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Pharmaceutical Manufacturing and Packing Sourcer

Turning up the Heat

Thomas Huxley said that: “The man of science has learned to believe in justification, not by faith, but by verification.” The 19th century biologist, often called Darwin’s Bulldog because of his fierce defence of his colleague’s theories, was not talking about the compliance landscape in 21st century pharmaceuticals. But he could easily have been talking about verification in pharmaceutical heating.

Heating Processes

Typical blister packs are thermoformed plastic containers sealed by aluminium foil or plastic to protect pharmaceuticals against humidity and contamination. In addition to thermoforming, two other heating processes that are common in the pharmaceutical sector are sterilisation and drying. All these processes are subject to the requirements of the US Food and Drug Administration’s (FDA’s) 21 CFR legislation and, thus, are highly regulated and demand close monitoring, traceability and validation.

The equipment used for drying, sterilisation and blister packaging can include single- or multi-loop temperature controllers, human machine interface (HMI) or temperature interfaces, solid-state relay (SSR) or thyristor power controllers, and paper-based or paperless graphic recorders. Key quality criteria for these include accuracy and repeatability, single-loop integrity, integration, and conformance to regulations. In the case of single-loop integrity, it should be possible to replace any part of the system if it goes down – something which can be difficult for bespoke manufactured systems.

Temperature Control

There are no specific rules for the use of temperature control and thyristor units, but sensors and paperless recorders for pharmaceutical production need 21 CFR certification. This means that files cannot be modified, allowing authorities to check for contamination and incorrect temperatures, as well as other factors that may impair the product. There are only a few 21 CFR-compliant recorders on the market.

It has become compulsory in the US to record information about all transactions involving a drug by using a unique number stamped onto the blister pack. Since the advent of 21 CFR, there has also been a great deal of debate about efficient serialisation, electronic pedigree and authentication.

21 CFR Part 11 has also become the de facto worldwide pharmaceutical industry standard and relates to guidelines for trustworthy electronic records. This regulation requires companies to utilise a set of procedures and controls to ensure the authenticity, integrity and confidentiality of electronic records. In addition, this section of the legislation helps certify that an electronic signature is genuine. It focuses on the impact that manufacturing and packing processes have on product quality and data integrity. Adequacy and timeliness of planned corrective measures is also high on the agenda. Another key aspect of the regulations is tracing the compliance history of a pharmaceutical company, especially with respect to data integrity.

Stringent Procedures

Part 11 spells out the minimum current Good Manufacturing Practice (cGMP) for preparation of drug products. This includes aseptic processing and encompasses any equipment used for pharmaceutical production which must be routinely calibrated, inspected 56or checked, according to a written programme designed to assure proper performance.

cGMP is fundamentally an extensive list of guidelines on how companies may create their own rules, with standards for how equipment should be maintained and checked. These standards are met using a plan drawn up by the company itself. The role of the FDA is to examine and approve the company’s plan and to ensure it is being followed.

As a result, the people writing these procedures make them stringent so they are more likely to be approved by the FDA. The automation designer or systems integrator has to follow them, which involves design concepts, design reviews and peer reviews. If there is a change, the company has to submit a change record, which must also be approved.

Audit Trails

Another facet of 21 CFR Part 11 mandates there be an audit trail when generating data. These audit trails must be secure, computer-generated and time-stamped to independently record the date and time of entries. Any activity that creates, modifies or deletes electronic records has to be stored and made available, should there be a need for the FDA to conduct an audit.

Audit trails are required to specify who did what to the records and when this was done. For example, if a robot cell is being used to control other elements of the plant’s equipment – which is possible if a robot incorporates a builtin programmable logic controller (PLC), for instance – this can be achieved easily. Where a robot is equipped with a vision capability, the PLC’s record can be complemented with another provided by the camera itself.

Quality Assurance

The pharmaceutical industry depends on automated process control and quality assurance systems to ensure that batch production is carried out repeatably, reliably and accurately. Like many other manufacturing industries, especially those concerned with the production of high-value products, pharmaceutical producers are constantly looking at ways to increase throughput, maximise yield and improve the flexibility of batch manufacturing. Furthermore, there is no other industry where good quality assurance and control can make the difference between life and death in quite the same way.

Critical to this level of control is incoming material inspection and proofreading of labels. FDA guidelines specify that each package must carry a label exactly the same as the one originally approved by the manufacturer.

