Nitrosamines on the run

There are a few key areas about nitrosamines that you should know:

A.     There are two structural classes of nitrosamine impurities

1.      Small molecules nitrosamine impurities

2.      NDSRI (nitrosamine drug substance related impurities)

Nitrosamine impurities have regulatory relevance in ANDA, NDA, BLA with chemically synthesized fragments, API (DMF), OTC, and 503B outsourcing facilities.

B.     There are several ways to look for nitrosamine impurities

1.      In API:

a.     When secondary, tertiary, or quaternary amines and nitrile salts react under acidic conditions

b.      When nitrous acid is used to quench (deactivate or decompose) residual azide in the presence of precursor amines

c.     When nitrites are used as reagents and react with amines

d.     Nitrate-containing materials (potassium nitrate) may contain nitrite impurities

e.     When fresh solvents (ortho-xylene, toluene, methylene chloride) with nitrosamines are carried over during transfer

f.      When a site may produce same API by more than one synthetic process that uses common solvents

g.     When recovery of raw materials (i.e. solvents, reagents, catalysts) is outsourced to third-party contractors

h.     When there is inadequate cleaning of equipment between customers or different materials

i.      When temperature, pH, or the sequence of adding reagents, intermediates, or solvents are poorly controlled

j.      When nitrogen oxides in the air can react with the APIs

2.     In drug product (DP):

a.     Nitrites can be found in excipients and potable water

b.     Nitrosamine precursors in a drug substance can react with nitrites in excipients or other sources to form small-molecule nitrosamines or NDSRIs

c.     Some container closure systems including secondary packaging components and mfg equipment could be a source of nitrite or nitrosamine impurities

d.     NDSRIs can be generated during manufacturing and may increase during storage of DP

e.     Nitrosating impurities present in DP can lead to nitrosation of the active ingredient to yield NDSRIs therefore higher NDSRIs are seen in DP than API

C.    Acceptable Intake Limit

1.     AI limit = 26.5ng/day is used if AI limit cannot be determined (all nitrosamine impurities including NDSRIs) – no safety data is needed if below this limit

2.     Refer to RAIL (Recommended Acceptable Intake Limit) guidance

3.     FDA has classified 5 potency levels: 1 (26.5ng/day) most potent, 2 (100 ng/day),

3 (400 ng/day), 4 (1500ng/day), and 5 (1500 ng/day)

4. Contact FDA at CDER-OPQinquiries@fda.hhs.gov when AI limits are exceeded

D.     How to mitigate nitrosamine impurities

1.      Assess risk for API and DP

                 a.    API

i.     Design route of synthesis (ROS) to minimize nitrosamine impurities

ii.    Control sequence of reactions, processes, and conditions (pH, temperature, and reaction time)

iii.   Audit supply chains (raw materials and intermediates)

iv.   Test potable water for nitrites and nitrosamines

v.    Quality oversight of any rework or reprocess activities

vi.   If a nitrosamine impurity is detected above the LOQ, the API

manufacturer should develop a strategy to ensure that the nitrosamine level remains at or below the recommended AI limit taking into consideration batch-to batch variations

vii.   For at-risk APIs with an impurity detected above 10 percent of the recommended AI limit, manufacturers should test each batch on release and the stability samples

viii.  A control strategy is recommended when the risk of formation of nitrosamines is inherent due to the API structure, the API ROS, or the manufacturing process of the API

ix.   Alternate approaches (e.g., upstream test of an intermediate) should be supported by sufficient process understanding and evidence of adequate statistical control and should be submitted to FDA in a supplement prior to implementation

x.    Any API batch found to contain levels of nitrosamine impurities above the recommended AI limit should not be released by the API manufacturer for distribution

           b.      DP

i.     Collaborate with the API manufacturer

ii.    Evaluate any pathway that may introduce the risk of nitrosamine formation during drug product manufacture or storage

iii.   Establish API supplier reliability

iv.   Establish specification

• If a nitrosamine impurity is detected above the LOQ especially >10% of AI limit, ensure it is below AI limit until expiration

• Test regulatory (primary or exhibit) and validation batches even if initial test results < 10% of AI limit especially when there are changes in the manufacturing process, excipients, API, or other critical elements that may result in nitrosamine formation

v.    Reduce NDRSIs

• Screen excipients for potential nitrite impurities

• Reformulate with an alternate excipient that has lower levels of nitrites

• Incorporate an antioxidant (i.e. ascorbic acid, ascorbate salt such as sodium ascorbate, alpha-tocopherol, or propyl gallate), which may inhibit NDSRI formation

• Modify the microenvironment to neutral or basic pH in the drug product to potentially inhibit NDSRI formation

2.     Perform confirmatory testing

                a.     Testing may be used to confirm that nitrosamine will not form (i.e. forced degradation).  If risk of nitrosamine formation exists, perform confirmatory testing on at least 3 batches

                b.     If nitrosamine < 10% of AI limit, then a specification (method and acceptance criterion) is not needed provided the root cause is well understood and manufacturing process controls are established and validated - confirmatory test results can be included in the annual report for approved drugs

                c.     If nitrosamine > 10% of AI limit, a specification should be established along with nitrosamines control in the release and stability specifications – submit a supplement as changes being effected (CBE) in 30 days for approved drugs

                d.    If the confirmatory testing indicates nitrosamine > AI limit and changes in formulation, manufacturing process, or packaging are warranted, implement changes to ensure that nitrosamine levels remain within the recommended AI limit

3.     Report changes to FDA (API, approved, and pending applications)

                a.    API

i.     If an API DMF holder makes process changes in the ROS as a result of the risk assessment and confirmatory testing, the DMF holder must submit an amendment to the DMF and inform each drug product manufacturer or applicant that references the DMF

ii.    If the API is manufactured by the applicant and not covered by a DMF, the manufacturer must report such ROS changes including rework or reprocess in the application. 

                 b.    DP

i.     Major changes to an approved NDA or ANDA require submission and approval of a supplement before distribution.

ii.    Changes (Level 3) which may have a significant effect on formulation quality and performance may need BE/BA study in addition to chemistry and dissolution documentation.  If an applicant pursues reformulation of a pending application, the applicant should submit an amendment.

Note: you may skip BE/BA studies if you can demonstrate that any other approach deemed adequate by FDA to measure bioavailability or establish bioequivalence per § 320.24(b)(6)

iii.   Applicants can use meeting requests to discuss with FDA formulation changes before submission of a supplement or amendment.  Such submissions should generally contain stability and BE studies to support the change.

iv.   Due to the lack of historical information on NDSRIs, FDA recommends that such changes be supported by manufacture and testing samples from three batches of drug products.

v.    For approved drug products, at the time of supplement submission, applicants should provide accelerated stability data for 3 months and long-term (0 and 3 months) stability conditions for three batches.

vi.   Applicants with pending applications should submit this information in an amendment but with 6 months of accelerated stability data before approval if analysis shows the potential for an upward trend in NDSRI levels that may lead to out-of-specification results.  Long-term stability data through the proposed shelf life from the first three production batches should be reported in the annual report.

vii. OTC and 503B outsourcing facilities should retain similar supporting information.

REMEMBER: Don't let FDA find deficiencies that you're already aware of because they can use the following regulatory tools to stop your products from entering the US market

1. Recalls

2. Import Alert

   1. Note: using an API on the import alert list (even if you do full testing and getting passed results) may still get your product stopped at Import because your product may be considered as adulterated - this can be done without physical inspection or via remote assessment

3. CGMP citations such as

   1. Lack of or inadequate method validation

   2. Lack of or inadequate method verification

   3. Quality release of products or API with nitrosamine impurities > AI limits

   4. Lack of or inadequate investigations of nitrosamine levels

4. Drug Supply Chain Security Act