STUDY OF ICH Q8 (PHARMACEUTICAL DEVELOPMENT)

1. Study of ICH Q8
(Pharmaceutical Development )
Presented By – Anand Gaikwad
Guided By – Dr. Sapna Ahirrao
Class – M Pharm First Year Sem I
Subject – Quality Management Systems

2. M. Pharm Sem-I Presentations
STUDY OF ICH Q8 (PHARMACEUTICAL DEVELOPMENT)
SUBMITTED TO
SAVITRIBAI PHULE, PUNE UNIVERSITY , PUNE
FOR
PARTIAL FULFILMENT OF REQUIREMENTS FOR THE AWARD OF
MASTER OF PHARMACY
IN THE SUBJECT
Quality Management system
IN THE FACULTY OF SCIENCE AND TECHNOLOGY
Bhujbal Knowledge City,
MET’s Institute of Pharmacy,
Adgaon, Nashik, 422003.
Maharashtra, India
Academic Year-2021-2022 2
Presented By-
Mr. Anand V. Gaikwad
(QAT)
SEM I
ROLL NO. 04
Guided By-
Dr. S. P. Ahirrao

3. 1. Introduction
1.1 Objective
2. Pharmaceutical Development
2.1 Components of Drug Product
2.1.1 Drug Substance
2.1.2 Excipients
2.2 Drug Product
2.2.1 Formulation Development
2.2.2 Overages
2.2.3 Physiochemical and Biological Properties
2.3 Manufacturing Process Development
2.4 Container Closure system
2.5 Microbial Attributes
2.6 Compatibility
3. Layout of Quality by Design
4. Conclusion
3
CONTENTS

4.  Introduction
The Pharmaceutical Development section provides an
opportunity to present the knowledge gained through
the application of scientific approaches and quality risk
management to the development of a product and its
manufacturing process.
 Objective
• This guideline describes the suggested contents for
the 3.2.P.2 (Pharmaceutical Development) section of
a regulatory submission in the Common Technical
Document (CTD) format.
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5. • ICH Q8 Pharmaceutical Development describes the
principles of QbD, outlines the key elements, and
provides illustrative examples for pharmaceutical drug
products.
• It is often emphasized that the QUALITY of a
pharmaceutical product should be BUILT IN BY
DESIGN RATHER THAN BY TESTING ALONE.
• The ICH Q8 guideline suggests that those aspects of drug
substances, excipients, container closure systems, and
manufacturing processes that are critical to product
quality, should be DETERMINED AND CONTROL
STRATEGIES justified.
• Some of the tools that should be applied during the design
space appointment include experimental designs, PAT,
prior knowledge, quality risk management principles, etc.
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6. • PAT (Process Analytical Technology) is a system
for designing, analyzing and controlling
manufacturing through timely measurements ( i.e.
during processing ) of critical quality and
performance attributes of raw and in- process
materials and processes with the goal of ensuring
final product quality.
• Pfizer was one of the first companies to implement
QbD and PAT concepts.
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7.  Contents for 3.2.P.2 of CTD Quality Module 3
1. Components of drug product ( drug substance &
Excipients)
2. Formulation Development
3. Manufacturing Process Development
4. Container Closure System
5. Microbial Attributes
6. Compatibility
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8. Components of drug product
• Drug Substances
• Excipients
 Drug substances
The physicochemical and biological properties of the drug substance
that can influence the performance of the drug product and its
manufacturability.
Examples of physicochemical and biological properties that might need
to be examined include.
• Solubility
• Water content
• Particle size
• Crystal properties
• Permeability
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9.  Excipients
• The excipients chosen, their concentration and the
characteristics that can influence the drug product
performance or manufacturability.
• The compatibility of the drug substance with
excipients should be evaluated. For products that
contain more than one drug substance, the
compatibility of the drug substances with each other
should also be evaluated.
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10.  Drug Product :-
• Formulation Development
• Overages
• Physicochemical & Biological Properties
 Formulation Development
• Identification of those attributes that are critical to the
quality of the drug product.
• Highlight the evolution of the formulation design
from initial concept up to the final design.
• Information from comparative in vitro studies (e.g.,
Dissolution) or comparative in vivo that links clinical
formulations to the proposed formulation.
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11. Overages
• Overages in the manufacture of the drug product,
whether they appear in the final formulated product
or not, should be justified considering the safety and
efficacy of the product.
• Information should be provided on the
1) Amount of overage
2) Reason for the overage (e.g., compensate for
expected and documented manufacturing losses )
3) Justification for the amount of overage
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12. Physicochemical & Biological Properties:-
• The physicochemical and biological properties
relevant to the safety, performance or
manufacturability of the drug product should be
identified and discussed.
• This includes the physiological implications of drug
substance and formulation attributes.
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13. Manufacturing Process Development:-
• Address the selection of the manufacturing process
and confirm the appropriateness of the components.
• Appropriateness of the equipment used for the
intended products should be discussed.
• The manufacturing process development programme
or process improvement programme should identify
any critical process parameters that should be
monitored or controlled (e.g., granulation end point)
to ensure that the product is of the desired quality.
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14. Container closure system :-
• The choice for selection of the container closure
system for the commercial product should be
discussed.
• The choice of materials for primary packaging and
secondary packaging should be justified
• A possible interaction between product and container
or label should be considered.
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15. Microbiological Attributes:-
• The selection and effectiveness of preservative
systems in products containing antimicrobial
preservative or the antimicrobial effectiveness.
• For sterile products, the integrity of the container
closure system as it relates to preventing microbial
contamination.
• The lowest specified concentration of antimicrobial
preservative should be justified in terms of efficacy
and safety.
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16. Compatibility:-
• The compatibility of the drug product with the
reconstitution diluents (e.g., Precipitation,
stability)should be addressed to provide appropriate
and supportive information for the labelling.
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17.  Case Study
“Understanding sources of variability and their impact
on downstream processes or processing, intermediate
products and finished product quality can provide
flexibility for shifting of controls upstream and
minimize the need for end product testing.”
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18.  Control of an API Critical Quality Attribute:
• The final formation and isolation of an API methane sulfonate salt
was performed as follows:
• Add solvent (ethyl acetate)
• Add solvent (acetone)
• Heat to 39°c
• Add MSA (methyl sulfonic acid)
• Acid solvent (iso octane)
API free base API Salt
• Cool
• Filter
• Wash with solvent (ethyl acetate)
• Dry in oven
• A risk assessment identified 3 genotoxic impurities (alkyl methane
sulfonates) that could potentially contaminates the API, these
genotoxins are Critical Quality Attributes of the API.
• Based on a Threshold of toxicological concern of <1.5µg/day and a
maximum drug dose of 150mg/day, these impurities had to be
controlled to <10 PPM
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19.  The Risk Assessment:
A risk assessment using prior process knowledge, identified the unit
operations that could potentially impact levels of the 3 genotoxins in
the API salt:
ROH + CH3SO3H CH3SO3R
Methanol MSA 3 genotoxins
Ethanol
isopropanol
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20.  Studies to Mitigate the Risks:
The risk assessment the design of a series of
experiments to develop process knowledge to reduce the
risk of producing API containing 3 genotoxins:
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21.  The Process Knowledge:
The ability to from the genotoxic impurities under the
process conditions was studied:
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Unit operations Conditions Alcohol Genotoxins Genotoxin
(ROH) Formed in API
Levels
Salt Formation Standard 2-150 ppm Not tested <1ppm
Standard 1000 ppm <1ppm <1ppm
Stressed 7500ppm 2-3 ppm <1ppm
(>time, >temp
>MSA)
Filtration and wash Stressed 2000ppm <1ppm <1ppm
(>time, >temp)
Drying Stressed 2000ppm <1ppm <1ppm
(>temp)

