API documentation from the perspective of WHO-PQP documentation from the perspective of WHO‐PQP 1 Mumbai, September 2012 3.2.S.3.2 Impurities, Malaysia, 29 September 2011 API documentation

API documentation from the perspective of WHO‐PQPMumbai, September 2012 1

3.2.S.3.2 Impurities,Malaysia, 29 September 2011

API documentation from the perspective of WHO-PQP

Antony Fake PhDWHO Medicines Prequalification Programme


Abbreviations

• API – Active Pharmaceutical Ingredient

• FPP – Finished Pharmaceutical Product

• APIMF – API Master File (DMF)

• CPQ – Confirmation of Prequalification Document


Overview

Technical assessment issues

API Amendments

Documentation issues


Technical Issues

Solubility data

Since early 2012, API manufacturers have been asked to provide quantitative solubility data for their APIs under specific conditions (250 mL, three pHs etc).

This is to assist PQ bioequivalence assessors in determining APIs that may be eligible for biowaivers.

It was found that typical qualitative data was not specific enough, and historically provided quantitative values often varied, or were non-comparable.


Technical IssuesManufacturing block information

For over a year PQ has been requesting that API manufacturers define the manufacturing blocks used for preparation of their specific API.

This is because some manufacturers do not have the same quality standards or quality systems operating across the entire site.

This information allows for a focus, in principle, of the GMP inspection to those specific blocks manufacturing for PQ.

The information is not mandatory, but without this information any activities related to this API at the site may be inspected


Technical Issues

Definition of the API Starting material

The number of requests to redefine the API starting material to an earlier molecule in the synthesis appears to be reducing, but still the number of requests is significant.

Recent WHO, EMA and ICH (Q11) guidance all identify the need to choose the API starting materials carefully.

What remains clear is that the API SM almost invariably a molecule one or more synthetic steps prior to the final API.


Technical IssuesRecovery of solvents

Almost all manufacturers undertake some recovery of solvents.

Although the general assessment approach has not varied significantly as a reminder:•The limits applied to recovered solvent do not have to be the same as fresh solvent.•The limits applied must be justified – based upon actual experience.•This is common deficiency. Either the choice of limits is not justified or the justification is not logical.

Unless the limits are so strict as to be obviously acceptable, the chosen limits must be justified by the demonstrated ability to manufacture acceptable API under the worse case scenario.


Technical Issues

For instance:

If the proposed limits are:Assay 98%Any single impurity 1%Total impurity content 2%

Then batch data for API and solvent batches should be provided where the API meets specifications and the solvents used had impurity content near 2%


Technical Issues

Proposed limits

Assay 92%

Single impurity NMT 2%

Total impurity NMT 8%


Technical Issues

Proposed limits

Actual solvent batches

Assay 92% 98%

Single impurity NMT 2% 0.8%

Total impurity NMT 8% 1.7%

Not justified


Technical Issues

Proposed limits

Actual solvent batches

Justified limits

Assay 92% 98% 98%

Single impurity NMT 2% 0.8% NMT 1%

Total impurity NMT 8% 1.7% NMT 2%


Technical Issues

Benzene in recovered solvents

Control may not be necessary, but a logical scientific argument is expected – See also skip testing

A test for non-volatile matter (0.1%)

For all recovered solvents.

Number of recovery cycles

There is normally no requirements to state the number of cycles a solvent will be recycled. Provided the solvent remains within specification it can be used.

Water or other components should be listed in the specifications


Technical Issues

Impurities discussion

This is often lacking.

It is not acceptable to just choose the pharmacopoeial impurities without providing a discussion over whether other impurities may occur.

Like residual solvents, the impurity limits chosen (if not pharmacopeial) should be justified.


Technical Issues

Class I solvents and Genotoxins

There should always be a comment in the impurities section on genotoxins even if this brief and concludes there are no potential genotoxins.

The European clarification over requirements for the control of class I solvents and genotoxins depending on their potential to be present is being used by PQP.


Technical Issues

For instance a class-1 solvent formed or introduced prior to the final step of the synthesis does not need to be present in the API specs, provided it is controlled in a suitable intermediate.

The latter condition is often overlooked.


