A new regulatory consideration has arisen that affects pharmaceutical facilities of a certain vintage: the risks associated with the aging plant. In many more established areas of the world, pharmaceutical facilities are passing various time marks: thirty years, fifty years and even longer. As many pharmaceutical companies seek to establish manufacturing facilities for new product lines in emerging markets (China, Eastern Europe, Asia, for example) some of the more established plants in regions like North America and Europe begin to look older and possibly need more maintenance. An aging pharmaceutical facility brings with it various risk considerations, and it is with some of these risks this article addresses. These risks are not universal, for some facilities will continue to function effectively without any additional considerations; however, many require additional checks and assessment.
One theme throughout this article is ‘drift’, centered on attempts make good the ageing plant through modifications, repairs and alterations to procedures, as well as responding to more frequent breakdowns and mishaps. By way of an example of drift, a small sterile manufacturing facility in Germany, built in 1995, began with a workforce of 50, a maximum batch size of 200 Liters, and 20 standard operating procedures. After one year of operation, the plant had raised 20 change controls and there had been 25 deviation reports.
By 2015, the plant had grown. Staffing had increased to 130 people, and the batch size had extended to 900 Liters. The number of procedures had risen to 80. As a consequence of the capacity and staffing rising above what was originally designed, and the need to maintain what was now an aging facility, there had been 5,100 change controls and 6,200 deviations. This example is to illustrate that aging facilities see increases in terms of risks, and ten of the most common types of risk category are discussed below.
What is an aging facility?
There is no exact definition of an aging facility (or what are sometimes euphemistically called “legacy facilities”). One plant, established one hundred years ago tom manufacture a simple tablet may, with careful upkeep and an eye on developing regulations, continue to operation perfectly well. A biotechnology process, established ten years ago, may become out-of-date if it cannot adapt to a necessary process change that might arise due to a change to product formulation or the need to meet a new regulatory recommendation, such as a viral inactivation step (1).
Moreover, the use of the aging facility may operate differently from its original intended use. For example, there could now be a higher production output with different staffing levels, with different types of equipment. With equipment there may be an increase in the number of breakdowns and with both mechanical and electrical components wearing out. Each of these presents challenges.
Significantly, with plants that pre-date more modern thinking, such as Quality by Design, these facilities face a greater risk of not being able to adapt to future opportunities or threats. Here upkeep and modernization efforts are quite costly, and if the drugs being manufactured are not profitable, the likelihood that production will be curtailed rises.
There are commercial and compliance reasons for continuing to maintain or even upgrade older facilities. In terms of compliance, the Code of Federal Regulations and other Good Manufacturing Practice (such as EU GMP) place a strong emphasis upon architectural issues pertaining to pharmaceutical manufacturing. For example, 21 CFR Part 211.42 states:
§ 211.42 Design and construction features:
(a) Any building or buildings used (a) Any building or buildings used in the manufacture, processing, packing, or holding of a drug product shall be of suitable size suitable size, construction and location to facilitate cleaning, maintenance, and proper operations
(b) Any such building shall have adequate space adequate space for the orderly for the orderly placement of equipment and materials to prevent mix-ups between different components, drug product containers, closures, labeling, inprocess materials, or drug products, and to prevent contamination.
The flow of components, drug product containers, closures, labeling, inprocess materials, and drug products through the building or buildings shall be designed to prevent contamination.
(c) Operations shall be performed within specifically defined areas of areas of adequate size adequate size.
Importantly, GMP Regulations specify what a particular requirement is (that is what is to be controlled), not how that requirement that requirement is to be achieved.
One commercial reason is the legacy of capital investment. The costs associated with constructing a new building structure, together with utilities and other infrastructure, will often outweigh the costs of maintaining an existing facility. Moreover, capital costs for equipment will have already been invested and the production operations well established. A secondary factor is personnel. The people employed at an existing facility, will have knowledge and experience of great value. A third reason is the logistical infrastructure. Here the location of the facility will presumably be integral to its operations. Simply moving the facility may lead to a less than optimal supply or delivery network.
However, the choice of continuing operations or with upgrading facilities carries risks and some of these risk areas are assessed below.
Risk 1: Incremental upgrades
With the reference to the unchanged tableting facility above, this type of aging facility is rarity. Most older facilities will have needed to have undergone an upgrade and, in most circumstances, such upgrades will have happened incrementally and over a prolonged period of time. Here changes will have been made to create more capacity and space for new product lines. With this interior spaces and the movement of material and personnel will have continually have been reorganized and new production equipment will have been added.
