The American Society of Mechanical Engineers' Council on Codes and Standards established an ad hoc committee to examine whether a standard to create uniformity and consistency in the bioprocessing industry is needed. This article describes the goals and current activities of the standards committee and its subcommittees.	

On 20 June 1989, the American Society of Mechanical Engineers' (ASME) Council on Codes and Standards issued a directive to the Board on Pressure Technology Codes and Standards to form an 

 committee to investigate and catalogue the biopharmaceutical industry's concerns about inconsistencies. Thus, the Bioprocessing Equipment (BPE) Standards Committee was formed and immediately met to establish a path forward. The committee, consisting of end-users, equipment manufacturers or suppliers, drug manufacturers, distributors and engineers, met in New York City at the ASME headquarters to discuss the need for a standard that could bring clarity and consistency to the bioprocessing industry and end miscommunications, misunderstandings, misinterpretations and ambiguities in the applicable entities. 	

It was agreed that the six parts of the new standard would be identified by the following titles and subcommittee designations:	

Dimensions and tolerances for stainless steel automatic welding and hygienic clamp tube fittings

Stainless steel and higher alloy interior surface finishes

The first edition of the ASME BPE standard was issued on 17 October 1997, followed by a second edition in 2002. The standard gives the industry a level playing field for the sector's engineers, manufacturers and end-users. It addresses the needs of those who purchase, specify and manufacture biopharmaceutical production equipment. The standard also provides a method of ensuring that the design, production and installation of bioprocessing equipment, tubing, fittings and components are consistent and uniform. 	

The number of subcommittees has recently increased from the original six to 10, with the addition of the European, Polymers and Elastomers, Accreditation, and Metallic Materials of Construction subcommittees. What follows is an update regarding their current activities and a look ahead at their future challenges.	

 This subcommittee is developing a list of documentation that may be included in a turnover package. Contractors and owners will be able to review this list and decide which documents are needed.				

 The focus of this subcommittee is both clean-in-place and pure-water systems. Its goal is to record and depict solid designs that are agreed upon by the industry. The basics will be covered in the 2005 edition of the standard.	

 Subcommittee members are reviewing the standardization of face dimensions of hygienic clamp fittings, hygienic clamp nominal envelopes and angles. They are considering the same angle/slope on concentric/eccentric reducing fittings as are the Deutsche International Norm (DIN) and the International Organization for Standardization (ISO) for generating a shorter overall dimension. Members are also evaluating the need for a shorter ferrule length and are working with the Equipment Seals Subcommittee to establish seals dimensions to lessen or mitigate seal intrusion into the pipe stream.	

 This subcommittee is developing a standardized weld log for consistent, recordable data and formatting. This log will be similar to the standardized ASME Section IX, "

Weld Procedure Specification and Procedure Qualification Record

," because it will lessen the need to search the form for specific data. Thus, required data and their locations will be consistent.	

 Members of this group are evaluating the need to create colour photographs that depict various defects found on process surface finishes. This action will simplify the interpretations of written standards across the industry.	

 This subcommittee is working on defining the criteria for integrating hygienic clamps into pipe streams. These criteria will be created in conjunction with a hygienic clamp type-fitting standard that is being developed by the Dimensions and Tolerances Subcommittee.	

 A section about polymers and elastomers will be the standard's newest addition. It will describe practices for the use of polymer-based materials that have demonstrated the ability to attain cleanability and sterility as they relate to bioprocessing equipment. The committee is currently working on the application of polymer materials and how they relate to fire codes and fire safety issues in compliance with regulations for all new buildings.	

In addition, the committee is interested in incorporating these codes and standards into the BPE and is adding other items such as flexible hoses that will have additional applications (silicon rubber or tubing type applications, for example). This new section will be included in the 2004 addendum to the standard.	

 Buying equipment from a manufacturer that is well versed in the standard's requirements is essential for establishing clear communication. However, some manufacturers claim to conform to the requirements, when in fact they do not. For this reason, a subcommittee has been established that will research the methods of accrediting manufacturers. Similar to the way in which ASME authorizes manufacturers that produce ASME Section VIII pressure vessels to hold a "U Stamp," companies that claim to provide equipment and components to the BPE standard will be required to pass an accreditation process.	

 This newly formed subcommittee was created to address European philosophies and methods and to evaluate issues that are of concern to the European biopharmaceutical industry. Its intent is to add European design, installation methods, philosophies, and terms and definitions to the standard.	

 A new section of the standard that will address metallic construction materials is under development. This subcommittee will help clarify weld and surface finish criteria for metals other than 316L stainless steel. This will include nickel-based alloys as well as stainless steels that are more commonly used in Europe. 	

