slide 1 walters april 2007 training workshop on pharmaceutical development with focus on paediatric...

Walters April 2007

Training Workshop on Pharmaceutical Development

with focus on Paediatric Formulations

Protea Hotel

Victoria Junction, Waterfront

Cape Town, South Africa

Date: 16 to 20 April 2007

Pharmaceutical DevelopmentPharmaceutical Development

Walters April 2007

Pharmaceutical DevelopmentPharmaceutical Development

Quality Specifications & Testing of the Finished Pharmaceutical Product

(FPP)

Presenter: Susan Walters

Email: [email protected]

Walters April 2007

Quality Specifications & Testing of the FPPQuality Specifications & Testing of the FPP

My backgroundPharmacist

PhD Pharmaceutical Chemistry

2.5 years pharmaceutical manufacturing

27 years regulation of prescription medicines (TGA Australia)

Now:

Teaching pharmaceutical development of medicines (UNSW)

Ad hoc consultancies for WHO and others

Walters April 2007


Outline of presentation

We will:

Discuss the meaning of ‘quality’ in the context of FPPs

Define key terminology

List relevant pharmacopoeias & guidelines, & discuss their roles

Outline typical tests for finished products

Discuss the development & validation of dissolution test methods & acceptance criteria

Walters April 2007

What does ‘quality’ mean in the context of FPPs? - 1What does ‘quality’ mean in the context of FPPs? - 1

“Quality:

The suitability of either a drug substance [=API] or drug product [=FPP] for its intended purpose”

ICH Q6A (1999)

Some of the elements of FPP quality:

Meets suitable criteria for content of active(s)

Meets suitable criteria for content of impurities

Does not contain toxic excipients or unexpected contaminants

Walters April 2007

What does ‘quality’ mean in the context of FPPs? - 2What does ‘quality’ mean in the context of FPPs? - 2

The product:

Is reproducible from batch to batch in terms of all characteristics that may affect the patient

Has container labelling & prescribing information that is clear, contains all the necessary information, & accurately represents the FPP’s efficacy & safety profile

For FPPs containing new APIs: Has the same efficacy & safety profile as the batches used in pivotal clinical studies

For generics: Has the same plasma concentration/time profile as the innovator whose efficacy & safety profile is known

Walters April 2007


How to ensure the quality of FPPs

Know your API!– Ensure you have the results of pharmaceutical development studies

Validate:– Manufacturing procedures– Test methodology – Acceptance criteria

Implement Good Manufacturing Practice at all sites of manufacture

Undertake appropriate end-product testing for conformance to specifications

Conduct stability studies on the FPP exactly as it is to be marketed

Validate any subsequent variations

The message :End-product testing is one element of the

quality package

ICH :“Specifications are

part of a total quality strategy… designed to ensure product

quality & consistency”

Walters April 2007


Some terminology

Walters April 2007

“Specification” - 1“Specification” - 1

“A list of tests, references to analytical procedures, ranges or other criteria for the tests described”.

“[The specification] establishes the set of criteria to which [an API or FPP] should conform to be considered acceptable for its intended use.”

– [and for excipients, containers, intermediates & others]

“ ‘Conformance to specifications’ means that the [API or FPP], when tested according to the listed analytical procedures, will meet the listed acceptance criteria”.

ICH Q6a (1999)

Walters April 2007

“Specification” - 2“Specification” - 2

“Specifications are critical quality standards that are proposed & justified by the manufacturer & approved by regulatory authorities”.

“Specifications are chosen to confirm the quality of the [API or FPP] rather than to establish full characterization, & should focus on those characteristics found to be useful in ensuring … safety & efficacy”.

ICH Q6a (1999)

Walters April 2007

“Acceptance criteria”“Acceptance criteria”

“Numerical limits, ranges or other suitable measures for acceptance of the results of

analytical procedures”

ICH Q6a (1999)

Quantitative acceptance criteria are sometimes referred to as ‘limits’.

