FORMIRANJE STERILNIH OBLIKA U FARMACEUTSKOJ INDUSTRIJI

13. međunarodni simpozij o kvaliteti „KVALITETA I DRUŠTVENA ODGOVORNOST“, Solin, 15.-16.3.2012.

STERILE DOSAGE FORM IN PHARMACEUTICAL INDUSTRY FORMIRANJE STERILNIH OBLIKA U FARMACEUTSKOJ INDUSTRIJI

Dražen Kostelac JGL d.d., Pulac b.b., 51 000 Rijeka, Croatia E-mail: drazen.kostelac@jgl.hr Damir Požgaj Termo - plin projekt d.o.o.

Osječka 26, 51 000 Rijeka, Croatia E-mail: damir.pozgaj2@inet.hr

UDK/UDC: 54.08:005.6 Prethodno priopćenje/Preliminary communication Primljeno: 10. siječnja, 2012./Received: January 10th, 2012 Prihvaćeno: 6. veljače, 2012./Accepted: February 6th 2012

Izvor: Zbornik radova 13. međunarodnog simpozija o kvaliteti Kvaliteta i društvena odgovornost, Hrvatsko društvo menadžera kvalitete, Zagreb, Solin, 2012, str. 135-147.

ABSTRACT In this article there will be presented the manufacturing of the fictious sterile parenteral solution. The special emphasis will be put on the sterilization method, which should be selected from all the available methods. Those methods will be compared and selection arguments will be stated. The selected method will be described in details, including all the required activities, premises and equipment, as well as the critical points.

Key words: pharmaceutical quality management, sterile products, sterilization methods.

1. PRE-FORMULATION DATA A new sterile product should be developed as parenteral solution with active ingredient concentration of 50 mg/ml.

1.1. Basic data During the pre-formulation studies the following data were discovered: • Active ingredient is water soluble, with solubility more than 200 mg/ml; • Melting point of the active ingredient is about 220 °C; • Aqueous solution undergoes decomposition of 4-5 % when stored 4 days at 80 °C; • Decomposition is independent of pH in range of 4-9.

2. PRODUCT SPECIFICATION After the basic pre-formulation data are known, but before the development of the new product, a basic specification should be prepared. This specification will give the precise direction for development activities.

From the pharmaceutical point of view there is no simpler formulation than water solution of a highly soluble drug. However, the situation is dramatically changed only if we say that the same solution will be administered parenterally, so all the other parameters have to be harmonized with and modified to this fundamental demand. The general specification of the particular product could be as follows: 1. Product type - solution; 2. Route of the administration – parenteral, injection; 3. Sterility – sterile product; 4. Pyrogens – the product must be non-pyrogenic; 5. pH of the solution – anything within the range of 4–9, preferably in range 5.5–8; 6. Tonicity - the product should be isotonic, or close to that; 7. Content of the active ingredient – 50 mg/ml; 8. Container/closure – to assure required quality of the product during the shelf life and also in the case of the repeated application; to enable simple and easy use; 9. Health hazards – product must not show any toxicity or side effects according to the parenteral route of administration, e.g. pain during the injection, local irritancy, etc.; 10. Stability – product must be stabile during the shelf life which means that its safety and efficacy on the last day of shelf-life must be the same as on the day of release.

Creation of basic specification should be followed now by two main groups of development activities: 1. Product development, which includes formulation, container/closure and analytical methods development, and 2. Manufacturing process design, including sterilization method, equipment, utilities, premises and procedures.

However, although those activities are separated in two groups, many of them are strongly inter-connected, so all design and development activities must be concerned as a part of one integral process.

It should also be stated here that product development process very often is only compromise between ideal product specification and real manufacturing capabilities which can be limited due some technical, economical or other reasons. However, product safety and efficacy must not be challenged in any case.

3. PRODUCT FORMULATION This stage includes activities required to define product formulation. As the main focus of this assignment is on sterilization process, only one activity will be addressed here: • Product formula development – type and amount of excipients should be defined.

