Transcript Document 7215802

Workshop on GMP and Quality Assurance of
Multisource Tuberculosis Medicines
Kuala Lumpur – Malaysia
21-25 February 2005
Dossier Requirements
(quality part)
Theo Dekker, D.Sc., consultant to WHO
Research Institute for Industrial Pharmacy
North-West University, Potchefstroom, South Africa
[email protected]
Feb 2005
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TG Dekker – WHO, Malaysia
Some abbreviations
API
BP
CEP
CPP
EOI
FDC
FPP
ICH
Int.Ph.
JP
Ph.Eur.
SmPC
TB
USP
Feb 2005
Active pharmaceutical ingredient
British Pharmacopoeia
EU certificate of suitability
WHO-type Certificate of a Pharmaceutical Product
Expression of interest
Fixed dose combination
Finished pharmaceutical product
International Conference on Harmonization
International Pharmacopoeia
Japanese Pharmacopoeia
European Pharmacopoeia
Summary of product characteristics
Tuberculosis
United States Pharmacopeia
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5th Invitation for EOI (July 2004) (1)
First-line anti-TB products
1.
2.
3.

9.
Ethambutol hydrochloride (Eth) 400 mg tablets
Pyrazinamide (Py) 400 mg tablets
Isoniazid (INH) 300 mg tablets
Fixed dose combinations:
4. 2FDC: Rif/INH 150/75 mg tablets
5. 2FDC: Rif/INH 150/150 mg tablets
6. 2FDC: Eth/INH 400/150 mg tablets
7. 3FDC: Rif/INH/Eth 150/75/275 mg tablets
8. 4FDC: Rif/INH/Py/Eth 150/75/400/275 mg tablets
Streptomycin Sulfate 1g vial (injection)
Feb 2005
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5th Invitation for EOI (July 2004) (2)
Second-line anti-TB products
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
Water for injection 5ml vial (injection)
Amikacin 500mg/2 ml vial (injection)
Kanamycin 1g powder for injection, vial
Capreomycin 1g powder for injection, vial
Cycloserine 250mg tablets
Ethionamide 125 mg or 250mg tablets
Ofloxacin 200 mg tablets
Protionamide 125 mg or 250mg tablets
Para-Aminosalicylic Acid 100 g or 4 g granules or powder
Moxifloxacin 400 mg tablets
Feb 2005
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5th Invitation for EOI (July 2004) (3)
Formulations for children
 Dosage forms should be
1.
2.
3.
 soluble tablets,
 tablets with break line, and or
 sachets
Rifampicin 60 mg / Isoniazid 60mg / Pyrazinamide 150 mg
(R60/H30/Z150)
Rifampicin 60 mg / Isoniazid 30mg (R60/H30)
Rifampicin 60 mg / Isoniazid 60 mg (R60/H60)
Total number of products on current list: 22
Feb 2005
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Product characteristics
 When developing, evaluating and considering
finished pharmaceutical products (FPPs), the
following are the main characteristics:
 Safety
 Efficacy
 Quality
 These aspects are to some extent interrelated
 Quality (as part of GMP) must ensure
consistency of safety and efficacy of all batches
produced
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Guideline (ICH registered products)
Guideline on Submission of Documentation
for Finished Pharmaceutical Products (FPPs)
used in the treatment of HIV/AIDS, malaria
and tuberculosis and approved by Drug
Regulatory Authorities (DRAs) in the
International Conference on Harmonization
(ICH) region and associated countries,
including inter alia the European Union, Japan
and USA (handout)
Feb 2005
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ICH registered products - requirements
1.
2.
3.
4.
Certified copy of WHO-type CPP
Assessment report(s) issued by DRA
WHO-type batch certificate
Primary packaging differs from ICH approved?

Stability data in new packaging
5. Formulation, strength (??), specs., etc. differ?