Large equipment with a number of different processes will involve multiple machines, requiring integration through fieldbus communications, like Ethernet or Profibus for example, to take the information upstream to supervisory control and data acquisition systems.

Sterilisers

Sterilisers, traditionally known as autoclaves, are used for glass and metal containers. Sterilisation to a temperature of 180ºC is typical to destroy microorganisms, but a subsequent stage might require a temperature of 250ºC to destroy pyrogens and endotoxins. In some cases, tunnel-shaped drying ovens are used where the temperature is gradually increased in a number of different processes.

For example, on one particular application, an Italian sterilising machine builder offers a range of depyrogenating tunnels for processing ampoules, carpoules, vials and syringes. They sterilise and depyrogenise glass containers in a continuous process, maintaining an ISO5 environment throughout the length of three different chambers: the inlet chamber, hot chamber and cooling chamber. Sterilisation of the cooling chamber, closed tunnel and automatic air balance are a few of the features.

All tunnels are made in compliance with the cGMP and 21 CFR Part 11 requirements, as well as the UKoriginated Good Automated Manufacturing Practice (GAMP), founded in 1991 to deal with the evolving FDA expectations for GMP compliance, and followed by a partnership with the International Society for Pharmaceutical Engineering.

Now a recognised good practice worldwide, GAMP describes a set of principles and procedures to ensure pharmaceutical product quality, which cannot be tested in a batch of products but is instead monitored at each stage of the manufacturing process from raw material and equipment, to training and staff hygiene.

Another Italian manufacturer makes horizontal steam autoclaves that allow for optional operation by air/steam mixture. Thanks to flexibility in design, layout, chamber sizing and load handling, the autoclave’s components are easily replaced to increase the lifespan of the equipment. The company also makes oven sterilisers for depyrogenation of various solids such as glassware, parts of machines for filling containers, and stainless steel parts for production where variability of products, batches and formats does not allow the use of continuous sterilisers, such as tunnels.

The oven’s sterilisers are suitable for treating solid heatproof materials such as empty glassware and metal, materials sensitive to humidity, thermostatic basic pharmaceutical products, and chemical compounds including non-aqueous liquids like oils and glycerine.

Blister Packaging

Blister packaging involves two processes: one to form a plastic container, and another to seal it with cardboard or foil. A typical application would require the production of a complex pack containing the drug blister, literature, vanity wallet and desiccant bag. A sample application would involve everything being flow-wrapped in an 85 micron thick wrapping material, able to guarantee a seal at a pressure of half a bar at a speed of at least 200 parts per minute (ppm).

Using flow-wrappers in pharmaceutical applications means cost reduction both in terms of packaging and waste, together with efficiency increases, less human involvement and extremely tight sealing achieved at high speeds. They provide ease of integration of different devices and check points, flexibility of hardware and software, and tracking of the production batch.

A typical wrapping process involves inserting blister containers into a vertical loader, as well as dispensers on a conveyor for literature and vanity wallets. The desiccant bag is then inserted before sealing. The whole process is monitored by sensors along the production line – often at speeds of up to 220ppm.

There may be three or four heaters in the process, requiring multi-loop control which is implemented in a controller with its own HMI and powered by a single-phase 15A or 25A SSR or thyristor.

A heater break alarm is often required in pharmaceutical packaging production. This is a feature of thyristors that will send an alarm signal to a relay contact to shut down the process if any heater short- or open-circuits, or falls below 20 per cent of nominal current.

Quality Planning

Documentation should be developed within a structure to set up the procedures and methodologies to be used, according to a quality plan. It is advisable to prepare a plan of the tests with relevant documents to confirm, point by point, the correspondence between functional and system design specification, as well as to subject the whole integrated system to a factory acceptance test.

After the installation at the customer's factory, a system should be further checked and validated through activities described in a site acceptance test, which consists of two basic documents – the installation qualification and operational qualification.

So, while Huxley was not referring to process heating when he spoke about verification, it is a key element in three types of pharmaceutical production activities – sterilisation, drying and blister packaging – all of which are subject to 21 CFR. This limits the number of process heating suppliers to the pharmaceutical industry, but also assures patient safety and confidence.


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About the author

Jez Watson is the managing director of CD Automation UK, a manufacturer and supplier of industrial controllers, drives and automation products, including power switches and filters. The company specialises in thyristor controllers, having started development of micro processor-based technology in 1990. Jez studied Electronics and Communications at Brighton College of Technology, graduating in 1987, and spends his spare time studying neuroscience.

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