In addition, the committee is researching whether recommendations for improvements to pharmaceutical equipment design are needed, particularly in the areas of active pharmaceutical ingredients and personal care products.	

The next edition of the BPE standard is scheduled to be released in 2005 and will continue to provide uniformity and consistency for international biopharmaceutical equipment and system design. However, significant challenges will accompany the committee's plans for a wider scope and global expansion. For instance, the standard must gain worldwide recognition and acceptance while existing in harmonization with other recognized regulations. 	

Articles

Features

The American Society of Mechanical Engineers' Council on Codes and Standards established an ad hoc committee to examine whether a standard to create uniformity and consistency in the bioprocessing industry is needed. This article describes the goals and current activities of the standards committee and its subcommittees.

Uniformity of Bioprocessing Equipment Manufacturing

The FDA guidelines that stipulate the conditions for starting materials are currently being superseded. PhRMA and several European pharmaceutical manufacturers have already added their voices to the ongoing discussion and, as this editorial explains, the debate is far from over. Rules are important, but industry is looking to a future when health care authorities are less inclined to impart total control over every aspect of production.	

The discussion surrounding the definition of active pharmaceutical ingredient (API) starting materials (SMs) for registration documentation has recently come to the fore again with the appearance of a new draft of the "Guideline for Submitting Supporting Documentation in Drug Applications for the Manufacture of Drug Substances, "originally published in 1987.

 The issue has been debated within the industry and, more specifically, at a recent conference in Budapest (

6th APIC/CEFIC European Conference on Active Pharmaceutical Ingredients

, Budapest, Hungary, 5-7 November, 2003), where members of the US Food and Drug Administration (FDA) and representatives of both the North American and European sector were present. Interestingly enough, when the views of all three parties were examined, there was a considerable degree of agreement.

 This coincidence, however, was only superficial. The pharmaceutical industry on both sides of the Atlantic is concerned about some of the criteria being used in this document to establish the nature of starting materials for drug substance manufacture.	

The defining criteria, contained in the new draft as "Attachment I," is the topic that this editorial wishes to address. As the old guideline states: "What constitutes the 'starting material' may not always be obvious." Because this is indeed the case and discussions mainly focus on this point, FDA has tried to remodel the old definition of a starting material - with less rather than more fortune. The importance of specifying the starting material at some point of the development process is indeed evident. From a regulatory point of view, the action of defining (industry) and accepting (agency) a defined starting material stipulates the starting point of the drug substance registration documentation. From a good manufacturing practice (GMP) stance, and according to the globally accepted International Conference on Harmonization (ICH) guideline ICH Q7a, from this step of the synthesis onwards it is the obligation of the API manufacturer to apply GMPs to the production and control of the API in question, with few exceptions.	

It is useful to recall that there is a well thought out definition of SMs in the ICH Q7a guideline. This states that "An API starting material is a raw material, intermediate or an API that is used in the production of an API and that is incorporated as a significant structural fragment into the structure of the API." And, it adds, as typical characteristics, "An API starting material can be an article of commerce, a material purchased from one or more suppliers under contract or commercial agreement, or produced in-house. API starting materials normally have defined chemical properties and structure."	

A more precise definition, however, has proven extremely difficult to establish - like any intent to define the multiplicity of reality. The options are, it would seem, either to define an SM as something with so many criteria that it becomes impractical or too difficult to comprehend, or to allow so much freedom in the definition that its existence would be meaningless. Thus, the question arises: Is there a real need to define a starting material 

 in a form that could add precision to the well known and widely accepted definition given by ICH Q7a? Or dare we give industry the chance to define an SM on a case by case basis according to the characteristics of the particular process in question, considering risk and science as contributing factors in the decision? 				

The latter would mean an exact classification, putting the burden on industry to define a starting material for API synthesis on an 

 basis, avoiding any prejudgement derived from formalistic or non-scientific reasons. The starting material could be the final intermediate - or indeed any other intermediate - right back to the benzene ring if it proves necessary. But the decision would have to be based on scientific rationale and not on arbitrarily predetermined, peculiar-to-the-process criteria. In some instances, this might make sense, but has proven inadequate in the majority of them.	

An additional advantage of this proposal would be to accept, for regulatory purposes, a definition and sum of characteristics of an object given in a GMP document such as ICH Q7a. This would have the bonus of eliminating two statements on the same topic. There is a trend in these discussions to separate - perhaps artificially - the GMP needs from the filing ones. The only acceptable criterion should be the only really essential one: the quality of the API. An adequate starting material could then be defined as something that allows the production of a substance, distinctively showing an appropriate, clearly specified and reproducible quality. 	