Justification in favour of acceptability (BE?)
6. Submit sample(s) of FPP
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Guideline (Not ICH registered products)
Guideline on Submission of Documentation
for Prequalification of Multisource (Generic)
Finished Pharmaceutical Products (FPPs)
used in the Treatment of HIV/AIDS, Malaria and
Tuberculosis (hand-out)
Based on
Marketing Authorization of Pharmaceutical
Products with special Reference to Multisource
(Generic) Products: a Manual for a Drug
Regulatory Authority (Blue Book)
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Quality assessment - summary
The quality assessment includes the following aspects:
1 Characteristics of FPP 2/33
2 API (impurities, stability, specifications, etc) 3/33
3 Finished pharmaceutical product (FFP) 8/33
1. Pharmaceutical development 8/33
2. Formulation 9/33
3. Manufacturing process/validation 9/33
4. Excipients 12/33
5. Product specifications/control 12/33
6. Packaging 14/33
7. Stability testing (shelf-life) 14/33
8. Labelling/SmPC/PIL 19/33
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Administrative 1/33
A: Covering letter
 Statement: information is true and correct
B: Application (FPP dossier)
 Four main sections (with subsections)
 Stick to the sections prescribed
 Sections should be clearly marked
(preferably with securely fixed tags)
 Number all pages
 Table of contents
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Section 1. Characteristics of FPP 2/33
1 Details of product
2 Sample for visual inspection of product and
packaging
3 Regulatory status in other countries. List
countries in which:



Feb 2005
This product has been granted a marketing
authorization
this product has been withdrawn from the
market
the application for marketing has been rejected,
deferred or withdrawn
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Section 2. Active pharmaceutical
ingredient (API) 3/33 separate topic
2.1
2.2
2.3
2.4
2.5
2.6
2.7
Nomenclature (INN, Systematic, CAS, etc.)
Properties (structure, stereochemistry, etc)
Site of manufacture
Route of synthesis (impurities, etc)
Specifications (pharmacopoeia?)
Container closure system
Stability testing – re-test period & storage
-
 Open part of Drug Master File (DMF)
 CEP
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Section 2. API 3/33
The API (name) & strength per unit dose can be
considered the only constants when starting to
development the dosage form and to chose primary
packaging materials. Thus, it is important to
understand:
 The physical properties, which should be well studied and
dealt with (e.g. flowability, particle size, polymorphism,
hygroscopicity, solubility)
 The chemical properties, especially aspects such as
- stability (mainly hydrolysis, oxidation & photolysis)
- possible API-excipient interactions
- API-API interactions in FDCs
(API details will be dealt with in separate session)
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Section 3. Finished pharmaceutical product
(FPP) 8/33
3.1 Authorisation 8/33
 Submit valid manufacturing authorisation for
pharmaceutical production
 Submit marketing authorisation
 To demonstrate that product is registered or
licensed according to national requirements
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3.2 Pharmaceutical development 8/33
separate topic
Pharmaceutical R & D provides the foundation of the
activities aimed at ensuring that the patient receives
an FPP (product) that consistently meets established
standards & specifications of
 Safety
 Efficacy
 Quality, including stability
Typical aspects covered in development studies:
 Choice of dosage form, excipients & packaging
 Compatibilities of API with excipients, primary packaging
materials, and other APIs (in FDCs)
 Development/validation of analytical methods
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Pharmaceutical development
1. Learn about the product through desk research:


Collect & analyse available information on e.g. APIs,
formulas, excipients, compatibility, stability, dosage form,
strength, packaging & analysis.
Compile a Product Profile Report
2. Development according to plan, including:






Preformulation studies
Formula / dosage form development & packaging
Development/validation of analytical techniques
Comparative dissolution studies
(Accelerated) stability
Final formula / manufacturing process
3. Provide a development report
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3.3 Formulation 9/33
 Formula in tabulated form for:
 Administration unit (e.g. one tablet)
 Typical batch
 Excipients
 State function (e.g. lubricant, disintegrant)
 Special technical grade (e.g. micronised, purified
water)
 Also those removed during process (e.g. water)
 Also those not always added (e.g. acid & alkali)
 Capsule shells, inked imprints on dosage form
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Formulation table example
Quantity per Quantity per
Ingredient
Purpose
tablet (mg)
batch (kg)
Isoniazid
300.00
30.00
Active
---------------- ---------------- ---------------- -------------Mg Stearate
2.00
0.20
Lubricant
Pur. Water‫٭‬
60.0
6.00
Solvent
Total
450.00
45.00
100 000 tablets
‫ ٭‬Removed during process (not in total mass)
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3.4 Sites of manufacture 9/33
For each facility where all/part of manufacturing
occurs, including production, packaging & QC:




