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WHO API prequalification and APIMF procedure tutorialMumbai, September 2012

WHO API prequalification and APIMF procedure

Antony Fake PhDWHO Medicines Prequalification Programme

1


Overview

APIMF Procedure

API PQ Procedure

API-related changes – Amendments & Variations

Documentation requirements

Common deficiencies

3


Abbreviations

• API – Active Pharmaceutical Ingredient

• FPP – Finished Pharmaceutical Product

• API PQ – API Prequalification

• APIMF – Active Pharmaceutical Ingredient Master File (DMF)

• CPQ – Confirmation of API PQ Document

• SRA – Stringent Regulatory Authority

• GMP – Good Manufacturing Practice

• PQP – Prequalification of Medicines Programme


APIMF Information

API

FPP

S & E

+

+

An application to prequalify an FPP typically has three parts:

Information on the preparation and control of the API.

Information on the preparation and control of the FPP.

Safety and efficacy data, e.g. commonlya bioequivalence study.


API

FPP

S & E

or or

+

+

There are 4 ways to submit API information for a FPP.

APIMFProcedureAPI-PQ CEP Full

dossieror

APIMF Information


Two uses of APIMFs in PQP

APIMFsAPIMF

ProcedureAPI

Prequalification

APIMFs are used to support FPP Prequalification and API prequalification.

7


APIMF Procedure


APIMF Procedure

+

+

FPP Manufacturer

API Manufacturer

APIMF assessment is conducted in conjunction with an FPP application

AP

RP

9


The APIMF Procedure• This procedure is only used to support the evaluation of FPP

prequalification applications.

• Active since March 2008.

• It is inspired by the Active substance master file (ASMF) procedure in the EU.

• Most APIMF evaluations occur at bimonthly assessment meetings held in Copenhagen.

• The use of APIMFs in the PQ programme is described in Technical Report Series 948 (TRS948).


The APIMF Procedure

APIMF holder FPP applicant

APIMF submission to APIMF focal point

FPPsubmission

APIMF assessment

APIMF acceptance FPP assessment

FPP prequalification

Letter of Access


APIMF holder responsibilities

• To submit the latest APIMF version to the WHO.

• To provide the WHO PQ with letters of access.

• To respond and resolve questions from the APIMF assessment.

• To inform the APIMF focal point of all changes, updates, amendments, new versions.

• To inform associated FPP applicants of all changes stipulated in the APIMF amendment letter.


FPP Applicant responsibilities

• To submit the open part of the APIMF and Letter of Access as part of the FPP application.

• To submit minor or major API-related variations to the WHO as required.

• To ensure such variations are approved before these changes are adopted in the preparation or control of the FPP.


Advantages of the APIMF Procedure

• It allows the submission of confidential information by the API manufacturer without disclosure to the FPP applicant.

• One APIMF may be used to support multiple FPP applications without the need for repeated evaluations.

• It is applicable to both pharmacopoeial and non-pharmacopoeialAPIs.

• FPPs supported by an APIMF have reduced variation requirements (see draft variation guidance).

• The APIMF holder prepares and maintains the APIMF information and answers all queries directly.

14


Statistics

Sept 2012April 2012April 2011

164 APIMFs155 APIMFs112 APIMFsTotal number of active APIMFs

94 APIMFs85 APIMFs48 APIMFsAccepted

52 APIMFs38 APIMFs58 APIMFsIn progress

18 APIMFs28 APIMFs10 APIMFsQueued for assessment

All APIMFs active in PQP


Choosing your API supplier

Manufacturer with APIMF and GMP compliance – API Prequalification

Manufacturer withan APIMF, or CEPavailable

Manufacturer without APIMF available


API Prequalification


What is API Prequalification?

API Manufacturer

API Prequalification

It is a scheme for API manufacturers only

There is no involvement by FPP manufacturers

18


What is API Prequalification?