This approach would also place the concept in line with the widely accepted idea of validation. The point at which validation activities are normally initiated is not defined in a general way for API synthesis, but on a case by case basis, for it is very clearly a function of the process itself. Finally, it would comply with the ideas that FDA has been promoting during the last 2 years, establishing a risk- and science-based approach as an effective way of fixing and controlling manufacturing processes. 	

Perhaps now we can answer the rhetorical question posed earlier. Attachment I of the Guideline should be reduced to two of the sentences included in it, which read: "The starting material should be selected and controlled so that the risk from future changes in the quality of the starting material affecting the identity, quality, purity or potency of the drug substance is minimized. A proposed starting material should be chosen so that sufficient information will be available to FDA on the manufacturing process to evaluate the safety and quality of the drug substance."	

The pharmaceutical industry needs rules to be able to ensure that its products are safe and of good quality. Yet, the myriad production and analytical techniques developed by scientists during the last few decades, combined with sophisticated equipment and electronic monitoring devices, allow for thorough process design and controls such that health agencies are now able to place their trust in the pharmaceutical industry. The tendency to regulate every single aspect of the industry's activities should, therefore, become a thing of the past. Many of the current health agency guidelines were written in the 'spirit of authority,' with the attitude that they may and should control everything - otherwise there is no guarantee of quality. This attitude has often produced a climate of mistrust on both sides. The governmental health care institutions of developed countries have begun to realize that this kind of control is simply no longer possible (FDA gives a good example with its new risk- and science-based approach, which industry has unanimously welcomed). One reason for this is the ubiquitous lack of resources but, on another much more important level, it is just no longer adequate. We don't need a guardian, we need a partner. The etymology of the word 'authority' is significant in this environment. It is derived from the Latin 'auctoritas' and this from 'auctor' (creator, historical source). It stems originally from the verb 'augere,' and this, surprisingly enough, means "let something progress." Such health authority, triggering progress through an open attitude, is the dream of our highly regulated industry.	

Guidance for Industry, Drug Substance, Chemistry, Manufacturing and Controls Information

 (US Food and Drug Administration, 5600 Fishers Lane, Rockville, Maryland, USA, 9 January 2004).				

2.	S. Miller, "Status of BACPAC II and of the Revision of the 1987 FDA Drug Substance Guidance," presented at the 

 (Budapest, Hungary, 5-7 November 2003).	

3.	W. Mavroudakis, "Revision of the 1987 FDA Drug Substance Guidance - The US Pharma Industry View," presented at the 

4.	C. Hemmingsen, "Revision of the 1987 FDA Drug Substance Guidance - The EU API Industry View," presented at the 

The FDA guidelines that stipulate the conditions for starting materials are currently being superseded. PhRMA and several European pharmaceutical manufacturers have already added their voices to the ongoing discussion and, as this editorial explains, the debate is far from over. Rules are important, but industry is looking to a future when health care authorities are less inclined to impart total control over every aspect of production.

A New Definition for API Starting Materials

The article describes the basic principles of blow-fill-seal (BFS) technology together with the advantages it offers. Although BFS technology is an ideal process for aseptic filling of liquid pharmaceutical products there is still a risk of contaminating the product inside the filling area. This, together with regulatory requirements for the microbiological control of critical areas in pharmaceutical production, makes microbiological monitoring a necessity.	

Two concepts will be presented in this article, describing how microbiological monitoring of BFS machines can be carried out in the critical filling zone during production without any risk of contamination and complying with the relevant guidelines.		

Figure 1 The stages involved in the BFS process (courtesy of Rommelag AG).(Click to enlarge)	

Blow-fill-seal (BFS) technology is being increasingly used for aseptic liquid filling. The European Union (EU) Guide for Good Manufacturing Practice (GMP) (revision of Annex 1, Manufacture of Sterile Medical Products) defines BFS machines as "... units that are purpose-built machines in which, in one continuous operation, containers are formed from a thermoplastic granulate, filled and then sealed, all by one automatic machine."

 Thus, BFS machines manufacture the containers to be filled, fill them and then seal them immediately, with all steps performed rapidly and within a small space.

 The individual stages of the BFS process are illustrated in Figure 1. 	

BFS technology allows containers to be unit doses, multidose ampoules, vials or bottles. Compared with conventional methods, the technology has the advantages of 	

increased product safety (microbial-free).

Despite these advantages, BFS technology always entails a potential risk of contaminating the product within its small space. For this reason, the liquid to be filled and the container are protected from any possible contamination during the filling process by a stream of filtered sterile air. The relevant guidelines1 are increasingly calling for testing the microbiological quality of BFS machines. EU guidelines classify the filling area of a BFS machine as a grade A environment; that is, the concentration of micro-organisms must be ,<1 cfu/m

 air (where cfu is colony-forming units). Figure 2 shows a typical set-up for microbiological monitoring of BFS machines, such as that used at Holopack (Abtsgmund-Untergrï¿½gen, Germany).