Name of manufacturer
Street address
Phone & fax numbers
E-mail addresses
 For major production sites submit
 WHO type of CPP
 Valid GMP certificate
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3.5 Manufacturing process 9/33
a. Flow diagram

Indicate critical steps – in-process controls
b. Description of manufacturing/packaging




Feb 2005
Scale
Equipment by type (e.g. tumble dryer) & capacity
Process parameters for steps, e.g. time, temp,
pH
Environmental conditions, e.g. rel. humidity for
hygroscopic FPPs.
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Manufacturing process (continued)
Proposal for reprocessing – justified with data
Copy of master formula
Batch manufacturing record – real batch
Sterile products – sterilisation steps &/or
aseptic procedures
g. Description of in-process tests
h. Data for ≥ 3 full scale batches to support
achievement of predetermined specifications
c.
d.
e.
f.
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3.6 Process controls 10/33
 Critical steps
 Acceptance criteria (justified)
 Tests (cross reference)
 Intermediates isolated during process
 Acceptance criteria (justified if not compendial)
 Tests (cross reference)
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3.7 Process validation & evaluation 10/33
Differentiate between the following generics:
3.7.1 New FPPs (new for manufacturer)
 FPPs that have been newly developed by the
manufacturer, though it will be a generic
 Full validation required
3.7.2 Established FPPs
 The manufacturer has manufactured & marketed
this FPP for quite some time and now wishes to
prequalify the FPP
 ≥ 10 recent consecutive batches –
result/trend/statistical analysis & discussion
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3.7.1 Validation “new” product 10/33
Demonstrate validity of the process
 Report for 3 production batches, including




Batch analytical data
CoAs
Batch production records
Conclusions
 Otherwise validation protocol – with commitment
 See guidelines for protocol requirements (page 11/33)
 Report will be available for inspection
 Validation report to be submitted (page 11/33)
Sound pharmaceutical R&D and a valid process
= reproducible product of good quality
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3.8 Excipients - specifications 12/33
 Of natural origin?
 Microbial limits (skip-testing)
 Of human or animal origin? Info on
adventitious agents, such as:
 TSE/BSE (e.g. Mg-stearate from animal origin)
 Asbestos in talc (test included in current
BP/Ph.Eur. – IR and XRPD)
 Colours permitted by:
 EU, FDA, Japan (references bottom p. 12/33)
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3.8.1 Excipients not in compendia 12/33
 Such excipients not recommended
 See guideline for requirements
 Some standard mixtures comprising excipients
in pharmacopoeia, e.g. Opadry colours
 Table with composition of such mixture
 Specifications with tests (normally from supplier)
Compendia (pharmacopoeias) considered:
 International Pharmacopoeia (Int.Ph.)
 BP, JP, Ph.Eur, USP (ICH region)
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3.8.2 Excipients described in compendia
12/33
 Provide a copy of monograph
 Also copies of methods referred to in monograph
but not appearing in monograph
 Current pharmacopoeial monograph always
applicable
 If monograph change, new monograph valid
 Details of any specifications additional to
monograph
 E.g. particle size, residual solvents
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3.9 Control of FPP 12/33
Four subsections:
1. Specifications
2. Analytical procedures
3. Validation of analytical procedures
4. Batch analysis
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3.9.1 Specifications for the FPP 12/33
Specifications are one part of a total control
strategy for the FPP designed to ensure
product quality and consistency (ICH: Q6A).
 Others include adherence to GMP; e.g., suitable
facilities, a validated manufacturing process, inprocess testing, stability testing, API testing, etc.
 Product specifications (as in pharmacopoeia)
or split into:
 Release specifications
 Shelf-life specifications (may differ if justified)
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3.9.1 FPP specifications – continued
Important reading for setting specifications:
 ICH guideline Q6A (also good for generics):
 Specifications: Test Procedures and Acceptance Criteria
for New Drug Substances and New Drug Products:
Chemical Substances.
Specifications based on pharmacopoeia:
 Additional product related specifications, e.g.
 Those standard for the dosage form (e.g. friability, tablet
hardness, mass uniformity)
 ID of (coating) colorants, microbial limits (skip testing?)
 Related substances in USP monograph for TB 4FDC
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3.9.1 FPP specifications – typical
1. Appearance
2. Identification of the following in FPP



APIs
Colorants (skip testing possible)
Preservatives
3. Physical tests appropriate to dosage form e.g.

