EQUIPMENTS
The pharmaceutical industry uses different equipment at each stage of drug product manufacturing. The equipment may be a single piece—such as a weighing machine or a granulator—or a group of equipment working in a process to deliver a single outcome, such as a purified water system.
The ingredients of a formulation come into intimate contact with the equipment at every step. Naturally, the quality of this equipment plays a major role in determining the quality of the final products. Equipment must be designed and constructed to prevent contamination or any other adverse impact on the drug material.
Design and Construction
Equipment must be designed and constructed to suit the
purpose of its use. The material of construction must be adequate to the nature
of the processing to be undertaken. Equipment surfaces that come into contact
with drug products must not be additive, reactive, or absorptive. If the
surface of equipment adds chemicals from its surface into the drug material or
reacts with it or absorbs the formulation ingredients, there can be a serious
impact on the identity, safety, strength, purity, and quality of the final
product.
Equipment must be designed for closed operation as far as
possible to reduce the risk of contamination of material it holds. If open
equipment is unavoidable, it must be designed and handled in a way that
minimizes contamination. Diagrams of critical equipment must be maintained.
Lubricants used in equipment maintenance should be of non-toxic or edible grade.
Such lubricants or coolants used on the equipment must not come into contact
with the drug product, its containers, or closures. Failure to ensure this will
contaminate the drug and render it unsafe for use.
Location
Equipment must be located in a clean, hygienic area that is
suitable for the operation being performed. When several equipments are to be
used as part of a process, they must be located in such a way as to allow the
linear and sequential flow of the production process. The equipment must be
situated in a way that allows ease of cleaning and maintenance.
Installation
Equipment must be installed in keeping with the
manufacturer’s specifications. All necessary utilities must be provided and
there must be arrangements to access the equipment for maintenance work without
having to enter the production areas. Pipework leading to and from any
equipment must be labeled with contents and direction of flow. Any defective
equipment must be removed to a separate area outside the production or quality
control area. In case this is not possible, the equipment must bear a
conspicuous label that states its defective status.
Cleaning and Maintenance
Written procedures must exist for the cleaning of equipment
and their regular maintenance. Cleaning must be done at regular intervals to
avoid the entry of contaminants; equipment must also be cleaned thoroughly
between different batches of product to avoid the risk of cross-contamination.
For equipment used in manufacturing sterile products, additional steps need to
be taken to sanitize and sterilize the equipment to maintain it in a sterile
condition. Regular maintenance must be performed for all critical equipment to
ensure there are no malfunctions during a processing run. Cleaning validation
studies must be performed to ensure equipment cleaning leads to the desired
levels of cleanliness.
Qualification and Calibration
Qualification of equipment begins right at the design state
when it is designed to be constructed in a particular manner suitable to its
intended purpose. Steps of design qualification (DQ), installation
qualification (IQ), operational qualification (OQ), and performance
qualification (PQ) must be carried out to ensure the equipment is designed,
installed, operated, and performed as expected to give a quality product.
Once the equipment has become operational, with wear and
tear over time, there is a chance of a drift in its performance from expected
profiles. So, it is vital to have a regular calibration program in which the
equipment and any associated instruments are checked to obtain a measure of how
accurately it is performing. These calibration results can help to identify
defects in the equipment, which can then be dealt with appropriately. Records
of calibration and qualification must be maintained for all equipment.
When computers or related systems are used, there must be
sufficient control to ensure that any changes in records take place only after
due authorization by higher management. Backup files of data must be maintained
and stored in a way that is protected from alteration or loss. Hard copies of
backup data must be maintained, too.
Documentation
All the major equipments should have a unique identification
code or number, and this must be recorded in the batch manufacturing record
(BMR). Separate cleaning and maintenance logs must be maintained for each of
the major equipment, and any cleaning or maintenance activity must be recorded
in these. Standard operating procedures must exist for operating all equipment,
and they must be placed close to the equipment for use by the personnel
handling them.
The major equipment being used in manufacturing a given
batch must be labeled with details of product name and batch number at all
times to indicate the contents within.
Purchase Specifications for Equipment
Pharmaceutical industry equipment is quite expensive and
therefore, selecting the right equipment is a critical process. Some of the
most important factors to be considered in making this decision are as follows:
• Desired output capacity: Equipment purchased must
be capable of processing the desired quantity of product at the desired speed
of operation. Understanding one’s production scale in terms of batch size
requirements and comparing this with the load capacity of the equipment being
considered is an important first step when choosing equipment.
• Product characteristics: The nature of the product,
its reactivity, and any special conditions necessary to ensure retention of its
safety, efficacy, and quality are all important while choosing equipment.
• Ease of operation: Equipment operation must be
simple, and not involve complex maneuvers or require special skills. The
equipment must be easy for the operator to operate after receiving proper
training. It is important to strike a balance between the efficiency of
performing the given operation and the ease of operating the equipment.
Digitally enabled equipment can help to manage the manufacturing process
better; it will however require special skills for operation and the capacity
of one’s workforce to learn those skills must be considered.
• Ease of cleaning and maintenance: Equipment will
require regular cleaning and special, more thorough cleaning between batches of
different products. The time used for cleaning is time lost from the production
run. So equipment must be easy to clean (either in-place or by disconnecting
and taking to a special cleaning area). It must also be easy to maintain and
not require frequent maintenance activities which again are a time-consuming
process.
