A clean resorbable plastic implant

When installing a cleanroom production site in existing buildings, many obstacles must be overcome. Consistent and comprehensive planning is extremely important. It is advisable to set up a project team that considers the framework conditions of the planned production site and is able to estimate and prevent risks.

In the course of expanding production, a cleanroom production site for the medical engineering sector was to be set up at Createchnic AG, Nürensdorf/Switzerland. Among other things, the cleanroom was intended for the manufacturing of dispenser systems, of disposable items for cardiology and orthopedics, and of resorbable human implants for traumatology. The classification of the products complying with MDD/93/42/EWG ranges from IIa to III.

The new production facility had to be integrated in an existing infrastructure in order to be able to carry out a general audit. Finally, the cleanroom facility had to be planned complying with US Fed. Stand. 209 / DIN EN ISO 14644 and qualified according to GMP standards, whereby acceptance tests had to be done according to the effective recommendations.

An injection-moulding machine had to be installed in the cleanroom. In the course of further processing, the plastic parts were glued, welded, assembled and packaged. Manufacturing is supported by an integrated quality laboratory for deliveries, process and final tests as well as for integrating external labs as e.g. for further biological tests. In addition, the facility is equipped with an integrated monitoring for the most important operating data.

The bio-resorbable implant to be manufactured is an interference screw made of polyactid for cruciate ligament plastics at the human knee.

Polyactid screws offer stable primary fixation of the transplant and show a good tolerance. A decisive aspect is the complete degradation of the screws and its substitution by osseous (bony) neoformations. The complete degradation and substitution of the less than 1g heavy screw occurs within 12 to 24 months. In case of repeated surgery, the often difficult removal of the implant is not necessary.

Of course, design and construction of the interference screws must consider the specific features of the used materials. Two important aspects were the requirements in terms of consistency and easy handling. The screw does not have a standard thread, but a thread profile that considers the consistency conditions between spongiose (spongy internal tissue of the bones) and screw material, and which is adapted to the macrostructure of the spongiose. The thread profile is nearly symmetric, because the implant is exposed to diametrally opposed transverse forces at the bone-cone side and the bone-bed side. The screws are fitted with the help of a special screwdriver without pilot drilling and thread cutting.

Numerous physical and biological features stand for product quality. In order to ensure product quality, it is required that prior to, during and after the manufacturing process various measuring and testing procedures be carried out:

• Initial tests – – check the primary packaging of the screws in terms of bioburdens, – sight checks to ensure that the poly D, L-lactid granulates are particle-free.

• In-process tests – – determine the residual moisture of the granulates, – test to determine deviations and tolerances of the screws (30 minutes), – test to ensure that surfaces are particle-free and perfect (30 minutes), – prove adequate consistency of the product via scissors test.
• Final tests – – check packaged screws in terms of bioburdens, – prove that there are no endotoxins on the sterile product, – prove that the product is sterile.

To deal with the project in a purposeful way, a project study was initiated to clarify various points:

• if the required cleanroom engineering is sufficient,
• if there are any reciprocal effects between the product and the techniques, or if the existing infrastructure could cause problems,
• which technical and personnel-related solutions are needed to draw up a preliminary balance sheet of funding and operation expenses.

Initial inventory and analysis of the actual condition of the building and existing technology made obvious that for this project a standard solution would not do. The back assembly of the existing and installed process facilities itself would be quite difficult. This first result already confirmed that the decision to make a project study was the only right way to proceed.

A further objective of the project study was to define, with the help of the given product specifications possible solutions, derive from them various facility versions for realising the project and then determine the best concept.

Altogether five proposals were worked out, each designed for a cleanroom facility with classes 8, 7 and 5 in accordance with DIN EN ISO 14644. The descriptions, calculations and drawings were submitted with all facility versions, including the necessary construction data and detailed funding and operation cost calculations.

Ultimately, the project study of the extended basic planning was used to determine the most favorable combination in terms of architecture, energy and costs. Of course the adherence to the allowed threshold values for air cleanliness (particles and bacteria) had to be ensured.

