OVERVIEW
Pharmaceutical quality control
Since 1998, Alkaloid AD Skopje has invested close to €60 million, mainly in the Pharmaceuticals Manufacturing Division.
In 2002 the company finished the new plant for solid dosage forms and the plant for semi-synthetic cephalosporins. It is located around 10 kilometres from the company’s headquarters in the western industrial zone in Gjorche Petrov.
With the quality of the production process in mind, in 2005, Alkaloid built and equipped a new department for packaging of drugs, compliant with the Good Manufacturing Practices (GMP) standards. The department has six automatic blister-pack lines and one strip-pack line for the packaging of Caffetin tablets.
As part of the investment in a new drug packaging plant, Alkaloid allocated and adapted a new warehouse for intermediates compliant to the highest performance standards for pharmaceutical companies. This additional investment brought huge advantages to the speed and efficiency of the manufacturing process. The existing reserves of intermediates are now prepared for different markets, depending on the demand and needs.
To further automate manufacturing, Alkaloid installed a new automatic line for dosage, sealing, labelling, and packaging of oral liquids.
In 2018, following a complete reconstruction of the facility, the company launched the semi-solid dosage forms plant compliant with the GMP requirements. It purchased and installed new equipment for production of eye and topical ointments and topical creams and gels.
In 2020 it launched a new drug packaging plant, equipped with two high-speed blister pack lines, increasing the packaging capacity by 25%.
A second automated liquid oral dosage line was installed in 2021, introducing the dosage of new volumes and a new type of packaging units.
Production Capacity
The Pharmaceuticals Manufacturing Division consists of the following production units:
- Manufacturing – solid forms
- Manufacturing – cephalosporins
- Manufacturing – liquids
- Manufacturing – semi-solid forms
- Packaging of drugs
- Production of pharmaceutical raw materials
All manufacturing lines for pharmaceutical dosage forms are equipped in full compliance with the European GMP standards.
The strict GMP norms require regulatory compliance, which is especially important for the smooth and highly sophisticated process of production of drugs.
The full pharmaceutical product line of the Pharmaceuticals Manufacturing Division consists of the following pharmaceutical forms:
solid oral dosage forms: conventional and modified-release tablets – film-coated tablets, dragees, capsules, and dry powder for oral suspension;
liquid oral dosage forms: oral solutions, syrups, and suspensions;
topical preparations: creams, ointments, solutions for external use, gels, and vaginal and rectal suppositories.
In addition to the pharmaceutical dosage forms plant, Alkaloid’s Pharmaceuticals Manufacturing Division also has an opioid extraction plant. It produces morphine and morphine derivatives as pharmaceutical raw materials.
The annual manufacturing capacity, produced in three shifts, is as follows:
4 billion solid oral dosage forms;
200 million tablets, 85 million capsules, 5 million bottles of dry powder for oral suspension, and 10 million individual packs of ready drugs, semi-synthetic cephalosporins as solid oral dosage forms;
6 million vaginal and rectal suppositories;
10 million tubes of ointments, creams, and gels;
1.8 million bottles of solutions for external use;
9 million bottles of oral solutions, syrups, and suspensions;
160 million individual boxes for packaging of drugs;
10 tons of pharmaceutical raw materials;
Quality Control
The Quality Control department of the PC Pharmaceuticals has laboratory premises of around 3000 m2. The QC department employs a large number of highly trained and experienced professionals and over 70 % of them have obtained at least a university degree. The equipment and instrumentation in its state-of-the-art laboratories are controlled via high-end software and complies to all Data Integrity requirements, which enables improved laboratory productivity and increased traceability. All computerized systems and instruments comply to the 21 CFR part 11 and Data Integrity regulations which ensure that the generated data are e-signed and safely stored, backed up and archived throughout its lifecycle.
The Quality Control department comprises coordinated activities for quality control of all the incoming and raw materials, through the manufacturing process until the production of final product with specified shelf life in appropriate storage conditions and specification compliant to the strictest European and International standards. The Quality Control is consisted of several coordinated activities and processes that are integrated in the Alkaloid’s Integrated Pharmaceutical Quality System, based on the cGMP requirements. Continuous and efficient processing, monitoring and management of all information regarding the processes is done via AlkaSAP system.
Control of the raw materials, contact and secondary packaging
The control of the active pharmaceutical ingredients, the other compounds and the contact packaging includes activities for control of their physical and chemical properties and microbiological characteristics in accordance with the European and internationally recognized standards. The secondary packaging should provide sufficient and understandable information to the medical personnel and patients. These activities are performed using modern validated instruments and techniques such as: Near-Infrared and RAMAN Spectroscopy for each container of incoming raw-material, Infrared spectroscopy, TOC analyzers that analyse the total organic carbon in the water as a medium for pharmaceutical production, Gas chromatography and high-performance liquid chromatography, automatic titration measuring devices, etc. These instruments and generated data are controlled via software that complies to all applicable current standards and regulations.
Control of the phase production and control of final products
The products are monitored in all the phases of their manufacturing process, with all their specifics by phase, until the final product is delivered. The final products, from the aspect of physical, chemical and pharmaceutically-technological properties aspects, corresponds to the specifications set forth by the strictest international regulations.
The activities are performed by employing modern validated instruments and techniques such as: HPLC and GC chromatographs, spectrometers, dissolution systems etc. There are several software platforms such as CDS – Chromatography Data System that capture and safely store the data, in compliance with all applicable Data integrity guidelines and regulations.
The analytical methods used for the analyses are continuously upgraded and modernized and accordingly validated resulting in highest level of safety and confidence of their performances.
Microbiological control
The microbiological activities are performed in separate laboratory premises constructed in compliance with the most sophisticated cGMP standards. In the microbiologically classified areas appropriate equipment has been installed such as: bio-safety laminar cabinets, incubators, dry sterilizers, autoclaves, coolers/freezers, microscopes, microorganism identification systems etc. The following activities are carried out by applying coordinated and strictly determined procedures: control of the products and systems, control of purified water and other media for pharmaceutical manufacturing, supervision of the premises and equipment hygiene in the manufacturing facilities as well as all other activities in compliance with the DPP standards.
As part of the biological tests, the tests for absence of bacterial endotoxins are performed by modern kinetic turbidimetric methods onto the incoming raw materials and the finished product that are specific for sterile production.
Stability of the pharmaceutical finished products
Samples from the commercially produced batches are stored in special stability rooms in conditions that simulate the worst case of outdoor climate conditions at which the products are exposed during their lifecycle until the declared expiry date. The conditions in the special stability chambers are being continuously monitored and controlled using a software as an integral part of the stability chambers and also via an additional independent software system for monitoring. By performing stability studies, the declared expiry date and the specified storage conditions of the products are proven to be in accordance to the previously defined specification.
Validation activities and monitoring
In accordance with the GMP operations, the following process are implemented in relation to: validation of analytical methods, validation of the production processes, cleaning validation of the premises and equipment, validation of the water systems for pharmaceutical application, compressed air, steam, cleanness of the equipment etc. With previously defined scheme of critical points in previously defined time frames the routine monitoring of all defined activities is continuously performed.
The quality inputs of raw materials for manufacturing together with the other controlled conditions for pharmaceutical production are preconditions for providing of safe and high-quality final products.
Registration activities
The Quality Control department works on development of the analytical part of the documentation required for the registration files of the products, which are integral part of the internationally recognized CTD registration format for pharmaceutical products.