Walters April 2007

A typical monograph for an FPP might include: - 1


• Description• Eg size, shape, colour

• Identity tests for API(s)

• Assay of API(s)

• Purity tests• API-related impurities

• Solvents (often water)

• Physicochemical properties as appropriate to the dosage form (includes performance/functionality testing)

• Eg particle size of API(s) in suspensions

• Dissolution rate of tablets

Walters April 2007



• Identification & assay of any critical excipients• Eg antimicrobial preservatives, antioxidants

• Uniformity of dosage units for solid dosage forms

• Eg uniformity of weight (high dose tablets)

• Content uniformity (low dose tablets)

• Microbiology• Eg sterility (injections etc)

• Microbial load (non-sterile oral products & others)

Walters April 2007

The monograph as a wholeThe monograph as a whole

“A product is not of pharmacopoeial quality unless it complies with all the requirements stated in the [relevant monograph]” my emphasis

WHO TRS 908 (2003)

Walters April 2007

Sources of guidance as to the content of monographs for FPPs

Sources of guidance as to the content of monographs for FPPs

• Pharmacopoeias• General monographs

• Eg for parenteral products, capsules

• Specific monographs • Eg dapsone tablets, artemether injection

• Guidelines• WHO PQP

• Especially p16/26 Control of the FPP

• ICH

• Technically ICH guidelines apply only to new APIs. In practice regulators apply them more widely (eg PQP)

Walters April 2007

Internationally recognised pharmacopoeiasInternationally recognised pharmacopoeias

• International Pharmacopoeia (Ph Int) • Published by WHO

• United States Pharmacopeia (USP)

• Japanese Pharmacopoeia (JP)

• European Pharmacopoeia (EP)

• British Pharmacopoeia (BP)

Walters April 2007

Pharmacopoeias – PQP’s view?Pharmacopoeias – PQP’s view?

• PQP has not published a formal decision as to acceptable pharmacopoeial monographs for FPPs

• But precedents suggest that monographs of all of the preceding pharmacopoeias would be acceptable, with the caveat that monographs in Japanese are not easily understood outside Japan

Walters April 2007

ICH guidelines & FPP specificationsICH guidelines & FPP specifications

From ICH’s early days, there have been working groups that focussed on harmonisation of pharmacopoeial requirements among the three ICH regions

But to date no harmonised monographs have been published on the ICH website

These are the three relevant topics that appear on the ICH website

– Q4 Pharmacopoeias

– Q4A Pharmacopoeial Harmonisation

– Q4B Regulatory Acceptance of Analytical Procedures and/or Acceptance Criteria (RAAPAC)

Of these, only Q4B has published a draft consensus guideline. It deals with bureaucratic processing of documentation.

– Keep an eye on the ICH website for updates

Walters April 2007

An important ICH guidelineAn important ICH guideline

Q6A: Specifications: Test procedures & acceptance criteria for new [APIs] & new [FPPs]: Chemical substances

Applies to products containing synthetic APIs (including antibiotics), semi-synthetic antibiotics, & synthetic peptides of low molecular weight, but not to higher molecular weight peptides, & complex biotechnological or biological APIs.

This ICH guideline is referenced by PQP in its guidelines for generics, & is a key guideline for this training course.

I recommend that you read it in detail !

Walters April 2007

Other relevant ICH guidelinesOther relevant ICH guidelines

Q3A(R2) Impurities in new [APIs] (2006) Q3B(R2) Impurities in new [FPPs] (2006)

Q3C Impurities: Guideline for residual solvents (1997)

Impurities in non-new APIs

– Pharmacopoeial monographs

– Review route of synthesis

– Compare chromatographic profiles with those of innovator

Walters April 2007

Impurities in non-new FPPsImpurities in non-new FPPs

“Generally specifications for impurities in an existing API &/or an associated finished product are acceptable if one or more of the following criteria are met:

– Levels of impurities are below ICH qualification thresholds

– Nature of impurities & their limits match those of a transparent [pharmacopoeial] monograph

– The new product does not contain impurities in concentrations that exceed those in a market leader (normally the innovator)”

TGA (2004)

Walters April 2007

Deciding acceptance criteriaDeciding acceptance criteria

The justification (for acceptance criteria) should refer to relevant development data, pharmacopoeial standards, test data for [APIs & FPPs] used in toxicology & clinical studies, & results from long term stability studies, as appropriate.

