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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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Active Pharmaceutical Ingredient (API)

Lynda Paleshnuik

Training workshop: Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

  • CTD organization of the API
  • Common deficiencies on a section-by-section basis
    • Overview
    • Use of the DMF/APIMF procedure
  • Use of a Certificate of Suitability (CEP)
  • Dossier assessment regarding the API
ctd structure of api sections
CTD Structure of API Sections
  • 2.3.S.1General Information
  • 2.3.S.2Manufacture
  • 2.3.S.3Characterisation
  • 2.3.S.4Control of Drug Substance
  • 2.3.S.5Reference Standards or Materials
  • 2.3.S.6Container Closure System
  • 2.3.S.7Stability
2 3 s drug substance 2 3 s 1 general information
2.3.S DRUG SUBSTANCE2.3.S.1 General Information
  • 2.3.S.1.1 Nomenclature

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.

  • 2.3.S.1.2 Structure

Include structural formula with relative and absolute stereochemistry, molecular formula, and the relative molecular mass.

  • 2.3.S.1.3 General Properties

Physicochemical and other relevant properties of the API.

2 3 s 1 common deficiencies
2.3.S.1 Common Deficiencies

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

2 3 s 1 common deficiencies6
2.3.S.1 Common Deficiencies

S.1.3: General Properties

1) The water solubility of the API should always be characterized:

  • Quantitatively (over the physiological pH range 1.2-6.8)*
  • As a function of dose solubility volume:

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.

s 1 deficiencies cont d
S.1 Deficiencies Cont’d
  • Shortcut: for most of the API’s in the PQP, solubility class (BCS) is stated in TRS 937.
  • BCS class 1 and class 3 are high solubility.
s 1 deficiencies cont d8
S.1 Deficiencies Cont’d

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.

s 1 deficiencies cont d9
S.1 Deficiencies Cont’d
  • Similarly, for a low solubility API, particle size should be characterized (based on the lot used in clinical or bioequivalence studies).

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.

2 3 s 2 manufacture
2.3.S.2 Manufacture
  • Information on the manufacturer;
  • A brief description of the manufacturing process (including, for example, starting materials, reagents, solvents, critical steps, and reprocessing) and the controls intended to result in the routine and consistent production of API.
  • A flow diagram;
  • A description of the Source and Starting Material and raw materials used in the manufacture of the API;
2 3 s 2 manufacture cont d
2.3.S.2 Manufacture Cont’d
  • A discussion of the selection and justification of critical manufacturing steps, process controls, and acceptance criteria. Discuss critical process intermediates;
  • A description of process validation and/or evaluation.
  • A brief summary of major manufacturing changes made throughout development and conclusions from the assessment used to evaluate product consistency. The QOS should cross-refer to the non-clinical and clinical studies that used batches affected by these manufacturing changes.
2 3 s 2 common deficiencies
2.3.S.2 Common Deficiencies
  • The starting material (SM) is not available commercially or is only one or two steps from the final API, or is not of simple structure.

- 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

2 3 s 3 characterisation
2.3.S.3 Characterisation
  • A summary of the interpretation of evidence of structure and isomerism.
  • When an API is chiral, it should be specified whether specific stereoisomers or a mixture of stereoisomers have been used in the nonclinical and clinical studies, and information should be given as to the stereoisomer of the API that is to be used in the final product intended for marketing.
2 3 s 3 characterisation cont d impurities
2.3.S.3 Characterisation Cont’d:Impurities
  • Summary of the data on potential and actual impurities arising from the synthesis, manufacture and/or degradation, and should summarise the basis for setting the acceptance criteria for individual and total impurities.
  • Summary of the impurity levels in batches of the API used in the non-clinical studies, in the clinical trials, and in typical batches manufactured by the proposed commercial process. The QOS should state how the proposed impurity limits are qualified.
  • A tabulated summary, with graphical representation, where appropriate should be included.
2 3 s 3 common deficiencies
2.3.S.3 Common Deficiencies
  • If the API is racemic: A one-time study should demonstrate the racemic nature (optical rotation results close to 0◦).
  • The impurities discussion should identify which of the potential impurities are degradants.
  • Impurity limits must be suitably qualified (ICH Q3A).
  • All potential residual solvents should be discussed, and controlled in specifications unless adequately justified.
2 3 s 3 common deficiencies16
2.3.S.3 Common Deficiencies

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.

