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OPTIMIZATION OF FORMULATION
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DEFINITION

Optimization of a formulation or process is defined as process of finding the best

possible composition or operating condition.

The key outputs from this stage of development will be:

 a quantitative formula defining the grades and quantities of each excipient

and the quantity of candidate drug

 defined pack

 defined drug, excipient and component specification

 defined product specification

The approach to product optimization will depend on the nature of the product to
be developed

It will always involve testing a range of options:

a. a variety of excipients from different sources, with different grades and

concentration and in different combination

b. range of pack sizes or different packaging materials

c. testing a range of particle size distribution of the candidate drug and of the
excipients

Particle size may be critical for drug delivery e.g. material with mean particle size
distribution of 2-5 micron will be required for effective pulmonary delivery of
aerosol suspension and dry powders whereas even smaller particle size range
(nanoparticles) may be required for dissolution of poorly water soluble drugs in
parenteral formulation.

The manufacturing process used during product optimization should be designed

with large scale manufacture in mind.
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EXCIPIENT SELECTION AND OPTIMIZATION CONSIDERATIONS

excipient selection - historically, excipients have been regarded as inert additives,

but this is no longer the case. each, additive must have a clear justification for its
inclusion in the formulation and must perform a defined function in the presence
of active drug and other excipients included in the formulation.

The International pharmaceutical excipient council (IPEC) define pharmaceutical

excipient as -

Any substance other than active drug or prodrug which has been appropriately
evaluated for safety and included in drug delivery system to either

 aid processing of the system during manufacture

 protect, support or enhance stability, bioavailability or patient acceptability

assist in product identification

 enhance any other attribute of the overall safety and effectiveness of the
drug product during storage or use

Excipients used must be compatible with the formulation and pack effectively
perform its desired function in the product.

For excipients the product design acceptance criteria should include following
considerations –

 The excipient should be well established .

 Its intended route of administration should be safe and acceptable to

the regulatory authorities .

 It should comply with the pharmacopoeial requirement .

 It should be globally acceptable and meet the propose design

specification.

There are clearly cost and time savings of using well established excipients that
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have already been approved for use in other registered products and have an
established safety profile. The regulatory status of excipients can easily be
checked by consulting the FDA's, inactive ingredient guide, various
pharmacopoeias.

For new chemical excipients that are not registered usually require a full
development programme, including comprehensive toxicological testing, to gain
approval by the regulatory authorities.

PACK SELECTION AND OPTIMIZATION CONSIDERATIONS

Product optimization of the pack should initially focus on defining the primary
packaging (referred as primary container or immediate container)

This is most relevant to regulatory authority because it is the primary packaging

that is in direct contact with the drug product, including the closure, liner and any
other surface contacting the product

Secondary packaging is that outside the primary pack, and by definition is not in
direct contact with the product. Secondary packaging is often a carton or blister,
which may also function to protect the product from light and moisture , to be
elegant in its appearance , provide clear labeling instruction and project a good
marketing image.
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Optimisation criteria for primary packaging include:

 Satisfies environmental and legislative requirements for world wide

markets

 Availability of a Drug Master File

 Ability to source from more than one supplier or country

 Acceptable cost of goods

 Consistency of dimensions

 Consistency of pack performance

 Ability to meet function/ user tests, customer requirements and

specifications

Role of Packs:

The role of packs include -

1. protection of the product

2. presentation to the user or administration of the product

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1. Protection of the product

The formulation must be protected from environmental elements of heat,

light, moisture, gaseous and sometimes chemical or microbial attack as well as
physical protection during transport and handling. The product licenses will
not be granted unless the product quality, safety and stability of the
formulation in the pack over the declared shelf-life has been demonstrated to
the regulatory authorities. The regulatory authority looks for acceptable
stability when the product is stored both under normal or accelerated
conditions.

Appropriate stressed stability studies should demonstrate the integrity of the

container and closure and any possible interaction between product and
container.

Other stress test to establish the robustness of the product and pack include
vibration and impact testing.