Additionally a reasonable range of expected analytical & manufacturing variability should be considered.

Adapted from ICH Q6A (1999)

Walters April 2007

Parametric release & end product testingParametric release & end product testingSterility testing is probably the most well known example

of the parametric release option

Q6A describes it as “an operational alternative to routine release testing”

In the case of sterility, “release of each batch is based on satisfactory results from monitoring specific parameters, eg temperature, pressure & time during the terminal sterilization phases of...” manufacturing (Q6A)

In principle parametric release can be substituted for other end product testing, but there are few examples

All batches must nevertheless meet the full product specification if tested

Walters April 2007

Periodic & skip testing - 1Periodic & skip testing - 1“Periodic or skip testing is the performance of specified tests

at release on preselected batches &/or at predetermined intervals, rather than on a batch-to-batch bases”

All batches must nevertheless meet the full product specification if tested

Once a manufacturer has developed confidence in the manufacturing process & a number of consecutive batches have passed the test in question, testing may be reduced to one in every x batches, or once every x months, where x is a number that varies with the test in question

Walters April 2007

Periodic & skip testing - 2Periodic & skip testing - 2

Certain tests are considered ‘critical’ in terms of GMP, & must be conducted on every batch. Examples include identification & assay of the active(s).

Regulatory approval must be obtained (on a product-specific basis) before periodic testing may be implemented

In the event that a batch is tested & fails to meet acceptance criteria, regulatory authorities must be immediately informed. The batch may be recalled. The reason for the failure must be identified in order to assess the consequences for other batches.

Walters April 2007

Release & expiry limitsRelease & expiry limits

Manufacturers (almost always) have separate release & expiry limits for tests that have a quantitative result. The main reasons are:

– To allow for any observed deterioration of the measurement during stability studies

– To incorporate a safety margin so that batches are less likely to be recalled in the event of testing by a regulatory laboratory

• Effect on product image

Immediately after a batch has been released, the expiry limits apply.

Some regulatory authorities consider this ‘in-house’ information & do not require disclosure of the release limits. Most do.

PQP seeks both sets of limits.

Walters April 2007

Alternative test proceduresAlternative test proceduresPharmacopoeias & regulators allow manufacturers to use

alternative test methodology

In the event of a dispute, the approved methodology must be used.

Why?

– Science moves on ! Methodology improves. Regulators should not discourage improvements.

– Alternative methodology may be simpler &/or cheaper to conduct, but equally effective. For example if the product has been shown not to degrade during manufacture, a titration method may be more accurate, precise & cheaper to perform than HPLC/MS, although less specific for the target analyte.

Walters April 2007

Dissolution testing

Walters April 2007

Dissolution test methods & acceptance criteria:Available guidelines

Dissolution test methods & acceptance criteria:Available guidelines

– “Dissolution Testing of Immediate Release Solid Oral Dosage Forms”

• FDA, CDER (1997)

– <1092> “The Dissolution Procedure: Development & Validation “

• USP– “Dissolution testing of solid oral dosage forms”

• BP, Supplementary Chapter E– “FIP Guidelines for Dissolution Testing of Solid Oral Products”

• http://www.fip.org/www2/statements/index.php

– “Dissolution testing”

• WHO PQP: Guideline on Submission of Documentation for Prequalification of Multisource (Generic) FPPs: Supplement 1.

Walters April 2007

For what purposes are dissolution studies conducted?

For what purposes are dissolution studies conducted?