LOD, friability, hardness (tabs), relative density
4. Uniformity of dosage units (mass / content)
5. Pharmaceutical tests, e.g. dissolution
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3.9.1 FPP specifications – typical (con.)
6. Purity tests


Degradation products (related substances)
Residual solvents (solvents used in process)
7. Microbial count / sterility / bacterial endotoxins
8. Content of APIs in FPP (assay)

Limits 95.0% – 105.0%, unless justified
9. Content of preservatives

Feb 2005
Limits 90.0% – 110.0%, generally acceptable
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Example - FPP specs – uncoated tablets
Attribute
Release limits
Stability limits
Appearance
Full description
Same as release
Identification
At least 1 method
Dimensions
Diameter, etc
Average mass
w.r.t. theoretical
Not required for
stability studies.
Not regarded as
variables for
product.
Mass uniformity
Ph.Eur/USP/Int.Ph
Tablet hardness* product specific
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Same as release
TG Dekker – WHO, Malaysia
Example of FPP specs – uncoated tabs (con.)
Attribute
Release limits
Stability limits
Friability*
≤ 1 % (normally)
Same as release
Dissolution
Set per product
Same as release
Disintegration
Not required if dissolution is done
Rel. substances
(degradants)
Only if formed
during production
95.0-105.0%,
unless justified
Assay (content)
Microbial limits
Required. Limits
to one decimal
May be 90.0105.0, justified
Skip-testing
* Tests not necessary at release if done in-process
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FPP specifications – special for FDCs
 Degradants (related substances) must be stated &
calculated in % with reference to the parent API, not
the sum of the APIs, e.g.
 Rifampicin / isoniazid tablets. Rifampicin quinone
(degradant) as % of rifampicin.
 If 2 APIs react with each other, then the degradant to
be stated with respect to worst case, e.g.
 Rifampicin / isoniazid tablets. A Hydrazone forms from the
2 APIs. Specification: % hydrazone with respect to
rifampicin (worst case in mass balance).
 Unknown degradants – with respect to worst case
 Dissolution – include all APIs (e.g. FDCs in the USP)
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3.9.2 Analytical procedures 13/33
 Methods to be described in detail
 Copy of standard monograph tests (e.g. friability)
 System suitability included in HPLC methods
 Pharmacopoeial based control:
 Copy of monograph (latest edition)
 Methods of additional tests (e.g. ID of coating
colorants)
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3.9.3 Validation analytical methods 13/33
 Non-pharmacopoeial methods
 All methods should be validated
 Validation reports, including data & conclusions
 Stability of sample/standard solutions
 Pharmacopoeial methods
 Partial validation (to show validity for this
formulation – specificity important)
 Validation study - ICH guidelines:
 Q2A & Q2B
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ICH (Q2A) table - validation parameters 13/33
Test
ID
impurities
quantitative limit
Accuracy
Precision
Repeatability
Iterm. precision
Specificity
Detection limit
+
Quantitation limit
Linearity
Range
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Assay
Incl. diss.
+
+
+
+
+
+?
+
+
+
+
+
+
+
+
+
+
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3.9.4 Batch analysis 14/33
Results of at least 3 batches










