Learn from your Metrics Using Operational Data to Improve Operations in Pharmaceutical Manufacturing and QC Labs

to pinpoint a single factor that causes the PHTN as there are multiple factors contributing to the pathogenesis of PHTN that make the treatment challenging.

Recently the COVID-19 pandemic has raised concern for PHTN as a future complication for COVIDaffected patients. Increased production of cytokines such as interleukin (IL)-1, 2, 6, 10, tumor necrosis factor – (TNF- ), and monocyte chemoattractant protein-1 (MCP-1) in the setting of COVID19pneumonia leads to oxidative stress and subsequent damage to the pulmonary vessels. In addition, the residual effects of the above mechanism can lead to vascular remodeling resulting in PHTN.

Animal studies

The therapeutic target of PHTN has evolved through various animal studies. The result of the studies has guided further clinical trials to find out the efficacy of different treatment options. Mutations of transforming growth factor B (TGF B), bone morphogenic protein receptor 2 (BMPR-2), activinlike kinase type 1 receptor (ALK1), and mothers against decapentaplegic homolog 9 (SMAD 9), endoglin gene, caveolin 1, serotonin transporter gene have shown a role in the pathogenesis of PHTN. Targeting those genes to treat PHTN is an emerging field of development for future treatments for PHTN. Animal studies have shown that 14 days of sacubitril/valsartan treatment has improved the hemodynamic and histological status of PHTN by inhibiting the renin-angiotensin-aldosterone system, increasing natriuretic peptides, and by the anti-inflammatory effect of sacubitril/valsartan. The positive results from the animal studies are the forerunners of future therapeutic options for PHTN patients.

Available treatment

Several medications are already available for the treatment of the PHTN. Voltagegated calcium channel blockers (CCBs) are indicated for patients with PHTN who show a positive response to vasoreactivity testing. A positive response to vasoreactivity testing is defined as a decrease in the mPAP by 10 mm of Hg to an absolute value of less than 40 mm of Hg after administering a short-acting vasodilator agent such as inhaled O2.

The endothelial receptor antagonists Bosentan, Ambrisentan, and Macitentan, are noted to be beneficial in PHTN. Intravenous prostacyclin is another treatment option. Triggering the prostacyclin receptor stimulates pulmonary vasodilation resulting in a decrease in the pressure in the pulmonary vessels. Phosphodiesterase type 5 (PDE5) inhibitors have been shown in clinical trials to improve six-minute walk distance and hemodynamics in PHTN patients. In October 2013, the Food and Drug Administration approved Riociguat to treat adults with PHTN. It is also approved for treating adults with chronic thromboembolic pulmonary hypertension (CTEPH), which is persistent or recurring following pulmonary endarterectomy. Another medication for the treatment of PHTN is Selexipag, an oral, selective, and long-acting non-prostanoid agonist of the prostacyclin receptor. Waxman et al. showed that Treprostinil, initially approved for group 1 PHTN, can be used to treat PHTN in patients with ILD. Inhaled Treprostinil improved exercise capacity from baseline. Thrombogenesis has been proposed to play a role in developing PHTN use of anticoagulation may play

a role in PHTN patients. However, clinicians should be careful about possible interactions of anticoagulation medication with other anti-PHTN drugs. The drug interaction can increase the bleeding risk for patients with PHTN. Sotatercept is a fusion protein that binds activins and growth differentiation factors to balance growth-promoting and growth-inhibiting signalling pathways. Humbert et al. reported that treatment with sotatercept reduced pulmonary vascular resistance among patients with PHTN.

There are treatment options available for PHTN, which include nonpharmacologic management. Treatment of sleep-related disorders using continuous positive airway pressure and non-invasive ventilation helps patients with PHTN. The prevention of nocturnal hypoxemia helps alleviate the development of precapillary PHTN. Advances in percutaneous technology opened new possibilities for the management of PHTN. Interventional procedures including balloon atrial septostomy, transcatheter Potts shunt, balloon pulmonary angioplasty, and pulmonary artery denervation have shown promising results in haemodynamic and functional improvements in PHTN patients.

Management of PHTN in COVID-19 patients

As mentioned before, special attention is required for people with COVID19 infection as they are at high risk of developing PHTN. For the COVID-19 patients with pulmonary hypertension, inhaled nitric oxide improved blood oxygenation and decreased pulmonary vascular pressure. Puk et al. have shown that endothelin receptor antagonists, phosphodiesterase 5 inhibitors, riociguat, and prostacyclin could help treat PHTN in COVID-19. Clinicians must be cautious while following up on patients with COVID-19 as a low threshold to diagnose PHTN in these patients is important not to miss the complication. Studies are going on to show the effects of sodium-glucose transporter inhibitors to improve pulmonary vascular resistance for patients with COVID-19 infection. Hopefully, the gliflozins will be a future possible treatment option for PHTN, particularly for COVID-19 patients.

Future potential treatment for PHTN:

In rodent models, mineralocorticoid receptor antagonists have a promising role in preventing or reversing PHTN and right ventricular failure. Decreasing circulating estrogen by inhibiting the conversion of androgens to estrogen using the aromatase inhibitor anastrozole and inhibition of the estrogen receptor with tamoxifen inhibited PHTN in animal models. Tyrosine kinase inhibitors can attenuate platelet-derived growth factor signaling and reduce calcium-sensing receptor expression. This makes the kinase inhibitors to be an effective treatment for PHTN. Inhibition of histone deacetylase and Keratin-1 have the potential to reverse the changes in pulmonary vasculature and PHTN. The role of hypoxia-inducible factor (HIF)2 in the initiation and development of PHTN has been an area of future research. 5-hydroxytryptamine (5-HT) pathway inhibition, activation of vasoactive intestinal peptide (VIP) pathway, pyruvate dehydrogenase kinase (PDK) inhibitors, and targeting the mechanistic target of rapamycin (mTOR) are some areas of limited knowledge that can prove their benefit in the treatment of PHTN in the near future. Results from meta-analysis have shown that stem/progenitor cell therapy is associated with significantly improved pulmonary haemodynamics in animal models. Future studies have scope for exploration of this field.

Challenges for treatment of PHTN

We cannot ignore the fact that there are still multiple challenges associated with PHTN management. Patients can have multiple types of PHTN together. For example, patients may have heart disease, chronic obstructive pulmonary disease, and connective tissue disorders. The presence of multiple co-morbidities makes the pathogenesis of the PHTN complex and the treatment more difficult. Finding a guideline for treating these patients is often not easy. Most of the clinical trials have excluded patients with a combination of etiologies for PHTN, and thus treatment of these patients is not evidencebased. Dealing with PHTN in patients with idiopathic pulmonary fibrosis (IPF) is also not straightforward. Recently, a multi-centre, international, double-blind, randomised, placebo-controlled, phase 2b study did not show any treatment benefit after adding sildenafil to pirfenidone versus pirfenidone plus placebo up to 52 weeks in patients with advanced IPF and risk of PHTN. More studies are required to find an optimum solution for these complex patients.

Conclusion

Managing patients with PHTN should always be a multidisciplinary decision. There are already different options available for the treatment of PHTN. In addition, newer studies are coming up to show the potential therapeutic benefit of the new drugs/molecules in the management of the PHTN. References are available at www.pharmafocusasia.com

Adrija Hajra is an Internal Medicine physician, currently affiliated with Montefiore Medical Center/Albert Einstein College of Medicine, New York, USA. Her research interests are heart failure, pulmonary hypertension, diabetes, hyperlipidemia with special focus on cardiac complications in COVID-19 patients.

AUTHOR BIO

LEARN FROM YOUR METRICS

Using Operational Data to Improve Operations in Pharmaceutical Manufacturing and QC Labs

Operational excellence (OPEX) is the philosophy summarising numerous technical and social practices aiming at improving operations. However, the complexity of the practices and multiplicity of the initiatives hinders to always identify and set the most promising priorities. Being able to take decisions based on data and measured situations can improve the efficacy of the strategic initiatives. The St. Gallen manufacturing and quality control (QC) benchmarking programmes support pharmaceutical companies with a rich base of information needed to inform their decision making processes.

Matteo Bernasconi, Research Associate, University of St.Gallen Gian-Andri Steiger, Research Associate, University of St.Gallen Marten Ritz, Post-doctoral Researcher, University of St.Gallen Thomas Friedli, Director, Institute of Technology Management

The importance of jointly analysing the manufacturing facility’s maturity and performance was outlined in the article The Link between Plant Performance & Maturity – Seeing the whole picture. The St. Gallen Model for OPEX depicts the synergies between technical & social sub-systems (Friedli & Bellm, 2013) and serves as backbone of the OPEX benchmarking, which has been supporting pharmaceutical companies in identifying potentials for improvement since 15 years. As discussed in the article St. Gallen OPEX Benchmarking for Pharmaceutical Manufacturing Sites – Measure Yourself Against the Best but Do It Right, the benchmarking helps to support continuous improvement in manufacturing. However, to advance in the lean journey, an end-to-end consideration of the value chain is required to systematically identify bottlenecks (Ritz, 2022). In the case of pharmaceutical industry, QC can strongly affect operations (Barbarite & Maslaton, 2008; Friedli et al., 2018)) and QC labs have been moved under the spotlight form the FDA in the recent years (FDA, 2016, 2022; Friedli et al., 2019). The QC lab benchmarking, which was presented in the article Benchmarking Pharmaceutical Quality Control Labs – Holistically assess Operational Excellence in Pharmaceutical Companies, supports firms in improving lab processes to systematically progress in operations along the entire value chain.

This article discusses two practical examples of how data driven improvements can be initiated and derived from a benchmarking. Firstly, an example from the manufacturing and OPEX benchmarking is presented. Secondly, a project that emerged based on QC lab benchmarking results is illustrated and discussed. Finally, the benefits of data driven decision are highlighted.

Data-based identification of improvement potentials: An example in the area of pharmaceutical manufacturing

The possibility of identifying the right levers to improve, based on a holistically comparison against peers, is a key

element to define and start strategic improvement initiatives. As a balanced approach for performance and maturity calculation, the OPEX benchmarking report provides the basis to make a meaningful comparison and define the next steps. In the general procedure, a benchmarking can be further enriched by a structured result workshop, in which the operations team receives further insights from the results and guidance to act on the results. In the case of multiple facilities participating in the assessment, the sites are compared, and the network intern-learnings are highlighted and discussed. This facilitates the recognition of site-specific capabilities and the knowledge sharing within the manufacturing network.

The result workshop provides the possibility to better understand the link between plant maturity and performance, by deep diving into the individual maturity items and key performance indicators. For example, during a benchmarking we observed a situation of high Total Productive Maintenance (TPM) maturity but low TPM outcome performance across all participating facilities of the production network. The low TPM performance was mainly driven by a low level of Overall Equipment Effectiveness (OEE).

The link between good maintenance practices and good quality is well established in manufacturing literature (Cua et al., 2001; McKone et al., 2001), nevertheless some very quality oriented industries, such as pharma, have still good potential in improving OEE (Friedli et al., 2013). Setting the focus on TPM maturity and performance, in this case, was very relevant because of two reasons. On the one hand, TPM is the first pillar on which companies should concentrate to progress in achieving OPEX. In fact, TPM practices guarantee a stable equipment which is fundamental to allow for stable and reliable processes before finally reducing inventories to increase efficiency. On the other hand, all participating sites form this companies were suffering from the same conditions irrespective of the manufactured types of products. The systematic OEE performance problem across the manufacturing network provides the ideal setting for a corporate initiative targeting the issue not only in one plant but across the sites and therefore contributing to the stability of the equipment in the whole organisation (Figure 1). The OEE is composed as a sum of three elements: OEE availability, OEE performance and OEE quality (see Figure 1). The OEE availability represents the percentage of the time that the equipment has operated over the scheduled time. The OEE performance denotes the amount produced by the ideal cycle time over the available time in which the equipment was producing. The OEE quality shows the percentages of outputs without defects as percentage of the overall inputs.

The St. Gallen team analysed the situation and identified that the low OEE was mainly driven by high down times. These can be divided in two categories: planned (setup & cleaning) and unplanned (breakdown, etc.). Thanks to the workshop, the team was able to deep dive into the maturity of the TPM practices and link them back to the low performance due to downtimes. Analyses revealed that unplanned downtimes were not the main driver of the low OEE, the setup & cleaning was the cause. TPM practices showed a high maturity in the category of housekeeping but a very low maturity in setup time reduction. Thus, the low performance in OEE (especially setup & cleaning) can be improved by focusing on the blank spots of the maturity and better training as well as better scheduling of the setup times. The workshop provided the unique opportunity to take a closer look to the results, investigate the cause-and-effect relationship of the low performance findings, and discuss the most suitable initiatives to target the problem. One initiative, for example, is focusing on improving the whole planning/scheduling.

Figure 1: OEE Calculation

Data to action: How benchmarking data allows the derivation of improvement actions in the field of quality control labs.

Data-driven improvement actions are not solely a topic in the field of manufacturing. Also St. Gallen’s dedicated Quality Control (QC) Benchmarking is intensively used for the systematic definition of improvement strategies. In the following a practical example, how lab specific and company-wide improvement actions may be derived, will be presented.

In the presented case, the QC lab benchmarking was individually conducted for 15 different sites of the company. The overall performance based on the sites’ KPIs showed significant differences among the various QC labs within the corporation. Besides the actual performance the labs’ maturity levels were assessed using specific enabler questions in addition. Those questions aim at assessing how advanced the respective process structures and management approaches in