The more often this is attempted, the less likely the alterations will be optimal. Eventually there is a good chance that the random placement of production areas and lack of integration into existing flows, will lead to facilities which have less than ideal material and personnel flows, as well as increased handling and staging (2). The end result will be a less efficient operation and, in turn, concerns with compliance.
Regular inspections are important. The types of areas to inspect include:
- Is the facility suitable for the operations being carried out?
- Is the facility readily cleanable?
- Are there proper controls against cross-contamination?
- Is there adequate ventilation while still keeping out sources of contamination?
- Are there adequate sanitary facilities?
- Are there operational areas separate to prevent mix-ups and cross-contamination?
- What is the source of the water supply?
- Are there adequate systems for the handling and disposal of waste?
- Is there proper segregation between incoming and released components?
- Are environmental factors, such as temperature and humidity, monitored and controlled properly?
- Is there adequate storage space under the required environmental conditions?
- Are in-process materials properly stored?
- Is the facility equipment suitable for its intended use?
- Is equipment designed to facilitate cleaning?
- Are there proper filtration systems adequately and properly functioning?
- Does equipment design prevent contamination from external sources?
These points can form the basis of an inspection check-list.
Risk 2: Obsolescence
As facilities age, a risk arises that processes and analytics become obsolete and lose key performance parameters. Furthermore, the original manufacturers of equipment may no longer stock spare parts or have engineers available to make necessary repairs. Obsolesce can be a major factor with electronic equipment in particular.
Obsolescence is caused by a failure to invest in new technologies. There are examples of facilities having computer programs written using BASIC programing language and as DOS run commands, and of systems that still require the use of floppy discs. Putting aside the issue of 21 CFR Part 11 compliance, such programs can breakdown and it is most probable that the author of the compute program is no longer available.
Computer related matters also extend to equipment that has been upgraded or replaced. Due to the need to retain and archive data, it could be that data captured from one system is no longer readable on another; this becomes a concern should the original data capture system is unavailable.
Such matters can be costly. For instance, obsolescence of a simple component or software can require replacement of an entire control system. This can become a matter of considerable investment. Moreover, replacement requires downtime for the installation and delays to manufacturing.
Risk 3: Insufficient time allocated to upgrade
With many facilities running 24/7, the time for upgrading machinery or making repairs, both to equipment and fabric, comes during shutdowns. The time for engineering maintenance is, however, often constrained and many of the activities constitute what Jornitz refers to as a “Band-Aid” approach, drawing the analogy of placing sticking plaster over the wound rather than carrying out the necessary surgery to prevent further wounds from occurring (3). Here time saving from truncated shutdowns can lead to costly (both time and expenditure) issues later on.
Sometimes allocating insufficient time to upgrade can back fire. One facility was informed two years in advance that a control system for two if its autoclaves required an upgrade. Repeatedly the facility failed to schedule a controller replacement due to the downtime required. The end result was both autoclaves required upgrading at the same time, and the downtime was doubled.
Risk 4: Brining new products on-line
Should the pharmaceutical facility wish to expand its product range or introduce a new product stream, if the plant has not been sufficiently invested in then there is the real risk that the facility will be unable to adopt a new process and its associated technology.
In other circumstances, a new product may be brought on-line. However, the layout of the facility does not lead to the optimal work or process flow. This can mean introducing time delays or even increasing the risk of cross-contamination. An example might be the path of clean (or sterilized) equipment needing to cross the path of dirty (yet to be cleaned) equipment.
Risk 5: Failing to embrace new innovations
There are several drivers for new innovations within pharmaceutical facilities, designed to improve yield or product units, or to lower contamination risks and lower energy costs. One example, embracing both a reduction in microbial contamination and conserving energy, is with single use sterile disposable technologies (4).
Some aging facilities could overcome design difficulties by making greater use of such technologies. However, the implementation of these can be hampered by an inadequate facility in terms of layout, structure and supporting services. The application of these technologies needs to be embraced holistically.
Risk 6: Microbiological contamination
The aging facility presents various microbiological contamination risks (and some more recent pharmaceutical product recalls associated with microbial contamination have related to older facilities) (5). These risks include:
a) Poor facility management
General poor upkeep, leading to peeling paint or torn lagging, presents opportunities for microbial contamination to occur. Risks are more acute for spore forming organisms, such as Bacillus and related genera and with fungal spores (6).
b) Changes to facility use
Changes to facility use, in terms of people and equipment, presents potential risks. For example, if a facility was designed for a specific number of personnel and the operational level increases, this could present new challenges for contamination control especially where cleanroom occupancy rates increase (given that people are the primary contamination source within cleanroom environments) (7).