Figure 2 Bottlepack machine (located at Holopack) with the filter holder attached near the filling zone and with the MD8 airscan.  (Click to enlarge)	

Monitoring air directly at the point of filling means that a few obstacles must be overcome: limited space, poor accessibility, movable parts and a latent risk of contamination. This makes it necessary to withdraw the air sample from the interior of the BFS machine whilst the air sampler remains outside. The monitoring system (as used in Figure 2) consists of an air sampler (pump and flow rate meter), a reusable metal filter holder connected to the air sampler by a hose and an easy-to-exchange disposable gelatin filter. 				

The hose connection enables sampling to take place within the filling area whilst the air sampler itself remains outside the critical area. During sampling, the air sampler draws a defined volume of air through the gelatin filter; after sampling, the filter is placed on a suitable culture medium in a petri dish and incubated. The colonies formed are counted and evaluated as the number of cfu/m

Water-soluble gelatin filters have a pore size of 3 μm. They are sterilized by gamma irradiation and are capable of retaining 99.9995% of 

 spores (at an air flow rate of 0.25 m/s)

 and 99.94% of coliphages T3 (at 80% relative humidity [RH]).

 The air sampler can be calibrated on site and has been optimized for use in critical areas such as grades A and B (class 100) clean rooms, isolators and BFS machines. Two different concepts for air monitoring in BFS machines are introduced below. 	

Concept 1: measurement with the hose between sampling point and filter holder.

 This concept describes the example of Excelvision, a pharmaceutical manufacturer based in Annonay (France). At the company's plant, BFS machines (

; Rommelag, Switzerland) were monitored. The machine is used to fill plastic vials of capacities ranging from 0.3-5 mL with eye drops. Sampling was performed using a polyvinylidene fluoride (PVDF) hose of sufficient length (Figure 3) that was connected directly to the filling area (classified as grade A). The hose was routed approximately 2 m to the outside, where it was attached to a metal filter holder specifically designed for use with disposable gelatin filters (Figure 3 inset). The hose was attached to the disposable gelatin filter (

) by a bayonet catch. To prevent secondary contamination, the filters were changed inside a 

 clean bench, the interior of which was also classified as grade A. Through a further connected hose, the air drawn from the clean bench was pumped through the air sampler into the grade C clean room environment, where the air sampler was located. 		

Figure 3 Bottlepack sampling (located at Excelvision) using the PVDF hose, which is connected directly to the filling area.  (Click to enlarge)	

To monitor the filling area of the BFS machines, one air sample per machine per week was taken at an air flow rate of 6 m

/h for 10 min. This corresponded to a total sampled air volume of 1 m

 in 10 min, which meets the requirements of EU GMP regulations. The culture media (tryptic soya agar [TSA]) were incubated for 3-5 days at 32.5±2.5 Â°C. The results showed that the values were less than the limits of <1 cfu/m

 required for grade A clean rooms. For example, no microbes (0 cfu/m

 of air) were detected from 29 June 2000 to 13 February 2001 for 31 batches. The standard operating procedure (SOP) for air monitoring has been in place at Excelvision for 3 years and no contamination has ever been detected.	

Concept 2: measurement using a metal filter holder containing a gelatin filter and connected directly at the filling zone.

 Another possibility for air sampling in BFS machines is using the 

 with a specially manufactured, reusable metal filter holder (Figure 4) in which a disposable gelatin filter (

) is inserted. For sampling, the gelatin filter disposable in the filter holder is located in the direct vicinity of the filling zone. This concept is based on the example at Holopack, which uses a 

 to fill sterile products (small volume parenterals, water for injection and isotonic physiological saline) in plastic vials with capacities ranging from 10-40 mL. In this measurement set-up, the filter holder with the disposable gelatin filter is located near the filling zone (grade A), in which the filling needle is located (Figure 2). The specially fabricated metal filter holder, which has to be sterilized before each sampling procedure, is connected to the BFS machine by a special sanitary fitting. In this example, air sampling was performed once per lot (after filling) at an air flow rate of 6 m

 of air was sampled in 10 min per lot. The culture medium (CASO) was incubated at 30-35 Â°C for 5 days. The results showed that during 2003, from week 3 to week 25, no contamination was found for a total of 90 lots (that is, 0 cfu/m

 air). Hence, the filling zones of the BFS machines complied with EU GMP requirements (1 cfu/m3 room air in grade A environments).		