Those excipients are required to obtain product characteristics required by specification. Possible excipients are: preservative(s), buffer(s), tonicity-adjusting substance(s). However, number and concentration of excipients should be as low

as possible to avoid any toxic effects and irritancy. According to that, seems that co-solvent could be avoided, due to satisfactory solubility of the active ingredient.

4. STABILITY Following parameters should be determined: • Incompatibilities between ingredients, or between ingredients and packaging materials; • Product shelf life; • Shelf life after the first use in case of multi-dose product, in order to prevent product contamination; • Storage conditions.

5. CONTAINER/CLOSURE SYSTEM DEVELOPMENT Container/closure system should be designed to assure the product overall quality (but with special emphasis on sterility, endotoxins and particles) during the product shelf life, even if the product is used repeatedly. Glass vial with a rubber closure and aluminium overseal could be used, so the following should be addressed: • Type I glass has to be used; • Rubber closure should be resistant to steam sterilization, with low coring and good re-sealing properties in case product is repeatedly used; • Interactions between packaging material and formulation have to be known and prevented (leaching from rubber or glass to formulation or ingredient(s) adsorption to rubber).

6. SELECTION OF THE STERILIZATION METHOD There are few different sterilization methods that are routinely employed for the sterilization of the medicinal products, although some of them are more common than other.

6.1. Available sterilization methods Those methods could be divided in two general sterilization approaches – terminal sterilization and filtration. However, all methods are not appropriate for all products, so according to product characteristics the best possible method should be selected.

Terminal sterilization • Saturated steam in autoclave – preferred method whenever possible, however its application significantly depends on the product sensitivity on heat and moisture.

• Gamma irradiation – special equipment (source of irradiation) and protection procedures required.

• Ethylene oxide – due to penetration limitations cannot be applied for this kind of product. Ethylene oxide must be in contact with object of sterilization (solution), which is not possible here.

Filtration •

Filtration – process without employment of sterilizing agent, because passive sterilization is obtained by filtration in aseptic conditions.

6.2. Discussion on the proposed sterilization methods •

•

•

Saturated steam – although preferred method, there is a huge limitation – product sensitivity to the heat and moist, regardless whether it is product ingredient, or container/closure system. All the other aspects are strongly on the side of the sterilization by saturated steam – sterilization effect is well known and proved (of course the method should be performed properly), validation and routine monitoring are not so complex. Furthermore, today’s autoclaves are very sophisticated with all required control equipment already implemented. Finally, steam sterilization is a widely applied method worldwide, so it is hard to say that today there is anything unknown about this.

Gamma irradiation – there is also a slight heating of the material during the sterilization process. However, this is not the only problem. In terms of critical parameters this is a very simple method which is not so hard to validate and monitor routinely, because sterilization effect only depends on the absorbed dose.

Nevertheless, gamma irradiation is not commonly used by the pharmaceutical producers for the sterilization of the final medicinal product. That is mostly because irradiation equipment is required and due to possible health hazards special precautions and area design have to be applied. Furthermore, the irradiation source cannot be switched off, so from the economical aspect it should be used as more as possible during the day (week, month, year…) which in most cases would not be possible and feasible for pharmaceutical company. The alternative is to outsource gamma irradiation, but this again is not common, because sterilization as perhaps the most critical process in the production of medicines obviously should be performed “at home”.

Filtration – sterilization method of the first choice for the heat sensitive medicinal products in the form of solution. Aseptic process has to be applied here. However, the main problem is that this is not an active sterilization, but the passive one, so there are much more potential risks for the product quality than in the case of terminal sterilization (to be discussed later).

6.3. Selection of the sterilization method According to the pre-formulation data, introduction of elevated temperature could cause degradation of active ingredient in the particular product, so sterilization in autoclave cannot be applied. Furthermore, I find gamma irradiation also inappropriate, due to explained practical and economical reasons. Therefore, only sterilization method which can be used in this situation is filtration in aseptic conditions.

