SOUTH DAKOTA PHARMACEUTICAL RECEIVES WARNING LETTER (3/17/11)

FDA CITES DAKOTA LABORATORIES FOR FAILURE TO ADEQUATELY VALIDATE ASEPTIC PROCESS

Comment

Excerpts and comments from specific violations follow.  Please obtain the complete Warning Letter from FDA’s web site.

CGMP

1. Your firm has not established appropriate written procedures designed to prevent microbiological contamination of drug products purporting to be sterile per 21 CFR 211.113(b). For example,

Comment

211.113 Control of Microbiological Contamination (b) Appropriate written procedures, designed to prevent objectionable microorganisms of drug products purporting to be sterile, shall be established and followed.  Such procedures shall include validation of all aseptic and sterilization processes.

a. Your firm released several batches of sterile ophthalmic eye drops without adequately validating your aseptic process. According to your raw material specification sheets and your list of batches manufactured, your aseptically manufactured products are filled into 15mL bottles; however, your process (b)(4) bottles which did not represent the products that would be manufactured (my italics).

In your response, your firm states that (b)(4) were successfully completed by the time the product was shipped to the customer. Your response is inadequate because you have not provided any assurances that your aseptic process was in a state of control during the manufacture of sterile drug products which were subsequently distributed. 

Comment

211.192 Production Record Review.  All drug product production and control records, including those for packaging and labeling, shall be reviewed and approved by the quality control unit to determine compliance with all established, approved written procedures before a batch is released or distributed.  In this situation, no validation was in place during the manufacture. 

b. Your firm has not established written and approved specifications to assure suitability of each lot of the (b)(4) filters used for sterilization.

In your response, your firm provided a draft specification sheet for the (b)(4) sterilizing filter. Your response, however, is inadequate because your firm has failed to provide a justification for the specifications (e.g. (b)(4)) listed for each filter. In addition, we note that your specification sheet allows for the use of multiple filter manufacturers. The validation of each approved model of sterilizing filter should be assessed and documented.

Comment

Product should not be released without a final specification sheet.  In addition, if multiple filters are permitted from multiple filter manufacturers, each of these filters should be validated through Filter Integrity Testing  prior to its use in providing an aseptic product (see FDA Guidance for Industry, Aseptic Processing, September 2004).

2. Your firm failed to establish time limits for the completion of each phase of production to assure the quality of the drug product per 21 CFR 211.111.  For example,

a. Your firm has failed to provide a justification for the hold times (i.e., (b)(4)) used in current batch records for sterile ophthalmic eye drop products. 

In your response, your firm provided a report entitled “ (b)(4) Study Report” to justify your use of a (b)(4) day hold time. This report, however, is inadequate because your study tested lots on Day (b)(4) that did not correspond to or match the lots tested on Day (b)(4).  Your study should compare the same lot for microbial recovery on Day (b)(4) to Day (b)(4) to determine whether the bulk products originally tested still had levels of bioburden within your validated sterilization ranges.

b. In addition, your response failed to address the inadequate investigations for those batches where the hold times of the bulk product exceeded your hold time limits.

3. 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, as per 21 CFR 211.192.  For example,

a. You failed to investigate environmental monitoring data recorded in your aseptic processing suite, which failed to meet your established limits.

Your response states that you have revised your environmental monitoring form to allow space for explanation when needed; however, your response is not adequate.  You have not investigated the cause of the environmental monitoring results that exceeded the limits on your “Performance Qualification Data HVAC Validation” and “Routine Environmental Monitoring” worksheets, nor have you justified your assessment of the product impact caused by those excursions.

Comment

See also: 211.113 Control of Microbiological Contamination (b) …Such procedures shall include validation of all aseptic and sterilization processes.

b. Your firm failed to investigate the failure to sample and test water used in the manufacture of Ortho-K Eye Drops (batch 021008) and Women’s Eye Drops (batch 031011).  

Your response states that there is no microbial requirement in the USP for purified water as a reason for not testing water for microbial quality.  Routine evaluation of the acceptability of the quality of water used in the manufacture of drug products is a fundamental part of good manufacturing practices.  In addition, we also note that your procedures require the microbial testing of your purified water.  Your response is inadequate because you failed to identify corrective actions to prevent a recurrence. 

Comment

USP 34 General Information Chapter <1231> maintains a requirement of <100 CFU/mL for Purified Water

4. Your firm does not have an adequate system for monitoring environmental conditions in aseptic processing areas, as per 21 CFR 211.42(c)(10)(iv)].  For example,
a.  Your firm does not have written procedures for environmental monitoring during aseptic processing, including sampling frequency, sampling locations, or procedures for alert and action levels.

In your response, you state that you have revised your environmental monitoring form to include a place for explanations and that you are developing an environmental monitoring procedure. You also state that your acceptance criteria currently listed on your worksheets is your action limit. You are required to ensure all sampling locations, sampling frequency, and alert and action levels are justified by a scientific rationale. We request you provide your alert levels. If these levels have not already been established, provide the timeframe within which they will be established. 

Comment

21 CFR 211.42(c)(10)(iv) states “A system for monitoring environmental conditions” is required.