Figure 4 The special metal filter holder (located at Holopack).  (Click to enlarge)	

As part of validating the two methods, it must be ensured that 1 m

 of air per procedure must be sampled; therefore, it is necessary to calibrate the air sampler. Additionally, it must be ensured that the risk of secondary contamination is eliminated during sampling to prevent false positive results. As shown here, this can be done by using a clean room grade A clean bench when changing the disposable gelatin filter, among other measures. Further, any microbes present in the filling zone must not be allowed to escape detection through impaction within the hose, which could lead to false negative results. This means that for sampling according to concept 1, the length, inner diameter and the roughness of the hose must be optimized and validated. If concept 2 is applied, validation of the hose is not necessary as the filter holder with the gelatin filter is connected directly to the filling zone.				

Today, the gelatin membrane filter method is a recognized procedure for air sampling in critical clean room environments and isolators. As described in this article, it is also ideal for monitoring air in the critical filling zone of BFS machines because it can be used during production without entailing any additional risk of contamination and it complies with the relevant guidelines. In the future, it is expected that BFS technology will continue to gain significance similar to isolator technology. With its advantages, the gelatin membrane filter method will be increasingly used for testing BFS systems, as is already the case for isolators.				

I would like to thank Benoit Carles, microbiology control head at Excelvision, and Walter Matheis, QC manager at Holopack Verpackungstechnik GmbH for providing images and data.				

1.	EU Guide for GMP. Revision of Annex 1, Manufacture of Sterile Medicinal Products (1997); New Revision September 2003.				

2.	Rommelag Product Information, "The Bottlepack Aseptic System in the Pharmaceutical Industry," current English issue.	

, "An Assessment of the Sartorius MD8 Microbiological Air Sampler," 

4.	H. Jaschhof, "Sammlung von Virusaerosolen mit dem Gelatine-Membranfilter," 

The original German-language version of this article was first published in the journal 

, 3rd issue, no. 2, Sept. 2003 (3. Jahrgang, Nr. 2). 	

The article describes the basic principles of blow-fill-seal (BFS) technology together with the advantages it offers. Although BFS technology is an ideal process for aseptic filling of liquid pharmaceutical products there is still a risk of contaminating the product inside the filling area. This, together with regulatory requirements for the microbiological control of critical areas in pharmaceutical production, makes microbiological monitoring a necessity.

Monitoring Airborne Micro-organisms in Blow-Fill-Seal Technology

The content and quality of information supplied with drug products are among the most specifically defined areas associated with the products for sale. For patient or drug user, the information is presented in patient information leaflets (PILs) placed in the package. The readability testing of PILs is an important stage in the process of making the texts contained in the summary of product characteristics comprehensible to users, as this article discusses.	

Despite its small size, drug packaging provides a great deal of information for the patient and user of the treatment - both on the packaging itself and on the leaflet inside the package. The information on the outer package ensures that the correct drug is supplied. The patient information leaflet (PIL) within the package contains information concerning the indications, the dosage and any potential adverse effects. All these details should be based on the approved summary of product characteristics (SPC) of the drug. The primary responsibility for the accuracy of the information and for its comprehensibility lies with the marketing authorization holder and the manufacturer. The authorities assess the factual contents of the information at the processing stage of the marketing authorization.		

The SPC is a drug description designed on the basis of research results and aimed at medical prescribers and other health care professionals. The purpose is to give adequate and up-to-date information regarding the drug and, thereby, ensure successful treatment. The SPC, approved in association with the marketing authorization approval process, is an essential part of the marketing authorization and should form the basis of all the information given concerning the drug and its marketing. After approval, the SPC may not be changed without the consent of the authorities.				

The marketing authorization holder draws up a legible and comprehensible PIL based on the SPC and intended for the drug user. Naturally, the text of the SPC intended for drug prescribers is not the same, and is not appropriate, as that directed at patients. The PIL follows the normative headings given by the authorities and an established order of presentation. The PIL contains headings taken from questions frequently asked by patients and the replies are presented in clear language. Typical questions are, for example:				

As an aid in the design of the PIL, a legibility study can be used from which it is possible to assess the clarity of the information given in the PIL, the sequence of the details offered and the actual presentation.	

A good PIL has a clear, simple and short structure that is comprehensible to the user. The user is generally only interested in the type of information that will give a clear answer to questions regarding what he/she should do and what results/side-effects are to be expected. Clear instructions for use and dealing with possible emergencies are essential. The text of the PIL should avoid unnecessary general information that may obscure any message essential for the use of the drug. Positive instructions and active language targeted directly at the patient are preferred.	

The presentation is of great importance from the point of view of readability and comprehensibility. The text should be of sufficiently large type and easily readable. Different colours and text sizes may be used for distinguishing purposes. Clear listings of adverse effects, for example, improve the ease of understanding of the message. The following is a list of some general observations associated with readability:	

It is recommended that the headings be emphasized with different colours.

