Pharmaceutical Development Workshop

Pharmaceutical
Development
Lynda Paleshnuik
Training workshop: Training workshop on regulatory requirements for registration of Artemisinin based combined medicines and
.assessment of data submitted to regulatory authorities, February 23-27, 2009, Kampala, Uganda
Acronyms
 ACT – artemisinin-based combination therapy
 API – active pharmaceutical ingredient
 BCS – biopharmaceutics classification system
 BE – bioequivalence
 CTD – common technical document
 FDC – fixed dose combination
 FPP – finished pharmaceutical product
Artemisinin based combined medicines

February 23-27, 2009, Kampala, Uganda
2|
Pharmaceutical Development
Overview
Important Background Information
- ACT’s in the Expression of Interest (EOI)/Comparators
- The Role of BE in Quality Assessment
- Requirements for “Established” Generic Products
- WHO Guidelines for Pharmaceutical Development

3|
Overview
Definitions
Formulation Development
Approaches: Empirical vs Systematic
Reverse-engineering
API Characteristics
API-API and API-Excipient Compatibility
Excipient choices: function and concentration

4|
Overview
FPP Development Data
Dissolution
Scoring Requirements
Justification of Overages
Microbial Attributes
Compatibility with Reconstitution Diluents/Dosage Devices
Comparative Formulation Tables

5|
Overview
Process Development
Summaries/Conclusions of Developmental Work

6|
Expression of Interest (EOI)
The current EOI (6th) covers 7 API’s in 4 combination

products:
Artemether/Lumefantrine FDC
Artesunate/Amodiaquine FDC or co-blistered
Artesunate/Mefloquine FDC or co-blistered
Artesunate/Sulfadoxine/Pyrimethamine FDC or co-blistered

7|
Comparators
The current comparator list (October 2008) lists

comparators for each of the ACT’s:
Artemether/Lumefantrine: Riamet or Coartem
Artesunate/Amodiaquine: Arsuamoon and Flavoquine
Artesunate/Mefloquine: Arsuamoon and Lariam
Artesunate/Sulfadoxine/Pyrimethamine: Arsuamoon and

Fansidar

8|
The Role of BE in Quality Assessment
 Comparator products are available for each of the ACT’s, therefore
a biostudy should be provided for each dossier.
 In exceptional cases, (eg proportional strengths of a prequalified
product), a biowaiver may be acceptable. BCS-based biowaivers
are not appropriate for ACT’s.
 In either case, biostudy or biowaiver, a biobatch is used to
demonstrate bioequivalence or similarity to the comparator.
 This biobatch is the cornerstone of the quality assessment
process.
Biobatch: the test batch used in the biostudy to demonstrate
bioequivalence, or used in the biowaiver to demonstrate
similarity, compared to the comparator product.

9|
The Role of BE in Quality Assessment
Along with pharmaceutical development data, the biobatch

represents key information that is used throughout the quality
assessment.
The manufacturer must be careful to develop a production batch

which is representative of the biobatch.
The quality assessor must confirm during assessment that the

proposed production batches are representative of the biobatch.
To be considered representative of the biobatch, production

batches must have the same formulation and manufacturing
process (equipment, process and controls) as the biobatch.

10 |
Requirements for
New Versus Established Generics
Definition: Established Generic Product
A product which has been on the market for at least 5 years
AND
at least 10 batches were manufactured in the previous year.

11 |
Requirements for
New Versus Established Generics
Established Generic Requirements:
1) Pharmaceutical development report if available.
2) Annual report for the previous year.
Annual report = annual quality review or annual product review

(APR)
The annual report requirement fills the requirement for P.3.5 (3.2)
Process Validation (protocol/report), and for P.2 (3.7) sections
regarding pharmaceutical development data.

12 |
Annual Report Requirements
Objective: verifying the consistency of the quality of the FPP

and its manufacturing process
Requirements:
– Review conducted on NLT 10 consecutive production batches
manufactured over the previous year.
– Rejected batches should not be included in the analysis but
must be reported separately together with the reports of failure
investigations
– All data from batches manufactured during the review period
must be included in the review.
– Data should be presented in tabular form or in graphical form
(i.e., charts or graphs), when applicable.