• Equipment supplier: When buying equipment, price is
often considered an important criterion, but it is more important to focus on
the quality parameters on offer the industry reputation of the supplier and how
reliable their product is, their customer service, and their capability to
provide equipment troubleshooting service when necessary.
RAW MATERIAL
Between 1995 and 1996, Haiti saw incidents of around 80 children dying after ingesting a cold-and-cough syrup. An investigation fixed the responsibility of glycerol in the product being contaminated with diethylene glycol. This and other such incidents highlight the need for drug product manufacturers to pay attention to the quality of the starting materials they use.
While active pharmaceutical ingredients (APIs) may be
manufactured under cGMP (current Good Manufacturing Practices), excipients may
not be so produced, especially the ones commonly used in other industries like
cosmetics or food. This makes it even more important to ensure these excipients
are of a grade suitable for pharmaceutical use. Containers and closures must
also be evaluated because they play a vital role in ensuring the product stays
stable and safe throughout the shelf life.
Purchase of Materials
Purchasing must be done by staff with a thorough knowledge
of those materials and their suppliers. Materials must be procured only from
approved suppliers who have consented to provide materials in keeping with the quality
specifications of the drug product manufacturer. Pharmaceutical manufacturers
should enter into contracts with specific vendors after performing a vendor
audit that assures raw materials and packaging materials of the desired level
of safety and meeting quality standards.
Receiving, handling, and storage of materials
Specific written procedures must be prepared to describe how
materials (both drug components and drug containers and closures) will be
received, identified, stored, handled, sampled, tested, and accordingly
approved or rejected, and these procedures must be followed as written.
When receiving materials, the consignment must be visually
examined and the labels checked to confirm the content, quantity, and integrity
of seals and to verify that there is no damage or contamination. Any damaged
containers found must be separated, and details recorded and informed to the
supplier.
The materials must be stored under quarantine until samples
have been drawn and tests have been performed. They must not be issued for use
before approval.
Handling and storage of all materials in the storage area
must be done in such a way that there is no contamination. Boxes or bags
holding containers and closures must be stored off the floor. The storage must
be done in a way that suitable space is left for proper cleaning and inspection
of the materials.
Sampling
Representative samples must be drawn from each shipment of
each lot. If different batches are present in a single shipment, samples must
be drawn from each of those. The quantity must be sufficient to perform all
required tests and reserve when specified. Statistical criteria must also be
used to determine the quantity of samples drawn. Containers must be cleaned
before sampling to avoid introducing contamination, resealed after sampling to
prevent contamination of the contents, and appropriately labeled to show sample
has been taken. Samples must be drawn from the bottom, middle, and top of the
containers, and marked accordingly. Sample-holding containers shall be labeled
with details of the name of the material, lot number, container number, date of
sampling, and name of the person collecting the sample.
Testing of Samples
At least one specific test must be performed to verify the
material’s identity. Tests must be carried out to determine conformity with
predetermined specifications for quality, strength, and purity. In case
materials are supplied along with a certificate of analysis by the supplier,
the materials may be used without sampling and testing, provided the supplier
is a reliable, validated vendor and at least one specific identity test has been
performed and mentioned in the certificate.
Materials that are liable to contamination with adulterants,
insect infestations, or filth must be examined for such contaminants. If
materials are prone to microbial contamination, microbiological tests must be
performed to test for it.
Approval/Rejection of Materials
All materials that meet the manufacturer’s quality
requirements of identity, quality, purity, strength, and other tests are to be
approved for use. Materials not meeting these requirements must be rejected.
Labeling
Labels must carry the name of the product, the company’s
unique reference code, the manufacturer’s name and address, and their assigned
batch number. It must also state the status of the contents (For example –
“Sampled”, “Quarantined”, “Approved” and “Rejected”), manufacturing and expiry
dates, and re-test date. When attaching such labels, care must be taken that the
original information on the supplier’s label is not lost.
Approved materials must be so marked while rejected
materials must be conspicuously labeled and stored in a separate area to avoid
chances of mix-ups or misuse.
Using Approved Materials
Approved materials must be stored properly and issued for use so that the earliest approved stock is used first before more recently approved stock. Many companies use a FEFO (First Expire First Out) system for stock rotation. Another deciding factor is that the drug product’s shelf life must not exceed the shelf life of the APIs.
If materials have been stored for a very long period without
usage, or if they have been exposed to any condition that may have an adverse
effect on their quality or safety, they must be re-tested for the same
parameters as the initial test. Results of the re-test must be used to
determine if the materials are approved or rejected.
Handling Rejected Materials
Rejected materials must be identified with appropriate
labels and kept in quarantine until safely disposed of. Care must be taken to
prevent the use of such materials in manufacturing operations.
Containers and Closures
Containers and closures used for packing drug products must
not be additive, reactive, or absorptive. This is important to ensure they do
not cause a change in the identity, safety, quality, strength, or purity of the
drugs beyond specifications. Closures and containers must be capable of
protecting the drug product from external conditions that may cause its
contamination or deterioration. Containers and closures must be clean and if
required, sterilized to remove contamination by microorganisms and pyrogens.
Note: If computerized storage systems are used, they
must be fully validated to prove they work reliably.