Pharmaceutical Quality: Where Do We Need to Go from Here?

Since 2000, there have been significant changes in many aspects of pharmaceutical industrial practice, the most visible due to mergers and acquisitions, and globalization of pharmaceutical supply chains. In addition, the industry has seen the rise of biotechnology-derived drugs and appears to be moving away from blockbuster drugs to smaller-volume niche drugs. In the pharmaceutical sciences area, there has been an increase in the number of poorly soluble drugs. There is also a growing interest in continuous processing for the manufacture of both APIs and pharmaceutical finished products

Globalization includes the transfer of manufacturing operations off-shore, notably to India and China. Headlines concerning FDA warning letters and import holds may have contributed to some of the drug shortages. These shortages are a major concern for certain groups of patients, particularly cancer patients. What certain organizations (and individuals) fail to understand is that FDA can only have one set of standards, and that if offshore-based companies wish to sell or supply into the US market, they have to accept and adopt the US rules. These standards apply to the overseas manufacturing organizations as well as the organizations (and individuals) that are promoting overseas outsourcing of manufacturing and supply.

Continuous manufacturing
Traditionally, the manufacture of both APIs and drug products used batch processing. A number of companies are now investigating continuous manufacturing and real time release. The main drivers seem to be simplification of scale up and flexible batch sizes to match demand rather than true continuous manufacturing (i.e., 24 hours per day, seven days a week for 52 weeks per year). For continuous manufacturing, the equipment scale does not change; only the time of running changes once the dynamic steady state is reached. Process analytical technology (PAT) is an intimate component of continuous manufacture, and there are now sensors and detectors that can be installed in a continuous processing line to monitor (e.g., blend uniformity, granule size distribution, etc.) at high frequency; several times per minute in some instances. In addition, there are other at-line modules that can automatically sample and test for unit weight, tablet hardness, and tablet thickness at frequencies of several times per hour. More and more reliable data are going to provide added confidence that the output is within specification, and this confidence will allow organizations to move to real-time release protocols.

With all these data, however, there is a potential dilemma. What do we do with all the data we can generate? Yes, data gives us confidence and can be appended to the batch record, but moving to real-time release, one will not be undertaking end-product testing. So how are such data reported on the certificate of analysis (CoA)?
Consider the uniformity of dosage units test and the option to use weight variation for a tablet product (i.e., the API content is greater than 25 mg and 25% of the unit weight) (1). The sample size is not fewer than 30 tablets, and one is required to weigh 10 in the first instance, etc. With continuous weight checks through the production run, and the move to real-time release, there would be no end product testing. There is still a need, however, to address uniformity of dosage units for the release of the product because United States Pharmacopeia General Chapter <905> is mandatory, and FDA expects that the requirements of the USP general chapter will be met. All the data necessary to demonstrate compliance will be available. Indeed one will have much more data than is necessary, but how does one fit the in-process weight check data into the format stipulated in USP General Chapter <905>? The same concerns will apply to any test included in the CoA for the batch that relies on in-process data.

USP General Chapter <905> is harmonized, and any changes must be submitted through the pharmacopeias to the Pharmacopeial Discussion Group (PDG). The PDG has not yet begun to address the issues of continuous manufacture, PATs, large amounts of data, or real-time release. While the International Council on Harmonization (ICH) has not addressed continuous manufacturing, either, this subject needs to be addressed to avoid confusion and unnecessary end-product testing that does not add to patient safety. The USP–NF (USP–National Formulary) does have a general chapter on parametric release (of terminally sterilized products) (2). USP General Chapter <1222> provides some guidance as to how the issues concerning continuous manufacturing, PAT parametric release, and real-time release might be handled. An ICH guidance document and a harmonized general chapter addressing best practices for demonstrating control and the control strategy for continuous processing may be beneficial for industry. These documents would also need to address PAT, large data sets, real time/parametric release, and how to accommodate pharmacopeia requirements.

Excipient variability
Solid and semi-solid pharmaceutical products are targets for transfer to continuous manufacturing. An important concern for the quality of solid and semi-solid drug products is excipient (and API) variability. Excipient variability has become an issue in recent years, particularly with the adoption of quality-by-design (QbD) principles for the design and development of pharmaceutical finished products. QbD requires an enhanced understanding of the critical material attributes (CMAs) and critical process parameters (CPPs) that have the potential to impact critical quality attributes (CQAs) of the finished product. Enhanced understanding is obtained by means of an appropriate design of experiments (DoE) to establish an FDA-acceptable design space and control strategy. Because excipients are components of nearly all pharmaceutical products, it follows that excipient variability may impact the quality of the finished product. It should be acknowledged, however, that excipient suppliers are not going to be able to supply excipient samples covering the extremes of their specification. The excipient manufacturing plants are not designed for such operation. It may not be necessary; there may be other ways to obtain the necessary samples. The International Pharmaceutical Excipients Council of the Americas (IPEC-Americas) is about to publish a guide that describes ways in which samples simulating the extremes of specification may be achieved (3).

It is important to realize that the CMAs for a given formulation are likely to be specific to that formulation, and that the excipient CMAs will differ from formulation to formulation (i.e., application-specific). The link between excipient performance and excipient composition is generally poorly understood. CMAs for a particular application are likely to include parameters that are not part of the pharmacopeial monograph specification. An excipient monograph is focused on safety and composition. Perhaps that is the proper purpose of an excipient monograph, because it will not be possible to include all possible performance-related tests in a pharmacopeial monograph. The specification for performance-related parameters is properly for negotiation between the pharmaceutical product manufacturer and their excipient manufacturer.

Regulatory agencies and the pharmacopeias must continue to adapt to the changes occurring in the pharmaceutical industry, which will require new guidance documents and general chapters. The development of new guidance documents and general chapters, however, must be tempered with the realization that there can be too much regulation. The pharmaceutical industry needs proper guidance, but it also needs properly flexible guidance. We do not want to drift back to something analogous to the debacle of the three-batch validation paradigm that held back the pharmaceutical industry in so many ways.

References
1. USP, General Chapter <905> Uniformity of Dosage Units, USP 39–NF 34 (USP, Rockville, MD, 2016).
2. USP, General Chapter <1222> Terminally Sterilized Pharmaceutical Products-Parametric Release, USP 39–NF 34 (USP, Rockville, MD, 2016).
3. IPEC-Americas, Quality by Design (QbD) Sampling Guide (IPEC-Americas, Arlington, VA to be published in 2016), www.ipecamericas.org.

Disclaimer: The ideas expressed here are the author’s own, and should not be taken as representing the views of any organization with which he is associated.

Article DetailsPharmaceutical Technology
Vol. 40, No. 5
Pages: 58–59

Citation
When referring to this article, please cite it as R.C. Moreton, "Pharmaceutical Quality: Where Do We Need to Go from Here?," Pharmaceutical Technology 40 (5) 2016.