• It is a scheme for manufacturers of APIs that are used in medicinal products for HIV, TB, Reproductive Health and Malaria.

• It seeks to verify and identify APIs that are of good quality and manufactured in compliance with GMP.

• It commenced as a pilot project in October 2010.

• It is part of the Prequalification of Medicines Programme, WHO based in Geneva.

19


Prequalification of Medicines website

http://www.who.int/prequal

20


Benefits to API manufacturers

• Recognition as a source of quality API, manufactured in compliance with GMP.

• Serves as a point of difference between good quality and poor quality APIs.

• Opportunities to verify compliance with GMP.

• Opportunities to compile, revise and refine their regulatory documentation, leading to quicker acceptance by other national regulatory agencies.

• There is no fee.

21


Invitation

Application

Assessment(GMP)

Assessment(Quality)

Decision

Publishing

How are APIs Prequalified

22


3rd Invitation for EOI

Invited Active Pharmaceutical IngredientTherapeutic area

Abacavir, Atazanavir, Darunavir, Didanosine, Efavirenz, Emtricitabine, Etravirine, Lamivudine, Lopinavir, Nevirapine, Raltegravir, Ritonavir, Stavudine, Tenofovir, Zidovudine

HIV

Amodiaquine, Artemether, Artesunate, Dihydroartemisinin, Lumefantrine, Mefloquine, Piperaquine, Pyrimethamine, Sulfadoxine, Pyronaridine

Anti-malarial

Amikacin, Capreomycin, Cycloserine, Ethambutol, Ethionamide, Isoniazid, Kanamycin, Levofloxacin, Moxifloxacin, Ofloxacin, Para-Aminosalicylic Acid (PAS), Prothionamide, Pyrazinamide, Rifampicin, Streptomycin, Terizidone

Anti-tuberculosis

Desogestrel, Estradiol, Ethinylestradiol, Etonogestrel, Levonorgestrel, Medroxyprogesterone, Mifepristone, Misoprostol, Norethisterone, Norgestrel, Oxytocin

Reproductive health

Diethylcarbamazine, Mebendazole Neglected Tropical Diseases

23


Invitation

Application

Assessment(GMP)

Assessment(Quality)

Decision

Publishing

Application

24


Application

• An application for API Prequalification is made by the API manufacturer, or agent.

• An applicant does not need to be supplying API to a WHO Prequalified FPP to seek API prequalification.

25


Application

• The PQ application form.

• An APIMF (if not previously provided).

• A Site Master File (if not previously provided).

• Any further evidence of GMP at the facility (optional).

An application should consist of:

26


The APIMF in paper and CD version should be sent to Copenhagen

Only the CD version should be sent to Geneva

Application

27


Invitation

Application

Assessment(GMP)

Assessment(Quality)

Decision

Publishing

Assessment – Quality (APIMF)

28


APIMF submission

There are four options for APIMFs when seeking PQ.

Read the application form closely.

Option 4 allows referral to an existing APIMF already submitted for the APIMF procedure.

Remember the existing APIMF must meet all current requirements.

It might be a good time to submit a revised/updated APIMF.

29


APIMF - Technical content

Excellent technical guidance can be found in the module 3.2.S sections (pages 11 to 31) of the recently published guideline :

Guideline on submission of documentation for a multisource (generic) finished pharmaceutical product (FPP): quality part.

http://www.who.int/prequal/info_general/documents/generic_guide/GenericGuideline_Quality.pdf

30


Assessment - GMP

Invitation

Application

Assessment(GMP)

Assessment(Quality)

Decision

Publishing

31


Assessment – GMP

• By providing evidence of current compliance:

– GMP certificates, inspection reports, CAPAs, the most recently completed Product Quality Review (PQR) report.

or

• By inspection by the WHO.

There are two ways to demonstrate GMP compliance at the API manufacturing facility.

32


Assessment – GMP

• Inspections performed previously by WHO, a member of PIC/S, or an SRA.

• Inspection must have occurred within 3 years of application.