Furthermore, changes to production equipment and layouts can affect airflow directions, especially in relation to aseptic processing. The addition of more equipment to a working space can cause greater heat generation, placing a greater heat load upon air conditioning. If environments are not suitably controlled, this can cause personnel to shed higher levels of skin and thus increase the microbial load into the cleanroom. Additionally, as amounts of equipment increase this can make areas more difficult to clean and disinfect simply because operators cannot maneuver around the equipment footprint. Poor air circulation also brings with it other risks, such as undetected fungal growth.
A related area is with the air supply system from variable air volume boxes. Here the air volumes supplied into cleanrooms may not be as originally designed. This not only affects air supply volumes but also air exchange rates and clean-up times. These physical parameters are essential for keeping particles (viable and inert) in suspension and for removing them from cleanrooms. This factor can be overlooked because most cleanroom monitoring systems assess pressure differentials rather than air supply volumes (8).
c) Degradation to fabric
Cracks in walls, tears to vinyl, the degradation of construction joints can lead to microbial contamination events. Here unclean areas can become exposed to cleanrooms and microorganisms can reside in cracks. Where crack occur, cleaning solutions will often not be able to penetrate.
A further risk with weakened or broken joints is that high airflow velocities can drag unsuitable air into cleanrooms from plant areas. This can lead to turbulent mixing and the potential entailment of contamination. This can be assessed through airflow visualization.
Regular inspection and a sound repair program can overcome these problems, together with the fitting of high quality seals such as compressed rubber gaskets.
d) Building void spaces
The voids between adjacent cleanrooms or between cleanrooms and the outside environment will accumulate dust, and within the dust there will be spore forming microorganisms. Such environments will not have any impact unless they are disturbed. Here contamination will arise when facilities are modified, such as knocking through a wall in order to expand a cleanroom. Good control measures should be in place when modifications take place including partitioning off areas, vacuuming dust and regular cleaning followed by sporicidal disinfection.
Risk 7: Regulatory concerns
Regulatory concerns can present themselves at two levels. The first is with assessment of a new product or modification to an existing product. Technologies and processes that were acceptable some time ago may no longer be acceptable to regulators. For example, consider a product produced by aseptic filling. Such a product, registered thirty years ago, could have been accepted by a regulator as a filling set-up based around a unidirectional airflow device within a cleanroom. Today, regulators would expect a restricted access barrier system (RABS) or an isolator. The cost of upgrading to meet regulatory approval, in one go, may be too great compared with a phased upgrade of filling facilities.
The second regulatory concern relates to inspections. Damage to the fabric of cleanrooms, or rusting plant rooms, will raise Good Manufacturing Practice (GMP) concerns.
Regulatory bodies, such as the U.S. Food and Drug Administration (FDA) place a significant emphasis on cGMP, with the “c” representing “current”. For example, one FDA guidance document states (9): “…the “c” in cGMP stands for “current,” requiring companies to use technologies and systems that are up-to-date in order to comply with the regulations. Systems and equipment that may have been “top-of-the-line” to prevent contamination, mix-ups, and errors 10 or 20 years ago may be less than adequate by today’s standards.”
The FDA statement infers that simply stating that the facility cannot support the latest technologies designed to ensure quality or to protect patient safety is not an adequate or acceptable argument.
Risk 8: Knowledge base
Although the concept of a ‘job for life’ was more commonly associated with working patterns up until the 1980s, many established companies have employees who have been with the company for decades. As these people move into retirement, the ‘head knowledge’ and general experience that they carry also disappears. Such head knowledge often includes details on how and why certain processes were set up in a particular way. In order to prevent this knowledge drain, a forward thinking company will consider ways to capture this knowledge, through documenting as much as possible and through introducing schemes like succession planning (10). It is prudent for a forward thinking organization to draw up a description of leadership competencies, identify barriers, and have in place succession planning practices. These practices can include mentoring schemes (11).
Risk 9: Validation status
As equipment wears down and requires a higher level of repair or modification it could be that equipment and systems no longer operate as originally intended. While major changes, or things like software updates, will be captured through change control and assessed, the risk of drift exists with minor engineering modifications that systems may not operate as originally validated. This could lead to system unreliability and will certainly introduce regulatory concerns.
With all modifications it is important to ensure that drawing and plans have been updated and that they remain representative and accurate.
Risk 10: Quality systems
The quality system itself can become the subject of risk should the management of the aging facility be inadequately controlled. Examples of where the quality system can drift away from actual operations is when procedures become bolted on following updates (perhaps due to equipment modification or following a regulatory inspection) and end up contradicting other procedures or by failing to holistically integrate with other parts of the quality system.
