INTRODUCTION

The manufacture of injectable pharmaceuticals
presents challenges from many perspectives,
especially for products that must be processed
aseptically and cannot be terminally sterilized. Food
and Drug Administration (FDA) inspections for
Good Manufacturing Practice (GMP) compliance
in injectable drug product manufacturing facilities
commonly find problems in the following areas:

ISSUES WITH ENVIRONMENTAL CONTROL
PROBLEMS WITH EQUIPMENT,

ESPECIALLY OLDER EQUIPMENT

Media fill failures and/or issues with media fills
truly simulating actual practices
·  Lack of proper training of operators
·  Documentation failures

Besides the need to be in GMP compliance,
manufacturing requires competency and resiliency
in such matters as: inventory management, scheduling
of facilities, equipment and personnel, management
of changes in schedule, management of shutdowns
for maintenance and repairs, management of change
control, management of changes in product demand
and departmental growth.

It takes well-organized and competent management
and highly trained and competent operators and
manufacturing support personnel to deal with all
these challenges successfully. This article will focus
on a few of the challenges involved in the
manufacturing of injectable drug products - the
process, equipment, people and environment.

PROCESS

Unit operations in sterile product processing include:
c o m p o u n d i n g  ( o r  f o r m u l a t i o n ) ,  m i x i n g ,
homogenization (dispersed systems), filtration, filling,
stoppering, sealing and terminal sterilization
(although a significant majority of small volume
injectable products cannot be terminally sterilized
for stability reasons). All segments of the
manufacturing process present many challenges,
especially as the process is scaled-up from bench to
full production.

The pathway of a process is usually initially defined
in a lab setting at small-scale by scientists who are
frankly not highly experienced in the world of
manufacturing. Some process methods are simple
activities, such as weighing and mixing, while others
are more complex and require special procedures,
equipment, temperature control, inert atmospheres,
protection from light and explosion proofing.
Special criteria must be considered during the transfer
of a process from the development lab to the
manufacturing environment. Ideally, processes should
be designed to be transferable on multiple projects
in order to maintain a key principle in quality
manufacturing. That principle is consistency for the
manufacturing of sterile injectable products,
consistency is critical. It is well known that media
fills are only a snapshot in time, and merely
demonstrate that under the 'correct conditions', aseptic
filling of solutions is possible for that particular
filling line.

More importantly, however, is the fact that we base
the entire principle of media fill validation on the
ability, and expectation, to consistently perform each
operation in the same quality manner for each and
every batch. These 'correct conditions' include the

Current Challenges in the Manufacturing of Injectable Drug Products

 Mohammad Shakil Siddiqui1*, Ghulam Sarwar1

1Department of Pharmacy, Jinnah University for Women, Karachi-74600, Pakistan.

* Corresponding author: mshakil@hotmail.com

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proper environment, equipment, components,
personnel and process methods.

EQUIPMENT

Many challenges posed by manufacturing process
methods can be solved by the proper choice of
equipment. However, applying proper equipment
always has a price. Once the initial cost of the
equipment is considered, then come installation and
validation issues. It is imperative to consider space
and utilities required before getting started.
Once in place, the company budget must be prepared
to support a preventative maintenance programme,
including a sufficient spare parts inventory. There
is nothing more frustrating than loss of production
due to equipment failure and worse, not having the
means to repair or replace the parts necessary to
resume manufacturing. During annual budget
planning sessions, it is important to balance the push
for cost reduction and optimization with robust
processes and capable equipment-support
programmes.

Once the right equipment has been sourced for the
process, proper identification and control for all
product contact parts is vital to quality manufacturing
and preventing the risk of cross contamination.
Elements of this challenge include the handling,
cleaning, testing, release, storage, issuing and return
of each product contact part. Furthermore, the
importance of each of these areas is easily confirmed
by the fact that they are frequently primary auditing
targets.

PEOPLE

Some may believe that people are the source of most,
if not all, problems encountered in manufacturing,
particularly aseptic manufacturing. In fact, the
development of isolators and automation is driven
primarily by the desire (and possibly need) to remove
people from direct contact with sterile products
during manufacturing. The root cause, however, may
be better correlated to how the people are developed.

