Optimization and validation of manufacturing processes

Validation in the definition adopted by a Joint FIP Committee means that every essential operation in the development, manufacture and control of pharmaceutical products is reliable, reproducible and capable of providing the desired product quality if stipulated production instructions and control procedures are followed.

A pre-requisite for, and an integral part of process-validation is that people, premises and equipment should be qualified. In other words, validation activities rely upon the check of technical and physical parameters when measuring devices are being calibrated, equipment is being qualified as well as on chemical, physical and biological parameters when processes are being Validated.

As we know, validation starts with planning a new plant, a new machine or equipment as well as with the development of a new or changed product.

This way of development from the laboratory trial and the clinical trial until the production phase has to guarentee the manufacture of products conforming to the desired profile.

According to a new draft guideline prepared by the FDA this year, drug products which are produced for clinical trials have to comply with the GMP - regulations. For example, the drug product must be produced in a qualified facility and the process must be validated. This means that manufacturing processes for clinical trials should be validated at the end of the development phase, as soon as processes are at least partially optimized, even if scaling up has not yet been completed.

The results of all development studies i.e. the use of equipment, the tolerances of physical parameters in the manufacturing process and the approved specification of starting materials being summarized in such a validations-report, the latter mostly seems to be an optimization-report. This can be of special value when scaling up in the production facility is completed.

As far as a sufficient number of clinical trials batches are manufactured according to an approved procedure this process can be validated prospectively. The results of this validation as well as the Know-how gained during optimization provide the basis for the validation of production conditions.

The organization of our validation activities in the manufacture of sterile and nonsterile drug products will be described in this presentation and some examples of process-validation will be given.     

Validation of solid dosage forms the FDA view

In May 1987 the United States Food and Drug Administration published the final version of a guideline for process validation for pharmaceutical manufacturing. The document incorporated the comments from the pharmaceutical industry gathered after the publication of three draft versions in 1983, 1984 and 1986.

The presentation will cover the current definition of process validation as well as terms such as “worse case” and “installation qualification”.

The stages of process validation will be discussed including the written plan (protocol): records to be maintained; suitability of raw materials; equipment performance qualification; the number of runs required; and acceptance criteria.

Specifics for solid dosage forms will be presented along with details on batch record in instructions and establishment of acceptable range limits.

Circumstances and requirements for revalidation will be discussed as well as the validation of current finished dosage forms by retrospective validation.     

QUICK AND RELIABLE FILTER TESTS WITH A MODULAR FILTER TEST RIG

A technique is described which reduces the duration of the measurement period in filter testing by approximately a factor of 3 in comparison to existing techniques.

Information concerning filter performance must be obtained reliably, reproducibly and quickly, without incurring large costs and without the need for specialized staff.

The components used (generators for powders, fluids or NaCI, discharge gap, filter holder, dilution systems and particle counter) meet the requirements of various standards (for example, Eurovent, CEN EN 143, DIN 24183, DIN 24185, draft of DIN 71460 and draft of VDI 3926))M     

Dependence of Compression Phase on Elasticity of the Material

It is shown that the Pmax value obtained during the tabletting process is statistically independent of machine motor velocity

To explain this phenomenon, an analogic model composed of a spring and two or three Maxwell bodies grouped in parallel was used to represent the behaviour of powders during compaction. It was observed that during the compression phase, the recorded force may be represented by the response given by the set of springs alone

The shock absorbers intervene just before and after the Pmax, when the upper punch velocity is very low or nil

It was possible to obtain these results after determining the law representing elasticity in relation to the deformation applied to the powders

The consequences of these phenomena are discussed     

ESTIMATION OF THE AVERAGE ASPECT RATIO OF LAMELLAE-SHAPED PARTICLES BY LASER DIFFRACTOMETRY

Reinforcing properties for polymers and elastomers, rheological properties of high density aqueous slurries, hidding power, lubricating properties of platey particles strongly depend on their size distribution and shape factor or aspect ratio (A.R.).