There is no doubt that aseptic process, including sterilization by filtration holds many potential risks itself. However, by appropriate process design, selection and qualification of the equipment, well trained personnel and final validation and monitoring of the whole manufacturing process, sterilization of the product should be under control and there can be a high level of assurance that the final product will be sterile.

On the other hand, no activity can prevent drug degradation in the conditions of elevated temperature, which could seriously impact the product quality in terms of safety and efficacy. Two main and thus the serious consequences of the drug decomposition will be: • Decreased content of the active ingredient; • Possible toxic effects caused by degradation product(s).

7. DESIGN OF THE STERILIZATION METHOD A few times in this assignment it has already been mentioned (and it certainly will be several more times) that application of the sterile filtration and aseptic process are complex, with many factors affecting the final product quality. That is why this sterilization method, as well as whole aseptic process has to be well designed and established. However, what is it so special here? To answer that question, two main facts have to be addressed: 1) It is passive sterilization process, based mainly on the sieving properties of the filter(s). That means that no activity (physical or chemical) is applied to obtain sterility (heat, irradiation, gas). Furthermore, as there is no application of the particular activity, there is also no possibility to monitor the sterilization process by measuring any specific parameter (temperature, time, absorbed dose).

2) In the case of terminal sterilization the product is already in the sealed container.

On the other hand, after the product is filtered through the sterile filter it is still in direct contact with the environment (atmosphere or surface) for some time, until the container is filled and sealed. In other words it means that the product could be re-contaminated even if it was sterilized successfully. It could be described by the following scheme:

Figure 1. Scheme Preparation of the bulk solution NON CRITICAL Filtration by sterilizing filter

Filling the container

CRITICAL

Closing/sealing the container

NON CRITICAL Product packaging

Obviously, regarding the nature of sterilizing filtration, the special care is required to achieve a high level of sterility assurance. According to that, there are some design demands that should be met:

• • •

• • • •

Use of the certified sterilizing filter with nominal pores of at least 0,22 µm; Filtration through two sterilizing filters in series; The second filter has to be as close as it is technically possible to the filling point.

Depending on the filling machine design and required output, the sterilizing filter could also be applied to the filling piston, which would be an ideal position; Period of the product exposure to the environment after passing through the last sterilizing filter has to be as short as possible; Route of filled but still opened container also should be as short as possible; For the protection of sterilizing filters some pre-filter could be used, for instance the one with pores of 0,45 µm or 1 µm; Filling and closing have to be performed under the unidirectional laminar air flow

8. MANUFACTURING PROCESS DEVELOPMENT In addition to the sterilization method, the whole manufacturing process must be developed. Only the main topics will be stated here: • Filter/formulation interaction – it should be tested if there is any adsorption of the product ingredients to the filter. It should also check if there is any leakage of the filter components to the product. Those tests have to be done both for the prefilter and the sterilizing filter; • Mixing time - there should be found out the optimal mixing time to obtain absolute dissolution of the product ingredients and homogenous solution; • Maximally allowed filtration time – it should be determined if there are limitations in the filtration time regarding increase of the batch solution bioburden or the filter sterilizing capacity. According to that the batch size should be set; • Hold time of the bulk product – it should be defined how long bulk solution could be hold prior the filtration.

9. OTHER ASPECTS OF THE ASEPTIC PROCESS In the previous chapters the sterilizing method development has been discussed and particular method described. However, there are many other aspects of the aseptic process that are essential for the high assurance of the process reliability and the product quality. Some of those factors will be addressed now.

9.1. Personnel People are single greatest source of contamination in aseptic production, thus some special attention must be addressed to personnel.

9.2. Premises All premises in case of the aseptic process have to be designed and installed in order to minimize the risks of particulate and microbial contamination.