Training and experience are the primary solutions
to minimizing or eliminating operator errors.

TRAINING
A strong training programme is essential in the
manufacture of pharmaceutical products. Training
must be well organized to effectively maintain the
compliance of all operators, who must be trained on
the most current versions of all applicable standard
operating procedures (SOPs). A solid change control
process for procedures is required to properly
maintain compliance with operator training. Training
curricula are helpful tools that outline all SOP training
and qualifications required for each position. These
curricula are a valuable reference for auditing, and
an easy way for operators and management to
measure their development over time.

EXPERIENCE

Most manufacturing operations are SOP-driven and
are not conducive to classroom training for new
operators. Job shadowing, with repetitive SOP review
and hands-on demonstration, is the most direct
method of transferring knowledge to new operators.
For this reason, it pays in large dividends to develop
experienced operators into effective trainers by
investing in courses on effective communication and
training techniques.

Experienced operators are not automatically the best
trainers, but most can become quite capable with
proper guidance. It might seem obvious, but new
operators should always be paired with the most
experienced operators/trainers. Furthermore, they
should remain paired with the same trainer for as
long as possible. It takes some time for a trainer to
assess the trainee's strengths, weaknesses and rate
of learning, then adopt the best pattern to use in each
training opportunity. For example, some trainees
may require more verbal repetition, hands-on practice,
demonstrations, or SOP review.

Consequently, successful trainer/trainee teams will
more efficiently and effectively work their way
through all procedures on a training curriculum. A

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Vol 4 (1), January 2013; 47-49

strong training programme is also imperative for a
fast growth rate in personnel, which can introduce
a large number of new operators into the
manufacturing operations at the same time. Any
operation saturated with inexperience will likely
incur an increase in errors. Again, this can be managed
by pairing the new with the experienced.

ENVIRONMENT

The impeccable quality of manufacturing
environments for pharmaceutical processing is vitally
important. We routinely measure the suitability of
these environments with a variety of testing methods.
The air is evaluated for direction of flow, velocity,
pressure differentials, control of temperature,
humidity, non-viable and viable particle content.
Room and equipment surfaces are evaluated for
general debris, microbial contamination and chemical
contamination.

As people and equipment are part of the environment
during the process, monitoring must be performed
under dynamic conditions. The operators are also
monitored for proper gowning and handling
techniques using media contact plates in the search
for microbial contamination at multiple bodily sites,
such as chest, forearms, hands and fingertips. To
meet the challenging specifications for environmental
monitoring, the manufacturing operations must
include proven methods for proper room clearance,
cleaning and sanitization. Additionally, the gowning
and cleanroom behaviour techniques must be both
well trained and well practiced.

BATCH DEVIATIONS

At some point, the challenges of manufacturing
injectable products will eventually lead to some sort
of batch deviation or variance. Batch deviations are
typically due to a planned change or loss of control
in at least one of the 'correct conditions' as discussed
in this article. Some common root causes for
deviations include: documentation errors,
equipment/software problems, product/material
defects, performance errors and incorrect process

methods.

It should be noted here that the above challenges
with respect to people and environment have
generated great interest and progress in the area of
isolation technology. Successful application and
validation of isolators enables the manufacture of
sterile products to be distinctly separated from the
direct intervention of personnel and ideally provides
a safer environment for sterility assurance. However,
beyond the scope of this brief article, there are many
obstacles in the validation and routine use of isolators
in aseptic manufacturing.

CONCLUSION

We hear the common 'buzzwords' such as cost
reduction, optimization, efficiency and capacity
utilization. In our efforts to meet these goals it is
important that we do not swing the pendulum too
far from some other key manufacturing principles,
such as training, practice, validation, preventative
maintenance and availability of spare parts. It is
important to find a balance among all these needs
to meet the many challenges of manufacturing
i n j e c t a b l e  p h a r m a c e u t i c a l  d o s a g e  f o r m s .

REFERENCES

Reminngtons Practice of Pharmacy vol.1

ICH guidance for Industry Q2B Validation of
Analytical Procedures

FDA Code of Federal Regulations

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