copenhagen workshop may 2015 - · pdf filepharmaceutical engineering/pharmaceutical...

Lynda Paleshnuik | May 2015 1

Copenhagen Workshop May 2015

Quality assessment principles!

!

L. Paleshnuik!Lead Quality Assessor!

PQTm

1!

Lynda Paleshnuik | May 2015

Overview

• Challenges of the quality assessment process • Approaches to assessment

• Using QRM principles • Issues of outstanding importance • Starting the review - considerations • Critical versus low-importance sections • Reviewing the API – common critical issues • Reviewing the FPP – example issue • The assessment report

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Quality Assessment Challenges

!   Covers many fields of knowledge

!   Complex (issues have multiple factors involved)

!   Involves large amounts of data

!   No two products are the same (different dosage form, APIs, manufacturer, technology, etc)

!  First assessment (and report!) of the original dossier is the most important part of the process (broadest/deepest review).

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Quality Assessment – knowledge areas

Manufacturing sciences Pharmaceutical engineering/pharmaceutical technology

(production methods and systems, facilities, equipment, etc.)

Pharmaceutical sciences

Chemistry (organic, inorganic, physical, biochemical, analytical (e.g. methodology, validation, spectral analysis))

Pharmaceutical chemistry (study of drug design)

Pharmaceutics (study of drug formulation)

Pharmacognosy (study of drugs of natural origin)

Other fields: Math/statistics, microbiology, GMP 4


Assessment report (AR)

Understanding the dossier, the QOS and the AR.!

The QOS is a template (next slide), which is then filled in by the applicant with a summary of information on the product.!

The filled QOS becomes the basis for the AR.

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Empty QOS ≈25 pages Filled QOS ≈100+ pages


The assessor reviews the data in the dossier, confirming the QOS is summarized correctly, and adds comments, questions, discussions = AR!

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Dossier + QOS = AR


What is quality risk management


Understanding QRM

QRM: the overall and continuing process of managing risks to product quality!

QRM can be applied to the assessment process (TRS 981 Annex 2, section 5.4, 2013). For quality assessment:

!   making the most of limited capacity (e.g. not using limited resources on lower risk dossiers/information), to avoid:

!   delaying the availability of important products 9


The importance of critical thinking

Critical thinking, if it is applied throughout the process, allows for the greatest use of time to result in the highest quality of the review process.

Quality risk management is an aspect of critical thinking.

Critical analysis is most important when starting a review for time management (later in talk).

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The ABSENCE of critical thinking/QRM

Let’s call this the BRUTE FORCE METHOD

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Brute force method

In this model the reviewer:!

• Reviews the dossier exactly in CTD order!

• Reviews every section fully and in depth!

• Assigns equal importance to each section!

• Assigns equal importance to each dossier

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Assessing smart

Critical thinking – overarching approach • where to focus your attention • where to go lightly

BUT always

watch for red flags that require a closer look

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Have access to the critical reference sources

Compendia

NMRA guidelines and publications

ICH documents

Talks, course materials, etc

Published papers

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Officially recognized pharmacopoeia for PQTm

PhInt, USP, BP, EP, JP are recognized standards in PQTm

PhInt S4 is available as CD-ROM or on-line 15


Decisions during the process

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Brute force method versus using QRM principles

• You review the dossier exactly in CTD order!

Critical aspects are reviewed first, and significant aspects of the dossier are identified (FDC? Solid oral or more complex? Immediate release? Sterile?)!

• You review every section!

Non-critical, non-important sections are identified and how they will be reviewed decided on!

• You assign equal importance to each section!

Critical sections are identified to focus attention on 17


Making QRM choices

The ability to make QRM choices comes from experience.!

However, there are some basic considerations.!

1. Some aspects need to be reviewed out of CTD order, before starting the review.

2. Issues of outstanding importance identified!

3. Factors that add complexity identified!

4. Low-importance sections identified

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Issues of outstanding importance



The dossier and report are in CTD format – normal progression is to follow the CTD format!

BUT!

Some primary issues should be checked before beginning the assessment!

These issues may result in DELAY or TERMINATION of the assessment

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Primary issues: may result in delay of the assessment:

e.g. critical data is missing

This results in a delay while waiting for the data, which interrupts the assessment process and requires more time when we go back to the dossier.

The earlier we identify critical missing data, the less time is wasted.

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Primary issues: may result in termination of the assessment:!Issues of the biostudy!

• Biobatch size!

• Choice of comparator!

• Acceptable biostudy or biowaiver

Stability issues

Other issues e.g. general quality of the dossier 22


Why is the biobatch so important for

quality assessment?



If the biostudy is rejected, the quality data in the dossier is probably meaningless. Why?!

