled Environments, and Annex 1 Manufacture of Sterile Medical Products (revised, March 2009).  Various companies provide sterilants that are sterile and ready to use, e.g., bleach, hydrogen peroxide (6%) and hydrogen peroxide/peracetic acid (Veltek and Steris). 

The FDA notes, in particular, that “your firm’s disinfection program includes insufficient use of sporicidal agents.”  Within an ISO Class 5 environment, the primary microorganisms that are often found include Staphylococcus, Bacillus and various mold.  Isopropyl alcohol will kill the Gram positive cocci, but it requires a sporicide to kill any spore formers. 

Furthermore, we evaluated your environmental data from 2008 to 2010 and are concerned with the lack of comprehensive investigations when mold and bacteria were identified in your aseptic filling facility that exceeded action levels. Your aseptic process relies on manual manipulations and interventions where personnel are in close proximity to open product, and poor environmental control poses a significant risk of contamination. 

Comment

Airborne viable and non-viable environmental data must be evaluated, especially whenever an Action Level is exceeded.  Typically an Alert Level does not trigger an investigation; however, an Action Level does. Since Formatech’s “aseptic process relies on manual manipulations and interventions where personnel are in close proximity”, environmental control should be enhanced to assure the minimum potential for microbial contamination.

Please visit the FDA’s Warning Letter at Web site:  http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/ucm248216.htm  for additional information re: the Formatech observations.