– During product development, selecting formulations for further development

– During end-product quality control, determining whether each batch meets predetermined in vitro release criteria

– During stability studies, determining whether in vitro release rate changes with product age

– In the context of bioequivalence studies, to determine the extent to which in vitro dissolution results mirror in vivo results.

– During the product’s market lifetime, determining whether variations affect in vitro release rate

• Eg change of manufacturing site or equipment

Walters April 2007

What constitutes a good dissolution test?What constitutes a good dissolution test?

– Repeatability

• Within & between equipment, analysts, labs etc

• Over time (eg this year vs next year)

– Discriminatory power

• Discriminates between batches that perform well in vivo & those that do not

Walters April 2007

Formal ‘validation’ of dissolution test methodology

Formal ‘validation’ of dissolution test methodology

Examples: Repeatability studies

System suitability tests

– Eg using USP dissolution calibrators

Manual vs automated procedures

Analytical methodology

Walters April 2007

What should we take into account when choosing dissolution test methods & acceptance criteria? - 1What should we take into account when choosing dissolution test methods & acceptance criteria? - 1

– The APIs in question & their characteristics• Especially solubility in aqueous media• Known history of dissolution &/or bioavailability problems

• Biopharmaceutical classification (see FDA’s Waiver of In Vivo Bioavailability & Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System, 2000)

– The purpose for which the test is being conducted [this affects acceptance criteria]

• Routine batch release• Stability testing• For registration purposes• To support results of a bioequivalence study• To justify a waiver of in vivo BE data

Walters April 2007

– Recommendations made by FIP, by pharmacopoeias & in regulatory guidelines

– Regulatory requirements for registration• Eg those of WHO’s PQP

– Whether an in vivo/in vitro correlation (of any type) has been established

• May or may not have been published• See especially the website for the FIP Special Interest Group for BABE at

http://www.fip.nl/www2/sciences/index.php?page=pharmacy_sciences&pharmacy_sciences=sciences_bioavail_groupbcs

– Precedents • Concerning the API in question, related APIs or related dosage forms

– Published – Or known only to you

• But only if there are facts/data that you can cite in support

What information should we take into account when choosing dissolution test methods & acceptance criteria? - 2

What information should we take into account when choosing dissolution test methods & acceptance criteria? - 2

Walters April 2007

Dissolution testing: Decisions to makeDissolution testing: Decisions to make

– Apparatus

– Medium (solvent)

– Sampling times

– Acceptance criteria

Walters April 2007

Dissolution test methods: Apparatus - 1Dissolution test methods: Apparatus - 1

Options (all described in the Ph Int, BP & USP):

• Stirred methods• Rotating paddle• Rotating basket• Modifications

– For floating dosage forms, especially capsules– May need to change medium during the test, eg pH for enteric coated products

• Flow through methods

• Reciprocating cylinder (USP only)• Useful for modelling media changes & predicting in vivo profiles of modified

release products (Personal Communication David Elder 2007)

Walters April 2007


In general milder agitation conditions are preferred

– More likely to be able to discriminate between good & bad batches

– May have to increase speed in some cases in the event of coning due to insoluble excipients

Walters April 2007


• Recommendations by PQP for immediate release products:

• Paddle (USP Apparatus 2) usually at 50 or 75 rpm

• Basket (USP Apparatus 1) usually at 100 rpm

Walters April 2007

Dissolution test methods: Medium/solventDissolution test methods: Medium/solvent

Prefer media that are:– Not dissimilar to physiological conditions

• Eg avoid 50% acetone!

– Discussed in pharmacopoeias

– Defined in regulatory requirements• Eg WHO’s PQP Dissolution testing: Guideline on Submission

of Documentation for Prequalification of Multisource (Generic) FPPs: Supplement 1.