13 |
Annual Report Requirements
The annual report should include:
 A review of starting and primary packing materials used in the FPP, especially those from
new sources.
 A tabulated review and statistical analysis of quality control and in-process control results.
 A review of all batches that failed to meet established specification(s).
 A review of all critical deviations or non-conformances and related investigations.
 A review of all changes carried out to the processes or analytical methods.
 A review of the results of the stability-monitoring program.
 A review of all quality-related returns, complaints and recalls, including export only
medicinal products.
 A review of adequacy of previous corrective actions.
 A list of validated analytical and manufacturing procedures and their revalidation dates.

14 |
WHO Guidelines
 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
http://healthtech.who.int/pq/info_applicants/Guidelines
 QAS/08.251 January 2008 – Draft Pharmaceutical
Development for Multisource (Generic) Pharmaceutical
Products
http://www.who.int/medicines/services/expertcommittees/pharmpre
p/PharmDevelGener_QAS08_251_11012008.pdf

15 |
WHO Guidelines
 TRS 929 Annex 5: Guidelines for Registration of fixed-dose
combination medicinal products.
Key sections:
6.3 Quality
6.3.2 Development considerations for FDC’s.
Appendix 3: pharmaceutical development (or preformulation)
studies.
 Supplement 2 to the Generics Main Guide.

16 |
Guidelines
 ICH Q8R1 dated November 13, 2008
 CDER Q8R1
http://www.fda.gov/cber/gdlns/ichq8pharmann.pdf
– Gives clarification of ICHQ8 concepts
– Describes the principles of QbD (quality by design)
– Shows how key concepts and tools such as design space can
be put into practice.

17 |
Definitions
Critical quality attributes (CQA’s):
Physical, chemical, biological, or microbiological property

or characteristic that should be within an appropriate limit,
range, or distribution to ensure the desired product
quality. CQAs are generally associated with the API(s),
excipients, intermediates, and drug product.
CQAs include the properties that impart the desired

quality, safety, and efficacy. CQAs of solid oral dosage
forms are typically those aspects affecting product purity,
potency, stability, and drug release.

18 |
Definitions
Critical quality attributes (CQA’s): [continued]
For APIs or intermediates, the CQAs can additionally include those

properties (e.g., particle size distribution, bulk density) that affect
downstream processability.
Drug product CQAs are used to guide the product and process
development. Potential drug product CQAs can be identified from
the target product profile and/or prior knowledge. The list of
potential CQAs can be modified when the formulation and
manufacturing process are selected and as product knowledge and
process understanding increase. Quality risk management can be
used to prioritize the list of potential CQAs for subsequent
evaluation.

19 |
Definitions
Critical Process Parameters (CPPs):
A process parameter whose variability has an impact on a

CQA and therefore should be monitored or controlled to
ensure the process produces the desired quality.

20 |
Definitions
Target product profile:
A prospective and dynamic summary of the quality characteristics

of a drug product that ideally will be achieved to ensure that the
desired quality, and hence the safety and efficacy, of a drug
product is realised. The target product profile forms the basis of
design for the development of the product.
Considerations should include dosage form and route, strengths,

API release or delivery and PK considerations (eg delayed vs
immediate vs controlled release) appropriate to the dosage form,
and quality criteria (eg sterility, purity) appropriate for the intended
marketed product.

21 |
Definition/Purpose
The information and knowledge gained from
pharmaceutical development studies and experience with
the manufacture of primary batches provide scientific
understanding to support the proposed CQAs of the FPP
(quality control (QC) and in-process control (IPC)
acceptance limits) and CPPs and their manufacturing
controls, which can be essential inputs for quality risk
management. [Draft QAS 08.251]

22 |
Definition/Purpose
Studies conducted to establish that the dosage form,
formulation, manufacturing process, container closure
system, microbiological attributes and usage instructions
are appropriate for the specified purpose.
Studies should identify formulation and process attributes

(critical parameters) that can influence batch
reproducibility, product performance and FPP quality,
including stability.
[Generics Main Guideline]

