Deficient Cleaning and Transfer of a Non-Validated Manufacturing Process Lead to a Warning Letter

During an inspection of an Indian pharmaceutical manufacturer by the FDA, several serious deficiencies were discovered. Not only was the cleaning of multipurpose equipment was criticised, the transfer of a non-validated manufacturing process led to further complaints.

Cross Contamination

In the course of the inspection, it was noticed that non-dedicated equipment such as a tablet press had not been adequately cleaned. The inspectors had noticed residues in a tablet press that had been released as 'clean', as well as in an air conduit.

Later, it had turned out that the residues in the tablet press were residues of the previously manufactured product. The residues in the air conduit even consisted of two different APIs. It is worth mentioning here that the manufacturer uses this equipment to produce both highly potent and non-potent medicinal products.

The Indian manufacturer had also failed to test the retained samples of batches exported to the USA that had been manufactured with this equipment for cross contamination. The manufacturer is now required to remedy this and to develop an assessment that addresses the improvement of cleaning effectiveness as well as the prevention of cross contamination. A CAPA plan should identify all weaknesses in the cleaning procedures, taking into account each piece of equipment. The cleaning validation programme shall be improved by evaluating worst case scenarios (high toxicity and poor solubility of products and equipment that is difficult to clean). The manufacturer should also outline how it will improve its change management system before implementing new equipment or introducing new products into the facility.

Lack of Process Change Management

Inadequate change management may also be a reason for the second serious deficiency. The manufacturer had transferred a non-validated capsule manufacturing process to a new building. Changes were also made to the manufacturing process and equipment without evaluating them adequately in advance. Some of the batches manufactured in this way showed OOS results in the content uniformity test. In a reply letter, the manufacturer had stated 'suboptimal process performance' as the reason for the OOS results. However, the manufacturing process has since been validated and all batches are within specification. This is not sufficient for the FDA, as no statements were made about batches manufactured for the US market that had been manufactured prior to this validation. The additional monitoring for content uniformity initiated by the manufacturer says nothing about the other required quality parameters, according to the FDA.

The Indian manufacturer must now submit a detailed summary of the validation programme that demonstrates the state of control over the entire product lifecycle via the inter- and intra-batch variance. Risk analyses, validation reports and continuous process monitoring are also mentioned here.

Lack of Quality Oversight

However, the performance of the Quality Unit (corresponding to quality assurance) is also being criticized. According to the FDA, the Quality Unit has failed to have any influence on cleaning validation. The processes of cleaning validation, such as the definition of test procedures or the definition of MACO (maximum carry over) values, do not require a review by the Quality Unit. Also, the Quality Unit has failed to complete some APRs (Annual Product Reviews). To aggravate the situation, the deficiencies identified were repetitive. For example, similar deficiencies had been identified at other manufacturing sites of the company in India and had been addressed by Warning Letter. These repeated GMP violations show the FDA that the company lacks an overview and control over its manufacturing processes. The Warning Letter that has now been issued thus affects all of the company's global manufacturing sites.

The Warning Letter to the Indian pharmaceutical manufacturer can be found on FDA's website.