This document discusses Process Analytical Technology (PAT) and Quality by Design (QbD) approaches to pharmaceutical manufacturing. Traditional methods involve collecting samples for off-site laboratory testing, which can delay results and potentially discard good batches. PAT/QbD enable real-time monitoring of critical quality attributes using techniques like spectroscopy. This allows for fast adjustment of processes to ensure quality products and reduce waste from failed batches. Key goals are continuous monitoring, feedback control, and understanding sources of variability to consistently produce quality medicines.
This document discusses Process Analytical Technology (PAT) and Quality by Design (QbD) approaches to pharmaceutical manufacturing. Traditional methods involve collecting samples for off-site laboratory testing, which can delay results and potentially discard good batches. PAT/QbD enable real-time monitoring of critical quality attributes using techniques like spectroscopy. This allows for fast adjustment of processes to ensure quality products and reduce waste from failed batches. Key goals are continuous monitoring, feedback control, and understanding sources of variability to consistently produce quality medicines.
This document discusses Process Analytical Technology (PAT) and Quality by Design (QbD) approaches to pharmaceutical manufacturing. Traditional methods involve collecting samples for off-site laboratory testing, which can delay results and potentially discard good batches. PAT/QbD enable real-time monitoring of critical quality attributes using techniques like spectroscopy. This allows for fast adjustment of processes to ensure quality products and reduce waste from failed batches. Key goals are continuous monitoring, feedback control, and understanding sources of variability to consistently produce quality medicines.
This document discusses Process Analytical Technology (PAT) and Quality by Design (QbD) approaches to pharmaceutical manufacturing. Traditional methods involve collecting samples for off-site laboratory testing, which can delay results and potentially discard good batches. PAT/QbD enable real-time monitoring of critical quality attributes using techniques like spectroscopy. This allows for fast adjustment of processes to ensure quality products and reduce waste from failed batches. Key goals are continuous monitoring, feedback control, and understanding sources of variability to consistently produce quality medicines.
The pharmaceutical companies are engaged in the discovery, development, and production of high- quality, safe, and efficacious medicines. Conventional pharmaceutical manufacturing involves either collecting sample during batch processing for laboratory testing which represents the quality of the whole batch, or performs end- product testing, to ensure quality of the product.
In order to ensure if the in-process materials or the final product meets the predetermined quality specifications or not, samples are collected from each step of the production process and tested into the lab for different quality control parameters, and the results which are obtained from the tests of the collected samples represents the quality of the entire batch. Some examples of the quality control parameters include homogeneity of mixture, particle size, moisture content, potency, content uniformity, dissolution profile, microbial limits, etc., depending on the dosage form being manufactured. This way of collecting the samples and then taking the samples to the laboratory, which is away from the production site is a traditional approach or traditional way of measuring the quality control parameters of the product.
The problems associated with the traditional approach of determining the product quality are as follows- • The collection of samples from the process stream and transportation to a lab for analysis results in a delay between process sampling and when the results are available • If that particular representative sample does not meet the predetermined quality specifications but the overall batch is good, in that case the whole batch will be discarded based on the result of the sample • It may also happen that the representative samples pass the test but the overall batch is of low quality and based on the result of the test sample, product is released, only to be recalled later from the market • If a product fails to meet the predetermined quality specifications at final testing the whole batch has to be discarded which would incur a huge loss to the company
These problems can be overcome-
✓ If the quality control attributes of the incoming materials, in-process materials, and finished drug products are monitored periodically and controlled in a real time manner by integrating the manufacturing equipment with suitable product analyzing tools. ✓ The real time analysis also helps to understand how the components and related processes affect the final product, and may include a feedback loop to modify the process conditions based upon real-time analysis. This real-time data may aid both process control and product quality.
In order to ensure that the critical quality attributes or parameters of the final product or the in- process materials meets the predetermined quality specifications a quality by design (QbD) approach was introduced.
✓ Quality by design is an approach that aims to ensure the quality of medicines by employing statistical, analytical and risk-management methodology in the design, development and manufacturing of medicines. ✓ One of the goals of quality by design is to ensure that all sources of variability affecting a process are identified, explained and managed by appropriate measures. This enables the finished medicine to consistently meet its predefined characteristics from the start - so that it is 'right first time'.