2 3 s 4 control of drug substance
2.3.S.4 Control of Drug Substance
  • A summary of the specification(s), the analytical procedures, and validation should be included.
  • A tabulated summary of the batch analyses.
2 3 s 4 common deficiencies
2.3.S.4 Common Deficiencies
  • The specifications should have tests/limits meeting existing compendial monographs.
  • The purity and potency methods should be fully validated for house methods, and verified for compendial methods. If a compendial impurity method is used, but impurities are specified which are not in the monograph, the compendial method must be fully validated for these impurities.
  • The API specification should be from the company responsible for release testing (the manufacturer of the FPP.) It should be dated and signed by authorized personnel.
2 3 s 5 reference standards or materials
2.3.S.5 Reference Standards or Materials
  • Information on primary and working standards of the API and specified impurities.
2 3 s 5 common deficiencies
2.3.S.5 Common Deficiencies
  • Where a compendial reference standard (RS) exists, this should be the primary standard against which all house standards are qualified.
  • Where no compendial RS exists, the primary standard should be highly purified and fully characterized. Potency should be based on mass balance.

3) Whether any additional purification solvents used for the reference standard could result in modified properties (e.g. polymorphism).

2 3 s 6 container closure system
2.3.S.6 Container Closure System
  • A brief description and discussion of the primary and secondary packaging components.
2 3 s 6 common deficiencies
2.3.S.6 Common Deficiencies
  • Container specifications should be provided by the applicant or FPP manufacturer or API packager, not the packaging supplier.
  • Specifications for components in contact with the API should include a specific test (eg IR) for identity.
2 3 s 7 stability
2.3.S.7 Stability
  • This section should include a summary of the studies undertaken (conditions, batches, analytical procedures) and a brief discussion of the results and conclusions, the proposed storage conditions, retest date or shelf-life.
  • The post-approval stability protocol should be included.
2 3 s 7 common deficiencies
2.3.S.7 Common Deficiencies

1) It should be clear that the container used in studies is representative of that intended for storage.

dmf apifm overview
DMF/APIFM overview

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.

apimf dmf
  • The APIMF is provided in two parts:

1) Closed or restricted part containing confidential information, largely dealing with details of the API synthesis,

2) Open part containing non-confidential information.

apimf restricted part rp
APIMF Restricted Part (RP)


  • Detailed description of the synthesis (reaction operating conditions, data on validation and evaluation of critical steps, QC during manufacture, control of materials and intermediates).
  • Characterization of impurities related to the synthesis, where justification is provided to show control is not necessary in the API.
  • Justification of specifications related to the detailed description of the manufacturing process.
apimf open part op
APIMF Open Part (OP)

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.

use of the apimf procedure
Use of the APIMF Procedure
  • An APIMF is reviewed in conjunction with product dossiers and variations.
  • It is not approved as such, it is accepted in relation to specific dossier(s).
content of the dossier with apimf
Content of the Dossier with APIMF
  • The dossier content (API sections) depends on whether there is an associated APIMF.
  • If an APIMF is filed (in conjunction with a dossier), the dossier assessment (API sections) is generally limited to the data in the OP of the APIMF.
  • A similar situation occurs with submission of a CEP; a CEP covers review of the synthesis, specifications, and sometimes stability data.
certificate of suitability cep
Certificate of Suitability (CEP)

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.

use of certificate of suitability cep
Use of Certificate of Suitability (CEP)
  • Availability of a CEP should be checked on the EDQM database – shows availability, current version and whether valid.
  • An applicant/supplier is not obligated to use a CEP if one exists, however this can be encouraged.
  • Use of a CEP allows for an abbreviated review of the API
    • Just the equivalent of the “open part” of a DMF
    • Stability may also be established (retest listed on CEP)
dossier assessment api
Dossier Assessment - API

Each item below affects how the dossier assessment should proceed:

  • Screening/pre-assessment
  • API basic research
  • APIMF and/or CEP
  • API solubility
screening pre assessment
  • Confirm all screening criteria are met. In prequalification this takes the form of the Technical Screening Template.
  • If screening criteria are not met, consult. It is possible that an abbreviated review is required or the dossier may be rejected.

