Monographs submission

For each dmg substance, the maximum acceptable levels of the various impurities are described in the drug substance monograph or the specification included in the submissions to the regulatory authorities. In this chapter, the ICH Q6A [4] and Q6B [5] definition of specification is used. A specification consists of three parts the test (e.g. moisture content, impurities), references to the analytical procedure (e.g. high-performance liquid chromatography [HPLC], gas chromatography [GC]), and the acceptance criterion (e.g. not more than 0.50%). 

The Federal Register advance notice is a preliminary notice, offering opportunity for comment and submission of new data for consideration. When all comments have been collected and evaluated, the FDA publishes a rule, also termed a tentative final monograph. This publication incorporates all changes that were made on the basis of the results of the first publication. There is a review of comments made and a summary of the basis for decisions regarding these comments. That is, the FDA prints a review of the nature of the comments or objections that were filed in response to the first notice and is obligated to respond to these comments. This should be carefully studied, because it reflects both the scientific viewpoint of the advisory panel and the FDA policy decisions. 

The publication of the tentative final monograph also provides further opportunities for submission of more data, additional comments and objections, or requests for a hearing with the Commissioner of Food and Drugs. Again, full instructions for submitting comments are provided at the end of the Federal Register entry. 

Reference to pharmacopoeial monograph for medicinal plant included in recognised pharmacopoeias or submissions of a monograph. 

The MEB works with the Drug Master File (DMF) procedure. The applicant has the choice to mention the complete data on the s5mthesis in part IIC or to submit a DMF. When a DMF is submitted separately it is necessary that in an accompan5dng letter it is clearly stated to which product of what company the DMF belongs to including a letter of access. The submission of complete data on the synthesis of a DMF is necessary for every active substance regardless of whether a Europecin Monograph exists. With line extensions an applicant may refer to a DMF when this is present at the MEB. 

Once the company has compiled the necessary information, they submit the proposed monograph to USP so it may be adopted as an official standard. The appropriate USP expert committee reviews the information, to assess its completeness and scientific merit, and subsequently approves it for publication in Pharmacopeial Forum (PF), USP s bimonthly journal of scientific review and compendial revision. Once a monograph has been published in PF, any interested person, company, or regulatory authority, including USP Expert Committee members, may comment on the contents of the proposal. The USP may chose to accept the comments and revise the original proposal, or reject the comments and proceed to adopt the original submission as initially published. 

The validation requirements for USP monographs are addressed in General Chapters <1225> Validation of Compendial Procedures and <1227> Validation of Microbial Recovery from Pharmacopeial Articles. Chapter <1225> provides guidance for validating chemical and physical methods intended for submission as an official standard. The test is aligned with ICH documents Q2(R1), Q3A, Q3B, Q3C, Q6A, and Q6B [5-12]. The verification of the compendial procedure should be performed based on General Chapter <1226> Verification of Compendial Procedures and FDA guidances on analytical procedures, method validation, and CMC documentation. 

Additional information related to the absorption, distribution, metabolism and excretion of these agents and of structurally related agents has been reported since the submission of the original monograph (Annex 1, reference 144) and the first addendum (Annex 1, reference 167). These data are cited below. 

---