22.  Conclusion :
The genotoxic impurities are not easily formed under the process conditions,
even when large excesses of the alcohols are present.
• Extreme spiking experiments were carried out by adding the genotoxin
impurities directly into the process stage to study the ability to purge the
impurities.
• The following results were obtained when 4500-7000 ppm of genotoxins
were added to the final solution prior to API crystallization and isolation:
 Conclusion:
The genotoxin impurities are easily purged under the process conditions.
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Cake Wash Genotoxins in wet API Cake
No wash
1 wash
2 washes
1-2 ppm
<1ppm
<1ppm

23.  Conclusion:
• The Quality by Design principles outlined in ICH and
other guidance provide a structured approach to gaining
process knowledge and developing robust manufacturing
control strategies.
• Significant amount of process knowledge are now
included in regulatory submissions in order to justify the
control strategy.
• There are significant benefits to the approach..
o For patients… a quality product is placed on the market
o For regulators.. The scientific rationale for the control
strategy is transparent.
o For pharmaceutical companies.. A clear control strategy is
identified which ultimately facilitates product launch and
subsequent manufacturing changes.
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24.  REFERENCE
• ICH Q8 Pharmaceutical Development. ICH step 5. Note for
Guidance on Pharmaceutical Development., May 2006
(http://www.ich.org/cache/compo/276-254-1.html)
• Pharmaceutical development. Q8(R2). ICH Harmonized
Tripartite Guideline. Accessed from
(https://www.ich.org/fileadmin/Public_Web.../Guidelines/.../Q8
_R2_Guidelines.pdf)
• ICH final concept paper . Q8: Pharmaceutical Development.
19 September 2003
(http://www.ich.org/LOB/media/MEDIA3096.pdf)
• https://admin.ich.org › files PDF Control Strategy Case
Studies
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