By Elomatic India and Heikki Niskanen
Processing of sterile medicinal products is one of the most critical operations in pharmaceutical manufacturing due to the highly technique-driven processes and the potential detrimental impact on patients. Since sterile manufacturing is subject to inspections by different regulatory authorities, such as the US FDA, WHO and EMA, it is imperative to be thoroughly familiar with Good Manufacturing Practice (GMP) regulations and their application.
It is noteworthy that most GMP regulations describe what needs to be accomplished, rather than how it should be accomplished. A disciplined approach is, therefore, required to meet the requirements.
This article provides an overview of the regulatory guidelines and the fundamental GMP requirements with regards sterile manufacturing of medicinal products, with a particular focus on engineering aspects. It should be remembered, however, that engineering is only the basis and that quality assurance is vitally important. Manufacturing must strictly follow the carefully established and validated methods of preparation and prescribed procedures. An overview of the relevant regulatory authorities and their publications is provided in the info box (see overleaf ).
Sterile manufacturing processes require close coordination and interaction between personnel, equipment systems, cleanroom and support facilities, and sterilized components.
Recommendations by the various authorities regarding premises, room classification, area classifications for various processes, equipment, personnel, processing, and sterilization are outlined in the following paragraphs (according to WHO’s guidelines and with comparison to guidelines of other regions).
Risk management concepts (ICH Q9 guidance) and modern pharmaceutical quality systems (ICH Q10) should be introduced in the design and during production of pharmaceutical preparations. These concepts are already noted in the Sterile Product Manufacturing Facilities guide (Volume 3, Sept. 2011, ref. 9) by ISPE (International Society for Pharmaceutical Engineering) and are under preparation and discussion in the EU (Concept paper on the revision of Annex 1, February 2015) as well as in the Pharmaceutical Inspection Convention’s co-operation scheme (PIC/S).
It needs to be kept in mind that the manufacture of sterile preparations should be carried out in clean areas, and operations are divided into two categories:
Tables 1a and 1b illustrate typical production operations in different clean room areas in these two sterile manufacturing categories.
Manufacture of sterile preparations
Each manufacturing operation in the manufacture of sterile products requires an appropriate level of environmental cleanliness of the operational state to minimize the risk of particulate or microbial contamination of the product or materials being handled (ref. 5).
For processing it is recommended that separate facilities be used for products that contain live microorganisms and those that don’t, except when the product contains properly inactivated organisms, or the deactivation/containment can be demonstrated/validated. All possible efforts should be made to reduce the bio-burden even before sterilization. These guidelines also guide the media fill procedure, media selection, batch size, frequency, and interpretation of simulation results for the validation of aseptic processing.
Minimizing and validating the time interval between various processing stages is recommended, for example, between equipment cleaning and sterilization, equipment sterilization and formulation, as well as between formulation and product sterilization. These guidelines also highlight specific precautions and advantages of isolator and blow-fill-seal technologies. The EU GMP and WHO focus on routine monitoring and frequent leak testing of isolators and glove/sleeve systems.
One of the most important laboratory controls is the environmental monitoring program. The monitoring program should cover all production shifts and include air, floor, walls, and equipment surfaces, in particular surfaces that come in contact with the product, container, and closure.
Various sterilization methods such as heat sterilization, filtration sterilization, radiation sterilization, and ethylene oxide sterilization are accepted by the authorities; but where possible, heat sterilization should be the method of choice. Each load type and load pattern has to be validated. Biological indicators should be considered as an additional method for monitoring sterilization and indicators such as autoclave tapes and radiation sensitive colour discs should be used to clearly distinguish the sterilization statuses of objects.
Whenever possible products intended to be sterile should be terminally sterilized with heat in the final container (ref. 5). Filtration sterilization is acceptable when sterilization in the final container is not possible due to the instability of a formulation or incompatibility of a pack type. Since sterile grade filters (≤0.22 μm or less) cannot remove all viruses and mycoplasma; consideration should be given to some degree of heat treatment to complement the filtration process.
It is recommended to use another sterile grade filter immediately prior to the filling point. The maximum usage duration of a single filter should be demonstrated by validation. Filter integrity testing requirements are also suggested in the guidelines and filters should be non-shedding and not affect the product composition via absorption/ leaching.
The FDA requires sterility testing methods to be accurate and reproducible while the EU GMP and WHO point out that sterility tests applied to the finished product should only be regarded as the last in a series of control measures whereby sterility is assured. The test should be validated for the product(s) concerned.
