Updated 11/15/2019 to include the warning letter issued to Mylan Laboratories Limited on November 5, 2019.
Health authorities worldwide have overseen the recall of many ‘sartan’ products in the past few years. These recalls began in the US as early as 2013 with a recall of product by Teva Pharmaceuticals. Authorities in the US, EMA, Canada, and Australia, just to name a few, have taken enforcement actions and implemented drug product recalls.
Because the impurity originated with the API, and because the generic version of the drug(s) in question are manufactured by a variety of firms, this impacts many products from many companies. While the initial problem began with a valsartan API, studies have demonstrated that this may include many other ‘sartan’ products and other related nitrosamine impurities.
Below we address some of the enforcement actions taken against a few of the notable players in this ever-expanding series of events.
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Zhejiang Huahai Pharmaceutical
This firm was among the first API manufacturers identified to have produced valsartan API contaminated with the probable carcinogen NDMA. The form 483 issued at the end of the inspection on August 3, 2018 was 11 pages long and included 11 observations. Only the first three observations are directly included in the warning letter, though some of the other observations are mentioned in passing or incorporated into the two warning letter violations.
Again, the length of the form 483 and number of observations may have been to convince the recipient that the issues were serious, and they may also have been intended to convince FDA management that additional enforcement action was necessary. The later certainly was effective because the warning letter was issued a quick 3 ½ months after the close of the inspection.
The two violations identified in the warning letter issued November 29, 2018 were:
- Failure to adequately investigate customer complaints and consider all possible sources of the contaminant in the valsartan API.
- Failure to adequately assess manufacturing changes for any impact they may have on the resulting API.
The EDQM and EMA joint for-cause inspection on September 13, 2018 that identified nine ‘major’ and eight ‘other’ observations resulted in a report of GMP non-compliance and suspended the certificate of suitability.
The major observations included but were not limited to failures in the following:
- Investigations into the presence of NDMA.
- Risk assessments conducted to support the manufacturing changes that may have led to the NDMA formation.
- Management of complaints for the presence of NDMA.
- Inadequate OOS investigations into unknown peaks in valsartan manufactured by the new process.
It is interesting to note that no critical observations were identified.
In conclusion, both the FDA and the EMA/EDQM identified failure to adequately address customer complaints, failure to adequately assess potential risks based on the manufacturing changes that were made, and failure to address OOS events of unknown peaks in the GC-MS analyses.
Aurobindo is a manufacturer with early involvement in the ‘sartan’ story starting with a recall initiated on December 31, 2018. The reasonably short, 4-page, form 483 issued on February 9, 2019 identified a failure to investigate unknown peaks, a risk analysis that did not include assessment of cleaning validation and testing of starting materials, and finally batch records that didn’t adequately document whether solvents were sent for recovery or were sent for disposal. This was by far the shortest of the forms-483 addressed in this post.
The firm received a warning letter on June 20, 2019 regarding their API manufacture. The warning letter identified the following violations:
- Investigations into impurities were inadequate. The violation notes that the firm was notified by the EDQM about the impurity and then recalled the product. The risk assessment performed by the firm identified recovered solvent performed at a contract manufacturer as the probable cause of the impurity.
- Investigations did not consider poor equipment maintenance, particularly product contact surfaces in the assessment of the impurity and residua liquid remaining in tanks.
- And finally, impurities that exceeded the firm’s internal reporting threshold, and the ICHQ3A(R2), were not reported to the DMF supporting the API.
Again, we see the commonality of problematic and incomplete investigations and risk assessments in both the form 483 and warning letter.
Lantech Pharmaceuticals Limited
The 13-page form 483 from March 15, 2019 includes nine observations. It begins by identifying inadequate investigations and risk assessments into the presence of suspected carcinogenic compound(s) in their solvents. The second observation addressed inadequate cleaning, particularly that it did not extend to all non-dedicated equipment and did not assess all products.
Similar to the warning letter, the 483 identified lack of controls over electronic data in the QC lab. Lack of process validation for solvent recovery was also identified.
Lantech Pharmaceuticals Limited received a warning letter on August 8, 2019. The firm is a solvent recovery facility, and API intermediate manufacturer, a manufacturer for valsartan APIs, and appears to be implicated in the NDMA contamination of at least some of the ‘sartan’ drugs. They also manufacture ‘sartan’ APIs for distribution to countries outside the US.
However, the fact that equipment is not dedicated means that potential cross-contamination may affect drugs that are distributed in the US. Neither the 483 or warning letter identifies their customers but it is reasonable to assume there is more than one or two. Thus, the impact of their failures can be felt across many API manufacturers and many dosage form manufacturers.
Use of Lantech Pharmaceuticals for solvent recovery represents, in my opinion, a failure in vendor qualification and failure in ongoing oversight by the Quality Unit and should be a lesson to others.
The warning letter identifies four violations:
- Quality related complaints were not adequately investigated and resolved. These included complaints about the detection of NDEA by their customers.