Feb 2005
Testing against for full set of specifications
Test date
QA certified
Batch number
Date of batch manufacture
Place of manufacture
Batch size (kg & units)
Primary packaging materials
Purpose of batches (stability, commercial, etc.)
API batch number
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3.10 Packaging 14/33
 Container/closure system
 Suitability for storage, transport, compatibility
 Detailed description, including liner/wadding
 Specifications:
- Description
- Identification (Typical: IR - specific)
- Drawings and critical dimensions
 Outer packaging
 Description, material
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3.11 Stability testing 14/33 separate topic
 The purpose of stability testing is to provide evidence
on how the quality of a FPP varies with time under
the influence of a variety of environmental conditions
such as temperature, humidity and light and to
establish a shelf-life for the FPP (from current EMEA
guidance CPMP/QWP/122/02).
 Stability studies should be performed
- on each individual strength
- each type of commercial container and
- each container size (unless bracketing/matrixing)
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Stability parameters (attributes)
Stability studies should include testing of those
attributes of the FPP that are
 susceptible to change during storage and are
 likely to influence quality, safety, and/or efficacy.
 The testing should cover, as appropriate, the
physical, chemical, biological, and microbiological
attributes, preservative content (e.g., antioxidant,
antimicrobial preservative), and functionality tests
(e.g., for a dose delivery system)
From ICH Q1A(R2)
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Tablets – stability parameters
 Parameters specifically for tablets (often
omitted)
 Tablet strength, friability and moisture can change
with time
– if not in release specs, include in stability
– these are interrelated, also with dissolution
 Microbial limit at release and end-of-shelf
 Dissolution specification must be same as for
release
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Stability report
See Annex 2 (Guidelines)
1. Info on batches tested
2. Unit composition (or cross-reference)
3. Container closure system (commercial!!)
4. Literature and/or supporting data
5. Methods – stability indicating (cross-reference)
6. Stability plan (schedule)
7. Tabulated test data (including specifications)
8. Analysis/discussion of data (statistical if negative trend)
9. Shelf-life proposal (including storage condition)
10. Post approval commitments
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Testing frequency & storage conditions
Solid oral dosage forms (tablets, capsules):
Condition▼
Month►
0
3
6
9 12 18 24 36
30ºC / 65% RH (zone IV) X X X X X X X X
40ºC / 75% RH (accel)
X X
25ºC / 60% RH (zone II)
X X X X X X X
 Zone IV is real-time condition for prequalification
project unless otherwise justified
 Zone II only if justified (may be fall-back for zone IV)
 ASEAN proposal for zone IV: 30ºC / 75% RH
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3.12 Container labelling 19/33
1. Outer packaging (where no outer packaging,
on immediate packaging – e.g.securitainer)
2. Blisters and strips
 All the elements as listed on pages 19-20 of:

Feb 2005
Guideline on Submission of Documentation for
Prequalification of Multisource (Generic)
Finished Pharmaceutical Products (FPPs) Used
in the Treatment of HIV/AIDS, Malaria and
Tuberculosis.
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SmPC and PIL 20/33
3.13 Summary of product characteristics (SmPC)
 To appear in WHOPAR
 Changes to SmPC to be approved by WHO
 See Annex 3 of guideline
3.14 Patient information leaflet (PIL)
 To appear in WHOPAR
 In conformance with SmPC
 From quality side, include in SmPC & PIL:
 Identification of dosage form in detail
 Presentation in detail
 Storage requirements and approved shelf-life
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Variations
Draft guidance on variations with respect to
the dossier submitted and accepted in the
Prequalification Programme
(Handout)
 ANNEX I (p. 3) - minor changes
 ANNEX II (p. 27) - major changes in general
 ANNEX III (p. 29) - types of changes requiring
a new application
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Minor changes
 A minor change is a change concerning an
amendment to the contents of the documents such as
they existed at the time of listing as prequalified
 The request, with documentation, for a minor change
must be submitted for approval
 The minor changes in the guideline are listed in
numerical order, with the conditions to meet and
documentation required
 Currently 41 minor type of changes listed
 A few examples to follow (follow guideline numbers)
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4. Change in the name and/or address of a
manufacturer of the API (where no CEP is available)
Condition