9.3. Layout and the air-cleanliness According to GMP (EC GMP, Annex 1 on sterile production) production and other areas should be divided as follows: • Filling and closing – class A established as unidirectional laminar air flow with air velocity of 0,45 m/s (+/- 20 %); class B should be the background environment; • Sterilization/depyrogenation of the components – class D for loading, class A for unloading; • Preparation of solution to be filtered – class C; • Washing and handling components after washing – class D. Furthermore, the most critical area (class A/B) should be placed in the middle of the facility layout, surrounded with other areas, for maximal protection.

There should also be pressure differences between areas of different air cleanliness.

The highest positive pressure has to be in the filling room (class A/B). The pressure is then decreased by cascade in the direction of the lower cleanliness (differences between areas should be between 5 and 20 Pa).

Finally, the areas of different air-cleanliness classes have to be separated by appropriately designed air locks. Each air lock should be equipped with an inter-lock system in order to prevent opening of the both side doors at the same time.

9.4. Equipment The most critical equipment is that in the filling area as it is the most critical stage of the process.

9.5. Water production and distribution The water quality is one of the most important demands in the production of parenteral products. According to recognized pharmacopoeias, for parenteral solutions pyrogen-free water must be used, which is Water for injection. European Pharmacopoeia requires that WFI is prepared by distillation. Although USP allows employment of reverse osmosis also, I will choose distillation as a more appropriate method. Equally important as water preparation are water storage and distribution, because in those stages re-contamination can occur easily if the system is not designed and operated properly. However, due to heat sensibility of the particular active ingredient, water has to be cooled before use. The best approach (although not the cheapest) is the employment of heat exchangers at the point of use.

9.6. Other utilities All other utilities have to be produced and distributed on the manner which does not employ possibility of contamination. All gases (e.g. compressed air) used in the clean area should be filtered through sterilizing filters before use.

9.7. Sanitation Premises and equipment should be cleaned and disinfected regularly, according to the established procedures. Cleaning agents and disinfectants should not be sourced of microbiological contamination, which means that must be sterile prior the use. Furthermore, disinfectants should be rotated (e.g. on weekly basis) to avoid development of resistance.

9.8. Sterilization and depyrogenation of the packaging materials Packaging material used in aseptic process must be sterile and pyrogen-free prior the filling/sealing. For the containers and closures used, the following could be applied: • Glass bottles – sterilization and depyrogenation by dry heat at temperature more than 250 °C (compendial cycle); • Rubber closures - combination of washing, rinsing and steam sterilization should ensure sterile and endotoxin/free material. However, as depyrogenation in this case can be influenced by many individual factors (rubber quality, washing agent, number of washing/rinsing cycles), validation of depyrogenation process is required here and should be based on 3-log reduction of endotoxins.

9.9. Qualification and validation The conclusion on the sterility of the whole batch cannot be done according to results of sterility testing on few samples. Even when it is proved that all those samples are sterile, it does not mean a lot. Sterility can only be assured as a sum total of properly designed and performed activities, supported by trained personnel, established procedures as well as appropriate and qualified equipment and utilities. That is the reason why the validation of the aseptic process is of a paramount importance.

9.10. Media fills Media fills is final stage of aseptic process validation. It covers all stages relevant to obtain sterile product, however, all systems and processes should be qualified/validated prior the media fills.

9.11. Routine control and monitoring Although validated, the sterilization process, related activities and environmental conditions must be monitored routinely. This is particularly important for sterilizing filtration, because the sterilization itself cannot be controlled by exact physical parameters.