Technical IssuesSkip testing

PQP sees skip testing as of useful way to ensure post-acceptance integrity of the API quality.

The exclusion or inclusion of tests in the API specifications is often the subject of considerable debate and internal discussion.

From a practical perspective once a test is excluded from the API specifications the chances of this being considered during subsequent post-approval reduces.

There is therefore an increasing preference to include “marginal”tests in the API specifications, but as skip tests.

It is a useful risk strategy and reduces the time taken to resolve “marginal” issues.


Skip testing

Some further points:

It is recognized that under GMP even “routine tests” may be skip tested by the manufacture if justified. Regulatory notification is not required.

The identification of a particular test as a skip test in the specifications by a specific statement is unnecessary but is acceptable.

There is no requirements to include a statement over the frequency of the skip testing within the specifications.

Technical Issues


Technical Issues

Holding times for intermediates

This is considered to be a GMP matter and unless there is a particular reason to do so, the statements or justifications of holding times is not considered necessary.

It is expected that under GMP an intermediate will not be introduced in further steps unless they are known to be of adequate quality.


API-Related Changes


API related changes

There are four ways in which API information can be submitted

1.Use of a Prequalified API (submission of CPQ)

2.Use of an EDQM Certification (submission of a CEP)

3.Use of an APIMF (APIMF Procedure)

4.Provision of Module 3.2.S as part of dossier (full dossier)

Regardless of the manner of submission the technical informationultimately provided remains the same.


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)


API related changes

Currently, this means

1.The submission of an APIMF amendment to PQP.

2.Receipt of the amendment acceptance letter.

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

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


New APIMF Amendment Guidance

A new APIMF amendment guidance will be circulated for comment imminently.

It is very closely based upon the circulated Guidance on the Submission of Variations for PQ FPPs.

It features the use of “self-assessable” changes.

It offers a reduction in the burden upon both PQP and manufacturers.

When considered alongside the variation guidance, it recognizes users of the APIMF procedure and in particular PQ’d APIs.


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)


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.


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.


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 amendment can be implemented if no objection letter has been 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.


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.


APIMF Amendment Process

Three phases

1.Screening

2.Audit or Assessment

3.Implementation or Acceptance

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









Issues arising?





Assessment

Rejection

Notifications are accepted by default









Issues arising?





Assessment

Rejection

Notifications will be audited rather than

assessed.









Issues arising?





Assessment

Rejection

This could lead to questions and

potentially the reversal of the change









Issues arising?





Assessment

Rejection

Minor Amendments maybe implemented 30 days after acknowledgment if there are no objections raised.









Issues arising?





Assessment

Rejection

If there are no objections, no further correspondence

will be received









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



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 and the new guidance will not offer the benefits it should.

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


Correct assessment of the change also relates to conditions and documentation



The success of the amendment process relies on three things




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



For each amendment supporting data will be specified – minimum data



The success of the amendment process relies on three things




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



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.


APIMF Documentation

The new Amendment guidance highlights the need for good documentation identification and maintenance.

Traceability of documentation over time has become an increasingburden for PQ as the number of APIMFs increases, restricting theamount of assessment that occurs.

Traceability of amendments is particularly important.

APIMF traceability is a critical feature of API Prequalification since the APIMF version number is published.

A move to electronic-only submissions can only occur if good quality documentation and traceability exists.


APIMF Documentation

PQ documentation requirements have been published for sometime.

As part of the amendment guidance consultation, comments on documentation requirements will also be sought.

Consultation is being undertaken because these requirements will then be strictly enforced.


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.


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.

•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


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.

For instance: WHO/Lam/AP01/Amendment August 2012


APIMF Documentation

These requirements should not be beyond the abilities of currentmanufacturers.

If good quality electronic documents, with systematic version control are routinely submitted by the majority of manufacturers, we will be able to:

•Dispense with sending paper copies to Copenhagen.

•Consider the submission of applications via a web-based system.

Further informationThe 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]

One email could save you a lot of time.


Thank you

API documentation from the perspective of WHO-PQP documentation from the perspective of WHO‐PQP 1 Mumbai, September 2012 3.2.S.3.2 Impurities, Malaysia, 29 September 2011 API documentation

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