A new biostudy usually means a new biobatch. The quality data assessment revolves around the data on the biobatch. The comparison of biobatch vs proposed production batches is critical to the quality review. The quality assessor must establish that the formulation and process (equipment, parameters and controls) are the same or that differences are not significant.!

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Assessors must know at the beginning of assessment, which test biobatch was used in the biostudy.

There should be an understanding of the acceptability of the biostudy – if it was accepted (continue Q assessment), if it was rejected (stop), or if there are outstanding questions that will likely lead to future acceptance (continue).

The heart of the quality assessment is a comparison of the test biobatch to the proposed production batches (using blank records).

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Issues that may result in termination of the assessment:

Issues with the biostudy as above.!

Issues of the stability studies (before reviewing the data): acceptable conditions (“room temperature” vs 30±2ºC/75±5%RH), packaging (representing proposed), batches (sufficient number, size).

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Early detection of essential issues

Stability data is required on the required number of batches of the appropriate size, in all packaging formats, at the required conditions. Example: product to be provided in blisters and strips, but stability data provided for product only in strips. Blisters and strips are two completely different formats, needing separate studies.

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Other issues:

Is the product invited or an acceptable strength (may depend on NMRA, i.e. innovator strengths)

Other critical issues noted, e.g. applicant does not have a good understanding of basic requirements. !Note that a good screening process is helpful here. If a critical issue is identified, can decide to stop the assessment.

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The importance of screening


Dossier screening process

• Examines the completeness of a dossier!

• Checks for key data!

• Only dossiers meeting the minimum standards are accepted for assessment!

Without a (good) screening process, lower quality dossiers are submitted/assessed, increasing assessment time. One of the largest factors for assessment time is the quality of the dossier accepted for assessment.

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Starting the review


Considerations when beginning the review:

Two factors to know before starting:! 1. the solubility of the API! This topic is covered later in this talk!

The API solubility is an important factor throughout the assessment process

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When beginning the review:

!!

2. Are there are related dossiers that have been reviewed.! This is important both for consistency of approach, and to minimize duplication of effort.

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Factors that add complexity

• Unfamiliar or less common dosage form!

• Complex API synthesis or complex dosage form (e.g. inhalation products)!

• FPPs with additional safety issues (e.g. sterile products)!

• Combination products (especially where the APIs are incompatible)!

• Forms with modified release (EC, transdermals, ER)!

• Novel excipients 34


Understanding low-importance sections

Not all data is of equal importance.!

When capacity is limited, agencies can decide on areas to spend less time on. (This should be defined, or each assessor will make their own decisions.)!

General low-importance sections:!

• Batch packaging records (most solid orals)!

• Compendial excipient specifications and COAs!

• Validation of GC methods for common solvents 35


Understanding low-importance sections

Examples of agency-specific low-importance sections:!

• Less/no assessment of validation of methods for companies with a good track record!

• No review of batch records when there is a strong inspectorate!

The decision is based on the capacities of the NMRA, including laboratories, assessors and inspectors

Understanding what your inspectors focus on is helpful.

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Applicant - dependent QRM decisions e.g. validation

• Applicant is new to stringent requirements: review their validation data in detail; check their calculations for precision, linearity, etc; review their chromatograms, SSTs!

• Applicant is not new but errors have been identified in the past: review their validation summary, at minimum spot-check raw data, review chromatograms, review SSTs!

• Applicant is established: review validation summary, review impurity/assay chromatograms for separation, SSTs

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API – applicants must…

Applicants must demonstrate:!

They have a valid source of the API Isabel’s talk next!

They have adequate understanding of the API (physico-chemical properties, impurities, etc) Later in this talk!

They can adequately control the quality of the API (specifications, validated methods, reference standards) Andrew and Hua’s talks!

The API is sufficiently stable stability talk tomorrow

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Elements of API sections

Applicants must:!

Provide data on the API according to one of the 4 options (PQ’d API, CEP, APIMF, full data). !

Regardless of the option used, the dossier should include sufficient info to show their understanding of the API (solubility profile and hygroscopicity are critical, as well as the impurity profile)

The elements that must be demonstrated by the applicant, must be understood and discussed by the assessor in the AR.

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Factors that add complexity: API

API is a product of fermentation – an understanding of fermentation processes is required!

API is sterile – understanding of sterilization processes is required!

API is low solubility – common issue with additional considerations (covered next)!

API is hygroscopic or moisture sensitive – considerations for manufacture (e.g. avoid wet granulation) and packaging to ensure stability; one standard test = BP = EP 5.11

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API common critical issues


Low solubility API

The solubility of the API over the physiological pH should be determined for every API!

The dose solubility volume (DSV) should be calculated:!

