The term “pharmaceutical excipient industry” is somewhat of a catch-all for a diverse range of companies, from several industries, with varying degrees of pharmaceutical orientation or capabilities. Many excipient suppliers are chemical industry subsidiaries whose pharmaceutical output may only be a small fraction of the parent’s production. There may be varying degrees of dedicated pharmaceutical R&D and technical service. Both the market and the manufacturing base are increasingly on a global scale. The nature of pharmaceutical excipients is much more diverse than active pharmaceutical ingredients and includes synthetics, semi-synthetics, mined minerals, harvested and cultivated vegetation, formulated products, biotechnology with/without genetic modification and animal by-products. Regardless of origin and technology, the principles of Process Analytical Technology (PAT) can be applied.
PAT essentially applies knowledge of the materials and the process such that end-product specifications and quality attributes are known functions of identified critical variables. By understanding all critical process variables and their relationship to control variables, compliance to specification is ensured and release without further testing is possible. An early pharmaceutical example of this concept of parametric release (PR) was in 1985, with the first sNDA approvals for large-volume parenterals using PR in lieu of end-product sterility testing.
The current FDA initiative on PAT is radically different from the traditional regulatory systems of control, which, although delivering high standards of safety and efficacy, do not strike an adequate balance in terms of risk and cost/benefit. Zero risk, regardless of cost, is disadvantageous to pharmaceutical manufacturing and inhibits product and process improvement. The PAT initiative offers appropriate and proportionate relief where justified by scientific knowledge of materials and processes.
The quality focus shifts from post-production testing to guaranteeing intrinsic quality by virtue of the process itself. Knowledge and control of material and process ensures quality, functionality, safety and efficacy. If changes and improvements can be made with sufficient certainty of the quality outcome, then the need for regulatory oversight is minimized.
Excipient industry PAT predates this FDA initiative. There are many sectors within the excipient industry that are much more advanced than pharmaceutical manufacturing in the application of process knowledge and controls in pursuit of quality, efficiency, functionality and safety. Most large-scale continuous production is only economically feasible with state-of-the-art PAT. Continuous production generally reflects continuous improvement and optimization with ever more efficient process control.
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However, supplier PATs are not necessarily congruent with pharmaceutical PAT as the former focuses on the raw material as a product, whereas the latter is focused on the end (medicinal) product. It is not uncommon to run into emulsion or suspension production problems, only for the user to belatedly discover that the supplier has improved or purified the polymer or surfactant. The minor component, or pattern of substitution, on which the users unwittingly relied for their product functionality has disappeared. The pharmaceutical PAT initiative should foster closer collaboration between user and supplier, especially where the supplier may currently be unaware of the user functionality. It is difficult for excipient suppliers to guarantee the consistent functionality of their excipients in an application or formulation of which they have no knowledge.
Many excipients are common to both the food and pharmaceutical industries, but pharmaceutical industry practice differs from that of the food industry. Food users purchase agreed functionalities and pay relatively less attention to the composition of multi-ingredient or grade of single-ingredient, food-grade excipients. Pharmaceutical specifications tend to focus on Pharmacopoeial compliance, and functionality is generally conspicuous by its absence.
Pharmacopoeial compliance generally does not address user functionality and is not an absolute guarantee of safety as the site, or method, of manufacture may potentially introduce contaminants or residues not envisaged by the framers of the monographs. In Europe, the Certificate of Suitability provides supplementary protection in this respect, and an increasing number of European Pharmacopoeial excipients are so controlled, with additional tests specified by the certificate.
In the absence of agreement between the user and supplier, predominant physical functionality-surrogates or grade-specifiers (technical characteristics, label parameters, functionality related characteristics) may be included. These may or may not be correlated with specific user processability or product functionalities.
Physical testing of excipients is necessary—but insufficient—for characterization of functionality, which transcends intrinsic excipient properties.
Specific agreed user requirements may be included in an excipient specification, but many of these are case-specific rather than generally applicable to all uses of that excipient. If based on perception rather than true cause and effect, they may be irrelevant to functionality. When multiple users all demand specific, often conflicting, specifications within specifications, the supplier is placed in a difficult position, especially if the original specification limits (in the spirit of PAT) are set with regard to validated process capability.
Pharmaceutical users demand absence of significant changes that also puts the supplier in a no-win situation. How does a supplier determine what is significant to the several hundreds or thousands of applications and formulations in which the excipient may be (ab)used and of which he or she has no knowledge? Without pharmaceutical expertise, the supplier may be innocently unaware of the significance of any changes they make, especially if their product remains within specification.