Numbering of the main headings will help the reader to follow the text of the PIL; this is particularly important when the PIL is double-sided or folded several times.

The main headings should be placed on the left, not centred.

The text size of the main headings should be a minimum of 13 point.

The less important information (the marketing authorization holder and manufacturer, addresses) may be written using a smaller font.

Types of text should be indicated rather than the texts themselves.

The European Union (EU) drug legislation requires that the PILs should be clear and comprehensible. The current guidelines also mention a readability test, which is to be conducted among the PIL users, and which will allow the comprehensibility and clarity of the PILs to be studied. 

The Guideline on the Readability of the Label and Package Leaflet of Medicinal Product for Human Use

 (published in Rules governing medicinal products in the European Community; Notice to Applicants, Vol. 2C) was approved in 1998. The guideline recommends the use of a readability test developed in Australia to be used in the assessment of clarity and comprehensibility of PILs. If other methods than the EU model are used in the design of the PIL, the testing of readability is entirely the responsibility of the marketing authorization holder. 				

For several years, there has been particular attention paid to associating the readability test with the centralized procedure of marketing authorization approval processes. The PILs of a number of drug products have been put through the readability test in accordance with the EU guideline. These tests have permitted better understanding of the problems associated with PILs.	

The readability is tested with a series of questions, some of which directly concern the factual content of the PIL. A typical question could be, for example: Imagine that you are allergic to penicillin; could you, in that case, use this medicine? Some of the questions are aimed at testing the general structure of the PIL (for example, the ease or difficulty of finding required information) and could typically be: What are the disadvantages of the PIL, and how could the PIL be improved? The time allowed for the test is naturally limited. The readability test can be done in two stages, which will provide an opportunity to find out whether the improvements made on the PIL have had any effect on its readability.	

There are complexities involved in the readability test. The test methods are not yet quite established and the testing of the reliability of the various methods is inadequate. The question is, are we testing the readability of the PIL or the comprehensibility of the list of questions?	

In accordance with the EU guideline, the various languages are divided into three groups, and one language of each group is required for the testing of readability:	

(A) French, Italian, Portuguese and Spanish

Some of the languages, particularly those in group C, are not related to each other, which makes it doubtful whether any conclusions can be drawn from the results. A review of the analysed tests shows that there have seldom been any important differences between the results from different countries, which is why the testing of various language versions should be expanded.	

The content and quality of information supplied with the drug products are among the more specifically defined areas associated with the products for sale. The size of drug packaging is rather small; inserting adequate labelling that would satisfy everybody on the outer package is consequently impossible. Including all information essential for the choice of over-the-counter (OTC) drugs in the PIL is, of course, difficult. In the selection of services they offer, pharmacies should focus on whether it is possible for patients to familiarize themselves with the information leaflet.				

Patient information leaflets are sources of information that complement the package labelling. The readability testing of PILs is an important stage in the process of refining the texts contained in the SPCs to make them comprehensible to the users. Readability testing of PILs is not legally required by the authorities, but such tests may improve PILs. The responsibility of PILs lies distinctly with the marketing authorization holder, whereas the correctness of the factual contents is checked by the authorities. From the patient's viewpoint, the implementation of readability testing could be a step towards improved drug information. 	

The European Council of Ministers has adopted the new EU pharmaceutical directive. As part of the proper use of medicinal products, the rules on packaging have been updated to take into account the experience acquired. Based on the new directive: "The package leaflet shall reflect the results of consultations with target patient groups to ensure that it is legible, clear and easy to use." Additionally, more requirements are set for the applicants of the marketing authorization as it is stated that concerning packages and PILs: "The results of assessments carried out in co-operation with target patient groups shall also be provided to the competent authority." 	

The content and quality of information supplied with drug products are among the most specifically defined areas associated with the products for sale. For patient or drug user, the information is presented in patient information leaflets (PILs) placed in the package. The readability testing of PILs is an important stage in the process of making the texts contained in the summary of product characteristics comprehensible to users, as this article discusses.

What Does Drug Packaging Tell Us About its Contents?

This article introduces the application of high-resolution ultrasonic spectroscopy (HR-US) for the analysis of emulsions and suspensions. The authors outline the principles of the technique and illustrate its application for analysis of the crystallization of lysozyme and the formation of a microemulsion.	

High-resolution ultrasonic spectroscopy (HR-US) is a novel approach for the analysis of materials that uses the important ability of ultrasound to probe systems non-invasively and report their constitution, microstructure and intermolecular interactions. The analytical power of ultrasound is well known through its application in medicine, for example, in the screening of unborn babies wherein the ability of the waves to pass through opaque media without causing damage is particularly important. 	

