Updated 12/23/2019 to include the latest EMA publication.

The past year and a half has seen a flurry of enforcement and investigative activity in the US, Canada and Europe regarding the contamination of pharmaceuticals with potential carcinogens.  The enforcement ranges from a report of GMP non-compliance issued by the competent authority of Italy based on a September 13, 2018 inspection of Zhejiang Huahai Pharmaceutical Co. Ltd in China associated with an inspection of a Valsartan API, to dozens of recalls of various ‘sartan’ medicines by multiple health authorities, and finally to warning letters issued by the FDA.

The FDA warning letters include those issued to:

The manufacturing changes that resulted in the formation of the potential carcinogen was introduced into the manufacturing process of the valsartan API in approximately 2012, or earlier, but was not uncovered by regulators until more than five years later.  Since its discovery, recalls have been conducted by a variety of firms who purchased the contaminated API from either the same or a limited number of API manufacturers.

On September 13, 2019 FDA reported that the same carcinogen, N-nitrosodimethylamine (NDMA) has been identified in Zantac and other generic versions of the drug.  This identification was based on work initially conducted by a Connecticut online pharmacy Valisure.  We now see multiple recalls of these drugs being conducted in the US and Europe.

The EMA has been active in investigating the origin and prevalence of these contaminants in human medicines.  Both EMA and the FDA have established limits for nitrosamines in these medications.

In this article, we look at the most recent EMA publication in this area, which imposes requirements on Marketing Authorization Holders (MAHs) that many firms may have missed.  (Question 7 below provides a quick overview of the associated deadlines.)

EMA’s First Nitrosamine Publication for MAHs

The EMA published Information on nitrosamines for marketing authorization holders on September 19, 2019.  On October 9, 2019 the EMA published “Questions and answers on ‘Information on nitrosamines for marketing authorization holders.’”  On December 20, 2019 the EMA revised the Q&A, modifying the responses to questions 11 and 12 and adding questions and answers 13 through 16.  The two publications should be read together.  These include important requirements for MAHs and the firms to manufacture API and dosage forms for them.

The first publication requires MAHs to:

  • Perform a risk assessment of their products containing chemically synthesized APIs in a risk-based manner to determine whether nitrosamines are present.  Note that these assessments are not limited to only the “sartan” or ranitidine products where the contaminant has been found but are intended for products that include chemically synthesized APIs.  The risk assessment does not need to be submitted to the regulatory authorities, but it would be prudent to assume that it may be requested during GXP inspections. This risk assessment is to be completed within six months of the September 19, 2019 publication date.  It is prudent to work with suppliers of APIs and, where appropriate, suppliers of raw materials. 
  • Second, if nitrosamines are identified, these results should be confirmed using qualified and validated analytical methods and results should be reported to health authorities.  The confirmatory testing and changes that will be made in the manufacturing process are to be submitted within three years of the September 19, 2019 publication.  As above, the confirmatory testing and manufacturing changes are to be prioritized in a risk-based manner.
  • As mentioned above, when nitrosamines are identified, changes are to be made in the manufacturing process and MAHs should apply for the appropriate variation to support this change(s).

EMA’s Q&A Response Publication

The Questions and Answers document identified above lists twelve questions to assist MAHs to address these requirements.  We will address each of the twelve questions and answers.

Before starting with the questions, it may be prudent to develop a protocol to guide this effort and provide consistency and justification for all actions, particularly because this effort will likely require coordination with other sites and firms.  Corporate GMP audit groups might consider including assessment of this activity in their audits for the next few years.