23 |
Pharmaceutical Equivalence Definition
Products are pharmaceutical equivalents if they contain the same
molar amount of the same API(s) in the same dosage form, if they
meet comparable standards, and if they are intended to be
administered by the same route. Pharmaceutical equivalence does
not necessarily imply therapeutic equivalence, as differences in the
excipients and/or the manufacturing process and some other
variables can lead to differences in product performance.
i.e: same amount of same API in the same dosage form with
the same route of administration. Excipients may differ.
Therapeutic Equivalence is demonstrated by BE studies.
Ref: TRS 937 Annex 7: Guidelines on Registration Requirements to
Establish Interchangeability

24 |
Approaches to
Pharmaceutical Development:
Empirical vs Systematic

25 |
Empirical vs Systematic
 Empirical (traditional): relies on experience and

observation, rather than theory and systems
 Systematic: exemplified by QbD (quality by design)
This talk deals with new generic drugs, solid orals, and
development via the empirical approach.

26 |
Formulation Development:
Reverse Engineering
Reverse Engineering: formulating a drug based on the qualitative
and quantitative (Q&Q) formulation of the comparator drug.
 Note that reverse engineering is not practical when there is more

than one comparator for a single FPP-FDC.
– Example: an artesunate/amodioquine FDC is unlikely to be made Q&Q to
Arsuamoon Tablets plus Flavoquine Tablets.
 Reverse engineering can be a starting point. However, the

establishment of bioequivalence between the finished product
and the comparator is the definitive measure of product
equivalence.

27 |
API Characteristics
 Solubility
Low solubility API (all ACT API’s with the exception of

amodioquine HCl):
- Particle size distribution and polymorphism are

important.
- Particle size distribution and polymorphic form in the

final product should be the same as the lot used in
biostudies.

28 |
API Characteristics

29 |
API Characteristics

30 |
API Characteristics
 Stability – intrinsic stability of API, compatibility studies
 Hygroscopicity –in relation to the manufacturing process

and final FPP
 Flowability
Reference to peer-reviewed literature is accepted.

31 |
Compatibility Studies
API-excipient compatibility: note that if an excipient is in
the comparator, the compatibility of that excipient may be
considered established. The applicant should therefore
include in the dossier the qualitative composition of
the comparator product(s).
For FDC’s, API-API compatibility must be established.
Guidance is provided in TRS 929 appendix 3 Table A.1

(2005) and Supplement 2 (2006).

32 |
Compatibility Studies: TRS 929

33 |
Compatibility Studies: S2
Provides a table of possible conditions for stress testing
the dose-proportional mixture of the APIs in solution or
suspension, and in solid state.
Provides a format for reporting of results.
Note: A visual description is not adequate, reporting

should include chromatographic results (purity/potency).

34 |
Excipient Choices
 The function and concentration of excipients should be
discussed.
 Where a functional excipient is used, eg pH-adjusting

agents, buffers, stabilizers (eg antioxidants and chelating
agents), preservatives and dissolution modifiers (eg
surface active agents), their ability to perform throughout
the shelf-life should be demonstrated.

35 |
Excipient Choices
 Some excipients are multi-functional by nature; different grades of
the same excipients (ie those with different physical properties)
may have different functional characteristics.
 In these cases, the pharmacopeial specifications may not be

sufficient, and user requirements may be additionally required.
 See Annex 5 in QAS 08.251, “Usual range of excipients in Tablets

and Capsules”. This table presents common excipients with their
various uses (eg MCC as binder, diluent or disintegrant) and the
usual concentration.

36 |
Excipient Choices

37 |
Excipient Choices
Additional sources of information
FDA Inactive ingredients database:
http://www.accessdata.fda.gov/scripts/cder/iig/index.cfm
Eg. pregelatinized starch:
Entries for starch 1500 pregelatinized, starch pregelatinized, starch

pregelatinized corn, and starch pregelatinized tapioca
Health Canada inactive ingredients site:
http://www.hc-sc.gc.ca/dhp-mps/prodnatur/legislation/docs/nmi-
imn_list1_e.html

38 |
Excipient Choices
NOTE: clearly identify all excipients in the formulation,
including grade used, in the executed biobatch records
and the blank production records.