According to a topical branch study, plastics in medical engineering are with 45% the largest materials group. They are processed to e.g. such products as one-way syringes, blood bags, infusion tubes, and parts for dialysis facilities or for artificial hearts. In this specific case the screws are to be manufactured using the injection-moulding procedure.

Suitable for injection moulding under cleanroom conditions are the so-called "unpolluted rooms" (class ISO 8) and "cleanrooms" (classes ISO 5 to ISO 7). "Super cleanrooms" (classes ISO 1 to ISO 4) have been more rarely used in plastics custom moulding so far. There is however a trend in favor of such high-quality manufacturing. Requirements on production facilities are among other things:

• equipment must qualify for cleanrooms, calibration and validation must be possible,
• no or very reduced particle emissions,
• anti-static equipment and easy cleaning.

Integrating an injection-moulding machine in a cleanroom class 100 involves great efforts, especially when the products are to be manufactured for medical, biotechnological or pharmaceutical purposes. The requirements on such production facilities are much stricter than is the case with technical products.

In the ideal case, the setup of the machine in the manufacturing area is done in consideration of the ventilation installations. It is best to have the locking unit directly underneath an air outlet in order to ensure a largely regular flow of the (cleaned) air over the tool.

In clean room class 3 it is generally the case that an almost laminar airflow is directed through the locking unit, and thus through the tool. The interference-freer the directed airflow through the machine is, the easier it is to obtain the desired quality level.

The manufacturing of cleanroom suitable injection-moulding tools is quite complicated, since no lubricants are supposed to be used as far as possible. If this cannot be prevented, care must be taken that the lubricant does not get anywhere near to the work area (cavity). On the contrary, it must be directed inwards with the help of an appropriate differential pressure. For deforming forcibly actuated, mechanical ejectors should be preferred. Hot runner moulds are not appropriate in all cases because the nozzles are not always 100% leakproof. The best solution is a pin-point gate.

Depending on each individual case and the regulations, the preforms may fall out of the machine freely or they must be taken out. Class 100 cleanroom production requires a handling device for taking out preforms. The fact is that despite special protective clothing and all precaution measures, the operating personnel are always the greatest creators of dust and dirt.

The changing of tools involves great efforts in cleanroom manufacturing, especially in class 100. The new tool must be completely disassembled and cleaned under cleanroom conditions. Quite suitable for this purpose is a laminar box in which assembling can be carried out.

As far as machine maintenance is concerned, a difference must be made between regular maintenance work and the cleaning work that must also be carried out on a regular basis. Machine maintenance is quite important because virtually any defect can lead to a contamination of the machine, the tool or the environment. This would make very extensive cleaning work necessary. So for this reason it is essential that the maintenance intervals defined by the machine manufacturer be strictly observed.

For the manufacturing of preforms in a class 100 cleanroom, only plastics are permitted that have been produced under especially clean conditions. Lactid is processed for the interference screws, a cyclic dimer of lactic acid that exists in two optical isomers. Poly L-Lactid (PLLA) is a semicrystalline material with good mechanical features like ultimate tensile strength and low elongation.

Of importance for the manufacturing of the products are approvals in accordance with ISO 9001, EN 46001 and MDD/93/42/EWG, appendix II, item 3. The approval in accordance with MDD/93/42/EWG was granted after an auditing by the authorities thus simplifying the product approval by the customer. The quality system is process-driven. The five most important are:

• management processes
• resource processes
• customer relationship processes
• realisation processes
• supporting processes

Within the realisation processes there are 25 subprocesses that regulate the specifics for medical engineering.

The product-related quality requirements have a considerable influence on the infrastructure of the cleanroom. For injection moulding manufacturing and in-process control a cleanroom with process exit air was selected. Final inspection and packaging in primary and subsequently in secondary packaging (without labels) is carried out in a separate part of the cleanroom facility. The concept is acknowledged as being reliable. In this case the cleanroom class 10,000 was defined in accordance with US Fed. Standard 209E and qualified in accordance with the effective recommendations.