9.12. Description of the manufacturing process Finally, when all development, qualification and validation activities have been properly performed, the production route can be described as follows: • • •

• • • •

Washing and drying of the glass vials; final rinse has to be with WFI; Sterilization and depyrogenation of the glass vials by dry heat, two hours at 250°C; Washing and sterilizing of the rubber closures (however, applied activities also can be assumed as depyrogenation) - use of integrated washer/autoclave is recommended; at least final rinse has to be with WFI; Preparation of the bulk product (weighing and dissolution of the ingredients, mixing); In-process control of the bulk solution (pH, appearance); Filtration and filling of the solution; Closing and sealing;

• • •

•

In-process control (filling volume or mass, appearance of the bottle, correctness of the applied closure); Labelling and packaging; In-process control (label presence, correctness of the label, leaflet and carton box, presence and correctness of the printed data – batch number, production and expiry date); Final testing of the end-product.

9.13. End-product testing Although the process is validated and routinely monitored, the final testing of the endproduct should be performed. However, purpose of end-testing is not only to check product quality, because total quality of the product (especially sterility) can not be assured by final testing. Actually it is about collecting the data which can be used for trend analysis and some statistical processing (data collected during the in-process control or monitoring should also be used). According to those data some process deviations could be recognised for the implementation of corrections and improvements. Final testings should include: • Solution appearance (colour and clarity); • pH; • Tonicity; • Particulate matter; • Sterility; • Endotoxins; • Active ingredient content; • Assay of preservatives; • Degradation products; • Container/closure and sealing correctness – leakage test.

10. CONCLUSION Parenteral products are with no doubt the most demanding type of the medicinal product. Although there are theoretically more than only one possible method for preparation of this kind of product, all critical aspects should be reviewed before the final selection of the method is done. Whatever method is chosen, the production process and all related activities should be designed, implemented, validated and routinely monitored in order to assure that the final parenteral product is safe and efficient.

Sažetak: FORMIRANJE STERILNIH OBLIKA U FARMACEUTSKOJ INDUSTRIJI U ovom članku predstavljen je proces pilot proizvodnje sterilne parenteralne otopine. Poseban naglasak u članku stavlja se na metodu sterilizacije proizvoda iz bezreceptnog programa tvrtke Jadran galenski laboratorij d.d. Rijeka. Ova metoda uspoređuje se s ostalim dostupnim metodama u farmaceutskoj industriji. Cilj usporedbe je opisati detalje, sve potrebne aktivnosti, prostorije i opremu.

U završnom dijelu prikazuju se sve kritične točke i način njihovog rješavanja.

Ključne riječi: upravljanje kvalitetom u farmaceutskoj industriji, sterilni proizvodi, metode sterilizacije.

11. REFERENCES 1. Draft Guidance on Sterile Drug Products Produced by Aseptic Processing – Current Good Manufacturing Practice, FDA, August, 2003.

2. EC Guide to Good Manufacturing Practices for Medicinal Products and Active Pharmaceutical Ingredients, 4th edition, Editio Cantor Verlag, 2002.

3. EC GMP, Annex 1, Manufacture of Sterile Medicinal Products, Revision of May 2003, The Rules Governing Medicinal Products in EU, Internet source.

4. Encyclopedia of Pharmaceutical Technology, 2nd edition, Vol. 3, Marcel Dekker, 2002.

5. European Pharmacopoeia, 4th edition, Council of Europe, Strasbourg, 2002.

6. ISPE Pharmaceutical Engineering Guide, Volume 3: Sterile Manufacturing Facilities, 1st Edition, ISPE, 1999.

7. ISPE Pharmaceutical Engineering Guide, Volume 4: Water and Steam Systems, 1st Edition, ISPE, 2001.

8. ISO 14644-4 Cleanrooms and associated controlled environments – Part 4: Design, construction and start-up, 1st edition, ISO, 2001.

9. Recommendation on the Validation of Aseptic Processes, PIC/S, 2001.

10. Pharmaceutical Dosage Forms: Parenteral Medications, Vol. 1 and 3, 2nd edition, Marcel Dekker, Vol.1, 1992, Vol.3, 1993.

11. Remington's Pharmaceutical Sciencies, 18th edition, Mack Publishing Company, 1990.

12. The United States Pharmacopoeia (USP 25), USP Convention, 2002.