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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 iiftgd@puk.ac.za
Feb 2005

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. 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) 3
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9.

Feb 2005

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 4
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Feb 2005

5th Invitation for EOI (July 2004) (3)


Formulations for children Dosage forms should be
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)

1. 2. 3.

Total number of products on current list: 22


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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 Justification in favour of acceptability (BE?)

5. Formulation, strength (??), specs., etc. differ?

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:

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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
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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

Feb 2005

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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
Preformulation studies Formula / dosage form development & packaging Development/validation of analytical techniques Comparative dissolution studies (Accelerated) stability Final formula / manufacturing process

2. Development according to plan, including:

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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Feb 2005

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


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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b. Description of manufacturing/packaging

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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 31
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Feb 2005

3.9.1 FPP specifications typical


1. Appearance 2. Identification of the following in FPP

APIs Colorants (skip testing possible) Preservatives


LOD, friability, hardness (tabs), relative density

3. Physical tests appropriate to dosage form e.g.


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 Limits 90.0% 110.0%, generally acceptable

9. Content of preservatives

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Example - FPP specs uncoated tablets


Attribute Appearance Identification Release limits Full description At least 1 method Stability limits Same as release Not required for stability studies. Not regarded as variables for product.

Dimensions Average mass


Mass uniformity

Diameter, etc w.r.t. theoretical


Ph.Eur/USP/Int.Ph

Tablet hardness* product specific


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Same as release
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Example of FPP specs uncoated tabs (con.)


Attribute
Friability* Dissolution

Release limits
1 % (normally) Set per product Only if formed during production 95.0-105.0%, unless justified

Stability limits
Same as release Same as release Required. Limits to one decimal May be 90.0105.0, justified

Disintegration
Rel. substances (degradants) Assay (content)

Not required if dissolution is done

Microbial limits

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 Accuracy Precision Repeatability Iterm. precision Specificity Detection limit Quantitation limit Linearity Range
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ID

impurities quantitative limit + +

Assay Incl. diss. + +

+ + +? + + + 39

+ +

+ +

+ +
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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 40
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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 45

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Testing frequency & storage conditions


Solid oral dosage forms (tablets, capsules): Condition Month 0 3 6 9 12 18 24 36

30C / 65% RH (zone IV) X X X X X X X X 40C / 75% RH (accel) 25C / 60% RH (zone II) X X 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: 30C / 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:
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 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

Documentation

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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
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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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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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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