• Inspections must be API specific.

Assessment of GMP compliance at the site of API manufacture takes into account:

The WHO will perform an inspection if, after assessment and requests for information, GMP compliance can not be established.

33


Assessment of GMP

An SRA is a medicines regulatory authority in a country that is:

• a member of the ICH: Japan, USA, EU member; or

• an ICH Observer, e.g. Swissmedic, Health Canada; or

• associated with an ICH member through a legally binding mutual recognition agreement, e.g. Australia, Iceland, Liechtenstein, Norway…etc.

34


WHO GMP Certificates• There are many certificates circulating that appear to be issued by the

WHO, but they are not.

• Certificates might be issued in the WHO format, or the inspection may have occurred against WHO criteria, but this is not a WHO inspection.

• Successful inspections conducted by the WHO are published in WHOPIR that can be found at this link:

http://www.who.int/prequal/WHOPIR/pq_whopir.htm

There is no such thing. The WHO does not issue GMP Certificates.

35


Decision

Invitation

Application

Assessment(GMP)

Assessment(Quality)

Decision

Publishing

36


Decision

• Once the APIMF is accepted the applicant will received an Letter of APIMF acceptance. This is not prequalification.

• A final conclusion over GMP status may still be required if this has not been achieved already.

• Once both the APIMF and GMP us accepted the application is considered for sign-off.

• The applicant will be contacted by WHO to confirm final details for publishing. Expressions of storage statement may differ to meet WHO requirements.

37


Publishing

Invitation

Application

Assessment(GMP)

Assessment(Quality)

Decision

Publishing

38


Publishing

List of PQ APIsWebsite (Public)

Confirmation Document (Private)

+ WHOPIRsWebsite (Public)

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WHO List of Prequalified APIs

• WHO application number.• INN name.• Date of prequalification.• Name of the applicant• Sites of API manufacture.• The APIMF version number.• The API specification version

number.

• The primary and secondary packaging components.

• The assigned re-test period.

• The recommended storage conditions.

• Confirmation of API PQ document issue date

Intended for: UN agencies, National medicine authorities, FPP manufacturers, public

Publically available

40


Confirmation of API PQ document

• The assigned WHO application number.

• The INN name of the active pharmaceutical ingredient.

• API manufacturer company name.

• The API specification version number.

• A copy of the API specifications.

• The assigned re-test period.

• The recommended storage conditions.

• A copy of the assay and related substances test methods.

discretiontheirProvided to the API manufacturer for distribution at

Intended for: UN agencies, National medicine authorities, FPP manufacturers

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Confirmation of API PQ document (CPQ)

It is intended that the CPQ is circulated to relevant parties.

FPP manufacturer’s can submit the CPQ and withdraw from the APIMF procedure.

This will have post-Prequalification benefits in terms of the number of variations they will need to file.

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API Prequalification Performance

• There is very positive feedback from FPP manufacturers whenever PQ of APIs is discussed.

• Applications and the number of prequalified APIs continues to increase.

1 Sept 20121 November 20111 April 2011

62298Total number of applications

1852Number of PQ APIs

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API Related Changes

Amendments and Variations


API-related changes

API manufacturers who have submitted an APIMF in support of:

•their own Prequalified API, or

•the prequalification of an associated FPP

Have obligations to maintain their APIMF with accurate information.

And

To seek approval for any API related changes (APIMF amendment)

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API-related changes

Since the FPP manufacturer is responsible for all changes to theFPP, this includes API details.

Therefore:

Associated FPP manufacturers participating in the PQ also have to obtain approval for the API-related change.

46


API-related changes

Currently, this means

1.The submission of an APIMF amendment to PQP for all API changes.

2.Receipt of the amendment acceptance letter for all API changes.

3.Passing of the letter to any associated FPP manufacturers.

4.The submission of an API-related variation by FPP manufacturers for all API changes.

