FDA IGNORES CONSIDERATION OF WRITTEN RESPONSES IN DRAFTING WARNING LETTER

CEPHAZONE PHARMA’S (APRIL 25, 2011) INITIAL RESPONSE LACKS SUFFICIENT CORRECTIVE ACTION

During our July 12, 2010 to August 26, 2010 inspection of your pharmaceutical manufacturing facility, Cephazone Pharma, LLC, located at 250 E Bonita Avenue, Pomona, CA, investigator(s) from the Food and Drug Administration (FDA) identified significant violations of Current Good Manufacturing Practice (CGMP) regulations for Finished Pharmaceuticals, Title 21, Code of Federal Regulations, Parts 210 and 211.  These violations cause your drug product(s) to be adulterated within the meaning of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (the Act) [21 U.S.C. § 351(a)(2)(B)] in that the methods used in, or the facilities or controls used for, their manufacture, processing, packing, or holding do not conform to, or are not operated or administered in conformity with, CGMP.

We have reviewed your firm’s response of September 2, 2010, and note that it lacks sufficient corrective actions.  In addition, we acknowledge your written responses, dated September 23, 2010, October 11, 2010, October 28, 2010, and December 16, 2010, to the Form FDA 483.  However, because these responses were received more than 15 business days after the Form FDA 483 was issued; these responses have not been considered.  We plan to evaluate your additional responses to the Form FDA 483, along with any other written material provided, as a direct response to this Warning Letter.

Comment

Written responses are due to the FDA within 15 business days after the Form 483 is issued.  As a result of the responses being received after this date, the responses were not considered in the issuance of the Warning Letter by the FDA.  These FDA comments are to my knowledge one of the first sets of comments where Dr. Margaret Hamburg’s comments from August 2009 are reflected within a Warning Letter.

Specific violations observed during the inspection include, but are not limited, to the following:

1. Your firm does not have appropriate laboratory testing to determine if each batch of drug products, purporting to be sterile, conform to such requirements [21 C.F.R. § 211.167(a)].

For example, your firm only uses (b)(4) IU of the required (b)(4) IU of beta-lactamase neutralizing agent (as per your validation studies) for the purpose of inhibiting the antimicrobial properties of Ceftriaxone during sterility testing. In addition, your firm does not include Escherichia coli as part of your test organisms despite your protocol, “Validation of Antibiotic Neutralizer Effectiveness,” (b)(4), stating that Escherichia coli is the most sensitive challenge organism for evaluating if the antibiotic was effectively neutralized.

In your response, your firm provided protocol (b)(4), “Method Validation Protocol for Recovery studies from PVDF Filter Membrane of Steritest EZ Sterility Testing System Surfaces,” that describes the amount of Ceftiofur Sodium recovered from the Steritest EZ Sterility Testing System and correlates it to the amount of neutralizer required by your original neutralizer effectiveness study. Your response, however, is inadequate because your firm has failed to provide any scientific data (my italics) to justify the correlation between the use of (b)(4) IU of beta-lactamase to (b)(4) of Ceftiofur Sodium or the use of (b)(4) IU of beta-lactamase to (b)(4) of Ceftiofur Sodium. 

Please provide scientific data to justify the correlation between the amount of beta-lactamase required to neutralize a specific amount of Ceftiofur drug product.  Further, please provide information that demonstrates the beta-lactamase effectiveness at this concentration.  Future validations should ensure that you include the rationale for your choice of cephalosporin(s) included in the validation. In addition, future validations should include those products that proved to be most difficult to neutralize in your original validation. 

Comment

Use of neutralizers is used to “excess” when attempting to eliminate microbial inhibition.  In addition, the use of microbial panels that challenge the sensitivity of the complete removal of a microorganism is an essential component of any control system.  The FDA noted that the most sensitive microorganism, E. coli, is not utilized on an on-going basis to assure that the neutralization system is properly operating and that no additional inhibition is present.

It also appears that the firm has failed to provide scientific data to justify the correlation between the use of betalactamase to various concentrations of Ceftiofur Sodium. Just as with sodium thiosulfate and chlorine, sufficient quantities must be present to eliminate any concern for residual chlorine killing the microorganisms.

2. Your firm has not established appropriate written procedures designed to prevent microbiological contamination of drug products purporting to be sterile [21 C.F.R. § 211.113(b)]. 

