Transcript 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 | Slide.

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
Presenter:
János Pogány, pharmacist, PhD
[email protected]
WHO expert
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April 2007
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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April 2007
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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April 2007
Critical factors of FPP quality
INACTIVE
INGREDIENTS
Manufacturin
g
authorization
Marketing
authorization
NATIONAL
DRA1
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April 2007
ACTIVE
INGREDIENTS
FPP
MANUFACTURE
R
PACKING
MATERIALS
GMP
standards
Pharmacopeia
standards
NATIONAL
DRA2
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)
Pharmacopoeia monograph
–
–
–

Literature evidence of stability
Synthesis impurities and degradants are controlled by
monograph
Class1 solvents excluded; class2 / class 3 solvents controlled
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
http://mednet3.who.int/prequal/
 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
–
–
–
–
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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
–
–
–
–
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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, Prismavägen 2, SE-141 75
Kungens Kurva, Sweden; Fax: +46 8 740 60 40; E-mail:
[email protected] )
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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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April 2007
Q3A(R2) Decision tree – Impurities
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April 2007
Decision tree – Polymorphism
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April 2007
Residual solvent impurities
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April 2007
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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April 2007
Batch number(s) of the FPPs used in
Clinical (bioequivalence) studies*
CH070101
Dissolution studies
CH070101
CH0701001
CH0701002
Child batch 1 (pack size: 30 tablets)
CH070101A
400x30
tabs
CH070102A CH0701003
400x30
A 400x30
tabs
tabs
Child batch 2 (pack size: 60 tablets)
CH0701001
B 800x60
tabs
CH0701002
B 800x60
tabs
CH0701003
B 53x60
tabs
Validation studies (approved batch size)
CH0701001
04/2006
CH070102
07/2006
CH0701003
11/2006
“Mother” batch
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Stability studies*
April 2007
CH0701003
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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April 2007
Flow diagram
 Flow diagram
of a process
Start
 Breaking the process down
into unit operations and
steps (activities)
Activity
Activity
Decision
No
Yes
End
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April 2007
Action
 Decision on sampling and
IPC results
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. 70°C.
3. Cool the mixture prepared in step 2 until the required temperature (NMT
60°C) 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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April 2007
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
 Conclusions
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April 2007
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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April 2007
Case summary of 20 batches
Statistics
Av. wt. mg
Dissolution %
Assay %
Mean
347,6
99,6
98,2
Median
346,9
100,0
97,5
STD
5,2
2.5
2.2
Range
22.3
10.0
8.8
Minimum
337.0
95.6
95.0
Maximum
359.3
105.6
103.8
2.4
1.3
1.0
350±5%
75%, 40'
90-110
Conf. level, 95%
Accept. Crit.
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April 2007
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
Analytical Procedure
(Type/Source/Version)
Test
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April 2007
Batch
release
Shelf life
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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April 2007
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
Dossier assessment
Quality standard
Not available
Innovator
methodology
WHO and ICH
guidelines
Innovator FPPs with
a single API (rarely
also FDCs) are
registered
Generic methodology for
FPPs with a single API
Official compendia or
in-house
specifications
Multisource FPPs are
registered
Generic methodology
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April 2007
Additional features for
fixed-dose combinations
Official compendia
and in-house
specifications
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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April 2007
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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April 2007
Solubility of Artesunate and stability of solutions
pH
1
Dissolved
material (mg/ml)
1,9
5
1,5
6
3,5
7
10,2
8
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12,2
April 2007
Conditions
Time (h) Degradation
(%)
Water
2
0
0.1N HCl
2
74
0.1N
NaOH
2
100
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
THANK YOU
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April 2007