47


API Manufacturer

APIMF Amendment

PQP

Acceptance

Notification to FPP manufacturer

API-related Variation

Acceptance

API-related change Process

48


Draft guidance on Variations to Prequalified FPP have been circulated. Guidance on Amendments to APIMFs is about to be circulated.

Both guidance documents have:

•A risk-based approach to changes.

•Rely upon manufacturer self-assessment of many changes.

•Detailed information on required supporting documents.

•Identical technical requirements.

API-related changes

49


The fundamental responsibilities of API and FPP manufacturers remain the same, but the revised guidance documents

•Offer a reduction in the burden upon both PQP and manufacturers.

•Recognition of API manufacturers using the APIMF procedures.

•Recognition of API manufacturers using a PQ’d API.

API-related changes

50


New APIMF Amendment Guidance

Four types of changes classes are envisaged

•Annual Amendment Notifications (AAN)

•Immediate Amendment Notifications (IAN)

•Minor Amendment (Amin)

•Major Amendment (Amaj)

51


Annual Amendment Notifications (AAN)

APIMF holders must satisfy themselves that they meet all of the prescribed conditions for the change.

ANs and the associated documentation should be submitted to WHO PQP within 12 months of implementation of the change.

APIMF holders may group several AN changes as a single submission, or coincide these notifications with the submission of an updated APIMF, or other amendment types.

52


Immediate Amendment Notifications (IAN)

APIMF holders must satisfy themselves that they meet all of the prescribed conditions.

APIMF holders must submit all required documentation with the notification application.

A change can be implemented immediately at the time of submission.

The change can be considered accepted if an objection is not issued by WHO PQP within 30 calendar days of the date of acknowledgement of receipt of the application.

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Minor amendment (Amin)

APIMF holders must satisfy themselves that they meet all of the prescribed conditions for the change and submit all required documentation with the amendment application.

A minor amendments can be implemented if no objection letter hasbeen issued within a time period indicated on the WHO PQP website.

Should questions arise during the specified period, the change can only be implemented on receipt of a letter of acceptance from WHO PQP.

A target assessment time will be published.

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Major Amendment (Amaj)

The documentation required for the change included in this reporting type should be submitted as a minimum.

Prior acceptance by WHO PQP is required before the change can beimplemented.

A letter of acceptance will be issued for all major amendments once the amendment is considered acceptable.

55


APIMF Amendment Process

Three phases

1.Screening

2.Audit or Assessment

3.Implementation or Acceptance

56


Amendment application

Screening Rejection email

Accepted for assessment

Annual notifications &Immediate notification

Minor AmendmentsMajor amendments

Acknowledgment email

Risk‐basedAudit process

AssessmentAssessment

Issues arising?

Notification acceptable by default Notification not acceptable by default Amendment acceptable after 30 days be default

No further action No further action

Issues arising? Issues arising?

Letter of refusalAcceptance letter

Assessment

Rejection

An email will be sent to the applicant

57










Issues arising?





Assessment

Rejection

Notifications are accepted by default

58










Issues arising?





Assessment

Rejection

Notifications will be audited rather than

assessed.

59










Issues arising?





Assessment

Rejection

This could lead to questions and

potentially the reversal of the change

60










Issues arising?





Assessment

Rejection

Minor Amendments are acceptable 30 days after

acknowledgment

61










Issues arising?





Assessment

Rejection

If there are no objections, no further correspondence

will be received

62










Issues arising?





Assessment

Rejection

If there are questions then assessment follows the

major amendment process and implementation can

only occur after receipt of the acceptance letter

63



The success of the amendment process relies on three things:

1.Correct assessment of the change type by applicants

2.Correct submission of supporting documentation

3.Correct submission of replacement sections

If all three do not occur the assessment burden will remain.

Consequently, in order not to disadvantage others these requirements must be strictly enforced. Applications will be rejected.