Suppliers can err on the side of caution and religiously update their users of every change, but then the users face a considerable administrative and experimental burden of assessing the significance of each notified excipient change to their tens to hundreds of products across several regulatory jurisdictions. This problem is further compounded by stability testing, regulatory approvals, multiple excipients, multiple suppliers and further notifications. In the current risk-averse regulatory climate, it is rare for a user to OK such excipient changes on expert opinion alone. With mutual cost, confidentiality and IP concerns on top, an adversarial don’t ask/don’t tell situation often exists between users and suppliers, analogous to the tension between users and regulators. It is to be hoped that the pharmaceutical PAT initiative will similarly foster closer user-supplier collaboration, facilitate change control and allow focus on scientific as opposed to procedural issues.
Post PAT specifications will include functionality, “PATability,” and consistency, all of which demand closer collaboration.
Functionality is in the hands of the user, is end-product specific and largely beyond supplier control (Moreton 2004). A more detailed knowledge of the end-use by the supplier, and of excipient manufacture and control on the part of the user, is required to reach agreement on functionality specifications, the methodology and assessment of multivariate effects. Users all too often unilaterally characterize their materials in great detail, deriving specifications that their suppliers are unwilling or unable to support.
The PATability of an excipient is a more novel concept. It refers to the effect on the process signature that the excipient imparts alone or in concert with other materials and which may be used as a critical control parameter. Excipients may also have multivariate effects and changes could inadvertently confound or switch off critical control parameters. Consistency is essential, but the supplier needs to know how the user applies PAT to ensure consistency. Suppliers will be placed in an untenable position if several users with different and conflicting PAT approaches independently demand “consistencies” using several different measures.
Excipients may contribute significantly to the overall process variability. Attempting to understand and control overall variability without collaborative insight from the supplier will be less effective. Notwithstanding validation and setting of critical control points, subtle changes in excipients and their interactions can produce surprises, especially where high-level multivariate chemometrics are applied.
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Pharmaceutical industry response to the PAT initiative has not (yet) been overwhelming, with only a few companies having found this door of opportunity and even fewer (“a handful”) venturing through the door as of January (Hussain 2005). Some hesitancy may be due to additional knowledge provoking greater regulatory scrutiny, especially if it precedes control. This somewhat adversarial approach is an unfortunate by-product of the current regulatory system. The PAT initiative is to be commended for more closely aligning producer and regulatory attention on quality. As more companies venture through the door, the switch to this 21st century cGMP will accelerate. We are in the early phase of a substitution curve, and PAT could become the norm in the next two or three years, as industry and regulatory experience accrues.
Clear agreement on defining pharmaceutical quality is essential. The end goal of safety and efficacy for every patient transcends intrinsic product quality, and it is possible that greater premium will be placed on those drug delivery technologies which lend themselves to tailoring for individuals in a future of personalized medicines.
It is fair to say that if the pharmaceutical industry has collectively not yet made up its mind on the PAT initiative, then the pharmaceutical excipient “industry” is generally even more unprepared, being one step removed from the dialogue between the regulators and the pharmaceutical industry.
The excipient supplier has to deal with user perception as opposed to actual regulatory requirements. Pharma users are often more demanding than regulatory agencies and seek to minimize any perceived risk of triggering a regulatory question.
The fact that the quality control test is a legal obligation, whereas parametric release is not, is constraining, in that much wasteful analytical work is being performed without giving any safety advantage (Goldberger 1991).
The user has legal liability for the choice of excipient and often acts toward the supplier in a legalistic and regulatory manner, with demands for six months notice in writing before changing anything being not uncommon.
Tablets are the preferred pharmaceutical presentation so it is appropriate to use tabletting technologies to examine the potential impact of pharmaceutical PAT on the excipient industry. Such technologies dominate the pharmaceutical operations section of the PATRIOT Training (PAT Review, Inspection and OPS {Office of Pharmaceutical Science} Policy Development Team).
Tabletting and related blending and wet/dry granulation technologies pose a particular challenge to PAT as there are significant gaps in the fundamental knowledge preventing prediction of finished product attributes, even using sophisticated methods including a compaction simulator, Instron tester and artificial neural networks:
“Quantitative prediction of compactability…only when model was trained with similar materials” “models could not predict the compactability of other new materials” “close indices…differ widely in compactability, especially tablet strength” “compactability cannot be expressed as a function of tabletting indices”—Kuppuswamy et al 2001. Many pharmaceutical companies still use un-instrumented tablet machines, which handicaps their ability to control force or weight on-line, hinders development optimization and introduces a higher degree of risk. There may be no advance warning of problems prior to a disconnect between tablet hardness and dissolution. Tablet development represents a complex and iterative trade-off of multiple conflicting technical requirements.