- Non-dedicated equipment did not have associated log-books and was not supported by adequate cleaning such that cross-contamination could occur.
- Failure to ensure that recovered solvents meet appropriate specifications before reuse. Further the firm “overlooked” performance of process validation.
- Finally, electronic GC data was not retained and access was not controlled in a way to prevent deletion, modification or editing of data.
Again, the commonality of inadequate investigations and risk assessments, inadequate equipment management and cleaning to prevent cross-contamination, and failure to control access to electronic data to authorized personnel is seen between the warning letter and form 483.
The unique feature of lack of process validation of the solvent recovery process is unique to Lantech. Just like an API made by a single manufacturer finds its way into products made by many dosage form manufacturers, solvent recovery firms with inadequate cleaning, labeling, and processes may impact multiple products made by many firms.
Torrent Pharmaceuticals Limited
Ten of the seventeen pages from this form 483 issued at the close of inspection on April 28, 2019 describes observations in the firm’s OOS management and resulted in a single violative action identified in the warning letter.
Generally, when FDA issues a form 483 of this length they are attempting to make a point with the recipient that the issues are very serious and widespread. It may also be the case that the three investigators were working to ensure that FDA management supported issuance of the warning letter.
In general, the order of observations/violations indicates their order of criticality. The process validation failures were the second observation in the form 483 but was the first identified violation in the warning letter. Inadequate management of OOS events was identified first in the form 483 but was the second item in the warning letter. The third observation in the form 483 describing failures in calibration and maintenance was not mentioned in the warning letter. The observations associated with API manufacture was not addressed in the warning letter, but it would be reasonable to assume that acceptable corrective actions put in place for drug product deficiency #2 would also address similar processes in API manufacture.
The warning letter issued on October 8, 2019 identified two violative actions. These enforcement actions were yet another associated with a manufacturer of ‘sartan’ drugs, so a very high visibility site. The warning letter identifies two violations and provides extensive details on both:
- The firm did not follow the written validation protocol meant to qualify the use of an alternate ‘sartan’ API. The firm appears to have developed a ‘workaround’ protocol revision to justify commercializing a product that failed process validation.
- OOS events weren’t managed adequately. FDA identifies that an inappropriately large number of OOS events were invalidated.
Mylan Laboratories Limited
Unit 8 in Andhra Pradesh, India received a warning letter on November 5, 2019, based on the outcome of an inspection ending June 5, 2019. The company manufactures APIs and is yet another firm that has been identified to have issues with potential carcinogenic impurities in solvents, including recovered solvents that were ultimately identified in drug products.
The 11-page form 483 includes six observations. The first four observations address failure to handle materials “…in a manner that minimizes the risk of contamination and cross-contamination.” This includes management of solvents including recovered solvents, lack of documentation in storage of lots of solvent, and inadequate cleaning of shared equipment that resulted in cross-contamination among products.
In comparing the form 483 to the warning letter, it is interesting to note that observations five and six, both with multiple examples, in the form 483 are not included in the warning letter. These observations identify shortcomings in analytical test methods and failure to qualify laboratory analytical instruments.
The warning letter specifically mentions the valsartan API. The FDA recommends the firm hire a qualified GMP consultant to assist them in coming into GMP compliance. The warning letter does not mention imposition of an import alert. Note that FDA asked for a “third party review” of some of the processes and procedures, suggesting they have little confidence in a review that may be performed by the firm itself.
Two previous warning letters were issued in 2018 and 2015. Before going into the specific details, the focus on solvents, their recovery/storage/use, should encourage all firms that use organic solvents to evaluate their practices and procedures to ensure these materials are not sources of contamination or product cross-contamination.
The larger story, including firms other than Mylan, address complications in the drug supply chain. The deficiencies described in this area are not ‘rocket science’ or new interpretations of requirements. Rather, this is simply failure to follow fundamental GMPs. The two deficiencies are well worth reading for their depth of detail.
The five warning letters, all associated with the ‘sartan’ drug contamination, document common observations in the forms 483 and associated warning letters. The warning letter to Lantech Pharmaceuticals is unique because the firm recovers solvents and inadequate solvent recovery may be one source of the nitrosamine cross-contamination. The common violations identified in the warning letters and EDQM report of GMP non-compliance include:
- Inadequate investigation into customer complaints regarding the presence of the impurity NDMA;
- Inadequate risk assessments of how change in manufacturing process may import product quality;
- Lack of, or workarounds, to process validation, either for manufacture of drug product or solvent recovery;
- Inadequate control over laboratory computer systems and inadequate investigations into OOS events including excessive invalidation of OOS results;
- Inadequate equipment maintenance including cleaning validation to prevent cross-contamination;
- Inadequate controls over the receipt, testing and management of raw materials.
The saga of these events isn’t over and nitrosamine contaminants have been found in ranitidine. For me, a take-home lesson is that due diligence in the selection of suppliers, along with ongoing diligent oversight is essential. Failure in this area has costly, and ever-expanding, consequences.
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