The importance of having a screening process in place:

If poor quality dossiers are accepted, poor quality dossiers will be submitted.

api basic research
API Basic Research
  • Check the USP dictionary. This provides basic information, including whether the API name may be found under different names in different compendia, eg rifampin/rifampicin.
  • Check for compendial monographs for the API:

- PhInt, USP, EP/BP

  • Check standards claimed by the applicant for API.
api fpp basic research
API/FPP Basic Research
  • Other sources of information:



FDA approved drug products:

api apimf and or cep
  • Has an APIMF (DMF) been filed? Assessed?

Refer to current guidelines for dossier assessment and APIMF’s.

  • Does a valid CEP exist?

  • Has CEP been submitted? Check as above that the version submitted is valid.

See current guideline for dossier assessment and CEP’s.

The presence of APIMF and/or CEP influence how the dossier is assessed.

api solubility
API Solubility
  • API is highly soluble if listed in the WHO BCS-based biowaiver guideline.
  • Solubility class (BCS) is given for most PQ API’s in TRS 937.
  • API solubility is not important if the API is fully dissolved during FPP manufacture.
  • If the API is low solubility (DSV GT 250 mL over the physiological pH range), then particle size and polymorphism must be investigated. Specifications may be required and should be based on the characterization of the API lot used in the biostudy.
  • Regardless of the solubility of the API, particle size is important for some FPP’s (inhalation products, low dose products (often RH’s)).
choosing your battles where to focus
Choosing Your Battles:Where to Focus

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.

Focusing on:

  • Sections and Documents
where to focus sections
Where to FocusSections

API (CTD sections):

S.1.3/S.3.1 General properties

S.2 Manufacture

S.3.2 Impurities

S.4 Specifications

S.7 Stability

where to focus documents
Where to FocusDocuments

Certain official documents comprise the heart of the dossier. For the API these are primarily:

Signed API specifications.

Signed stability protocol.

where to focus documents42
Where to FocusDocuments
  • It must be stated clearly in the assessment report that the official signed documents such as specifications were reviewed, and not just the summarized data (data in summary such as PQIF/QOS).
  • For example, under the specifications tables the assessor must state that the tests/methods are in agreement with information in signed documents, or differences should be listed and clarified.
  • If this is not done, it is not clear if the official documents were reviewed and it is possible that the most important deficiencies are overlooked.
where to focus documents43
Where to FocusDocuments
  • When referring to signed documents, it is important to include the document code including version number. Whenever updated API specifications are submitted, scanning the updated version into the report is very helpful for subsequent reviews and creating the final approval letter (SOQR for PQP).

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.)

where to focus capturing key data
Where to FocusCapturing Key Data


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

where to focus capturing key data45
Where to FocusCapturing Key Data

Confirmation statements:

  • Provide vital information.
  • Let the current and next assessors know what has been verified/assessed.

Examples regarding specifications:

  • “Specifications (in PQIF/QOS) were compared to signed applicant specs and are in agreement with the exception of…”
  • “Specifications include all those of the (PhInt/USP/BP/EP) monograph, with the exception of x, plus additional tests for y, z.”
  • “The applicant claims adoption of (PhInt/USP/etc) purity/potency methods. This was confirmed.”
other tips guidance documents
Other Tips: Guidance Documents
  • Memorization is not required/possible for quality assessment.
  • Familiarity with guidelines is necessary.
  • Having main guidelines open at the relevant section during assessment is helpful.
  • It is necessary to go through the main guidelines on a regular basis in order to remain familiar with them. Rather than memorization, a knowledge of where something can be referred to is essential.