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Pharmaceutical Development

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

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April 2007

Pharmaceutical Development
Applications for prequalification:
Dossier requirements


Jnos Pogny, pharmacist, PhD
WHO expert

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Pharmaceutical Development
Outline and Objectives of presentation
Multisource (generic) products Products from ICH regions New products developed by generic manufacturers Main points

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Guideline on Assessment Procedure

Guideline on Submission of Documentation for Prequalification of Multi-Source (Generic) Finished Pharmaceutical Products (FPPs) Used in the Treatment of HIV / AIDS, Malaria and Tuberculosis [Generic Guideline under revision]
Pharmaceutical Quality Information Form A properly filled out and signed original copy of the PQIF with all its annexes (including a copy on CD-ROM in WinWord format ) must be submitted.

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Critical factors of FPP quality


Manufacturin g authorization Marketing authorization NATIONAL DRA1


GMP standards

Pharmacopeia standards

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High-risk APIs
FPP is not registered in the ICH region and associated countries API is not official in the internationally used major pharmacopoeias and ICH guidelines should be used for evaluation Reference standard/comparator is not available for:
Pharmaceutical equivalence studies Bioequivalence studies

Require particular attention by national DRAs as regards assessment of applications for marketing authorization / prequalification

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April 2007

Low-risk APIs
Certificate of suitability (CEP) is submitted (DRA) Active Pharmaceutical Ingredient Master File

Open part (APPLICANT) Closed part (WHO or DRA) Literature evidence of stability Synthesis impurities and degradants are controlled by monograph Class1 solvents excluded; class2 / class 3 solvents controlled

Pharmacopoeia monograph

FPP is registered in the ICH region (DRA)

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April 2007

Guideline on APIMF procedure

Full details of development chemistry, scale up, manufacturing process and process controls, validation, specifications at batch release and stability are available for assessment

Once the APIMF is prequalified, reference may be made to it in subsequent FPP applications
Conditions for reference
Version number and date must be assigned Information on regular updates must be provided

Availability of APIMF is critical for API inspection


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April 2007

2.2 Properties of API(s)

2.2.1 API not described in PhInt, PhEur or USP
Considered new, used for the first time in a FPP Risk estimation high Full information necessary

2.2.2 API described in PhInt, PhEur or USP

In use for a certain period of time Information on safety and efficacy available Risk estimation low(er) Control by the monograph, additional information beyond the scope of the monograph necessary

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April 2007

API not described in PhInt, PhEur or USP

Any in-house analytical procedure needs to be validated ICH Q2(R1) Reference standards/materials should be well characterized with documented purity ICH Q2(R1) Source
Official pharmacopoeial standards In-house standards

Characterization and evaluation of non-official standards

Method of manufacture Elucidation of structure Certificate of analysis Calibration against an official standard (if available)

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April 2007

PhInt - Reference substances

International Chemical Reference Substances are established on the advice of the WHO Expert Committee on Specifications for Pharmaceutical Preparations. (The stability of the International
Chemical Reference Substances kept at the Collaborating Centre is monitored by regular re-examination.)

International Infrared Reference Spectra WHO Collaborating Centre for Chemical Reference Substances (Apoteket AB, Centrallaboratoriet, ACL, Prismavgen 2, SE-141 75
Kungens Kurva, Sweden; Fax: +46 8 740 60 40; E-mail: )

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April 2007

API described in PhInt, PhEur or USP

Properties relevant/critical for the performance of the API

potential polymorphic forms particle size distribution User requirement for low solubility drugs (dissolution, bioequivalence) additional characteristics (e.g. hygroscopicity)

All manufacturing steps covering aseptic processing or sterilization must be validated Proof of TSE-safety
CEP Letter of attestation

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Q3A(R2) Decision tree Impurities

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Decision tree Polymorphism

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Residual solvent impurities

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2.5.1 API described in PhInt, PhEur or USP

Name the monograph Name any test methods referenced in the monograph but not appearing in it List of tests beyond the scope of the monograph: residual solvents, particle size, polymorphs, loss on drying, etc. Whenever an API has been prepared by a method liable to leave impurities not controlled in the pharmacopoeial monograph, these impurities (based on 3 to 10 batch analysis results) including residual organic solvents, as well as their maximum tolerance limits should be declared and controlled by a suitable test procedure.

2.6 Container closure system 2.7 API stability


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Batch number(s) of the FPPs used in

Clinical (bioequivalence) studies* Dissolution studies Mother batch Stability studies* CH0701001 CH070101A 400x30 tabs CH0701001 B 800x60 tabs CH0701001 04/2006 CH070101

CH0701002 CH0701003

Child batch 1 (pack size: 30 tablets)

CH070102A CH0701003 400x30 A 400x30 tabs tabs CH0701002 B 800x60 tabs CH070102 07/2006 CH0701003 B 53x60 tabs CH0701003 11/2006

Child batch 2 (pack size: 60 tablets)

Validation studies (approved batch size)

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3.5 Manufacturing process

A flow diagram should be presented giving the steps of the process and showing where materials enter the process. The critical steps and points at which process controls, intermediate tests or final product controls are conducted should be identified. Stages of manufacture, at which sampling is carried out for in-process control tests, should be indicated. A narrative description of the manufacturing process, including packaging, that represents the sequence of steps undertaken and the scale of production should also be provided. For sterile products, details of sterilization processes and/or aseptic procedures used must be described.