64


Correct assessment of the change also relates to conditions and documentation

65



The success of the amendment process relies on three things






66


For each amendment supporting data will be specified – minimum data

67



The success of the amendment process relies on three things






68


Replacement sections for the APIMF are critical to ensure accurate documentation. Even if a small changes are made replacement sections are required. An updated APIMF would also be acceptable.

69


Several amendments can be grouped together especiallyAnnual amendments and other amendments.

If multiple amendments are grouped, then the change category of the most significant change will be applied to the application.

Don’t forget about consequential changes. These are not indicated in either guidance because there are too many scenarios.

API Amendments and variations

70


API-related changes: Variations

The variation guidance:

•Also incorporates risk based assessment.

•Recognition of API manufacturers using the APIMF procedures

•Recognition of API manufacturers using a PQ’d API

71


Risk based organization of change types

For example:

Requires assessmentSelf assessable

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Introduction of “self assessable” changesChange category

Description

Annual notification

May be implemented immediately.Have 12 months to lodge application.Documentation must be held but need not be submitted.

Immediate notification

May be implemented upon submission of application.30 day window for PQP objection.Documentation must be provided.

Minor variation Change may be implemented if no objection is raised X days after acknowledgement.Documentation must be provided.

Major variation Change may not be implemented until an acceptance letter is received.Documentation must be provided.

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Recognition of the APIMF procedure

74


Recognition of the APIMF procedure

75


Recognition of the use of PQ’d APIs

A variation is only required if there is a change to the CPQ

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APIMF DocumentationRequirements


APIMF Documentation

The submitted APIMF, or amendment should:

•be prepared in CTD format

•be separated into open (applicant) and closed (restricted) sections

•be paginated throughout the entire document. Restarting page numbers for each subsection section is not permitted

•include a contents page with page number references to each of the CTD subsections

•be assigned a manufacturer's version number that should be present in the footer or header of each page of the APIMF.

78


The electronic version of the APIMF should also meet:

•Separate files should be provided for the open and closed sections.

•Single files should not exceed 30MB in size. File path-length should not be excessive.

•The document should be provided in text-selectable PDF format. Document bookmarks for each of the CTD subsections should be added for each of the CTD subsections. In additional the use of hyperlinks within the body of the text is encouraged.

•A scanned copy of the paper version will not be accepted. The inclusion of scanned copies of supporting documents such as Certificates of Analysis, authorized specifications, signed protocols, etc are permitted.

APIMF Documentation

79


APIMF version numbers

Each APIMF should be assigned a unique version number.

FPP manufacturers and PQP should hold APIMFs with the same version numbers.

Amendments should be numbered to reflect the “parent” APIMF version they below to. Whereas an updated APIMF should be given a new version number.

80


Document submitted APIMF version

Initial APIMF Lamiv/AP00/May-2012Lamiv/RP00/May-2012

Lamiv/AP00/May-2012Lamiv/RP00/May-2012

Amendment Lamiv/AP00/May-2012/Amend 3.2.S.7 Lamiv/AP00/May-2012Lamiv/RP00/May-2012Lamiv/AP00/May-2012/Amend 3.2.S.7

Revised APIMF Lamiv/AP01/Dec-2012Lamiv/RP00/May-2012

Lamiv/AP01/Dec-2012Lamiv/RP00/May-2012

APIMF version numbers

81


Common deficiencies


Presentation of your APIMF

An APIMF, like a house, should be built on good foundations. These are scientific data and manufacture.

83


Presentation of your APIMF

But! If it is not presented well no one is going to buy it.

84


Common requirements

1. Numbers and traceability

• Make sure to include method numbers, specification numbers, batch numbers, method validation report numbers, etc.

• Any document numbers that would help a GMP auditor to verify documents when they visit.

There are common issues that should be considered for all sections of your APIMF.


Common requirements

2. State the obvious

It might be obvious to you, but it may not be to the reviewer.