It considers a maximum tolerable number of 30 germs per implant. This number is derived from the sterilisation method with gamma radiation from a Cobalt 60 source. The standard for radiation-sterilised implants demands a provable sterile guarantee of 10^-6. In other words, among one million sterilised implants one may be non-sterile. This must be proved within the scope of the validation with a so-called low dose method. What this actually means is that with the fewer germs per implant a validation is carried out, the easier it is to guarantee sterility.

To ensure the cleanliness of the cleanroom a disinfecting scheme was set up that amongst other things described the items to be cleaned, the allowed cleaning detergents, the cleaning intervals and the cleaning methods. The given instructions had to be strictly obeyed in order to stay below the given threshold values for germ levels. Ambient monitoring in the cleanroom requires:

• measuring of temperature, air humidity and impact pressure,
• measuring of particles in the room air,
• measuring of the air germ rate,
• measuring of germs on surfaces.

Temperature, air humidity and impact pressure are continuously measured and displayed from permanently installed, calibrated sampling points. The data is stored in a database. If given minimum or maximum values are exceeded, an alarm signal or error message is immediately set off that initiates a predetermined measure.

Particle measurement is carried out on a regular basis at predetermined sampling points. The target values are given for each room class. In case of limit exceeding, production must be stopped and remedied according to agreed measures.

Measurements of the air germ rate must also be carried out on a regular basis. Sampling is done with a RCS sampler "biotest". Tryptic-Soya-Agar is used as culture medium.

The germ levels of all relevant surfaces are measured on a regular basis through a proof using 25 cm-Rodac-dishes. Plate-Count-Agar is used as culture medium. Flocculation must occur in two steps.

The production process is divided into 13 steps starting with entry inspection of the raw materials up to the delivery of the finished items. Most of these steps are carried out under cleanroom conditions:

• entry inspection of the raw materials in the quality lab class 100 000,
• storage and transportation of raw materials into the cleanroom storing place,
• production preparation of the injection moulding tools under LF class 1 000,
• production preparation of the injection moulding machine and facility class 10 000,
• drying of the granulates under class 10 000,
• in-process inspection under class 10 000,
• final inspection of the products under class 10 000,
• primary and secondary packaging of the products under class 10 000,
• repackaging of the products under gray room conditions,
• bioburden test under lab conditions,
• gamma radiation of the products by means of Cobalt 60 source,
• checking for endotoxins under lab conditions,
• proof of sterility under lab conditions,
• storage and transportation of sterile products.

Clearing regulations check the individual steps against each other. The specifications and verification documentation in accordance with MDD/93/42/EWG are regulated in a DMF (Device Master File) and a DHF (Device History File). In this case the documents must be kept for 10 years.

Within the scope of the project study five different kinds of facilities were drafted, compared to one another, analysed and evaluated. The ultimately released version is a combination of all worked out proposals with consideration of the product-related specifications.

The detailed project study and the cooperation of all participants enabled an unproblematic project realisation, which was committed to a tight time schedule. The simultaneously running qualification process ensured best planning and execution. Through the sound preparation of engineering and qualification, a complete validation of the whole system at the end of the project was achieved.

In pharmaceutical manufacturing the GMP standards (Good Manufacturing Practices; guideline of the EU commission for the manufacturing of drugs) must be observed. FDA inspections (Food and Drug Administration) check how far these standards are being observed. Various recommendations set the standards in respect to which parameters are to be qualified and according to which measuring and checking procedures this must be done.

When qualifying a facility, you must distinguish between an already existing cleanroom facility and the first-time setup of a facility. The Createchnic AG project was a first-time facility setup – only the building existed – which is why a prospective qualification was carried out.

Generally, the project process for pharmaceutical or medical engineering manufacturing is subdivided as follows:

• feasibility study and concept planning,
• GMP review with FDA preapproval,
• basic engineering and detail engineering,
• execution planning and realisation,
• startup and operation

It is important and useful to consider the required qualification right at the beginning of all reflections, in other words, during the feasibility study. The fact is that the qualification process is fully integrated in basic engineering at the latest.

