CONTRACT PHARMACEUTICAL SERVICES OF AUSTRALIA PTY LTD (05/17/13) RECEIVES WARNING LETTER

HUMIDITY PLAYS A KEY ROLE IN THE PACKAGING OF A DRUG PRODUCT

Contract Pharmaceutical Services of Australia  was audited by the FDA from October 30 through November 1, 2012.  The FDA identified significant violations of cGMP for finished pharmaceuticals during the visit.  Based upon these violations, the drug products were deemed to be adulterated.

Specific violations during the inspection included the following:

“1. Your firm failed to provide equipment for adequate control over air pressure, micro-organisms, dust, humidity, and temperature when appropriate for the manufacture, processing, packing, or holding of a drug product (21 CFR 211.46(b)).

For example, blister rooms (b)(4), where (b)(4) capsules are packaged, had no mechanism to maintain and control the relative humidity (RH) at (b)(4)% – (b)(4)%, as specified in your master packaging batch record (MPBR). Process design studies on this product found that the capsules are sensitive to humidity and that after (b)(4), approximately 50% of the capsules exhibited brittleness. Significantly, the lack of humidity controls and storage conditions observed at your firm can lead to performance problems with this (b)(4) product due to the capsule brittleness. Dose performance problems as a result of changes in capsule brittleness and (b)(4) ((b)(4)) could potentially lead to a higher risk of severe (b)(4) in patients. Your response indicated that you have now installed a humidification unit for one of the (b)(4) blister lines and you expect to complete qualification some time in 2013.

Your response was inadequate because you did not adequately investigate and address the impact on the drug product already distributed to the U.S. market. Your response also does not indicate whether your contract packaging facility plans to use the blister line that still lacks adequate humidity controls to repack products for the U.S. market. Additionally, for the blister line that your firm commits to improve, the response did not explain how the RH will be controlled during packaging until qualification of the new humidification unit is completed.

In your response to this letter, provide a detailed action plan for ensuring adequate monitoring and control of the humidity in the packaging areas for the products. Also, include a qualification study that evaluates the effectiveness of the humidification equipment. We will verify the acceptability of packaging conditions during our next inspection.”

COMMENT: 

Relative humidity is often overlooked in the manufacture of non-sterile drug products to include capsules and tablets.  Companies involved in aseptic production of sterile drug products are more concerned because of the impact of both low and high humidity, i.e., outside of the range of 30-55%.  When humidity is too low in aseptic operations, personnel tend to shed more particulates and naturally occurring microflora from their bodies.  There also exists static electricity that may form.  When the humidity becomes too high in the same aseptic environment, personnel may “bled through” their gowns and again contaminate the environment.  Neither situation is desirable. 

In this particular Observation, the FDA extends this to “control over air pressure, micro-organisms, dust, humidity, and temperature when appropriate for the manufacture, processing, packing, or holding of a drug product (21 CFR 211.46(b)).”  The FDA goes on to state “the lack of humidity controls and storage conditions observed at your firm can lead to performance problems with this (b)(4) product due to the capsule brittleness. Dose performance problems as a result of changes in capsule brittleness and (b)(4) ((b)(4)) could potentially lead to a higher risk of severe (b)(4) in patients.”  One does not often think about “capsule brittleness” with humidity and the ramification of capsules dissolving prematurely because of this issue. 

“3. Your 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).

Specifically, your firm did not initiate an investigation to determine the root cause of a humidity excursion during the packaging of (b)(4) lots # (b)(4) (Master No. (b)(4)), # (b)(4) (Master No. (b)(4)), and # (b)(4) (Master No. (b)(4)). The humidity conditions in blister rooms (b)(4) fell below the lower RH limit ((b)(4)–(b)(4)% RH) specified in your master packaging record.

You indicated in your response that your investigation procedure was adequate and that personnel did not follow it. Your response is inadequate because you did not address the fact that your investigation documentation form lacks sufficient details of steps taken during the investigations. Additionally, you failed to identify the root cause of the humidity excursion and provide the appropriate corrective and preventive actions.

In your response to this letter, please provide a detailed description of the changes and improvements you have made to your investigation system, including improved procedures, provisions for root cause determination, and better staff training and qualifications.

As part of the pre-approval inspection for (b)(4), the investigator observed that your firm stores the bulk (b)(4) mg capsules in a warehouse that does not provide humidity control. However, your bulk standard specification for (b)(4) mg capsules, # SP-432, calls for humidity-controlled storage conditions, specifically, storage at (b)(4)%-(b)(4)% RH. In your response, your firm committed to completing a temperature and humidity mapping study of the warehouse by the end of Q1 2013. Provide a copy of the mapping study report and your plan to monitor and control the RH in the warehouse. Also, provide a copy of the bulk standard specification for the (b)(4) capsules.”

COMMENTS: 

The Client indicated in their response that the “investigation procedure was adequate and that personnel did not follow it.”  The FDA indicated that “Your response is inadequate because you did not address the fact that your investigation documentation form lacks sufficient details of steps taken during the investigations. Additionally, you failed to identify the root cause of the humidity excursion and provide the appropriate corrective and preventive actions.”  

CAPAs are an extremely important part of any Out of Specification (OOS) and subsequent investigation to identifying the root cause.  To simply state that the “personnel did not follow it” does not provide the investigation that the FDA was seeking.  

The “investigator observed that your firm stores the bulk (b)(4) mg capsules in a warehouse that does not provide humidity control. However, your bulk standard specification for (b)(4) mg capsules, # SP-432, calls for humidity-controlled storage conditions, specifically, storage at (b)(4)%-(b)(4)% RH.”  

 Specifications become an important component of maintenance of the capsules.  If a Company states that they are going to maintain certain ranges, especially where they know that exceeding these ranges (especially at the lower range) may create brittleness of the capsule (which appears to be a “critical” specification), it is difficult to understand how management can permit the storage of capsule in non-controlled environments.