GxP-Blog

Martin Nägelin

Hospitals have their own internal manufacturing departments that provide patients with required medical products. In particular, patients in intensive care units require special drugs, often with CMR substances (i.e. substances that are carcinogenic, mutagenic or toxic for reproduction), which must frequently be produced specifically for the patient concerned. However, the range of drugs produced in the hospital pharmacies is much larger, and includes the entire repertoire of solid, semi-solid or liquid forms of administration with ingredients that may likewise be very diverse, from simple alcohol-based disinfectant solutions to complex antibiotics or drugs containing cytostatic agents. The resulting requirements for the manufacturing departments are correspondingly tough and are increasingly becoming a focal point for the regulatory agencies.
Over decades, the situation has frequently developed that these hospital pharmacies function as suppliers for both public pharmacies and as direct internal suppliers for their own hospitals. However, most hospitals wish to separate public consumers from internal hospital customers. For example, pharmacies that function as so-called public pharmacies are installed in the entrance areas of the hospitals. The hospital pharmacy itself and the drug-dispensing station are thus frequented only by the nursing staff. Material flows and personnel workflows must adapt to these requirements.

Routine inspections by the authorities are uncovering long-standing shortcomings that have developed over time with regard to hygiene. These shortcomings involve not only the manufacturing areas, i.e. the cleanrooms, but the entire manufacturing process (including material and personnel workflows) in the hospital pharmacy. This includes cloakrooms/changing rooms, clothing requirements and thus the corresponding entry and exit airlocks, the laboratory adjacent to the manufacturing area and the entire warehouse and logistics area. There is frequently direct access to manufacturing rooms (cleanroom class D or C) without airlocks from access corridors (without cleanroom zoning).
The status quo that developed over time frequently cannot meet current regulatory requirements. There are deficiencies in many aspects of contemporary drug manufacturing. Materials used in the construction of the facilities are difficult to clean and disinfect, e.g. because properly designed channels are missing, and joints and grouting offer microorganisms protection from surface disinfectants. Moreover, ventilation systems are often obsolete or lacking entirely.

Pressure cascades cannot be made reliable, and particles are inadequately or not at all filtered. Cross-contamination of adjacent hygiene zones cannot be reliably excluded.

Comparison with the manufacturing conditions that are established standards in the pharmaceutical industry reveals a considerable need on the part of the hospital pharmacies to catch up to current standards. An additional challenge for many hospitals is the call for safety precautions and measures that facilitates safe handling of CMR substances. Accidents/emergencies that may occur during the preparation of customized solutions for individual patients (e.g. cytostatic agents) must be safely handled without exposing staff members to excessive concentrations of these agents. Contamination and the contaminated area must be kept to a minimum. Staff members must be protected from contamination by suitable personal protective equipment – in the event of accidents/emergencies as well. Please note that medical disposable gloves do not provide adequate protection from many chemicals and substances, and a surgical mask is no substitute for professional protective respiratory devices.

Accidents pose particular challenges that many hospital pharmacies are not equipped to handle. Potential contamination cannot be reliably contained or eradicatd and the spread of critical substances via ventilation systems cannot be precluded. During renovation measures this aspect is usually highlighted and the facility is adapted to current requirements.

A basic challenge in the context of renovation or new construction projects is the disentanglement of the various functions and reorganization of the rooms. Material and personnel paths must be designed to ensure safe operation of the hospital pharmacies.
Taking into account the manufacture of small quantities and the large number of medications, adequate safety can rarely be ensured with the existing manufacturing facilities. Hospital pharmacies are, in effect, small pharmaceutical companies and must thus comply with the drug-manufacturing regulations and recommendations.
Planners are faced with various challenges during the implementation phase. Hospital operations and supply must continue without disruptions during the remodeling phase. The move from existing rooms to temporary facilities requires detailed planning to ensure that continuous operation and supply are guaranteed during the construction or remodeling phase. If such interim solutions are not feasible, drugs must be purchased elsewhere during the remodeling phase or neighboring hospitals must provide support.

In the past, hospital pharmacies were generally renovated or newly built in a manner similar to conventional construction projects in accordance with familiar project phase models (SIA in Switzerland, HOAI in Germany). Current standards for the manufacture of medications now require comprehensive expertise in the field of pharmaceutical process planning. This necessitates the involvement of the «specialist trade» of pharmaceutical process planning in addition to the other trades such as construction, plumbing, electrics and HVAC.
With regard to project management in the public sector and private industry, there are differences in the processing depth and the definition of the project phases. However, Chemgineering does not see any general contradictions here; based on our experience in completed and ongoing projects, it is important for the success of the project that the specialist planners involved in the project are aware of and understand the sensitivity and relevance of these issues.
The structure of the planning fee of a pharmaceutical process planner is also noteworthy. Fees calculated on the basis of total fees for construction are not possible or do not correspond to the work required. This can be illustrated using the example of a single device or machine. If the pharmaceutical process planner specifies a GMP-compliant washing machine as a package unit and includes it in the floor plan in the manufacturing area, the media/power supply must still be specified. Obviously, when the machine is worth CHF 200,000.00, detail and implementation planning cannot be invoiced based on reference percentages. Individual systems must be planned in detail, while others are purchased «off the shelf».

The goal of renovation or new construction of a hospital pharmacy is GMP-compliant production of medications and obtaining the required manufacturing permit from the relevant regulatory authorities. The GMP expert, together with the user/ operator and quality assurance staff, prepares the required specifications and planning documents based on the manufacturing regulations and processes. The pharmaceutical process planning team is responsible for implementing these in a technical solution. Material and personnel workflows, the appropriately classified rooms (cleanrooms with airlocks), machines, equipment, overarching data-processing systems, etc. are specified and the corresponding layout planning executed. When the core of the project, i.e. a functioning hospital pharmacy as specified in the plans, has been documented, the most important step is accomplished. An inspection of the plans by the relevant regulatory authority provides certainty along the path to a project genuinely eligible for approval and helps to ensure that the manufacturing permit is actually granted when the project has been implemented.

Today, proof of qualification of technical equipment and facilities is either minimal or non-existent. The implementation of GMP programs for ongoing validation throughout the life cycle is only rudimentary. For example, devices are calibrated and samples are taken from ultrapure water systems only sporadically.
A qualification system with standardized instructions, generic processes and document templates must also be prepared in the course of new construction or remodeling projects. Maintaining the qualified status of these facilities poses a huge challenge to the technical service providers responsible for the maintenance and repair of GMP-relevant production facilities and equipment. Precise compliance with the procedures customary in the GMP environment and the corresponding evidentiary documentation must also be maintained by the technical service providers. The documented change management for systems that require qualification and training of the maintenance/repair personnel are particularly important in this regard.
Meticulous attention must be paid to the handover of new construction and remodeling projects with redesigned production rooms (cleanrooms) and new production and cleaning systems to the users. It is practical to prepare a corresponding training plan at an early stage and before the completion of the project, facilitating the advantageous involvement of the system suppliers.
Even when smaller systems are operated and smaller quantities processed in the hospital pharmacy, the requirements for the process systems, logistics, cleanroom planning and qualifications are identical to those of large-scale operations. Take advantage of our experience gained in numerous public and hospital pharmacies on the path to GMP-compliant manufacturing facilities.