As soon as the order has been placed, a qualification scheme should be set up in order to determine at which stage of the qualification the main points ought to be checked. It also defines the competencies and responsible persons for the individual stages: Design Qualification (DQ), Installation Qualification (IQ), Operational Qualification (OQ) and Performance Qualification (PQ). In so far as the user has a general master validation plan, the qualification scheme must adhere to it.

The master plans determine a processing scheme including the definition of terms, objectives, procedures, used work materials and the organization of the quality project.

In order to be able to determine the critical points and functions of the facility, a risk analysis must be performed. For this purpose, the facility components are tested in terms of functionality as well as analysed to what extent malfunctioning could effect the adherence to the specified values. Ultimately, risk analysis makes a comparison between the theoretical and practical measures in the qualification procedure. In so far as the results differentiate in terms of structure and statement, another comparison must be made.

Starting with the qualification scheme, the next step is Design Qualification (DQ). This is the systematic and recorded proof that the facilities and equipment have been planned in accordance with the GMP requirements. They must also comply with the requirements of general quality security as well as environmental and work safety. Some essential features of the GMP standards are:

• easy cleaning and easy accessibility,
• integrated control and logging systems,
• available user documentation,
• available qualification documentation,
• computer flow simulation.

After the facility is installed, Installation Qualification (IQ) verifies that the facilities and equipment have been built and installed in accordance with the specifications, installation regulations as well as other standardised rules and regulations. In this stage, the completeness of supplier protocols and documentation must be checked. IQ ends with a report that among other things can include a list of defects.

Operational Qualification (OQ) is also the first operational test of the facility over the total range of the setting parameters. In the planning stage, a decision must be made in terms of which operational tests should and ought to be executed for which facility components. Included are all function units that have a direct influence on the specified parameters of a cleanroom. Operational Qualification includes acceptance measurements of the cleanroom facility.

Performance Qualification is the last stage of the qualification. The facility is tested under operational conditions with all personnel and running production.

The final report summarises all listed qualification steps in a document. It is thus the formal release of facilities and equipment for manufacturing after having carried out the validation.

The documentation is an essential part of quality security besides GMP principles. It includes all qualification plans, the test plans and instructions as well as final report. Included are also all machine documentation, the relevant switching and facility plans, and user documentation containing operation instructions and detailed maintenance manuals. The principle of cleanroom engineering must be considered in this connection. What is meant is that any subsequent modifications call for a new execution of the total qualification and validation process. Other parts of the documentation include documents and recommendations concerning staff education and training, and the in-house implementation of given tasks.

In principle the acceptance of a cleanroom is merely a formal act that is preceded among other things by acceptance measurements and tests. The basis for the acceptance measurements and tests can be various recommendations that sometimes include details on the methods and measuring devices to be used. To ensure least possible disagreements within the scope of the acceptance measurements, it is best that cleanroom manufacturer and cleanroom user agree already in the specifications on the parameters to be tested.

As soon as the acceptance measurements of a cleanroom have been completed and the room has been taken into operation, it should be monitored continuously according to a monitoring plan. The monitoring of the cleanroom facilities is usually not precisely defined in the recommendations. Thus it is up to the user.

Costs for execution often have a higher priority for many clients than planning or quality of execution. But it is planning that influences decisively the development of costs. Conventional planning calls for much higher additional costs than this is the case with far-sighted planning. It is important that quality management includes modification and malfunction management.

Basically, it is not advisable to make any modifications within the described project stages. This may have hardly comprehendible consequences due to the inter-connection of individual cleanroom subsystems. In case such modifications are nevertheless required, the entire process for identification and determination of the parameters must be repeated, thus inevitably ruining every tight cost calculation scheme.

As far as qualification and validation is concerned, it is difficult to estimate the costs in advance. Experience has shown that these two stages make up for about 8-15% of total investments.

Prerequisites for concept and execution of an economical cleanroom system are specific knowledge and experience of the planner as well as of the facility manufacturer – and close cooperation with the operator.

Operators of a cleanroom-manufacturing site must be aware of the fact that such a complex facility causes additional costs. Adopting the idea of setting up a cleanroom production on a smaller space to save costs is quite risky. Ultimately, what actually matters is the required quality of the products to be manufactured.