Determinations of A.R. of fine particles by conventional methods are time-consuming and require sophisticated equipment. A method based upon later light diffractometry has been developed to meet control requirements in industry, the average A.R. can be determined within 5 to 10 minutes, depending upon the number of measurements made using a commercial laser granulometer.

The method relies on:

a cylindrical model (disc) of platey particles.

determinations of the projected area of particles in dilute suspensions of controlled solids concentrations.

calibration of the instrument, using isodiametric particles

simple material balance to derive the average thickness h of the platey particles from projected area measurements and volume of the solid.

A.R. is defined as d50(S)/h. where d50(S) is the mean projected area diameter and h the average thickness attributed to all particles occurring in the sample.     

Good pharmaceutical manufacturing practices

In order to assure the quality of medicines and to encourage the implementation of the international system for the certification of the quality of pharmaceuticals, it was deemed necessary to specify the conditions under which pharmaceutical establishments should operate to provide full assurance that their products are safe for public health.

The French Government Order of 1. October. 1985 therefore provides for the establishement of new recommendations on good pharmaceutical manufacturing practices: “Bonnes Pratiques de Fabrication et de Production Pharmaceutiques: BPF 1985”.

Within the system of quality assurance, good pharmaceutical manufacturing practices represent that part which is concerned with manufacture.

Their implementation requires that the specification of the raw materials and packaging materials, the manufacturing and packaging processes and the control methods be defined and written beforehand, that the premises and equipment be adapted to the intended uses and that the staff have received appropriate training.

Good pharmaceutical manufacturing practices directly concern production departments and packing area, control laboratories, storage areas, purchasing departments, departments receiving raw materials and dispatching finished products. They also concern departments issuing instructions and written or computerised documents intended for the departments previously mentioned.

Although the collection of recommendations thus published constitutes a detailed document, the possibility of there being different methods for attaining the same objective is recognised.     

Use of Colloidal Silica as a Separating Agent in Film Forming Processes Performed with Aqueous Dispersion of Acrylic Resins

Aqueous dispersion of polymers are going to take the place of the corresponding organic solution in the film forming process of tablets, pellets and granules, because of some definite advantages.

Among the additives used in formulation techniques, talc, that is normally utilized as an antiadherent and polishing agent, presents some problems connected with its tendency to form sedimentation. For this reason, during the film coating operation, the dispersion must be always kept under constant and proper agitation, however, the danger of blocking the piping and the spraying system of the equipment employed cannot be completely avoided.

On the bases of these observations, the aim of this research work is to evaluate the possibility of substituting talc with colloidal silica as separating agent in aqueous dispersion of film acrylic resins, normally used in the preparation of prolonged release systems.

Results concerning fluid bed coating processes of pellets prepared by extrusion-spheronization technique have been reported, with particular attention to usable concentration of colloidal silica and to possible influence of these on the drug release characteristics of the systems obtained.     

Crystal Engineering and Particle Design for the Powder Compaction Process

The historical background to the subject of crystal engineering of pharmaceuticals is briefly reviewed with reference to materials as diverse as insulin and direct compression tablet excipients. In the light of the limited scientific and practical information available on the topic two questions are posed -

Is it possible to prepare 'designer' materials with preferred processing, specifically compressive, properties giving optimised product characteristics?

How can such materials be efficiently manufactured?

In order to consider these questions, several important elements of data-base requirements are regarded as essential. These include knowledge of the crystalline phases of pharmaceutical solids, full understanding of the fundamental mechanical constants and moduli of particulate solids, and the relationships describing the influence of crystallographic structure on the mechanical properties of crystals and powders. At the same time the effects of preparation, pretreatment and processing effects on crystal structure, crystallinity and thermodynamic properties of powdered solids must be established.

The topics of material based compaction problems, property groupings of pharmaceutical powders with particular emphasis on crystal structure and mechanical properties are discussed. The review then considers recent and current research work examining the compaction behaviour of modified or engineered materials, prepared using alternative crystallisation conditions and the incorporation of low level additives. Specific examples include modern direct compression excipients, 'spherical' drug particle production and high purity lubricant (magnesium stearate) powders.

In conclusion, the future potential of the concepts of crystal engineering and particle design is considered in terms of predicting mechanical and processing properties from fundamental molecular and structural information.     

Research Papers: Preparation of Indobufen Pellets by Using Centrifugal Rotary Fluidized Bed Equipment Without Starting Seeds

ABSTRACT

Pellets containing Indobufen as model drug were prepared by using the centrifugal-rotary fluidized bed equipment without employing non-pareil seeds.

The influence of different amounts of spheronization enhancer (microcrystalline cellulose) and of different fillers (lactose, mannitol, calcium carbonate) on both processing and physical properties of the pellets were evaluated.

The preparation reproducibility was also investigated. The use of 30% w/w of microcrystalline cellulose was essential to produce a good quality pellets; the incorporation of filler decreased the qualitative characteristics of the pellets.

The water feeding rate proved to be an important parameter for the pellet growth.

Therefore, the results showed that this technology based on the rotary fluidized bed is a promising and alternative method in producing pellets.     

Disintegrants in Solid Dosage Forms

The dynamic approach to tablet disintegration, which is based on the measurement of the force that develops inside the compact upon water entrance, is basically taken up.

The combined measurements of force development and water uptake, simultaneously effected on the same compact, provide a novel parameter that is proposed to quantify and compare the efficiency of disintegrants.

The new parameter, which is based on the “force-equivalent” concept, expresses the capability of a disintegrant of transforming water uptaken into swelling (or disintegrating) force. A few examples, that illustrate the usefulness of this parameter for disintegrant characterization, are given.

In parallel to the quantification of swelling (or disintegrating) efficiency inside compacts, attention is also being paid to the characterization of swelling disintegrants as pure materials.

In particular the case of the so-called limited swelling materials, for which the quantification of intrinsic swelling (particle volume increase in swelling media) is critical, is considered.

The applicability of an instrumental method, which is based on the employment of a Coulter Counter, is discussed alternatively to microscopic methods.

Disintegrant characterization may also be considered in view of new possible exploitations of the swelling properties of polymers in controlling drug release.     

A COMPARISON OF TWO NaCl TEST SYSTEMS USED FOR MEASURING FILTER EFFICIENCY

The filter efficiency of materials to be used in respiratory protective devices is commonly measured by using a solid NaCl particle challenge and a flame ionization detector. The Moore's BS 4400 Bench Rig is an example of such equipment.

Recently, TSI, Inc. introduced their Model 8110. This system also produces a NaCl particle challenge. It uses a laser diode detector.

The filter efficiencies of two different filter materials were determined in a comparative study utilizing several Moore's and TSI systems. The results indicate that the two test systems are relatable and that the between-machine consistency of the Model 8110 is better than the Moore's system.     

Germanischer Lloyd规范Goodman曲线对某型动车组CFRP复合材料设备舱骨架疲劳校核的应用

为了解决国内对适用于复合材料Goodman曲线实验研究较少的问题,基于ABAQUS有限元,利用Python语言编程和计算,按照德国劳氏船级社（GL）规范Goodman曲线对某新型动车组碳纤维增强树脂（CFRP）复合材料设备舱骨架进行疲劳强度校核。通过不同平均应力下疲劳强度实验,绘制Goodman曲线及考虑一定安全系数下的Goodman曲线,并与GL规范的Goodman曲线进行对比研究。结果表明,在EN12663-1∶2010[13]和文献[14]规定的疲劳工况下,GL规范的Goodman曲线对新型动车组CFRP复合材料设备舱骨架疲劳强度校核具有可行性,CFRP复合材料设备舱骨架可满足设计要求,但考虑安全系数n=1.5和n=2时评价有一定的风险性。      

ELECTROCHEMICAL METALLIZING OF ADVANCED MATERIALS

Electrochemical metallizing provides sound metallurgical coatings for maintenance and production applications. The technique involves tankless electroplating, using a brush-on procedure.

Maintenance applications involve resizing, restoring, rebuilding or resurfacing worn, damaged, corroded, eroded or overmachined metal components. This paper deals with special production applications. The title may be a misnomer, since the paper deals with advanced materials, but also covers special unique applications and infrequently used metals and alloys.

For experimenting with new advanced materials, electrochemical metallizing is invaluable. Manually operated, not requiring large or expensive equipment, enabling rapid controlled deposition of numerous metals, alloys and composites, the system provides a low-cost experimental start-up procedure.

Advanced materials covered are primarily metal composites--nickel with a codeposited fluorinated carbon and a nickel-silicon deposit. The first has a decomposition temperature of 850° to 1000°F (460° to 535°C) and a very low friction coefficient. This makes it useful for high temperatures, low sticking and high wear applications, sometimes replacing Teflon or chromium. The second has a Vickers hardness of HV725 (at 100 grams load) and interesting high hardness applications. Also noted are nickel-silicon carbide, nickel-alumina-silicon dioxide and cobalt composites.

Special application deposits exist for preventing galling; improving brazeability; improved bonding of rubber or plastic to aluminum alloys; aluminum hard coatings; repairing electroless nickel; and light-absorbent surfaces.

Finally, the paper deals with electrochemical metallizing materials infrequently used, e.g. antimony, arsenic, bismuth, gallium, indium, palladium, rhenium, ruthenium, nickel-zinc, nickel-phosphorous, nickel-tungsten and tin-indium.     

Statistical Evaluation of the Results Obtained with the Analytical Methods used for the Quality Control of Medicines

To improve the way by which the quality control of medicines is carried out, general statistical concepts and methods are discussed for the evaluation of the analytical results obtained for judging the adequacy of drug substances and products for Pharmacopoeia requirements.

Statistical procedures to be adopted by the producer and the controller in the determination of characteristics are suggested when the drug substance is or is not homogeneous and when the precision of the analytical method is known or unknown.

For each of these cases, detailed numerical examples are given.     

Contemporary Techniques for Toe Production of Ultra-Pure Water in the Pharmflceutical Industry

The paper reviews the latest manufacturing techniques for producing ultra-pure water to meet the standards specified for the pharmaceutical industry.

The various water treatment techniques are considered in terms of their effectiveness in removing the multiplicity of contaminants found in raw water supplies. The concept of a water purification system is developed, and particular stress is placed on synergistic combinations of ion-exchange and membrane processes that produce high-purity water cost-effectively. Also highlighted is the importance of good system design and validation procedures.

Water treatment principles are illustrated by reference to case histories of pharmaceutical installations, including a low-cost, membrane-based system for providing apyrogenic water.     

Instrumented and Computer Interfaced Single Punch Tablet Press for the Rapid Evaluation of Compression and Lubrication Behaviour

A low cost instrumented and computer interfaced single punch tablet press was developed for the rapid data aquisition of compression and lubrication properties of powders arid processed materials.

A Manesty type F3 tablet machine has been modified to enable the fitting of piezo electric load cells to both upper and lower punch assemblies. The paper describes how the modifications permit interchangability of a range of punch sizes and shapes and yet ensure good accuracy and reproducibility of compression end lubrication data.

The instrumentation is interfaced with a dedicated A. I. M. 65 microcomputer for the rapid conversion of the instrumentation outputs into compression force units and for statistical evaluation. The computer software also incorporates a novel method for the evaluation of lubrication properties from a single or a series of pre-determined compression events, using the some sensitivity for force measurement from the lower punch lord cell.

The compression data and the physical properties of the compacts can be stored and retreived as fingerprints using a P. E. T. microcomputer and a digital plotter. A date bank may then be developed for the evaluation of raw materials, product development, monitoring of production performance and trouble shooting.

The paper further describes the evaluation of new lubricants in comparison with magnesium stearate using the instrumentation described.     

ULTRA-PRECISION DIAMOND MACHINING OF ADVANCED TECHNOLOGY COMPONENTS

The design, development, and application of ultra-precision CNC machines for

the single point diamond turning of non-conventional metal optical components (Al, Ge, etc. )

the diamond grinding of ferrite and, other ceramic components for magnetic disc flying heads, etc.

is described. In both cases, tolerances on workpieces in the order of ± 0·1 μm were specified and achieved, together with the overriding need to minimize degenerated surface layers, i.e. surface damage.

The effects of chip formation at low depths of cut are discussed. The factors affecting the depths of “damaged layers” formed in turning and grinding are mentioned. Typical advanced technology components for which ultra-precision diamond turning or grinding are widely used are:

Convex mirrors for high output C0₂ laser resonators

X-ray mirrors

infrared lenses in germanium for thermal imaging systems

scanners for laser printers. and drums for copiers

elliptical mirrors for YAG laser beam collectors

spherical bearing surfaces in beryllium, copper, and other materials

ceramics for magnetic read/write heads for computer memory discs

ceramics for cams, cam followers, valve seat inserts, cylinder liners, bearings, cylinder heads, turbo impell ers, etc.

Both single point and diamond grinding for ultraprecision low stress surfaces demand high precision machines that provide

high stiffness of structures and high band-width servo drives;

low rumble, high averaging bearings such as hydrostatic air or oil;

high internal damping of stuctures and drive systems;

multi closed loop control of many parameters, including temperature of coolant and temperature gradients across structures and sub-systems;

coolant delivery to the abrasive/workpiece interface is of critical importance for controlling high surface finish and minimizing surface tresses.

The paper gives examples of how these problems are satisfied in today's state of the art ultra-precision CNC machine tools.     

TRACER ANALYSIS OF FLUID CATALYST FLOW IN REFINERY CATALYTIC CRACKING UNITS

Tracer studies of fluid catalyst flow have been conducted in five different fluid catalytic cracking units containing from 200 to 1000 tons of circulating catalyst. A single pulse injection of about 2 pounds of catalyst labeled with Au198 or Sc46 can yield the following Information:

1. Catalyst circulation rate.

2. Mean catalyst residence time in specific parts of the circuit.

3. Catalyst Inventory in the corresponding vessels.

4. Catalyst residence time distribution in these vessels.

5. Total unit inventory by tracer dilution.

6. Attrition rate and average lifetime of the labeled catalyst.

Experimental methods and data analysis are described, and examples are given. The effects of residence time distribution on reaction kinetics are discussed.     

The use of optimazation techniques in pharmaceutical development

The lecture uses selected examples to illustrate the use of mathematical methods to optimize drug dosage forms:

Elucidation of compatibility between active ingredient and excipients required in the preformulation phase by factorial design.

Calculation of maximum allowable mean of particle sizes for active ingredient and the sum of auxiliary materials to achieve a sufficient content uniformity by applying the Stange-Pool equation.

Application of surface response research for identification of the working point in an “innocuous area of landscape” for scaling ups, handing over to production, of trouble shooting by using central composite desing and in the case of multiple constraints doing computerized grid search.

Only mentioned and not described in detail will be the methods for pharmacokinetical optimization, necessary for the development of modified release formulations.

Of course not for every development it is mandatory to use surface response research to get the necessary quality. But it is worthwile to apply refgularly factorial design for compatibility studies to calculate the necessary particle sizes and to compare in vivo results with dissolution rate data.     

Computer simulation and control of plasma spraying processes

An integrated technological system for modeling, experimental study, and practical realization of plasma spraying process was devised. The system provided simulation of the main plasma spraying process stages (heating and acceleration of particles in a plasma jet, coating structure formation, heat transfer, and stress-strain state in a coating-substrate system); experimental measurement of the main plasma spray characteristics and entering them in a computer in a real time mode; computer control of the spraying process; and plasma spray coating corresponding with the devised technological process.

This integrated system was upon the basis of vacuum plasma spraying “Plasmatechnik” equipment. An original opto-electronic system was used for experimental measurement of temperature, particle velocity, and coating temperature.