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FDA & Nitrosamine Impurities – The Proverb of the King with Long Arms

If the dictionary is to be believed, the expression that kings have long arms was first listed as a proverb in 1539 (see here).  Over time it has developed into the commonly recognized idea that governments have far-reaching law enforcement and legal powers.  Beginning in June 2018 the U.S. Food and Drug Administration (FDA) has showed industry that it has such a long arm and that it is willing to use it when confronted with the deluge of nitrosamine-related impurities issues.

In an earlier blog post I discussed some of the background on this issue and how industry can rely on correspondence from FDA to assist in setting up a comprehensive framework for reporting potentially mutagenic impurities in regulatory submissions beyond just responding to the nitrosamine related issues.

This blog is a companion piece and focuses on the myriad ways – the proverbial “long arm” - that FDA has deployed its manufacturing quality and CGMP compliance and regulatory enforcement tools to address these issues. I’ll start by broadly categorizing the various types of issues that have been common pitfalls for industry and have been the focus of FDA attention, then examine some recent Warning Letters that offer examples of how FDA has chosen to address these categories and then end with some remarks about the ongoing activities at FDA that are not necessarily in the public eye but are critical in how FDA develops and applies it policies for these issues.

Over the years, I have had colleagues – both in industry and at the FDA – remark that the FDA’s culture is infused with pattern recognition.  In the case of handling the nitrosamine-related impurities issues, FDA has published all its public information on three websites – see the website for nitrosamine-related impurities in the angiotensin II receptor blocker (ARB) class of drugs here, the website for the laboratory analysis of valsartan drug products, which is a member of the ARB class of drugs, here) and the website for nitrosamine-related impurities in ranitidine drug products here.

When the information on these three websites is combined with the Warning Letters (which are published here) sent by FDA to manufacturers of various active pharmaceutical ingredients (API), intermediates and drug products which have been identified as a significant risk for the presence of nitrosamine-related impurities, a clear pattern emerges for the types of issues which have caught the attention of the  FDA’s compliance and enforcement apparatus.  These categories of issues are:

  • Process development and changes to process chemistry for the synthesis of an API or intermediate.
  • Use of recovered solvents for subsequent synthesis of an API or intermediate.
  • Cross-contamination from input materials into the synthesis of an API, intermediate or formulation of a drug product.
  • Oversight of facilities performing contract operations.
  • Inadequate investigations.
  • Process drift for the impurity profile of an API, intermediate or drug product.
  • Inappropriate specifications (including attributes for specified identified and unidentified impurities, fit for purpose analytical methods and acceptance criteria).
  • Ineffective annual product reviews.

Between June 2018 and October 2019, the FDA issued four Warning Letters to firms which were involved in the manufacture of API and API intermediates where the presence of nitrosamine-related impurities was determined to be unacceptable and presented a significant regulatory violation or deviation. 

It’s more important to spot the issues that FDA has raised rather than examine the specific charge(s) that the agency used in the various Warning Letters. Even though the gist of the problems are associated with firms’ lapses in both establishing and maintaining a consistent regulatory impurity profile (which is discussed in ICH Q7A 11.21 and 11.22), the observations of each case can vary at the time of inspection and the agency has discretion in applying the statutory interpretation of CMGP for API and intermediates. 

That said, here’s the list of those Warning Letters and a brief discussion of the issues raised by FDA that contributed to the pattern of issues FDA has built because of its surveillance and enforcement activities.

Aurobindo Pharma Limited (June 2018)

  • The investigation into the root cause of nitrosamine impurities in API was deficient.
  • The firm’s risk assessment did not include an evaluation of the potential for key starting materials (KSM), other raw materials, and solvents to result in the presence of impurities.
  • The firm’s risk assessment documented contamination in API originated from recovered solvents at a contract manufacturer.  The firm’s investigation concluded the contamination was due to the use of recovered solvents supplied by a contract manufacturer.  The firm attributed the contamination to inadequate cleaning procedures.
  • The firm did not submit technical updates and supplemental applications to report specification changes in a Drug Master File (DMF).

See the Warning Letter here.