DSV = largest dosage strength (mg)! Minimum concentration of API (mg/mL)*!

DSV > 250 mL is a low solubility API!

* Lowest solubility determined over pH 1.2-6.8 at 37◦C

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Low solubility API

Polymorphism must be investigated and controlled if necessary, and particle size is critical.! These parameters are critical for any API with DSV > 250 mL, i.e. any low solubility API.! Exception: when the manufacture of the FPP involves fully dissolving the API. This is common with reproductive health products, where an organic solvent is often used for this purpose. In this case neither PSD nor polymorphism is relevant.

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Low solubility API

Identifying critical issues: Example: a dossier where polymorphism is critical (BCS low solubility, different polymorphs observed). Assessors sometimes correctly state polymorphism is critical, but don’t properly deal with the issue. Identifying criticality is not meaningful unless you understand the implications/necessary considerations and include them in the report. Polymorphism: are there various forms? is one preferred? IF YES is there a test in specs? Does the test ensure the desired form (e.g. XRD, DSC, IR)? What was the form of the API lot used in the BE study? Confirm the reference standard has the same form. Ensure the specs include the validated test/limits (validated to show it can distinguish possible forms), if API is micronized, show micronization does not change the form.

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API Solubility categories

BCS high solubility: the API is soluble over the entire physiological pH range (DSV < 250 mL) at 37◦C

BCS low solubility: The API insoluble at at least one pH over the physiological pH range. The API is often still soluble at other pH(s) in that range. (DSV > 250 mL)!

Critically low solubility: The API is insoluble over the entire phys pH range. (DSV > 250 mL)!

An example follows regarding the change in an API supplier.

Physiological pH range = 1.2-6.8

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PSD and solubility

There are three solubility situations:!

API is BCS high solubility, i.e. soluble over the physiological pH range! PSD is not critical!

API is BCS low solubility (DSV > 250 mL) but is soluble at some physiological pH!

PSD is critical, a test/limits must be in API specifications (based on biobatch profile)!

API is critically low soluble (API is insoluble over the entire physiological pH range)! PSD is critical, a test/limits must be in API specifications (based on biobatch profile) and PSD should be in the retest parameters

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PSD and solubility

Note that PSD should be carefully considered, case-by-case. Normal PSD limits are: d10 NMT x d50 xx-xxx d90 NMT xxxx For critically low soluble, consider the need for a range for d90.

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Low solubility API - assessing smart

Approach to low solubility APIs!

The API has been found to have low solubility!

This is an example of reviewing outside CTD order. Before we get into PSD and polymorphism, we check:!

Is it fully dissolved during manufacture. If so, PSD/polymorphism data are normally no longer relevant

PSD/polymorphism data may be in 21 QOS subsections!

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Common API Issue

Multiple suppliers or change in supplier

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API data required to support

a new API supplier


Common API issue #1 – multiple API suppliers or change in API supplier

It is acceptable to have more than one supplier of an API as long as the quality of the API is adequately controlled for each supplier.!

MOST IMPORTANTLY:!

When it is a low solubility API, the PSD and polymorphic form (if relevant) for API from each supplier should be representative of the lot(s) used in the BE study.

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Change in API supplier

A common FPP manufacturer complaint: they have conducted the BE study with API from supplier A, but that supplier is no longer available (or will not provide sufficient info on the API).!

Can they change the API supplier?!

Yes.

Can they change the supplier without having to repeat the BE studies using the new source? !

Probably.

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Change in API supplier from that used in biostudy

Full information is required on API from the new supplier,

AND!

The quality of the API must be adequately controlled for each supplier.!

This does not mean they must have the same impurity profile, but they must have adequate controls based on their impurity profile (according to potential impurities, residual solvents, etc)!

When it is a low solubility API, the PSD and polymorphic form (if relevant), for API from each supplier, should be representative of the lot(s) used in the BE study. (See details for PSD, next slides)!

If the above is established, new BE studies are not required.

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FPP data required to support

a new API supplier


FPP data required for a new API supplier

Do we require that stability studies on the FPP include API from each supplier?

This is preferred, but it is not required.

If the quality characteristics of the API from a different source may affect the FPP stability, then a commitment is required.

See PQTm variation GL variation 8 for details 55


Change in API supplier: PSD change

The generally accepted variations from biobatch PSD results are:!

D10 ± 45%!D50 ± 30%!D90 ± 45%!!Where the values are < 10 µm, the accepted variations are doubled.

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Change in API supplier: Accepting a PSD change

There are three situations:!

API is soluble over the physiological pH range! PSD is not critical!

API is low solubility (DSV > 250 mL) but is soluble at some phys pH!