It is suggested that personnel be minimized in clean rooms. All personnel including housekeeping and maintenance staff should be trained in manufacturing (aseptic techniques), cleanroom behaviour, personnel hygiene, gowning and basic microbiology (ref. 1). To avoid cross contamination dedicated persons should be employed unless rigorous and clearly defined decontamination procedures have been followed.
Wrist-watches, cosmetics, and jewellery shall be strictly avoided (refs 3, 6). These guidelines also suggest appropriate gowning requirements with respect to clean room grades, gown material quality, frequency of changing clothes and gloves, sanitization of gloves, and requirements for dedicated and separate laundry.
With regards premises all the regulatory authorities agree that the design of a given area needs to satisfy microbiological and particle criteria defined for the operational activities along with the fulfilment of requirements for equipment, components, and products. The recommendation is for smooth, impervious, and sanitizable surfaces with sealed false ceilings. They advise against drains in grade A or B areas. For other grades they indicate that equipment drains should be equipped with air gaps and floor drains with water seal/traps.
These guidelines also provide the necessary input for room pressure differentials, air flow rates, air flow patterns, interlocks for change rooms, and the number of change rooms (separate changing rooms for entering and leaving may be desirable, ref. 3). They also indicate that swing doors should open into high-pressure areas and be provided with self-closers and that unnecessary access should be restricted to critical manufacturing areas.
Nowadays ISO 14644-1 standards for clean room classification should be used for the classification of cleanliness regarding the concentration of airborne particles (ref. 8). The maximum permitted concentration of particles, Cn (particles per cubic meter of air), for each considered particle size, D (micron), is determined from the equation:
where N is the ISO Classification Number.
Table 2 presents selected airborne particulate cleanliness classes and the corresponding particle concentrations for particles equal to and larger than the considered sizes shown.
The US FDA defined area classification is provided in Table 3. USFDA considers only In-operation condition and for 0.5 μm particle size only.
The EU GMP & WHO defined area classification is provided in Table 4. EU GMP & WHO considers limits ‘at rest’ as well as ‘in operation’. Also, these regulations consider 5 μm particle size along with 0.5 μm particle size. These regulations don’t define ‘in operation’ limits for Grade-D; the company should establish in operation limits based on a risk analysis and on historical data where applicable.
During operation the manufacturer should monitor airborne particles and microbiological contamination. In this context FDA accepts the use of settle plates only as optional for continuous air sample measurements (Table 5a); while for WHO / EU GMP, the use of settle plates and glove prints are compulsory (Table 5b).
A new version of EU GMP Annex 15 (Qualification and Validation) has been published describing the principles of qualification and validation for facilities, equipment, utilities and processes. Annex 15 takes into account current changes to other sections of EudraLex, Volume 4, Part I, the relationship to Part II, Annex 11, ICH Q8, Q9, Q10 and Q11, QWP guidance on process validation, and changes in manufacturing technology. This version has been operational from 1 October 2015.
For equipment the guidelines suggest that a conveyor should not pass from a Grade A/B room to a lower grade room unless the conveyor is continuously self-sanitized. They also suggest that the technical parts of equipment should be placed outside clean rooms and that equipment and the clean room be cleaned, disinfected and/or sterilized after maintenance work (except when the cleanliness and asepsis is maintained during maintenance work). The WHO recommends using dry heat/moist heat to sterilize the equipment as far as possible.
It is further recommended that WFI be kept at temperatures (>70 °C or NMT 4 °C) that prevent microbial growth and that planned maintenance and validation of critical process equipment be conducted. Processing equipment and systems should be equipped with sanitary fittings and valves. The WHO also indicates that threaded pipe connections should be avoided.
The International Society for Pharmaceutical Engineering (ISPE) has prepared a guide for engineering Sterile Product Manufacturing Facilities (ref. 9). It is a valuable book offering consistent interpretation of facility design, construction, commissioning and qualification. It takes into account the guidelines referred in this article and provides practical and illustrated examples of the implementation of good engineering practice.
It should be kept in mind that other standards and guidelines are available in this subject area. One of these is the ISO 13408-1 standard “Aseptic Processing of Healthcare Products”, which adds value in the design of aseptic processes.
Careful and systematic adherence to the guidelines described in this article and others is key in delivering facilities and processes that can pass the strict Good Manufacturing Practice requirements. Getting it right is crucial in gaining access to markets and ensuring the safety of end users.
About the author
Mr. Niskanen has worked over two decades in the pharmaceutical and biotech industry as a scientist, qualified person and quality director. At Elomatic his specialty is pharmaceutical engineering. He currently holds the position of Senior Consulting Engineer at the Elomatic Turku office. firstname.lastname@example.org