  1. Are all products to be reviewed?  YES, all products that contain chemically synthesized APIs are to be reviewed.  Generics and over-the-counter (OTC) products are included in this requirement. Many, many products are included among this group so firms should prioritize in their evaluation and confirmatory testing.
  2. What factors should be considered in prioritizing the risk evaluation?  Prioritization of the risk assessments should be guided by the principles described in ICHQ9 guideline on quality risk management.  Attributes that may guide the prioritization include, but are not limited to, known vulnerabilities in the synthetic processes, daily dose of the product administered to patients, and length of treatment.  The concern with the “sartans” included consideration of their use as a long term treatment for elevated blood pressure and related chronic conditions.
  3. How should be risk evaluation be implemented?  MAHs should partner with the API manufacturer and dosage form manufacturer to perform the risk assessment. The participants in the evaluation should consider:
    • Does the API synthetic process suggest a potential risk of nitrosamine formation?  Features which should be assessed include, but are not limited to, starting materials, solvents, and catalysts along with known or potential degradation products and impurities.
    • Are ‘recovered materials’ such as solvents used in the manufacturing process?  This has been one source implicated in the contamination of the “sartans”. Details are provided in the FDA warning letter to Lantech Pharmaceuticals Limited.
    • Can nitrosamines be formed during the shelf life of the product?
  4. How should tests be conducted by MAHs and manufacturers?  The starting point for method development and validation can begin with the information available on the EDQM website.  Firms should be aware that other nitrosamines may be formed beyond those that have been identified so appropriately sensitive analytical methods must be developed, validated and implemented.
  5. When should MAHs report to competent authorities?  Initial risk assessments should be completed within six months and their completion should be reported to the health authorities although submission of the assessments is not required.  If nitrosamines are identified, then product must be subject to confirmation testing. If this testing confirms the presence of nitrosamines the firm should notify the authorities. The firm should also determine the risk to patient and consider mitigating practices.
  6. What limits will apply for nitrosamines detected in any products?  EMA admits this is a work in progress and final nitrosamine levels for sartan and non-sartan products are being developed.  Toxicology considerations should be part of the assessment and considered when determining the type of remediation in the manufacturing process.  Interim limits from the EMA may be found here.
  7. What are the deadlines for the evaluation?  Risk evaluations should be conducted within six months of September 19, 2019.  Where confirmatory testing is necessary, it should be submitted within three years.  The proposed manufacturing changes should also be submitted within three years. This should all be tempered by any finding that suggests an immediate public health risk which should be reported immediately.
  8. What changes would be required to Marketing Authorisations?  If nitrosamines are determined to be present, the MAH should identify remediation and seek input from the health authorities on the type of variation that should be submitted.  The potential changes can be in the control strategy, the manufacturing process or drug substance specifications. Additional details may be found in the Q&A document.
  9. What are the responsibilities of MAHs for APIs with CEPs or ASMFs?  All parties must work together but the MAHs must ensure the risk assessments are conducted with the appropriate level of rigor and detail.
  10. What about regulatory requirements in other regions?  Authorities in the EMA have been coordinating with their international partners including the US, Canada, Japan, Switzerland and others to ensure that nitrosamine levels are reduced in medicinal products.  Further, the partners are working to align their requirements.
  11. (Updated 12/20/2019) How will regulators ensure ongoing dialogue with industry?  EMA is planning to conduct a workshop on this topic before the end of 2019 and will invite industry and trade associations when a date has been identified.  The updated information states that the EMA has established a network of experts across the EU including EDQM and the EC to identify learning points from this “event” and determine how to prevent and be better prepared for these situations in the future.
  12. (Updated 12/20/2019) What are the currently identified root causes for presence of nitrosamines?  The answer to this question provides eight possible sources of nitrosamine contamination in human medicinal products.  Briefly these include, but are not limited to, the following taken directly from the Q&A document:
    • “Use of sodium nitrite (NaNO2), or other nitrosating agents, in the presence of secondary, tertiary amines or quaternary ammonium salts within the same or different process steps (if carry over can occur). 
    • Use of sodium nitrite (NaNO2), or other nitrosating agents, in combination with reagents, solvents and catalysts, which are susceptible to degradation to secondary or tertiary amines, within the same or different process steps (if carry over can occur). 
    • Use of contaminated raw materials in the API manufacturing process (e.g. solvents, reagents and catalysts). 
    • Use of recovered materials (e.g. solvents, reagents and catalysts), including recovery outsourced to third parties who are not aware of the content of the materials they are processing and routine recovery processes carried out in non-dedicated equipment. 