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Flow diagram
Start Activity

Flow diagram of a process Breaking the process down into unit operations and steps (activities)




Decision on sampling and IPC results


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Narrative of manufacturing process

1. Mix Amodiaquine hydrochloride, lactose monohydrate and maize starch in a high-shear, high-speed granulator for approximately 8 minutes 2. Mix maize starch and purified water in the heater until complete dissolution at approx. 70C. 3. Cool the mixture prepared in step 2 until the required temperature (NMT 60C) is reached. 4. Granulate the mixture prepared in step 1 whilst adding the mixture prepared in step 3 and mix until granulation endpoint is reached. 5. Add silica colloidal anhydrous and if necessary add purified water to the mixture from step 4 and mix until the granulation endpoint is reached. 6. .

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3.7 Process validation report

3.7.1 New (for the generic manufacturer) FPPs Tabulated batch analytical and in-process control data Certificates of analysis Batch production records Unusual findings, modifications or changes found necessary


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3.7 Process Validation and Evaluation

3.7.2 Established (for the generic manufacturer) FPPs Manufacturing as well as in-process and quality control testing data should be evaluated. All but NLT a total of 10-25 consecutive batches, manufactured over the period of the last 12 months, should be used when reviewing the results, to provide a statistically significant picture. Trend analysis should be presented. Rejected batches should not be included in the analysis but must be reported together with the reports of failure investigations.

See Notes page

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Case summary of 20 batches

Statistics Mean Median STD Range Minimum Maximum Conf. level, 95% Accept. Crit.

Av. wt. mg 347,6 346,9 5,2 22.3 337.0 359.3 2.4 3505%
April 2007

Dissolution % 99,6 100,0 2.5 10.0 95.6 105.6 1.3 75%, 40'

Assay % 98,2 97,5 2.2 8.8 95.0 103.8 1.0 90-110

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3.9.1 Specifications for the FPP

Standard Claimed (e.g., In-house, BP, PhEur, PhInt, USP) Specification Reference Number and/or Version Acceptance Criteria Test Analytical Procedure (Type/Source/Version) Batch release Shelf life

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3.9.1 Specifications for the FPP

Justification of the specifications (e.g., evolution of tests, analytical procedures, and acceptance criteria, exclusion of certain tests, differences from compendial standard):

Acceptance criteria for degradants in FDC-FPPs should be established with reference to the API they are derived from. If an impurity results from a chemical reaction between two or more APIs, then its acceptance limits should be calculated with reference to the worst case (API with the smallest area under the curve). Alternatively, the content of such impurities could be calculated in relation to their reference standards. Dissolution testing specifications should include all active components of the finished dosage form and utilize relevant media.

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Labeling and product information

3.12.1 Outer packaging or, where there is no outer packaging, on the immediate packaging. Typical deficiencies: List of excipients known to be a safety concern for some patients e.g. lactose, gluten, metabisulfites, parabens, ethanol, or tartrazine are not indicated. Storage instructions do not reflect stability conditions.

Summary of Product Characteristics (SmPC) is frequently not approved by the national DRA. (Particular problem with artemisinin-derivative FPPs.) The structure of SmPC does not follow that recommended by WHO.

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April 2007

Documentation for FPPs from ICH regions

An original or certified copy of WHO-type Certificate of a Pharmaceutical Product (CPP) Assessment report(s) issued by a DRA in the ICH regions If the composition, strength, specifications, materials, etc. are different from the product for which the CPP was issued, then pharmaceutical equivalence and bioequivalence should be demonstrated. If the primary packaging material of the product is different from the one approved by the DRA of the ICH regions, then stability testing data should be submitted. A sample should be provided. Change control: approved variations to the MA should be notified.

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April 2007

New products developed by generic manufacturers

Market authorization in ICH regions Not available Innovator FPPs with a single API (rarely also FDCs) are registered Dossier assessment Innovator methodology
Generic methodology for FPPs with a single API Additional features for fixed-dose combinations

Quality standard WHO and ICH guidelines Official compendia or in-house specifications

Multisource FPPs are registered

Generic methodology

Official compendia and in-house specifications

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Quality risks
Manufacture of APIs is not regulated
Pharmaceutical exports are not regulated Marketing Authorization (MA) is issued without evaluation by the NDRA Clinical studies are not required for generic MA Stability studies are not required for generic MA National GMP do not comply with WHO-GMP

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New products developed by generic manufacturers

Artemisinine-type antimalarial FPPs

Artesunate 60mg powder for injection is a life-saving FPP

Clinical studies on efficacy and safety should be evaluated High risk API (at the start of the PQ project) All issues described with non-compendial APIs and FPPs apply The FPP manufacturing process and its validation is complex It takes time to get into compliance

4-FDC antituberculotic FPPs and 3-FDC antiretroviral FPPs:

Compatibility testing of APIs Dissolution test development Non-routine manufacturing process

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Solubility of Artesunate and stability of solutions

pH 1 5 6 Dissolved material (mg/ml) 1,9 1,5 3,5 0.1N HCl 2 74 Conditions Water Time (h) Degradation (%) 2 0


12,2 0.1N NaOH 2 100

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Main points
Generic guideline is used for the assessment of dossiers submitted for prequalification
An electronic version of the PQIF facilitates evaluation

APIMF is the preferred form of presenting data and information on APIs Innovator FPPs are prequalified by a simple procedures
New products developed by generic manufacturers deserve special attention by quality assessors

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April 2007