For every CTD subsection there are a number of issues addressed in guidance. Not all will be applicable. If they are not applicable, say so.

e.g. If the manufacturing process does not use recovered solvents, include a sentence saying:

"No recovered solvents are used in the manufacturing process."


Common requirements

Data Summarised information Discussion

For example: Chromatograms, method

validation reports, spectra, signed API specifications, etc

For example: API physical properties,

impurities tables, specifications, stability

data, etc

For example: Explanations, justifications for

limits, reasoning for impurities, stability conclusions, etc

As appendices Main part of the APIMF Main part of the APIMF

Normally included Normally included Often missing

Necessary Important Essential

3. Discussion – An APIMF contains three types of information


Common requirements

3. Discussion

Whenever a section of the guideline uses words like discuss, compare, justify…etc, it is expected that the limit, specifications, conclusion or decision are explained.


• Starting material quality

• Polymorphism

• Specifications

• Stability deficiencies

• Impurities

Frequent API Issues

89


Traditional manufacturing

Rawmaterials Final API

Traditionally, the API manufacturer manufactured the API from simple raw materials at their own facility.

This meant it was safe to assume that the molecule used in the first step at the API manufacturer's factory was an appropriate API-SM.

90


Raw Material Final API

API-SM

API-SMIntermediate

Increasingly, intermediates late in the synthesis are being purchased.

This means the API-SM can not be assumed to be the molecule used in the first step at the API manufacturer's factory.

91

Contemporary manufacturing


API Starting Material

It does not matter if you only manufacture the last step in the process. Information on preparation of the API is required commencing from simple molecules (API stating material for synthesis).

N

NH

N N

OCH3

N

NH

N

O CH3

ClNH

Final APIToo complex to be API-SM

(1)(2)


The information on API SM preparation is not sufficiently detailed or is missing.

•Information on the API SM preparation is needed to determine theappropriateness of the specifications.

•Detailed information is usually not required, because the SM should be relatively simple.

•This information is often supplied in form of a flow-chart (synthetic transformation, reagents, and solvents).

•If there are two or more suppliers of the API SM, information on the preparation of the SM from each supplier should be provided.


93


Information on the API SM manufacturer is missing

•For each SM supplier, the name and manufacturing site address of the manufacturer should be indicated.

•If there are several manufacturers, it should be clarified whether the SM obtained from different sources is prepared by the same route ofsynthesis or if different routes are used.


94


The API SM specification is not satisfactory.

•The specifications should include: an ID test, assay test and limits, specified, unspecified and total impurities limits.

•The limits should be justified by the demonstrated ability to manufacture API from batches of SM with similar impurity levels.

•Each API SM supplier does not have to have the same specifications but a single SM specifications should be defined by the API manufacturer and applied to all sources of SM.

•The carry-over of impurities into the final API should be considered and discussed. The same applies for solvents, reagents, and catalysts used in the SM preparation, as needed.


95


Possible scenario

N

NH

N N

OCH3

N

NH

N

O CH3

ClNHN

NH

N

O CH3

ClClN Cl

Cl

O

N

CH3

NH2

Cl

+

NevirapineFinal intermediateAPI-SM

Detailed in appendices for each API-SM supplier

Detailed in main text ofsection 3.2.3.2

(1)(2)(3)(5) (4)

Starting material

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API polymorphism

• Polymorphic forms may possess different chemical and physical properties, that can have a direct impact FPP properties, such as stability, dissolution and bioavailability.

• Unexpected appearance or disappearance of a polymorphic form may lead to serious pharmaceutical consequences.

• We need to know what polymorph is consistently produced and if it is stable.

97


Polymorphism known Polymorphism not known

Highly soluble API

The polymorphic form produced should be assigned.

The crystalline form produced should be determined.

Non-highly soluble API

The polymorphic form produced should be assigned. Stability of the form should be determined

The crystalline form produced should be assigned. Crystallinity under different crystallisation condition should be investigated.Stability of the form should be determined

API polymorphism

98


• It is important that the manufacturer provides a signed, dated and version-numbered specification. This is to ensure traceability of testing requirements in case of GMP audits and future variations.

