Pharmaceutical Product

Development
-Mahesh Pawar
(http://www.authorstream.com/Presentation/Maheshd.pawar
-2340644-pharmaceutical-product-development/)
 Publications

“Formulation Development and Evaluation of pH and Time Dependent

Drug Delivery using Gantrez® S-97 and PVP K30” (Journal of Pharmacy
Research)

“An overview: Strategic shift of Indian Pharmaceutical Industry after

TRIPS” (Oxford university Press)
 Concept Development

Mission Statement
Identify Establish Generate Select a
Customer Target Product Product
Needs Specifications Concepts Concept
Analyze
Refine
Competitive
Specifications
Products
Perform Plan Remaining
Economic Development
Analysis Project
Development Plan
Identifying customer needs:
• customer need statements, organized in a
hierarchical list, priority and feasibility
• breakthrough innovations to address unmet
customer needs
Establishing target specifications:
• A precise description of what the product has
to do
- They are the translation of the customer needs
into technical terms
• The output of this stage is a list of
specifications
- Each specification consists of Parameters with
defined scale
Analysis of competitive products
(Competitive intelligence):
• critical to successful launch of a new product
• a rich source of ideas for the product and
process design
Concept generation:
• space to work within customer needs
• It includes a mixture of external search,
creative problem solving
• systematic exploration of the leads
• gives 4-5 concepts
Concept selection:
• various product concepts are analyzed and sequentially
eliminated to identify one preferred concept
(refinement)
• In some cases,
“proof of concept”- to evaluate the function of concepts
“form models”- to evaluate customer reaction to so called
product
Refinement of specifications:
• The target specifications set earlier in the
process are revisited after a concept has been
selected
• Team briefing regarding specifications,
constraints, technical modeling, Project time
lines.
Economic analysis:
• The team, often with the support of a financial
analyst, builds an economic model for the new
product
• This model is used to justify continuation of the
overall development program and to resolve specific
constraints due to cost issue.
• Cost : Benefit analysis (Empirical Data)
Then bench work starts
Traditional Product Development:

• Limited development and scale-up work

• Final confirmation by validation of 3 batches
• ‘Worst-case' scenarios supposed to be included
• Limitations: Market recalls and underutilization of capacity
QbD:
• Complete understanding of process and monitoring
of all critical steps. Corrective actions are taken to
prevent product failure.
• Acceptable quality of the product is ensured:
-No recalls
-Innovation encouraged
-Maximize utilization of capacity
 Generic product

• Same active ingredient(s)

• Same route of administration
• Same dosage form
• Same strength
• Same conditions of use
Compared to reference listed drug (RLD) -
(brand name product)
 APPLICANT
Generic Drug
ANDA
Review Process Refuse to Receive
Letter

Application Review

Acceptable & N
Complete

Request for Plant Chemistry & Micro Labeling Review Bioequivalence

Inspection Review Review

Pre Approval
N Chem/Micro N N Labeling N
Inspection Results Bioequivalence
OK? OK? OK? OK?

Y Y Y Y

Approval Withheld Not Approvable Bio Deficiency

until Results Letter Letter
Satisfactory APPROVED
ANDA
 Definitions
Pharmaceutical equivalences:
If they contain the same molar amount of the same API(s) in the same
dosage form, administered by the same route.

Difference in the excipients, manufacturing process can lead to differences

in product performance.

Therapeutic equivalence = Pharmaceutical equivalences + Bioequivalence

Target product profile:

A prospective and dynamic summary of the quality characteristics of a drug
product that should be achieved to ensure the safety and efficacy. The
target product profile is a base for product development.
Product profile should include dosage form, route of administration,
strengths, drug delivery pattern (eg delayed vs immediate vs controlled
release) and quality criteria (eg sterility, purity) as per target country’s
guidelines.
 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.
For APIs or intermediates- e.g., particle size distribution, bulk density that
affect downstream processability.
Drug product CQAs as per target product profile.
The list of potential CQAs can be modified as product knowledge and
process understanding increase.
 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.
eg. End point in granulation
 Formulation and Development
Approaches: Empirical / Systematic
Reverse-engineering
API Characteristics
API-API and API-Excipient Compatibility
Excipient choices: function and concentration
Mixing: segregation of ingredients
Binding solution: concentration, feasibility
Granulation / Direct compression / Pelletization / Extrusion and
spheronization
Lubrication: sequence of addition
Compression: tooling- punches
Packing: Alu-Alu, PVC, PVDC,PE
Analysis: Dissolution, assay, micro
Stability study
Biostudy
 Reverse Engineering

Qualitative and quantitative (Q&Q) analysis of the comparator

product.

• 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 is a starting point. However, the establishment of

bioequivalence between the finished product and the comparator is
the end .
 API Characteristics

• Impurity profiling
• Solubility- Low solubility API- surfactant
• Particle size distribution
• polymorphism
Particle size distribution and polymorphic form in the final
product should be the same as the lot used in biostudies.
 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.

 Excipient Choices

• Use and concentration of excipients

• Functional excipient eg pH-adjusting agents, buffers, stabilizers (eg
antioxidants and chelating agents), preservatives, dissolution
modifiers (eg surface active agents).
• Functional excipient: their ability to perform throughout the shelf-
life should be demonstrated.
• Some excipients are multi-functional by nature; different grades of
the same excipients may have different functional use.
• In these cases, the pharmacopeial specifications may not be
sufficient, and user requirements may be additionally required.
• (eg MCC as binder, diluent or disintegrant)
Compatibility Studies
 Compatibility Studies
API-excipient compatibility:

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 Fixed dose combination: API-API compatibility must be established.

stress testing mixture of the APIs in solution or suspension, and in solid
state.

A visual description is not adequate, reporting should include

chromatographic results (purity/potency).
 Dissolution
• A discriminating, multimedia (at least, pH 1.2, 4.5 and 6.8 and/or water)
dissolution method should be developed
• The dissolution method should be incorporated into the stability and quality
control final specifications.
• Multipoint dissolution profiles of both the test and the reference FPPs should be
compared.
• 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 Fixed dose combination : Multipoint limits should normally be established
for each active.
 Microbial Attributes

• For sterile products, the integrity of the container closure system to prevent
microbial contamination should be addressed.

• 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.

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

“No product in this world can be develop

within 6 month and to develop a simple
formulation for regulatory submission
require at least 2-3 years”
 Process Development

• The selection and optimization of the manufacturing process, in particular

its critical aspects, should be explained and documented.

• The progress from preformulation to formulation to pilot to production

scale batches (approved batch size) should be logical, reasoned and
continuous.
 Biostudy
•In case of biostudy or biowaiver, a biobatch is used to demonstrate
bioequivalence or similarity to the comparator.
•Production batches must have the same formulation and manufacturing
process as the biobatch.
3.5 X
Y
•Criteria for waivers of In Vivo Study 3.0

Concentration
2.5

-In vivo bioequivalence is self-evident 2.0

1.5
-Parenteral solutions 1.0

-Inhalational anesthetics 0.5

0.0
-Topical (skin) solution 0 4 8 12 16 20 24
Time
-Oral solution
-Different proportional strength of product with demonstrated BE
•AUC and Cmax
90% Confidence Intervals (CI) must fit between 80%-125%
Thank you