PSD is critical, values must be within the tolerances, OR!

Comparative dissolution may support differences outside these tolerances!

API is critically low soluble (API is insoluble over the physiological pH range)! PSD is critical, a change must be within the tolerances! Change outside these tolerances may require a new biostudy

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PSD change supported by dissolution data

For the low solubility API, where it is soluble at some phys pH:!

Comparative dissolution profiles may be used to justify a change in PSD outside the normal tolerances:!

Multipoint dissolution profiles in 3 media (pH 1.2 or 0.1N HCl, pH 4.5 and 6.8) without surfactant for:! • One FPP batch made with the API with the new PSD profile! • One FPP batch made with the API with PSD within the tolerances of the BE lot! • Dissolution profile data on the BE lot

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Change in or addition of API supplier

Conclusion:

There are ways to support this change, with the critical consideration being API solubility

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FPP example issue


Excipients

In general, excipients can be considered a

low priority section.

Certain aspects are generally not considered during assessment, for example excipient suppliers.

When a compendial standard is claimed, a very light review is required for most excipients.

There is one exception where safety is important.

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Capsule shells

Capsule shells are sometimes treated in reports as outside normal requirements.

Gelatin shells are a critical part of assessment.

Two critical aspects:

• potential BSE/TSE risk• potential contamination with chromium

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Capsule shells

Capsule shells have two sets of important specifications:

• shell specifications

• shell excipient specifications or standards

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Capsule shells

1. We need to know the supplier(s) of the capsule shells.

2. Capsule shell specifications (FPP manufacturer’s):

• must be reviewed

• should include microbial limits and chromium tests

PF 2015 Jan-Feb has a draft monograph for empty shells

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Capsule shell excipients

Capsule shell excipients are a separate but important aspect of the assessment.

We need the quantitative composition of the shells, with the standard and/or specifications for each excipient.

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Shell excipients are sometimes accepted without looking at their standards or specifications.

Excipients in shells (plus ink if used) should be treated like other excipients in the following ways:

• they must meet compendial standards when available,

• if a compendial standard is unavailable the in-house specifications must be reviewed.

Plus there are additional concerns.

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Additional concerns for capsule shell excipients:

Gelatin is an excipient of concern Note: there is no non-animal source of gelatin

First we need:

1. Information on the supplier(s) of gelatin

You are requested to identify the supplier(s) of gelatin to the capsule shell manufacturer X.

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Gelatin is an excipient of concern

2. Gelatin has potential for TSE/BSE contamination. At minimum a valid EDQM certificate of suitability (from each supplier) is required.

You are requested to identify the supplier(s) of gelatin to the capsule shell manufacturer X, and submit copies of the EDQM certificate(s) of suitability associated with these suppliers.

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Gelatin is an excipient of concern

3. There are concerns regarding gelatin supplied from China regarding chromium contamination.

You are requested to obtain confirmation from your capsule shell supplier, X, that the gelatin used conforms to USP, BP, Ph.Eur. or Ph.Int. standard including a limit of NMT 10 ppm chromium.

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Capsule shells

Additional concerns for capsule shells (beyond excipients):

Dissolution may be affected by:

• cross-linking in shells (particularly soft-gels)

• use of rayon with capsules

If dissolution issues are observed, these possibilities should be explored.

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Capsule shells

Additional concerns for capsule shells (beyond excipients):

Note that some shells are actually package units, e.g. lopinavir/ritonavir sprinkles, and vitamin A, and are intended to deliver the product but are not intended to be consumed.

However, because they MAY be consumed, they should be treated the same as other shells.

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Assessment report (AR)


Final assessment report (AR)

The quality of the AR is one of the biggest factors of the success of the assessment process.

That AR will be used throughout the rounds of assessment of the dossier, and beyond:

• In the review of variations

• As a reference document for other dossiers

• As a training tool 73


Data we need in the first assessment report/round

Characterization of API lot used in the BE study:

• Εspecially PSD/polymorphism of low solubility API

• FPP dissolution data (biobatch) in media over the physiological pH range

Discriminatory data for dissolution method when required (CR products, critically low soluble API)

This data should be requested as soon as possible.

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Final assessment report (AR)

The quality of the AR is one of the biggest factors of the success of the assessment process.

Taking the time to create a good AR can save a lot of time over the lifetime of the product.

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Summary

• Challenges of the quality assessment process • Approaches to assessment

• Using QRM principles • Issues of outstanding importance • Starting the review - considerations • Critical versus low-importance sections • Reviewing the API – common critical issues • Reviewing the FPP – example issue • The assessment report

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Thank you

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copenhagen workshop may 2015 - · pdf filepharmaceutical engineering/pharmaceutical...

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