The manufacturing site shall remain the same
Documentation


Feb 2005
A formal document from a relevant official body in which
the new name and/or address is mentioned
Replacement page(s) of Section 3.2 (A new name and or a
new address of the sites of manufacture) in the product
dossier
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9. Minor change in the manufacturing
process of the active substance
Conditions
1. No change in qualitative and quantitative impurity profile
or in physico-chemical properties
2. The synthesis route remains the same, i.e. intermediates
remain the same
Documentation
1. Amendment to the relevant sections 3.4-3.5 of the
product dossier and of the approved DMF (where
applicable), including a direct comparison of the present
process and the new process
2. Batch analysis data (in comparative tabular format) of at
least two batches (minimum pilot scale) manufactured
according to the currently approved and proposed
process
3. Copy of approved specifications of the API
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12. Change in test procedure for API,
starting chemicals, intermediate, or reagent
used in the manufacturing process of an API
Conditions (depending on change, not all applicable)
1. The method of analysis should remain the same (e.g. a
change in column length or temperature, but not a
different type of column or method); no new impurities are
detected
2. Appropriate (re-)validation studies have been performed in
accordance with relevant guidelines
3. Results of method validation show new test procedure to
be at least equivalent to the former procedure.
4. Any new test method does not concern a novel nonstandard technique or a standard technique used in a
novel way
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12. Change in test procedure for API,
etc. (cont.)
Documentation (depending on change, not all
applicable)
1. Amendment to the section 3.4 of the product dossier,
which includes a description of the analytical
methodology, a summary of validation data, revised
specifications for impurities (if applicable); amendment to
the section 3.5 of the product dossier if applicable)
2. Comparative validation results showing that the current
test and the proposed one are equivalent
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31. Minor change in the manufacture of the
finished product
Conditions
1. The overall manufacturing principle remains the same
2. The new process must lead to an identical product
regarding all aspects of quality, safety and efficacy
3. In case of a change in the sterilisation process, the
change is to a standard pharmacopoeial cycle only
4. Relevant stability studies in accordance with the relevant
guidelines have been started with at least three production
batches and at least three months’ stability data are at the
disposal of the applicant. Assurance is given that these
studies will be finalised and that the data will be provided
immediately to the competent authorities if outside
specifications or potentially outside specifications at the
end of the approved shelf life (with proposed action)
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31. Minor change in the manufacture of the
finished product (cont.)
Documentation
1. Amended relevant sections of the part 4: Finished product
of the product dossier
2. For semi-solid and liquid products in which the API is
present in non-dissolved form: appropriate validation of
the change including microscopic imaging of particles to
check for visible changes in morphology; comparative size
distribution data by appropriate method
3. For solid dosage forms: dissolution profile data of one
representative production batch and comparative data of
the last three batches from the previous process; data on
the next two full production batches should be available on
request or reported if outside specification (with proposed
action)
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31. Minor change in the manufacture of the
finished product (cont.)
Documentation (cont.)
4. Justification for not submitting a new BE study according
to the current WHO guideline (WHO TRS, No.863). In
case of a change to the sterilisation process, validation
data should be provided
5. Copy of approved release and end-of-shelf life
specifications
6. Batch analysis data (in a comparative tabulated format)
on a minimum of three batches manufactured to both the
currently approved and the proposed process. Batch data
on the next two full production batches should be made
available upon request and reported by the applicant if
outside specification (with proposed action)
7. The batch numbers of stability batches
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Major changes
 A major change is a change to the documentation
which can neither be deemed to be a minor change
within the meaning of preceding definition (therefore
exceeding the frame of a minor change) nor to be a
change for which a new application would be
necessary
 Most likely



Feb 2005
Change in the manufacturing process of the API
Change in the composition of the finished product
Change of immediate packaging of the finished product
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TG Dekker – WHO, Malaysia
New dossier
Certain changes to a prequalified FPP are so major
that they are considered to fundamentally alter the
terms of prequalification and consequently cannot be
considered as a change. For these changes a new
dossier must be submitted.
1. Changes to the API:




Feb 2005
Change of the API to a different API
Inclusion of an additional API to a multi-component
product (FDC)
Removal of one API from a multi-component product
Change in the dose of one or more APIs
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TG Dekker – WHO, Malaysia
New dossier (2)
2. Changes to the pharmaceutical form/dosage
form


Change from an immediate release product to a slow- or
delayed-release dosage form and vice versa
Change from a liquid to a powder for reconstitution, or
vice versa
3. Changes in the route of administration
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Conclusion from PQ objective
 “The objective of the [prequalification] project, is to
assess the acceptability in principle of TB drugs for
procurement by UN Agencies. The assessment
procedure is aimed at identifying products and
suppliers meeting WHO standards. Thus, the project
facilitates the procurement of TB related drugs of
acceptable quality” [Prequalification website]
 The quality assessment includes changes to
prequalified products
 ICH guidelines are used when a quality aspect
cannot be assessed by the WHO guidelines
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