• This may be a scanned copy as an appendix in addition to a tabulated version in the body of the APIMF.

• The API specifications should also include reference to analytical procedures and whether they are compendial or not (i.e. pharmacopoeial reference or in-house reference).

• Regardless of pharmacopoeial requirements, PQP expects a test for heavy metals to be included and a test for any unknown (0.10%)

API Specifications

99


Cross-validation data are not submitted when in-house methods are used for controlling pharmacopoeial APIs

If an officially recognized compendial standard is claimed and an in-house method is used (e.g. for assay or for specified impurities), equivalence of the in-house and compendial methods should be demonstrated.

Duplicate analyses of one sample by both methods or by spiking the API with impurities at concentrations equivalent to their specification limits.

API Specifications

100


PQP requires that a retest period and storage condition is assigned to an API.

Unlike some jurisdictions, notably Europe, the absence of a storage statement is not permitted.

PQP requires that this information is clearly stated in section 3.2.7.1 of the APIMF and clearly stated on the label.

101

Stability


PQP has specific storage statements that should be adhered to:

•Do not store above 25 C

•Do not store above 30 C

•Store in a refrigerator (2 C to 8 C)

•Store in freezer

102

Stability


“Protect from moisture” can be used when long-term trials at 30ºC were performed at the lower humidity (65%RH), or where there areknown concerns regarding the API.

“Protect from light” should be used when the API is known to be photosensitive, or where photo stability is unknown, i.e. no pharmacopoeial statement and no photo stability trials were submitted.

Stability


Words of a similar meaning can be used, for instance:

“Do not store above 25ºC” ≈ “Store below 25ºC”

But not

“Do not store above 25ºC” ≈ “Store 15ºC ± 10ºC”

Or the use of non-specific terms such as

“Store at room temperature”

104

Stability


If there is no data available at 30ºC then the API manufacturer is requested to commit to initiating long-term stability trials at 30ºC and to change the recommended storage conditions to stored below 30ºC once 24 months data has been accumulated.

If the API is known to be unstable at 30ºC then data is expected at 25ºC.

If there have been corrections or revision to the retest period and storage condition, this information must be incorporated in future revised APIMF versions.

105

Stability


ImpuritiesQuestion:

If a manufacturer controls impurity content in accordance with apharmacopoeial monograph can we accept the specifications?

106


Question:

If a manufacturer controls impurity content in accordance with apharmacopoeial monograph can we accept the specifications?

Unfortunately no, monographs are developed based upon how the API was prepared historically.

A particular manufacturer's manufacturing method may lead to unexpected impurities, due to a different route of synthesis, different reagents, etc.

Impurities

107


Setting an impurity limit

1.What are the potential impurities?

2.What impurities actually occur?

3.When to specify impurities.

4.Setting limits for impurities.

Impurities

108


All potential impurities

Observed impurities

Impurities needing to becontrolled in specifications

Impurities withindividual limits

109


What are the potential impurities?

• The first step in setting impurity specifications is to consider what potential impurities might be present, based upon all available information.

• This step is often poorly performed by applicants.

• There is a tendency to skip this step in discussions and just adopt pharmacopoeial specifications if a monograph exists.

110



• Impurities introduced during manufacture

• API degradation products

• API reaction by-products

Impurities can be divided into:

111


API SM

Reactionintermediate

Final API

ReagentsSolventsCatalysts

Degradation

By-products

By-products

SMimpurities

ReagentsSolventsCatalysts

Potential Impurities

Residue of the SMResidue of the intermediateImpurities in the SMReagentsSolventsCatalystsReaction by-productsDegradation products


112



What are the possible reaction by-products?

• Here some chemistry knowledge would be helpful.

Advice:

• Look for areas of functionality, particularly C-O, C-N, and double bonds.