However, the use of HR-US in analysing a variety of other materials and solutions has only recently evolved to become an essential laboratory technique. This process is extremely sensitive to the molecular organization, is non-destructive, requires no markers, and can be used on non-transparent and concentrated samples, making it advantageous compared with traditional methods.	

Stable dispersions can be divided into two main groups: suspensions and emulsions. A suspension is a dispersion of fine particles of a solid within a liquid, the particles being the dispersed phase, whereas the suspending medium is the continuous phase. Apart from the mixing of an insoluble solid in a liquid, a suspension can also result from the aggregation of dissolved solids; crystallization is an example of such a process.		

Figure 1 HR-US principles of operation.  (Click to enlarge)				

An emulsion is a dispersion of one liquid in another immiscible liquid, usually in the presence of stabilizer molecules. Emulsions may be either oil droplets dispersed in water or water droplets dispersed in oil, wherein the droplet diameters are in the micron range. Fat in milk is a familiar example of an oil-in-water emulsion. The droplets are usually formed by high shear mechanical processes and stabilized against coalescence by electrostatic and/or steric barriers around the droplets provided by the stabilizers. Often, this colloidal dispersion is complex because the dispersed phase is partially solidified or because the continuous phase contains crystalline material (such as in ice cream). 	

Emulsions and suspensions have two things in common: first, they are thermodynamically unstable and second, because they are mostly optically opaque systems, they are difficult to study using optical analysis methods. Examples of pharmaceutical emulsions include lotions, liniments, creams and vitamin drops. Except for the medicinal ingredients, the base vehicles in creams, ointments and lotions are quite similar in formulation to cosmetic preparations. 	

It has been found that properly formulated pharmaceutical emulsions and dispersions provide more accurate control of the dosage. They will also furnish a method of combining many immiscible ingredients into a single, stable product, which improves the ease of application. The proper formulation and control of particle size and stability bring about the controlled release of the active ingredients. Emulsions are difficult to characterize and their behaviour is challenging to understand, however, their application is universal and they are widespread in nature. 	

There is a special class of emulsions: microemulsions. In contrast to 'normal' emulsions, they are thermodynamically stable, the droplet size in microemulsions is small (in the range 10–100 nm) and they are transparent. Microemulsions have attracted considerable interest during the years as potential drug delivery systems because of their unique properties, which include stability, ease of preparation and their ability to form spontaneously.

Analysis of microstructure and intermolecular interactions in emulsions and suspensions is a challenging task. Many traditional analytical techniques require dilution to adjust the transparency of emulsion to an acceptable range. This often affects the weak balance of intermolecular forces in emulsion and its structure. (Microemulsions suffer from similar dilution problems to emulsions, although in the case of a microemulsion formulated with a short-chain cosurfactant, dilution often leads to the total destruction of the system. Hence it is imperative that most microemulsions are measured in their concentrated state.) Another limitation is the effect of the measuring device on the structure of emulsions, which is common for rheological (viscometry and dynamic rheology) and other measurements.		

Figure 2 Monitoring lysozyme crystallization by ultrasonic spectroscopy. The inset shows the measurements during the first 5 hours of crystallization.  (Click to enlarge)	

Proteins are a class of macromolecules found universally in living creatures. Mutation of a protein or a combi-nation of proteins working together can cause diseases such as bovine spongiform encephalopathy (BSE). Subsequently, having a good understanding of proteins can help fight disease. To appreciate the function of a protein and how it performs this specific function, scientists need to understand its structure.  				

The method used to study the molecular structure of proteins is X-ray diffraction, in which the protein must be in a pure crystal form. However, because of the complex nature of proteins, and their sensitivity to their environmental conditions, it is difficult to produce good quality crystals. By running thousands of protein crystal screens that use different variables such as pH, salt concentration and temperature, scientists can narrow down the conditions that are needed to produce high quality crystals. However, this can be a long and arduous process taking months or years. The use of a real-time analytical method that can follow the crystallization reaction can speed up this process. 	

HR-US is a novel technique for non-destructive material analysis based on precision measurements of parameters of high-frequency sound waves propagating through analysed samples (Figure 1). These waves propagate through most materials, including opaque samples, and allow direct probing of intermolecular forces. HR ultrasonic spectrometers provide an unprecedented range of new analytical capabilities for research, product development, quality and process control in the biotech, pharmaceutical, food, chemical and petrochemical, and polymer industries. This rapid, inexpensive and non-destructive technique has previously established itself as a powerful tool for 				

conformational transitions in polymers and biopolymers

formation of micelles and critical micellization concentration measurements

High-resolution ultrasonic spectrometers can be used for characterization of emulsions and suspensions, and the evaluation of their stability and structure (particle size measurements). The instruments measure two parameters, ultrasonic attenuation and velocity, which are physically independent, allowing the probing of different levels of the organization of the samples to be characterized. 	