39 |
Dissolution
 A discriminating dissolution method should be developed
for the final composition of the FPP.
 Limits should be set for each API in fixed-dose FPPs.
 The dissolution method should be incorporated into the

stability and quality control programs.
 Multipoint dissolution profiles of both the test and the

reference FPPs should be compared.

40 |
Dissolution
 For highly soluble and rapidly dissolving drug products
(BCS class 1 and 3), a single-point dissolution test limit of
NLT 85% (80% Q) in 30 minutes or less is sufficient.
 For slowly dissolving or poorly water soluble drugs (BCS

class 2 and 4), a two-point dissolution range is
recommended, for example one point at 15 minutes and
the other after 85% dissolution (eg 30, 45 or 60 minutes).
 For FDC’s (TRS 929), “Multipoint limits should normally

be established for routine quality control of each active.”

41 |
The EOI states: “The appropriate solid dosage formulations, which
are scored for flexible dosing purposes, should be supported by
relevant evidence on equal distribution of active ingredients in the
scored products, especially in the case of FDC’s.”
Supporting data should include content uniformity (CU) of tablet

halves. If weight uniformity is acceptable in FPP specifications, it is
acceptable for uniformity of tablet halves.
CU requirements: as specified in the WHO FDC guideline,

whenever ANY API in an FDC is < 25 mg or 25% of the tablet
weight, ALL API’s are subject to content uniformity requirements.

42 |
Establishing content uniformity of tablet halves is a one-
time study which should be presented with
pharmaceutical development data, and should include:
- a divisibility study in accordance with USP General

Chapter <905>, conducted on individual tablet halves.
- reporting of individual values of tablet halves as well as

the RSD.

43 |
Overages
Justification of Overages:
An overage is only possible for API’s.
The only acceptable justification is loss during

manufacture.
This can be demonstrated by product release results

(potency) that show that the overage has not survived the
manufacturing process, ie assay results close to 100%.

44 |
Microbiological attributes of the FPP should be discussed,
including:
- the rationale for not performing microbial limits testing for non-
sterile products
- the selection and effectiveness of preservative systems in
products containing antimicrobial preservatives.
- antimicrobial effectiveness of products that are inherently
antimicrobial
For sterile products, the integrity of the container closure system to
prevent microbial contamination should be addressed.

45 |
Selection and effectiveness of preservatives:
The formulation should include the minimum concentration of

preservative that gives the required level of efficacy through the
shelf-life.
To this end, the drug product should be formulated with different

concentrations of preservatives and a microbial challenge test on
each of the formulations conducted to determine the “least
necessary” but still effective concentration.
The microbial challenge test should be performed to establish and

justify the amount of the antimicrobial preservatives to be used.

46 |
 Wherever relevant, microbial challenge testing under test
conditions that simulate patient use (as far as possible)
should be performed and documented during
development.

47 |
FPP Compatibility Studies
Section 3.2.1 i) of the Generics Main Guide, and Section P.2.6
of the CTD.
Compatibility with Reconstitution Diluents/Dosage Devices
This is often erroneously filled in with API-excipient and API-API

compatibility studies. The latter are included in P.2.1.1 (CTD) or
3.2.1 a) and c) (Generics Main Guide).
Data included in this section should only be on compatibility studies

with reconstitution diluents and/or dosage devices to support claims
in the label.

48 |
Comparative Formulation Tables

49 |
Process Development
 The selection and optimization of the manufacturing

process, in particular its critical aspects, should be
explained and documented.
 Where relevant, the method of sterilization should be

explained and justified.
 The progress from preformulation to formulation to

pilot to production scale batches (approved batch size)
should be shown to be logical, reasoned and continuous.

50 |
Process Development
Common deficiencies:
Critical manufacturing steps were not identified
Failure to fully characterize key operating parameters of the

process, for example granulation end-point.
Failure to justify elements of the process, for example why direct

compression is chosen for one layer of a bilayer tablet, why extra-
granular disintegrants are added.
In-process tests to control the process were not discussed.

51 |
Pharmaceutical Development Reports
Summaries/Conclusions
Capturing Key Data
 When presenting formulation/process development data,

begin with the end in mind: what conclusions can be
drawn from the data?
 Large amounts of data on pilot formulations, scale-up etc,

without summarizing key information, are not
constructive.