    • Use of contaminated starting materials and intermediates supplied by vendors that use processes or raw materials which may allow nitrosamine formation. 
    • Cross-contaminations due to different processes run on the same line and due to operator-related errors such as inadequate phase separations. 
    • Degradation processes of starting materials, intermediates and drug substances, including those induced by inherent reactivity in combination with carry-over of sodium nitrite (NaNO2), or other nitrosating agents. This could potentially occur also during finished product formulation or storage. 
    • Use of certain packaging materials. Nitrosamine contamination has been observed by one MAH in a finished product stored in blister. The MAH has hypothesised that the lidding foil containing nitrocellulose printing primer may react with amines in printing ink to generate nitrosamines, which would be transferred to the product under certain packaging process conditions.”  The updated information adds that the specific processes in question can include heat-sealing blistering processes via vaporization and condensation onto the drug product.
  13. (Added 12/20/2019) What is the approach for new and ongoing marketing authorisation applications (MAA)?  Activities required depend on the stage of the submission and its review.
    • Original Submission:
      • The original submission should include a risk evaluation described in step 1 of the Information on nitrosamines for marketing authorisation holders.
      • If nitrosamines have been determined to be present, or there is a risk of their presence, then the applicant should complete an assessment of the risk benefit to the patient.  Data or testing plans should be submitted as mentioned in step 2 of the link in the previous bullet point.
    • During MA Evaluation:
      • If a risk assessment was not included with the original submission, it will be requested during the review process.  This will be expected to be submitted as a response to the list of questions.
      • Any outstanding issues must be addressed prior to the EMA issuing a final opinion on granting the MA approval.
      • Absence of this information may impact the granting of the Marketing Authorisation.
  14. (Added 12/20/2019) Are biological products containing excipients potentially at risk of contamination with Nitrosamines in the scope of the review?  At this time the request for review does not apply to biological products, however, if the firm identifies any biological products that contain nitrosamines they should report this to the competent authority.  This is an evolving situation and the CHMP will continue to evaluate the data and may extend the request for review to biological products and/or excipients.  The mere mention of possibly including excipients in this request for information in the future should prompt firms to begin evaluating these components in their drug product.  In addition, this should also be a consideration for antibody-drug conjugates where the drug is made by a chemical synthesis process.  Even if the agency never formally requests the information, it may be prudent to include it among the risk assessments performed for each product.
  15. (Added 12/20/2019) What to do if after completing step 1 and/or step 2 new information on new potential root causes is identified?  Risks for nitrosamine formation should be considered throughout the lifecycle of the product.  As changes in raw materials or processing are made, the risk assessment should be revised and updated to reflect new information and knowledge.  EMA states that they will continue to update the industry on any new sources of nitrosamines.
  16. (Added 12/20/2019) What limits will apply for nitrosamines in medicinal products based on lifetime and less than lifetime use?  The establishment of long-term limits remains a work in progress though interim limits for six different nitrosamines have been established and are provided in the new Q&A, question 16.  This table notes that where multiple n-Nitrosamines are found simultaneously the batches should be rejected.  The interim limits are calculated on a lifetime treatment basis.  The response provides some flexibility for adjusting the limit for products “with a limited treatment period or intermittent treatment”.  Nitrosamine impurities should be reported as “ng” and “ppm” and calculations used to describe exposure should be provided in the SmPC.  The calculations should include enough detail to reproduce the calculations.


Every MAH and manufacturer of chemically synthesized APIs and resulting drug products should carefully read the new EMA expectations on potential nitrosamine contamination.   Those who manufacture the APIs and finished dosage forms that are already identified with nitrosamine contamination are aware of the agencies’ concerns and have likely already started risk assessments.

The deadline for completion of the risk assessments is six months from the publication date of September 19, 2019.  Effectively performing gap assessments and potentially making changes in the manufacturing and control processes should be accomplished within three years. The sooner firms begin the process, the more likely they are to meet the stated deadlines.

It would be reasonable for corporate auditors and those who consult in this area to be aware of this requirement and ensure that their sites, CMOs, and others are aware of these requirements.

I am sure we will be hearing more from the EMA on this topic and FDA may also implement additional requirements beyond those already in place.  This is a fluid situation and the industry will be dealing with this for a while, and I would anticipate ongoing revisions and additions to these questions and answers as the knowledge and information evolves.

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