At other times, new procedures are needed to help maintain the aging facility. More equipment breakdowns, for instance, may require new procedures designed to keep equipment running. The inclusion of each new standard operating procedure adds to the existing workload, and brings with it time costs in terms of writing the procedure, reviewing it and rolling-out the training.
Managing the risks
While the risks described above are serious, steps can be taken to address them. Measures that can be taken including assessing each item (risks 1 to 10 above and any others) as part of an overall master plan, and with utilizing design space appropriately through modular cleanroom solutions.
Identifying required changes
To upgrade a facility, a number of areas require addressing. This requires consideration of:
- How to upgrade or replace equipment in an existing process?
- How to upgrade or modernize controls?
- How to implement improved technology supporting a process?
- How to capture years of process knowledge?
- Review changes and consider the significance to:
- Supporting systems
- The facility on the actual process
Thought process should be applied to:
- Process requirements,
- Personnel flows,
- Material flows (product, component and raw material movements),
- Equipment layout requirements,
- Operational access requirements,
- Maintenance access requirements.
These factors can be incorporated into a master plan.
The master plan
The future of an aging facility should be risk assessed and the risk considerations documented. If the decision is to continue with the facility, then the upgrades and modifications should individually be subject to risk assessment. The outcome of the risk assessment, charting a way forwards, should form the basis of master plan. Such a plan should provide a comprehensive analysis of the strengths and weaknesses of the facility and identify opportunities within constraints. Once agree, the specific improvements should be subject to regular review.
One faster way to upgrade infrastructure within the facility is through the use of modular cleanrooms. These can provide new processing areas to spaces that would otherwise it empty, or within areas that have been reconditioned. Modular cleanrooms have an advantage in that they come with their own Heating, Ventilation and Air Conditioning (HVAC) systems, where localized high efficiency particle air (HEPA) filters can minimize contamination. Such clean spaces can readily be fitted with the necessary utilities (air, water, steam, electricity and so on) to enable pharmaceutical processing to take place.
Modular cleanrooms (sometimes, inelegantly, called ‘podified’ cleanrooms) are cleanrooms assembled within an existing structure to provide a ‘clean’ environment. They are constructed out of many varying materials, providing either hard walls, or with flexible vinyl to produce soft-wall variants. A key point is with design and planning, and avoiding disrupting current operations and from increasing the contamination risk (12). Pre-engineering modular cleanrooms, for instance, allows for the development of components that collaborate with each other.
The main types of modular cleanrooms are (13):
- Soft-wall cleanroom systems: Soft-wall cleanrooms provide an economical solution to applications requiring light environmental control.
- Structural post and panel systems: Such cleanrooms consists of an “all-purpose” system that can be utilized for a variety of applications from GMP rooms.
- Framing/partitioning systems: This type of modular cleanroom is more common to the microelectronics sector.
- Aseptic systems: Due to the special requirements found within the pharmaceutical industries, modular cleanroom several manufacturers have developed robust systems for these applications.
The modular cleanroom approach also allows for future expansion or for process modifications. The pre-fabricated design allows a modular room to be expanded, relocated, separated into several smaller rooms, or rearranged into a different shape. Modular cleanrooms, since they aren’t an integral part of a larger structure, can even be dissembled and moved to a different facility, unlike fixed wall cleanrooms. The rooms can also be expanded by removing a wall and adding on another module.
Aging facilities are increasing within the pharmaceutical, especially within the developed world as economic drivers propel pharmaceutical manufacturing to become established in new territories. Such facilities carry risks in terms of compliance: from failing a regulatory inspection; or being subject to changes and upgrades which are beyond the design capabilities; or of being so unsuitable they are not granted pre-approval for a new product; or with becoming mothballed because they can no longer achieve the required levels of operational excellence.
Often the risks are multiple, in that aging facilities rarely show just one problem area. Dealing with one problem area is often challenging; when multiple issues arise at once, the risks become considerable.
This situation can be avoided if investment is orientated in the right directions, especially in relation to facility layout, and where periods of manufacturing shutdown are of an appropriate length to enable the necessary engineering and maintenance repairs to take place. To allow this to happen the appropriate management culture is needed, focused on the long-term rather than the short-term.
In terms of day-to-day operations, aging facilities will require an increased program of inspection to look for damage, cracks, leaks and so on. In relation, more resources need to be put into planned preventative maintenance (the level and type of which may be different to what was required a decade ago). In addition there may need to be increased environmental monitoring in order to ensure contamination issues are detected as early as possible.
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