Plastics and rubber materials used in container closure system can contain
certain additives like plasticizers, stabilizers, lubricants and mould release
agents. The regulatory authorities require that these additives should not be
capable of extraction into the formulation or leach from the container or
closure to contaminate the product.

Drug and excipient interaction with the container may involve leaching,
permeation, sorption, chemical reaction or modification of the physical
characteristics of the polymer or product.

There is also a possibility of constituents from label adhesives migration

through polyethylene or polypropylene containers. This is something to be
aware of when carrying out stressed compatibility testing.

2. Presentation to the user/Administration of the product:

For traditional dosage forms such as tablets and capsules the role of pack is
mainly for protection of the product during storage and presentation to the
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user. The design is not so critical for administration of the dose in the hands of
administrator.

For other dosage forms such as inhalers for respiratory drugs and self injection
devices for parenteral products like insulin, the pack is integral part of the drug
product. These are often referred as the drug delivery systems because the
packaging system or device in the hands of the administrator provides delivery
of the correct amount of active drug product to the site of action as easily,
reliably and conveniently as possible.

The packaging must also be convenient to use in order to promote good

patient compliance.

PROCESS DESIGN

The process design report should include all the factors that need to be
considered for the design of the process including the facilities and enviroment,
equipment, manufacturing variables and any material handling requirements.

Factor Requirement Purpose

Facility Organization and GMP
layout Health and safety
Space Product sensitivity to
Environmental control Temperature
Temperature Moisture
Humidity Particulates/micro-
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Air quality organisms

Electrical zoned (flame Allow solvents for
proof) cleaning
Barrier protection Operator protection

Equipment Type and design, e.g., Suitability for process

bottom- or top- Mixing efficiency
mounted mixing Compatibility,
elements, baffles, extractives
heating/cooling Ease of scale up
jacket, etc. Ability to
Materials of clean/maintenance
construction
Range of sizes
Access to internal
parts
Material Transfer Product protection Clean/sterile product
Transfer Operator protection Hazardous materials
Manufacturing Order of addition of Mixing effectiveness
variables active and excipients Stability/dissolution
Temperature Mixing effectiveness
Speed Mixing effectiveness
Time Robustness of process
Differences in
excipient batches

PROCESS OPTIMIZATION

Critical parameters include –

 Defining the order of addition of active and excipients

 Defining the optimum equipment settings e.g mixing speed

 Optimizing the time-dependent process parameters

 Defining the optimum temperature range

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 Evaluating the effects of different excipient/active batches (within

specification)

 Setting in-process targets and controls

 Development of cleaning procedure for the process

SCALE UP

The process used for initial clinical supply manufacture will probably be relatively
small scale (laboratory scale). As more drug substance becomes available the
product batch size will increase to pilot scale and the process has to be modified
during scale up.

Scale up is essential to transfer the product to the commercial production site.

Scale up may encompass changes in process equipment and operation, with an

associated increase in output.

Whenever scale up is to be undertaken, it is strongly recommended that an

experimental batch is manufactured to demonstrate that the process is still
acceptable and product is manufacturable on the increased scale and must meet
all appropriate in-process and product specification acceptance criteria.

TECHNOLOGY TRANSFER

The actual transfer of the manufacturing process from R&D to production, along
with necessary knowledge and skills to be able to make the product is referred as
“technology transfer”.

Objective of technology transfer is to have documented proof that the process is

robust and effective in producing product complying with the registered
specification and GMP requirements.
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CONCLUSION

Thus the optimization process may be successful when

 There is good documentation of product/process development and

technology transfer

 Equipment used at laboratory/pilot scale is similar to production

equipment

 Good scientific basis for product/process design

 Good communications are maintained with good R&D/production interface

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REFERENCES
1. Pharmaceutical Preformulation and Formulation – A Practical Guide from Candidate Drug
Selection to Commercial Dosage Form Edited by Mark Gibson, IHS® Health Group Publication.

2. www.google.co.in