• Consider all the impurities specified in relevant pharmacopoeialmonographs.

113



What are the potential degradation impurities?

•Pharmacopoeial monograph transparencies.

•Forced degradation studies.

114


What impurities actually occur?

Observed impurities



115



Potential impurities can be excluded by either testing the final API or FPP, or a relevant proceeding molecule.

Some pharmacopoeial impurities may not be present if a differentmanner of preparation,( reagents, synthesis) is used.

For degradants, look to long-term stability data. The presence of an impurity under accelerated conditions does not mean it will appear under long-term conditions.

Investigation of batch analysis and long-term stability data.

Impurities present at levels greater than the ICH reporting threshold should be reported by the manufacturer.



Analytical methods

• If you are looking for an impurity using a test method that can not detect the impurity then you are wasting your time.

• It is important for the manufacturer to detail the methods used.This is often not clear in submitted dossiers if different test methods have been used at different times.

• Full validation of investigative method is unnecessary. Demonstrated specificity and appropriate LOD/LOQs are important, especially for genotoxins.

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When to specify impurities



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Organic impurities

• Any impurity routinely observed in batch data or long-term stability trials should be controlled by the impurity specifications.

• Impurities observed below the ICH identification threshold need not be individually specified in the specifications. They can be controlled under the limit for any unspecified impurity.

• Impurities above the ICH identification threshold need to be identified and individually specified in the specifications.



• Drug 1 – ICH ID Threshold = 0.10%, or 1.0mg

• Maximum daily dose 20 mg

• Peak observed in batch data on average ~0.12%, should it be specified in the specifications?

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• Drug 1 – ICH ID Threshold = 0.10%, or 1.0mg.

• Maximum daily dose 20 mg.


• Yes

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• Yes

• Should it be identified?

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• Yes

• Should it be identified?

• Yes

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Setting limits for impurities


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Setting limits for impurities

• The limits must be qualified as safe.

• The limits should realistically reflect batch and stability data.


Setting limits – Organic impurities

Maximum daily dose

Qualification Threshold - The lower of:

% of API TDI

API < 2g 0.15% 1.0 mg

> 2g 0.05% -

Organic Impurities

An organic impurity above the applicable ICH qualification threshold needs to be qualified.


• Drug 1 – ICH ID threshold 0.10%, Qual threshold 0.15%

• Impurity routinely observed at 0.08%

• Should the impurity be specified and identified?

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• Impurity routinely observed at 0.08%.


• No, <0.10%

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• No, <0.10%

• Qualified?

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• No, <0.10%

• Qualified?

• No, <0.15%

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• Yes, >0.10%

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• Yes, >0.10%

• Qualified?

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• Yes, >0.10%

• Qualified?

• Yes, >0.15%

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• Impurity routinely reported <0.2%

• Should the impurity be qualified?

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• Impurity routinely reported <0.2%

• Should the impurity be qualified?

• It is impossible to tell. The applicant will be asked to represent data with sufficient accuracy. Otherwise, yes, it will need to be qualified.

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• By comparison to a limit specified in the Ph.Int., Ph.Eur., or USP for a specific impurity. It could even be in a monograph for another substance.

• Through toxicological trials.

• A statement in a monograph of "any other impurity NMT 0.5%" can not be used as justification for an impurity limit, as it is not specific.

Impurity limits > the ICH qualification threshold can be qualified:



• By comparison to levels found in an innovator or prequalified FPP.

• By comparison to a limit previously approved in a prequalified FPP. This is a last resort.

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• The limit for any unspecified impurity should be at the ICH identification threshold.

• The limit for total impurity content should reflect batch data.

• These concepts are applicable to synthetic APIs, but could be used on a case by case basis for semi-synthetic APIs.



Thank you!


Further information

The PQ website is a good source of information, please read.

http://www.who.int/prequal/info_applicants/API_info_applicants.htm

AND, ALSO

Please email me (or visit) if you have any questions.

[email protected]

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