Zhejiang Huahai Pharmaceutical (November 2018)

  • Inadequate investigation into unknown peaks - some tentatively identified as N-nitrosodimethylamine (NDMA) - which appeared on chromatograms during residual solvent testing for multiple API.
  • API batches that exceeded the specification for an impurity which has been classified as a probable human carcinogen.
  • Failure to verify the reliability of the analytical results for all API batches released using an original method.
  • Failure to evaluate the need for additional analytical methods to ensure that unanticipated impurities were appropriately detected and controlled in the API before a process change was approved for implementation.
  • FDA disagreed that the firm’s process development study was adequate.

See the Warning Letter here.

Lantech Pharmaceuticals Limited (August 2019)

  • The firm was acting as a contract solvent recovery facility for a customer’s API  manufacturing operations and as contract manufacturer for the API intermediate.  The firm was notified by its customer that solvent recovered by the firm contained the potential mutagenic impurity N-Nitrosodiethylamine (NDEA). The firm opened an investigation.  However, the investigation was inadequate for several reasons.
  • The firm did not keep logbooks for product use and cleaning of non-dedicated storage, receiving, and solvent recovery tanks.  The firm’s response did not discuss probable cross contamination or potential mix-up risks associated with these non-dedicated tanks.
  • The firm did not implement procedures to evaluate and control impurity risks associated with solvent recovery operations done under contract to API manufacturers.  This includes adequate testing to confirm their suitability for manufacturing processes in which they may be used, establishing an impurity profile for solvents to ensure that they meet appropriate standards and keeping an ongoing program for monitoring process controls to ensure stable manufacturing and prevent unanticipated impurities.
  • The firm also did not implement a procedure for investigating unknown peaks in recovered solvent chromatograms observed during analytical testing.

See the Warning Letter here.

Mylan Laboratories Limited - Unit 8 (November 2019)

  • The firm’s procedures for receiving, identifying, testing, and handling raw materials were inadequate to prevent contamination and cross-contamination of API with nitrosamine impurities.
  • The firm had not predicted the presence of nitrosamine impurities based on an assessment of the API manufacturing process.
  • The firm’s investigations concluded that nitrosamine contamination of multiple API originated from recovered solvents.  Without adequate scientific justification, the firm concluded that the recovered solvents having unacceptable levels of nitrosamine impurities would not result in significant levels of the impurities in the API.
  • Multiple contract manufacturers supplied solvents that were contaminated with nitrosamines, but the firm lacked documentation for how these solvents were stored and used.  The firm also did not provide an adequate investigation to determine whether other API could have been affected by use of storage tanks that held recovered solvents.
  • FDA requested that the firm provide a comprehensive, third-party review of the firm’s quality oversight of capability and acceptability of all material suppliers, including qualification standards for initial supplier selection and ongoing lifecycle evaluations to ensure continued supplier acceptability.

See the Warning Letter here.

Another observation from colleagues about FDA culture is that it resembles a mosaic – a picture or pattern that is made from an arrangement of smaller distinguishable or notable pieces.  That is an apt analogy for understanding how FDA is assessing the public health risk from the presence of nitrosamine impurities.

The Warning Letters are only a few tiles of the mosaic, and even those are highly varied – a firm cannot be assured that there is a reasonably low level of risk of encountering these regulatory issues by only reviewing process design and collecting test data.  To reach an acceptable and sustainable state of compliance, a firm must also address all the other issues collateral to specific levels of nitrosamine-related impurities that are also raised in these Warning Letters, such as cross-contamination, investigations, the selection and control of vendors and scrutinizing the adequacy of specifications on a regular basis.

Beyond the information that can be gleamed from the publicly available Warning Letters, FDA is also engaged in a parallel group of workstreams that includes application and DMF reviews, correspondence with industry, research and testing, public presentations and publications, meetings with manufacturers, regulatory actions other than Warning Letters such as “import alerts,” performing additional inspections, assessing the conditions observed in those inspections during case review, and holding regular inter-disciplinary meetings with global health authorities.

The king does indeed have long arms, but FDA has used several mechanisms to put industry on notice so becoming ensnared in them is not a forgone conclusion.