Attenuation is mainly determined by the scattering of ultrasonic waves in non-homogeneous samples (emulsions and dispersions) and fast chemical relaxation (in homogeneous mixtures). The density and the elasticity of the medium determine ultrasonic velocity. A major advantage of the ultrasonic technique is the ability to make measurements directly, in the original emulsion, without having to make dilutions. The following examples illustrate the application of the technology for analysis of the crystallization process and the formation of a microemulsion.	

Lysozyme protects the human body from bacterial infection by attacking bacterial cell walls, causing them to rupture. By varying the experimental conditions, different amounts and sizes of protein crystals can be produced. The amount of crystals as well as an assessment of their sizes and interactions is an important part of routine analysis in the pharmaceutical industry. HR-US spectrometers allow measurement as the crystal grows with time and temperature and assessment of the amount of crystals in a sample. Monitoring of crystal formation, in particular the kinetics of the reaction, is essential for the optimization of process control in the batch crystallization of pharmaceutical compounds. 		

Figure 3 Ultrasonic analysis of microstructural rearrangements and formation of microemulsion.  (Click to enlarge)				

Crystallization of lysozyme measured by HR-US is shown in Figure 2. In this measurement, 1 mL of a solution of lysozyme (40 mg/mL) in 0.1 M sodium acetate (pH 4.8) was placed into the ultrasonic cell. A precipitating agent was added to the sample and the kinetics of crystallization was followed. The spectrometer detects three stages in the crystallization process. During the first 3.4 h of the reaction, no significant change is detected. At the end of stage I the ultrasonic velocity and attenuation start to increase because of the formation of crystals. 	

This increase continues through stage II as the concentration and size of the crystals grow. The increase in ultrasonic velocity is caused by the increase in rigidity (decrease in compressibility) of the sample as a result of crystal formation. The rise in ultrasonic attenuation can be attributed to the scattering of the ultrasonic wave on the solid crystals that are formed. The scattering contribution is dependent on the ratio of crystal size and frequency (for example, the attenuation at the higher frequencies is more sensitive to the formation of small particles). Therefore, multi-frequency ultrasonic attenuation measurements allow analysis of the crystal structure and size. During stage II the ultrasonic velocity starts to decrease; in stage III the ultrasonic attenuation nearly levels off, indicating the end of crystal formation in the micron range size. However, the velocity continues to decrease, as a consequence of the sediment of a small percentage of large crystals from the system.	

This example describes the application of the technology for analysis of the formation of a microemulsion in a system consisting of pharmaceutically accepted components,

), n-propanol as a cosurfactant in a w/w ratio 6:1:1 and water.

 The measurements were performed at 20 Â°C using an HR-US spectrometer equipped with a standard 1 mL cell in the frequency range 2–20 MHz. 				

Figure 3 shows the typical dependence of ultrasonic velocity and attenuation on the concentration of water in the system (at 5 MHz). Molecular dissolving of water in the mixture at low concentrations (up to 2 wt%), which is accompanied by hydration of lipid and cosurfactant, is shown by the steady increase in ultrasonic velocity. Following this, a microstructural reorganization takes place, indicated by an additional increase in ultrasonic velocity in the range 2–6% water concentration. Formation of the microemulsion can be seen from approximately 8 wt% with ultrasonic attenuation quickly increasing, which is caused by the scattering of the ultrasonic wave on the particles. It should be noted that when compared with light scattering, good agreement above the break point was found whereas below the break point, the possible structuring of the system is not observable with the light scattering. This shows the potential of the technique in providing information previously unattainable by existing methods of analysis.	

1.	M.J. Lawrence and G.D. Rees, "Microemulsion-Based Media as Novel Drug Delivery Systems," 

2.	R. Aboofazeli and M.J. Lawrence, "Investigations into the Formation and Characterization of Phospholipid Microemulsions. I. Pseudo-Ternary Phase Diagrams of Systems Containing Water-Lecithin-Alcohol-Isopropyl Myristate,"

www.aapspharmsci.org/view.asp?art=ps020319

4.	K. Shinoda et al., "Lecithin-Based Microemulsions: Phase Behaviour and Microstructure," 

This article introduces the application of high-resolution ultrasonic spectroscopy (HR-US) for the analysis of emulsions and suspensions. The authors outline the principles of the technique and illustrate its application for analysis of the crystallization of lysozyme and the formation of a microemulsion.

Pharmaceutical Technology Europe-06-01-2004

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