• FDA/CDER’s Dissolution Testing of Immediate Release Solid Oral Dosage Forms

– Water is now out of favour because pH is uncontrolled

Walters April 2007

Dissolution test methods: Sampling times - 1Dissolution test methods: Sampling times - 1

Prefer sampling times that are:

– Recommended in pharmacopoeias

– Defined in regulatory requirements

Prefer:

– Profiles (multipoint) vs one or two point tests• Profiles are more discrimating than one or two point tests• Formulation comparisons should normally be profiles • One or two point tests may be adequate for routine batch release if fully

justified

Walters April 2007


Some relatively recent (but non-official) non-numerical terminology:

• ‘Very rapidly dissolving’

≥ 85% in 15 minutes

• ‘Rapidly dissolving’

≥ 85% in 30 minutes

Walters April 2007


The FDA guidance describes three categories of dissolution test:

– Single-point specifications– Two-point specifications – Dissolution profile comparison

From: Dissolution Testing of Immediate Release Solid Oral Dosage Forms FDA (1997)

Walters April 2007


• Single-point specifications. Can be used:– As a routine quality control test for highly soluble and rapidly

dissolving drug products• Definition of rapidly dissolving?• Recently defined as >85% in 30 minutes but the FDA dissolution guideline did

not define the termSingle-point specifications. Can be used:– As a routine quality control test for highly soluble and rapidly

dissolving drug products• Definition of rapidly dissolving?

• Recently defined as >85% in 30 minutes but the FDA dissolution guideline did not define the term

Walters April 2007


• Two-point specifications. Can be used:– For characterizing the quality of the drug product.– As a routine quality control test for products that contain

slowly dissolving or poorly water soluble APIs such as carbamazepine.

• Dissolution profile comparison. Can be used:

– For accepting product sameness in the context of variations.

– To waive bioequivalence requirements for lower strengths of a dosage form.

– To support waivers for other bioequivalence requirements, especially for BCS #1 APIs.

Walters April 2007


• So for routine quality control of immediate release products:Either specify a dissolution profile

Acceptable for most types of product

Or specify a two point dissolution testAcceptable for most immediate release products

Or specify a single point dissolution testAcceptable for most immediate release products that contain highly soluble & rapidly dissolving APIs

But each case must be considered individually

Walters April 2007

Deciding acceptance criteria - 1Deciding acceptance criteria - 1

Approaches for setting dissolution specifications for a new chemical entity

Approaches for setting dissolution specifications for generic products

From: Dissolution Testing of Immediate Release

Solid Oral Dosage Forms FDA (1997)

Walters April 2007


Considerations when setting dissolution specifications for a new chemical entity:

– pH solubility profile– pKa of active– GI permeability or octanol/water partition– Dissolution characteristics of batches used in pivotal

clinical trials and/or in confirmatory bioavailability studies.

– If the formulation intended for marketing differs significantly from the drug product used in pivotal clinical trials, dissolution and bioequivalence testing between the two formulations are recommended.

From: Dissolution Testing of Immediate Release Solid Oral Dosage Forms FDA (1997)

Walters April 2007


Considerations when setting dissolution specifications for a generic product:

– Has a pharmacopoeial dissolution test been published?

– Is a dissolution test publicly available for a reference listed drug product?

– Conduct comparative dissolution testing using test & reference products under a variety of test conditions

Walters April 2007

Comparing dissolution profilesComparing dissolution profiles

When comparing two immediate release products:

If both are >85% dissolved in 15 minutes, the profiles may be considered similar. Statistical calculation is not required. PQP (2005 )

Calculate the similarity factor f2 where………

– Need minimum of 3 points

n

tTtR

fnt

t

2

1

2

)()(

1

100

Walters April 2007

Summary and conclusionSummary and conclusion

It is important to understand the place of end-product testing in the total quality context

Monographs for FPPs should be based on:

– Pharmacopoeial general monographs

– Pharmacopoeial precedents

– ICH & PQP guidelines

– Characteristics of the API & FPP in question

The bottom line is safety, efficacy & reproducibility for the patient

slide 1 walters april 2007 training workshop on pharmaceutical development with focus on paediatric...

Documents

quality of fpps

terminology slide

elements of fpp quality

quality mean

meaning of quality

quality package ich

total quality strategy

context of fpps