For example, your firm’s written procedures for environmental monitoring, disinfection, and your process simulation media have not been validated. Specifically, your firm has not demonstrated the ability of reconstituted beta-lactamase at a concentration of (b)(4) IU (0.1ml/1L Sterile Water for Injection) to neutralize cephalosporins in the Tryptic Soy Broth (TSB) used in aseptic process simulation studies (i.e., media fills) or in your surface swab sampling solution. Furthermore, you have not demonstrated the ability of the neutralizing agents in the surface sampling plates purchased by your firm to neutralize the cephalosporin drug products manufactured at your firm.   

In your response, you state that you will determine the residual amount of cephalosporin and then determine the amount of neutralizing agent required. Your response is inadequate because you have not provided a scientific rationale that demonstrates a correlation between the residual cephalosporin recovered to the necessary amount of beta-lactamase. 

In addition, your firm provided procedure (b)(4), “Cephalosporin Residue Determination during Filling Process,” to demonstrate the effectiveness of the amount of penase enzyme used to neutralize residual antibiotic during environmental surface sampling. We cannot determine the adequacy and/or effectiveness of your corrective action because you have not provided the data from this study.  

Comment

Validations and their resultant SOPs should exist prior to attempting to perform environmental monitoring, disinfection and process simulation media fills.  Without the knowledge of the removal of cephalosporins in the various media, it becomes difficult to assure the sterility assurance of tests relating to the above areas.  To advise that these residuals will be determined at a future date throws into question all  of the lots historically released as well as those currently being manufactured.  Also, the indication of a successful study cannot be validated without the presence of data.

3. Your firm has not established scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that drug products conform to appropriate standards of identity, strength, quality, and purity [21 C.F.R. § 211.160(b)]. 

For example, your firm stores the recovered microbial isolates so that the microbes can be identified at a future date. Your firm stores these isolates for up to three months without any data to demonstrate that the microbial isolates would remain viable during the entire storage period. 

In your response, your firm states that you have revised your procedure (b)(4), “Microorganism Identification and Related Tests,” to reduce the storage period of the microbial isolates to (b)(4) days. Your response, however, does not provide your justification to demonstrate that the microbial isolates are viable at (b)(4) days.

Comment

With the ease of performing genotypic analyses, the firm had no requirement for holding microorganisms and becoming involved in determining for what period a microorganism might survive.  This would have completely eliminated the need for this SOP which created an FDA issue.  This is one additional example where a Company has added SOP(s) unnecessarily and created regulatory problems as a result.  In addition, if DNA Sequencing is performed, viable cells are not required.

4. Your firm has failed to exercise appropriate controls over computer or related systems to assure that changes in master production and control records, or other records, are instituted only by authorized personnel [21 C.F.R § 211.68(b)]. 

For example, your firm lacks control of the (b)(4) computer system which monitors equipment, room differential pressure, room humidity, and stability chambers. Although the system is password protected for temperature and humidity set points, all employees have access to the room where the (b)(4) computer system is located and the external hard drive is not password protected. During the inspection we observed that an employee was able to alter or delete data without a password and save the changed file.

In your response, your firm states that additional controls were implemented including validating the remote access to the (b)(4) computer, password protecting the room where the computer is stored, and limiting the (b)(4) control room to authorized personnel only. Although your corrective actions may adequately address the protection of the (b)(4) computer from non-traceable changes, your firm has not taken a global approach to this deficiency. It is our expectation that your other manufacturing and laboratory computerized systems will be reviewed to ensure similar deficiencies do not exist.

Comment

Sandoz, Inc (Wilson, NC ) received a Warning Letter dated August 12, 2008 for a very similar problem (see below).  The FDA encourages their Clients to read other Clients’ Warning Letters since history often finds itself repeating.    

Sandoz

“Failure to establish appropriate controls over computer or related systems to assure that changes in master production and control records or other records are instituted only by authorized personnel as required by 21 CFR § 211.68 (b).

For example, the Agilent Chemstation data acquisition system for the HP 8453 UV/Visible spectrophotometers allows your analysts to modify, overwrite, and delete original raw data files. The spectrophotometers are used for dissolution testing of finished product, stability samples, and process and method validation studies. All laboratory personnel were given roles as Chemstation Managers, which allowed them to modify, delete, and overwrite results files. The system also does not include an audit trail or any history of revisions that would record any modification or deletion of raw data or files.  Your laboratory computer system lacks necessary controls to ensure that data is protected from tampering, and it also lacks audit trail capabilities to detect data that could be potentially compromised.”