The excipient industry approach to pharmaceutical PAT will, in part, depend on the approach adopted by the pharmaceutical industry. A number of user-supplier scenarios can be envisioned.
The user can seek to reduce the susceptibility of the process to input raw material variability. This may be difficult for tabletting where the excipients contribute multiple and often conflicting functionalities. Hogan (2004, 2005) postulates new APIs with material properties so advanced as to render excipients superfluous (except for diluents). Pharmaceutical PAT will then not be required from suppliers and the effect will be commoditization of those excipients.
Given the difficulty of manipulating APIs, a more likely alternative is to replace the tabletting technology with something more amenable to process control and without the functional conflicts inherent in traditional tabletting (Carlin 2002, 2004). Examples include:
• Electrostatic deposition of precise doses of drug onto a film substrate, as used by Delsys, completely eliminates excipients, and the degree of charge neutralization is an effective control loop on precise dosing.
• Electrostatic dosing of drug in coatings, as used by Phoqus, allows the use of placebo cores, so that the tableting excipients and functionalities are uncoupled from the drug dosing and formation of the finished dose form.
• Aprecia utilizes free-form fabrication to create dosage forms by three-dimensional printing. Dosing and release rate control can be very precisely computer controlled.
• NRobe, a novel solid dose form from FMC, eliminates compaction constraints from the formulation used to carry the drug as a lightly tamped plug surrounded by polymer film.
All of these advanced solid dose form technologies afford more engineering control and are relatively scale-independent.
The Impact of PAT
PAT will undoubtedly accelerate the polarization of the excipient industry identified by Hogan (2004, 2005) into commodity vs. high tech research based. Indeed some suppliers, whose pharmaceutical business is a minor proportion of their overall business, may simply withdraw from the market if faced with demands for more sophisticated materials without commensurate compensation.
PAT will not only fuel demand for new and more precisely controlled excipients, but will also alter traditional formulation practices. Where justified by appropriate product, process and biopharmaceutical knowledge, formulations will become less rigid and evolve over time in step with continuous improvement. There will be a trend to continuous production where market demand is sufficient. Sophisticated suppliers utilizing PAT will be able to offer many more end-product-specific grades, rather than the traditional one grade that fits all. This will require coordination and collaboration with the user. As the process and formulation evolves, so too the excipient grades used may similarly evolve as part of continuous improvement during the product lifecycle. Growth will be seen in the high-value, low volume speciality end of the market. Higher raw material prices do not necessarily mean increased costs for the user. PAT will make quantification of benefit from high value materials much more transparent.
Shared knowledge between users and suppliers gives maximum potential for control. Excipient suppliers employing PAT in collaboration with users of their materials would hope to benefit from relaxations in procedural controls imposed by the user in the same way as the user seeks such flexibility from regulatory authorities. It is to be hoped that the regulatory authorities also recognize the value of such user-supplier collaborations to the implementation of PAT in this new era of 21st century cGMP.
The views expressed are those of the author and do not necessarily represent the position of FMC Corporation or any other user or supplier of excipients.
References
Carlin BA, Eino Nelson Research Conference 2002. “Pharmaceutical Development: The Rock on which the Discovery Wave Crashes?”Carlin BA, Pharmaceutical Technology, Excipients & Solid Dosage Forms, June 2004. “The Future of Compaction—Pharmaceutical Tableting in the Twenty-First Century.”Goldberger F, “Pharmaceutical Manufacturing—Quality Management in the Industry,” Ch 18 Regulatory Constraints, Ebur, Evereux 1991Hogan J, IPEC Europe News, Oct 2004. “Can the Excipient Industry Survive?” Hogan J, IPEC Europe Conference Jan 2005. “Excipient Industry’s Future under Debate,” http://www.in-pharmatechnologist.com/productnews/news.asp?id=57797Hussain AS, IFPAC Jan 2005. “Engineering a Proactive Decision System for Pharmaceutical Quality: Integrating Science of Design, Process Analytical Technology and Quality System” http://www.fda.gov/cder/OPS/hussain_1_2005.pdfKuppuswamy R et al, Pharm Dev Technol 6 505-20 2001 Moreton RC, Pharmaceutical Technology, May 2004, “Excipient Functionality.”
