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

 Use of a Certificate of Suitability (CEP)

 Dossier assessment regarding the API

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 CTD Structure of API Sections

 2.3.SDRUG SUBSTANCE

 2.3.S.1 General Information

 2.3.S.2 Manufacture

 2.3.S.3 Characterisation

 2.3.S.4 Control of Drug Substance

 2.3.S.5 Reference Standards or Materials

 2.3.S.6 Container Closure System

 2.3.S.7 Stability

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 2.3.S DRUG SUBSTANCE
2.3.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.

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 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

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 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.

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 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.

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 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.

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 S.1 Deficiencies Cont’d

3) 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.

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 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;

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 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.

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 2.3.S.2 Common Deficiencies

1) 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

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 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.

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 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.

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 2.3.S.3 Common Deficiencies

1) If the API is racemic: A one-time study should

demonstrate the racemic nature (optical rotation results
close to 0◦).

2) The impurities discussion should identify which of the

potential impurities are degradants.

3) Impurity limits must be suitably qualified (ICH Q3A).

4) All potential residual solvents should be discussed, and

controlled in specifications unless adequately justified.

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 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.

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 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.

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 2.3.S.4 Common Deficiencies

1) The specifications should have tests/limits meeting existing

compendial monographs.

2) 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.

3) 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.

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2.3.S.5 Reference Standards or Materials

 Information on primary and working standards of the API

and specified impurities.

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 2.3.S.5 Common Deficiencies

1) Where a compendial reference standard (RS) exists, this

should be the primary standard against which all house
standards are qualified.

2) 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).

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 2.3.S.6 Container Closure System

 A brief description and discussion of the primary and

secondary packaging components.

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 2.3.S.6 Common Deficiencies

1) Container specifications should be provided by the

applicant or FPP manufacturer or API packager, not the
packaging supplier.

2) Specifications for components in contact with the API

should include a specific test (eg IR) for identity.

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 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.

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 2.3.S.7 Common Deficiencies

1) It should be clear that the container used in studies is

representative of that intended for storage.

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 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.

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 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.

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 APIMF Restricted Part (RP)

Contains:

1) Detailed description of the synthesis (reaction operating

conditions, data on validation and evaluation of critical steps, QC
during manufacture, control of materials and intermediates).

2) Characterization of impurities related to the synthesis, where

justification is provided to show control is not necessary in the API.

3) Justification of specifications related to the detailed description of

the manufacturing process.

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 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.

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 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).

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 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.

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 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.

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 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)

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 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

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 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.

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 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.

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 API/FPP Basic Research

 Other sources of information:

WHOPARs:
http://healthtech.who.int/pq/WHOPAR/WHOPARPRODUCTS/WHO
PAR_Index.htm

EPARs: http://www.emea.europa.eu/htms/human/epar/a.htm

FDA approved drug products: http://

www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm

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 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?

http://www.edqm.eu/site/Databases-10.html
 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.

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 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)).

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 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

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 Where to Focus
Sections

API (CTD sections):

S.1.3/S.3.1 General properties

S.2 Manufacture

S.3.2 Impurities

S.4 Specifications

S.7 Stability
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 Where to Focus
Documents
Certain official documents comprise the heart of the
dossier. For the API these are primarily:

Signed API specifications.

Signed stability protocol.

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 Where to Focus
Documents

 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.

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 Where to Focus
Documents
 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.)

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 Where to Focus
Capturing Key Data
Specifications:

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

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 Where to Focus
Capturing 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.”
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 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.

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 Thank you

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