52 |
Capturing Key Data
Key information to capture in summaries:
1) Formulation development gives information on critical

quality attributes: which excipients are critical to product
performance/quality attributes (CQA).
Example: if formulation studies indicated that a particular

exicient, excipient grade or excipient amount was
required to obtain acceptable dissolution, this is a CQA.

53 |
2) Changes in process during development give
information on critical process parameters (CPP):
Example: if process development studies indicated that

particular parameter(s) (eg blend speed and time,
granulation end-point) were necessary to obtain a product
with the required quality characteristics, these are CPPs.

54 |
Summary/Conclusions
of Development Data
Including the summaries/conclusions in the previous slide in the
dossier will expedite the quality assessment.
The conclusions of pharmaceutical development should be
observed in:
1) executed biobatch records
2) blank master production records.
For manufacturers: information on CQA’s and CPP’s should be
reflected in the proposed formulation, manufacturing process and
controls in the master production documents and executed
biobatch records. These must be submitted in the dossier.

55 |
Summary/Conclusions
of Development Data
For assessors: There are two main considerations when assessing
master production documents:
1) information on CQAs and CPPs determined during

pharmaceutical development should be reflected in master batch
records.
2) Master batch records must reflect the formulation/process/

controls of the biobatch.
Formulation/process development leads to the batch used in

biostudies, which must be representative of the production
batches and reflected in master batch records.

56 |
Questions?

57 |

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Pharmaceutical

 ACT – artemisinin-based combination therapy

 API – active pharmaceutical ingredient

 BCS – biopharmaceutics classification system

 CTD – common technical document

 FDC – fixed dose combination

 FPP – finished pharmaceutical product

Artemisinin based combined medicines

- ACT’s in the Expression of Interest (EOI)/Comparators

- The Role of BE in Quality Assessment

- Requirements for “Established” Generic Products

- WHO Guidelines for Pharmaceutical Development

Artemisinin based combined medicines

Approaches: Empirical vs Systematic

API-API and API-Excipient Compatibility

Excipient choices: function and concentration

Artemisinin based combined medicines

Compatibility with Reconstitution Diluents/Dosage Devices

Comparative Formulation Tables

Artemisinin based combined medicines

Summaries/Conclusions of Developmental Work

Artemisinin based combined medicines

The current EOI (6th) covers 7 API’s in 4 combination

Artesunate/Amodiaquine FDC or co-blistered

Artesunate/Mefloquine FDC or co-blistered

Artesunate/Sulfadoxine/Pyrimethamine FDC or co-blistered

Artemisinin based combined medicines

The current comparator list (October 2008) lists

Artemether/Lumefantrine: Riamet or Coartem

Artesunate/Amodiaquine: Arsuamoon and Flavoquine

Artesunate/Mefloquine: Arsuamoon and Lariam

Artesunate/Sulfadoxine/Pyrimethamine: Arsuamoon and

Artemisinin based combined medicines

Artemisinin based combined medicines

Along with pharmaceutical development data, the biobatch

The manufacturer must be careful to develop a production batch

The quality assessor must confirm during assessment that the

To be considered representative of the biobatch, production

Artemisinin based combined medicines

A product which has been on the market for at least 5 years

at least 10 batches were manufactured in the previous year.

Artemisinin based combined medicines

1) Pharmaceutical development report if available.

2) Annual report for the previous year.

Annual report = annual quality review or annual product review

Artemisinin based combined medicines

Objective: verifying the consistency of the quality of the FPP

Artemisinin based combined medicines

Artemisinin based combined medicines

Artemisinin based combined medicines

 Supplement 2 to the Generics Main Guide.

Artemisinin based combined medicines

Artemisinin based combined medicines

Critical quality attributes (CQA’s):

Physical, chemical, biological, or microbiological property

CQAs include the properties that impart the desired

Artemisinin based combined medicines

Critical quality attributes (CQA’s): [continued]

For APIs or intermediates, the CQAs can additionally include those

Artemisinin based combined medicines

Critical Process Parameters (CPPs):

A process parameter whose variability has an impact on a

Artemisinin based combined medicines