Components of QbD • Quality target product profile (QTPP) • Critical quality attribute (CQA) • Critical material attribute (CMA) • Critical process parameter (CPP) • Design of experiment (DoE) • Control strategy (e.g., PAT) • Life cycle management
CQA: A critical quality attribute (CQA) is "a physical, chemical, biological, or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality". CQAs are generally associated with the drug substance, excipients, intermediates (in-process materials), and drug product. Example: According to USP, the friability of the tablet should not be more than 1%, moisture content should not be more than 2% w/w. CPP: A critical process parameter (CPP) is a process variable that can impact the CQA. Therefore, CPPs must be monitored to enable early and accurate detection of deviations outside acceptable limits and the parameters should be controlled to ensure the process produces products of desired quality. Example: temperature, pH, cooling rate, rotation speed, relative humidity, etc., depending on the dosage form being manufactured. Process Analytical Technology (PAT) Process analytical technology (PAT) has been defined as “a system for designing, analyzing, and controlling manufacturing through timely measurements (i.e., during processing) of critical quality and performance attributes of raw and in-process materials and processes, with the goal of ensuring final product quality” The PAT initiative is based on the FDA’s belief that: “quality cannot be tested into products; it should be built-in or should be by design.”
Advantages of incorporating PAT in QbD process:
• generates product quality information in real-time, so current and downstream operations
can be adjusted accordingly • ensure that all sources of variability affecting a process are identified, explained and managed. • seeks to provide fundamental, science-based insight into those parameters that are key to the stability of a process and resultant product quality. • provide processes which consistently generate products of a predetermined quality. • continuous monitoring, and feedback control • improved product quality and uniformity • process cost reduction • eliminates or minimizes product re-work, • speeds process cycle • enables data-driven decision making • facilitates regulatory acceptance and compliance
PAT tools
✓ In order to measure critical quality attributes, a PAT system needs to measure product quality in a real time, non-destructive way, and this often calls for the use of spectral instrumentation ✓ A variety of analytical techniques have been used in the pharmaceutical industry, including sensors/probe, mass spectroscopy, Fourier transform infra-red spectroscopy (FTIR), UV- spectroscopy, gas chromatography, high performance liquid chromatography (HPLC), X- ray diffraction spectroscopy, Raman spectroscopy, and near-infrared (NIR) spectroscopy. ✓ Selection of instrumentation is very specific ad depend on product type and quality control attribute we are trying to measure. ✓ NIR is the most popular and is used in a diverse set of applications including estimation of active content, powder flow characterization, raw material analysis, and dissolution rate. ✓ The various combinations of analyzers, software and statistical tools together form a PAT application. Software data is converted into statistical model producing quality predictions based on the data inputs.
PAT applications Sample testing can be performed in the following ways- ✓ off-line (sample removed and analyzed away from process stream in laboratory) ✓ at-line (sample removed and analyzed close to process stream). (Advantage: eliminated the transfer of samples to a different site and provides rapid results compared to the off-line method) ✓ on-line (sample removed for analysis from process stream and returned to process stream again) (diverted sample stream) the sample is taken from the process stream, analyzed and is then restored back onto the process stream. Here, the analytical tool or the measurement system is connected to the process via a diverted sample stream and the sample, after measurement, is returned to the process. ✓ in-line (sample not removed but analyzed in place) the sample is not removed but analyzed in the same place. In this process, any type of analytical tools or sensors are integrated directly into the In-line. Thus, measurement of any critical quality attribute is done in presence of the sample.
On-line and in-line provides a real-time monitoring of the critical quality attributes of the raw or in- process materials. Example 1 ✓ With solid oral drug products, for example, excipients and the drug substance are blended until they are uniform. This is done to ensure, to the individual tablet, composition is consistent. ✓ In traditional approaches, blend samples are taken in various positions in the blender to determine if the composition is homogeneous throughout. The act of blend sampling itself, though, may sometimes cause segregation within the sample and result in analysis bias. ✓ In a PAT approach, a spectrometer is attached to the blender and spectra are acquired in real time to monitor the mixing. Once the spectra do not change any further, the blend is considered homogeneous. Example 2 ✓ With a drug substance, for example, reactants A and B are combined to form product C. The process is monitored for the disappearance of reactants A and B, and the formation of product C and potential byproducts. ✓ In traditional approaches, samples are periodically taken from the reactor, quenched, if need be, and brought to the testing lab. The samples are often analyzed by chromatography, where the individual components are separated from each other (in a time-dependent fashion) and quantified individually (Figure 1).
✓ In a PAT approach, for example, the analysis technique is interfaced with the reactor for real-time analysis. ✓ Spectroscopic methods are often used, wherein a specific reactant, product, or byproduct molecular functional group characteristic (such as vibrational frequency or photon scatter frequency) can be monitored over time for disappearance (reactant) or appearance (product or byproduct). ✓ For example, if one is converting a carboxylic acid to an ester, one might monitor, by IR spectroscopy, the subtle shift in the carbonyl vibrational frequency (ca. 1700 cm-1) as the carboxylic acid is converted to an ester. Alternatively, other unique absorption frequencies may also be monitored (Figure 2).
Example 3 PAT can also be used, for example, to identify optimal formulations of sustained release tablets using multivariate mathematical approaches, such as statistical design of experiments, from the input of in vitro dissolution profile, and other physical attributes of the tablets and process parameters into suitable software (e.g., DoE software).
