1. World Health Organization
Pharmaceutical Development
19 April, 2017
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

2. Pharmaceutical Development
World Health Organization
Pharmaceutical Development
19 April, 2017
Quality Specifications & Testing of the Finished Pharmaceutical Product (FPP)
Presenter: Susan Walters

3. Quality Specifications & Testing of the FPP
World Health Organization
Quality Specifications & Testing of the FPP
19 April, 2017
My background
Pharmacist
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

4. Quality Specifications & Testing of the FPP
World Health Organization
Quality Specifications & Testing of the FPP
19 April, 2017
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

5. What does ‘quality’ mean in the context of FPPs? - 1
World Health Organization
What does ‘quality’ mean in the context of FPPs? - 1
19 April, 2017
“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

6. What does ‘quality’ mean in the context of FPPs? - 2
World Health Organization
What does ‘quality’ mean in the context of FPPs? - 2
19 April, 2017
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

7. Quality Specifications & Testing of the FPP
World Health Organization
Quality Specifications & Testing of the FPP
19 April, 2017
ICH:
“Specifications are part of a total quality strategy… designed to ensure product quality & consistency”
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

8. Quality Specifications & Testing of the FPP
World Health Organization
Quality Specifications & Testing of the FPP
19 April, 2017
Some terminology

9. World Health Organization
“Specification” - 1
19 April, 2017
“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)

10. World Health Organization
“Specification” - 2
19 April, 2017
“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)

11. “Acceptance criteria”
World Health Organization
“Acceptance criteria”
19 April, 2017
“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’.

12. A typical monograph for an FPP might include: - 1
World Health Organization
A typical monograph for an FPP might include: - 1
19 April, 2017
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

13. A typical monograph for an FPP might include: - 2
World Health Organization
A typical monograph for an FPP might include: - 2
19 April, 2017
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)

14. The monograph as a whole
World Health Organization
The monograph as a whole
19 April, 2017
“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)

15. Sources of guidance as to the content of monographs for FPPs
World Health Organization
Sources of guidance as to the content of monographs for FPPs
19 April, 2017
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)

16. Internationally recognised pharmacopoeias
World Health Organization
Internationally recognised pharmacopoeias
19 April, 2017
International Pharmacopoeia (Ph Int)
Published by WHO
United States Pharmacopeia (USP)
Japanese Pharmacopoeia (JP)
European Pharmacopoeia (EP)
British Pharmacopoeia (BP)

17. Pharmacopoeias – PQP’s view?
World Health Organization
Pharmacopoeias – PQP’s view?
19 April, 2017
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

18. ICH guidelines & FPP specifications
World Health Organization
ICH guidelines & FPP specifications
19 April, 2017
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

19. An important ICH guideline
World Health Organization
An important ICH guideline
19 April, 2017
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 !

20. Other relevant ICH guidelines
World Health Organization
Other relevant ICH guidelines
19 April, 2017
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

21. Impurities in non-new FPPs
World Health Organization
Impurities in non-new FPPs
19 April, 2017
“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)

22. Deciding acceptance criteria
World Health Organization
Deciding acceptance criteria
19 April, 2017
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)

23. Parametric release & end product testing
World Health Organization
Parametric release & end product testing
19 April, 2017
Sterility 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

24. Periodic & skip testing - 1
World Health Organization
Periodic & skip testing - 1
19 April, 2017
“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

25. Periodic & skip testing - 2
World Health Organization
Periodic & skip testing - 2
19 April, 2017
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.

26. Release & expiry limits
World Health Organization
Release & expiry limits
19 April, 2017
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.

27. Alternative test procedures
World Health Organization
Alternative test procedures
19 April, 2017
Pharmacopoeias & 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.

28. World Health Organization
19 April, 2017
Dissolution testing

29. Dissolution test methods & acceptance criteria: Available guidelines
World Health Organization
Dissolution test methods & acceptance criteria: Available guidelines
19 April, 2017
“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”
“Dissolution testing”
WHO PQP: Guideline on Submission of Documentation for Prequalification of Multisource (Generic) FPPs: Supplement 1.

30. For what purposes are dissolution studies conducted?
World Health Organization
For what purposes are dissolution studies conducted?
19 April, 2017
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

31. What constitutes a good dissolution test?
World Health Organization
What constitutes a good dissolution test?
19 April, 2017
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

32. Formal ‘validation’ of dissolution test methodology
World Health Organization
Formal ‘validation’ of dissolution test methodology
19 April, 2017
Examples:
Repeatability studies
System suitability tests
Eg using USP dissolution calibrators
Manual vs automated procedures
Analytical methodology

33. World Health Organization
What should we take into account when choosing dissolution test methods & acceptance criteria? - 1
19 April, 2017
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

34. World Health Organization
What information should we take into account when choosing dissolution test methods & acceptance criteria? - 2
19 April, 2017
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
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

35. Dissolution testing: Decisions to make
World Health Organization
Dissolution testing: Decisions to make
19 April, 2017
Apparatus
Medium (solvent)
Sampling times
Acceptance criteria

36. Dissolution test methods: Apparatus - 1
World Health Organization
Dissolution test methods: Apparatus - 1
19 April, 2017
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)

37. Dissolution test methods: Apparatus - 2
World Health Organization
Dissolution test methods: Apparatus - 2
19 April, 2017
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

38. Dissolution test methods: Apparatus - 3
World Health Organization
Dissolution test methods: Apparatus - 3
19 April, 2017
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

39. Dissolution test methods: Medium/solvent
World Health Organization
Dissolution test methods: Medium/solvent
19 April, 2017
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

40. Dissolution test methods: Sampling times - 1
World Health Organization
Dissolution test methods: Sampling times - 1
19 April, 2017
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

41. Dissolution test methods: Sampling times - 2
World Health Organization
Dissolution test methods: Sampling times - 2
19 April, 2017
Some relatively recent (but non-official) non- numerical terminology:
‘Very rapidly dissolving’
≥ 85% in 15 minutes
‘Rapidly dissolving’
≥ 85% in 30 minutes

42. Dissolution test methods: Sampling times - 3
World Health Organization
Dissolution test methods: Sampling times - 3
19 April, 2017
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)

43. Dissolution test methods: Sampling times - 4
World Health Organization
Dissolution test methods: Sampling times - 4
19 April, 2017
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:
Recently defined as >85% in 30 minutes but the FDA dissolution guideline did not define the term

44. Dissolution test methods: Sampling times - 5
World Health Organization
Dissolution test methods: Sampling times - 5
19 April, 2017
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.

45. Dissolution test methods: Sampling times - 6
World Health Organization
Dissolution test methods: Sampling times - 6
19 April, 2017
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 test
Acceptable for most immediate release products
Or specify a single point dissolution test
Acceptable for most immediate release products that contain highly soluble & rapidly dissolving APIs
But each case must be considered individually

46. Deciding acceptance criteria - 1
World Health Organization
Deciding acceptance criteria - 1
19 April, 2017
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)

47. Deciding acceptance criteria - 2
World Health Organization
Deciding acceptance criteria - 2
19 April, 2017
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)

48. Deciding acceptance criteria - 3
World Health Organization
Deciding acceptance criteria - 3
19 April, 2017
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

49. Comparing dissolution profiles
World Health Organization
Comparing dissolution profiles
19 April, 2017
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

50. Summary and conclusion
World Health Organization
Summary and conclusion
19 April, 2017
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