Active Pharmaceutical Ingredient (API). Lynda Paleshnuik. Training workshop: Assessment of Interchangeable Multisource Medicines, Kenya, August 2009. Overview. CTD organization of the API Common deficiencies on a section-by-section basis DMF/APIMF Overview Use of the DMF/APIMF procedure
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Training workshop: Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
Include INN, compendial name, chemical name(s), company/laboratory code, other non-proprietary names eg USAN, JAN, BAN and Chemical Abstracts Service (CAS) registry number.
Include structural formula with relative and absolute stereochemistry, molecular formula, and the relative molecular mass.
Physicochemical and other relevant properties of the API.
S.1.1 and S.1.2 (name and structure):
- check consistency of listed chemical names and structure with those appearing in the scientific literature
S.1.3: General Properties
1) The water solubility of the API should always be characterized:
Highest dosage strength (mg) = x mL
Lowest solubility* (mg/mL)
If x is LT 250 mL, the API is considered to be highly soluble in water.
2) For a low-solubility API, polymorphism should be characterized (based on the lot used in clinical or bioequivalence studies).
- is polymorphism a factor for the API? Solvent studies or literature search.
- if yes, is only a single form produced by the proposed method of manufacture? Is this form controlled in the API specifications?
- are there differences in solubility and stability of the various forms?
The possibility of polymorphic conversion during stability may have to be monitored.
See decision tree #4 in Q6A regarding polymorphism.
A limit should be included in API specifications (d10, d50, d90).
See decision tree #3 in Q6A regarding particle size.
4) If the substance is chiral, the identification and adequate investigation and monitoring of potential isomerism.
- the source and synthetic route (including solvents) of the SM should be provided, and the specifications for the SM should have tight controls on assay/impurities.
2) If the SM has an isomeric impurity which could lead to the API isomer, suitable controls should be in place
5) If catalysts are used in the synthesis, these should be controlled in specifications unless adequate justification (in the form of batch results) is provided.
3) Whether any additional purification solvents used for the reference standard could result in modified properties (e.g. polymorphism).
1) It should be clear that the container used in studies is representative of that intended for storage.
An APIMF or DMF is a means of:
- allowing confidential intellectual property of the API manufacturer to be protected
- allowing the applicant of a dossier to assume full responsibility for the FPP and the QC of the API
- providing assessors with all information necessary for an evaluation of the suitability of the API for the FPP.
1) Closed or restricted part containing confidential information, largely dealing with details of the API synthesis,
2) Open part containing non-confidential information.
1) A flow chart and brief outline of the manufacturing process. If the API is sterilized, full validation of the sterilization process (in cases where there is no further sterilization of the final product).
2) All other data on the API according to CTD structure, including characterization, control (specifications, batch analysis etc), reference standards, container and stability.
The procedure for Certification of suitability, is a complement and a bridge between European Pharmacopoeia monographs and the need to prepare a file for licensing, and therefore is also a bridge between industries and health authorities. The role of the procedure is to assess and to conclude suitability of monographs to control chemical purity, microbiological quality and TSE risk (if relevant) for any substances, covered by a European Pharmacopoeia monograph and to be used in medicinal products.
Each item below affects how the dossier assessment should proceed:
The importance of having a screening process in place:
If poor quality dossiers are accepted, poor quality dossiers will be submitted.
- PhInt, USP, EP/BP
FDA approved drug products: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm
Refer to current guidelines for dossier assessment and APIMF’s.
See current guideline for dossier assessment and CEP’s.
The presence of APIMF and/or CEP influence how the dossier is assessed.
We can always delve deeper. A good assessor also knows where to go lightly.
We can always argue for the importance of any given area. With limited time, our approach must be pragmatic and based on risk/benefit.
We cannot treat everything with equal importance.
API (CTD sections):
S.1.3/S.3.1 General properties
Certain official documents comprise the heart of the dossier. For the API these are primarily:
Signed API specifications.
Signed stability protocol.
Note that for the FPP dossier, it is the applicant’s or FPP manufacturer’s API specifications that are the official specifications of the dossier and are to be assessed. This should be ascertained at the beginning, and is also important to remember when reviewing A/D. (The original reviews may include both supplier’s and applicant’s specificatons.)
Include in report:
- Codes as above
- Method types (eg HPLC)
- Confirmation statements (see next slide)
Check for presence of, and assess/summarize:
- Methodology for all non-compendial methods
- Validation reports for all non-compendial purity/potency/residual solvent methods
- Verification reports for all compendial purity/potency methods
Examples regarding specifications: