Pharmacy

While much effort is spent in optimizing commercially operating plant, getting the process 'right first time' can be far more efficient. Real-time analysis of process parameters provides substantial support during development, streamlining and accelerating the evolution of successful process designs. A case study for investing in real-time process measurement for pilot studies is discussed.

Real-time process analysis systems      are      used increasingly   within   the manufacturing environment. Automating   analysis   dramatically reduces    operational    variability and its associated inefficiencies- Automation can pay big dividends by improving product quality and at the same cutting the cost of production. These   savings   quickly   offset installation   costs,   strengthening the economic argument in favour of investment.

The financial case for automation at the pilot scale may be less easy to make. Here, potential   benefits are not so immediately obvious,   and   can   be difficult to quantify, but are nonetheless   considerable. The   scope   for   more consistent operation, and the efficient correlation of 'cause and effect', accelerates and   improves   product and process development alike,    bringing    faster and     more     efficient commercialization.    This drives   down – Research &   Development   (R&D) spend an important goal in many sectors.

Pilot plant trials

As a product moves through early stage research towards commercialization,      the impetus is to develop a robust process that will secure consistent, profitable production over the long term.  Pilot scale trials often have an important role to play.

Operating small scale units, which replicate part or a!! of a proposed or existing full-scale plant, is a relatively inexpensive   way   to   experiment towards the best processing solution.

The term 'relatively inexpensive' is, however, used advisedly here, since pilot scale trials are often associated with     significant     expenditure. Furthermore, they are an upfront investment, cash spent now in anticipation of future, rather than immediate    reward.    Maximizing efficiency is essential.

In considering the contribution that real-time analysis can make, it is worth examining possible goals of a pilot scale study. These might include:

• Identifying the most cost-effective process design

• Proving the feasibility of a new technology

• Preparing representative samples for product testing

• Defining the process operating envelope; the range of conditions that will result in a product that meets the defined specification

• Developing an effective control strategy

Reaching these goals in a timely way demands rapid acquisition of understanding. The pilot scale may follow directly on from fairly basic lab work, designed to simply prove the viability of a product. Little may be known about the feasibility of different manufacturing options and it is important to learn fast.

The role of real-time measurement

The real-lime measurement of key process or product parameters eases pilot plant control and increases experimental efficiency. Consider the example of a trial designed to establish optimal muling conditions. When milling, particle size is a defining characteristic of the product so it is useful to examine what happens when using periodic particle size measurement compared with applying real-time analysis.

Periodic, off-line analysis provides a snapshot of the process each time a sample is taken. Material is extracted from the plant, taken away for analysis and the results returned some time later. Time lags between extraction of the sample and the return of results are unavoidable, returning to milling. A change is made to a mill parameter and there is an immediate impact on existing particle size. Sample is extracted from the exit stream, worked up and the results obtained perhaps an hour   later.   Careful correlation enables assessment of the impact of the initial change. However, it may prove necessary to take multiple samples to precisely quantify the result. Furthermore, if the mill does not normally operate smoothly it may be difficult to differentiate the effect of the change from baseline steady state variability.

Continuously   monitoring   the particle size of the exiting material provides a number of benefits. Firstly, because the operator can properly observe how the plant is running, it can be operated with greater smoothness, establishing an improved baseline    for    experimentation. More consistent steady state operation also makes it easier to provide representative material for product testing. Most importantly, as soonas a change is made the results are immediately obvious. Cause and effect can be rapidly quantified in a statistically relevant way and the rate of experimentation becomes limited solely by the dynamics of the process, by how long it takes changes to filter through the plant. The unit can be moved swiftly and efficiently from one experimental condition to another, and the results of each experiment captured rapidly and completely.

This   capability   of   real-time measurement   to   deliver   steadier pilot plan! operation, and precisely capture even the subtle effects of a process change can accelerate as well as improve developmental work and increase confidence m the resulting solution.

 The   following   study provides practical illustrations of the potential benefits.

Quick take

The case study provides an in-detail analysis for investing in real-time process measurement at the pilot studies stage.

While much effort is expended m optimizing commercially operating plant, getting the process correct in the first time can be far more efficient. Real-time analysis of process parameters provides substantial support during development, streamlining and accelerating the evolution of successful process designs- Takings; on-line prelude size analysis as an example, this paper considers the rationale for investing in real-time measurement for pilot-scale work. Case studies are used to illustrate the various ways in which on-line systems promote efficient process development, easing the transition into profitable manufacturing.

 Case study: Developing a generic processing solution

The pharma industry is currently engaged in a very critical analysis of its manufacturing practices. With a legacy of relatively inefficient batch production the sector is working to transform operations, increase its use of continuous processing and move closer to the goal of real-time product release. Catalyzed by the PDA's Process Analytical Technology (PAT) initiative, pharmaceutical manufacturers are actively seeking analytical techniques that will underpin the development of more efficient processing strategies.

For pharmaceuticals, milling is a common unit operation, used to process active and excitant particles to a defined size for the production of, for example, tablets or inhalable formulations.

 Here, the commercial availability of reliable real-time particle      size      measurement systems provides opportunities for automation that are less accessible for   processes    where   relevant continuous analysis is not yet feasible. Exploiting this potential, a global pharmaceutical manufacturer has recently commercialized a generic automated milling solution with widespread applicability.

The developed solution, which uses a comminutor mill. is simple but effective. Material entering the mill via the throat is broken up by rotating blades, which simultaneously apply cutting and impacting actions. Particles within a denned size range exit via the screen while oversized material

is retained for further combination. Although blade profile and screen specification both influence the size of the exiling particles, rotor speed is the principal control variable.

Pilot scale trials with an Insitec on-line particle size analyzer provided convincing evidence that this system could efficiently and continuously monitor,   in   real-time,   material exiting the mill. Having identified this solution, steps were taken to integrate the mill and analyzer such that the particle size data could be used to automatically control mill speed. A closed control loop was implemented to automate mill operation.

The operator interacts with the automated mill through the mill Human Machine Interface (HMI), which runs on a dedicated computer.  From here it is possible to input particle size set poults for the control loop, remotely start and stop the analyzer and mill, perform background tests and receive particle size results. Using the particle size set point, the mill programmable logic controller (PLC) will adjust speed within a defined control range to maintain the particle size specification.

The   loop   was   tuned   using proportional (P) control. The chosen feedback parameter was average Dv50 with a 30 second rolling average. In tests, set point was reduced from an initial value of 38 microns down to 50 microns and then back up to the original value. The mill stabilized at the first set point after about a minute, reached the second approximately 3t) seconds after the change had been made and completed the final transition in less than 2 miniiles.

This performance highlights the effectiveness of the control system. This      automated      solution, proven at the pilot scale and now commercialized, is applicable to any number of manually operated mills. In  pharmaceutical production, a widespread task is to mill a batch of material- from, for example a crystallizer, to establish a uniform particle size. Using manual control this is a potentially lengthy task that involves first setting processing conditions to hit the size specification, and then maintaining light control in the event of variation across the batch. In contrast, the automated solution rapidly identifies suitable operating conditions, and then automatically adjusts them in response to feed variability.

In this example, pilot studies were used to prove the on-line technology and the feasibility of automation, generating the confidence necessary to commercialize an efficient processing solution. There is clearly potential for this pilot scale work to be very amply rewarded if the solution is rolled out to both pilot and manufacturing plant across the company.

Benefits galore...

In the production environment, real-time process analysis supports the manufacture of better quality product, at competitive cost. With pilot studies the output is knowledge rather than tonnes through the gate. Here, real-time analysis supports the attainment of better understanding, at competitive cost. Continuous process analysis enables more controlled pilot plant operation and enhances investigative research. The result is a faster, more confident transition to profitable manufacture.