An error occurred while processing the template.
The following has evaluated to null or missing:
==> .vars['reserved-article-group-id']  [in template "161555#161602#ARTICLE-PAGE---HERO" at line 14, column 20]

----
Tip: It's the final [] step that caused this error, not those before it.
----
Tip: If the failing expression is known to legally refer to something that's sometimes null or missing, either specify a default value like myOptionalVar!myDefault, or use <#if myOptionalVar??>when-present<#else>when-missing</#if>. (These only cover the last step of the expression; to cover the whole expression, use parenthesis: (myOptionalVar.foo)!myDefault, (myOptionalVar.foo)??
----

----
FTL stack trace ("~" means nesting-related):
	- Failed at: #assign groupId = .vars["reserved-art...  [in template "161555#161602#ARTICLE-PAGE---HERO" at line 14, column 1]
----
1<#assign namespace = randomNamespace /> 
2<#assign JSONFactoryUtil = staticUtil["com.liferay.portal.kernel.json.JSONFactoryUtil"] /> 
3<#assign journalArticleLocalService = serviceLocator.findService("com.liferay.journal.service.JournalArticleLocalService") /> 
4<#assign containerId = randomNamespace /> 
5<#assign shareURL = themeDisplay.getPortalURL()+themeDisplay.getURLCurrent()/> 
6 
7<#-- Auto-assign ALL category to every article --> 
8<#assign assetCategoryLocalService = serviceLocator.findService("com.liferay.asset.kernel.service.AssetCategoryLocalService") /> 
9<#assign assetEntryLocalService = serviceLocator.findService("com.liferay.asset.kernel.service.AssetEntryLocalService") /> 
10<#assign journalArticleLocalService = serviceLocator.findService("com.liferay.journal.service.JournalArticleLocalService") /> 
11  
12<#-- Get current JournalArticle --> 
13<#assign articleId = .vars['reserved-article-id'].data /> 
14<#assign groupId = .vars['reserved-article-group-id'].data?number /> 
15<#assign journalArticle = journalArticleLocalService.getArticle(groupId, articleId) /> 
16  
17<#-- Get AssetEntry for this article --> 
18<#assign assetEntry = assetEntryLocalService.getEntry("com.liferay.journal.model.JournalArticle", journalArticle.getResourcePrimKey()) /> 
19  
20<#-- Your ALL category ID --> 
21<#assign allCategoryId = 4614994 /> 
22  
23<#-- Assign ALL category if not already set --> 
24<#if !assetEntry.getCategories()?seq_contains(assetCategoryLocalService.getCategory(allCategoryId))> 
25    <#assign categoryIds = assetEntry.getCategoryIds() + [allCategoryId] /> 
26    ${assetEntryLocalService.updateEntry( 
27        assetEntry.getUserId(), 
28        assetEntry.getGroupId(), 
29        assetEntry.getClassName(), 
30        assetEntry.getClassPK(), 
31        assetEntry.getUuid(), 
32        assetEntry.getClassTypeId(), 
33        categoryIds, 
34        assetEntry.getTagNames() 
35    )} 
36</#if> 
37 
38<div class="hero jmarticle__hero-main-container"> 
39    <div class="container"> 
40        <div class="row"> 
41            <div class="article__cont"> 
42                <h1 class="article__heading">${Title.getData()}</h1> 
43                <#if (SubTitle.getData())??> 
44                    <p class="article__para"> 
45                        ${SubTitle.getData()} 
46                    </p> 
47                </#if> 
48 
49                <#assign Date_Data=getterUtil.getString(Date.getData())> 
50                <#if validator.isNotNull(Date_Data)> 
51                    <p class="article__date"> 
52                        <#assign Date_DateObj=dateUtil.parseDate("yyyy-MM-dd", Date_Data, locale)> 
53                        ${dateUtil.getDate(Date_DateObj, "dd MMMM yyyy", locale)} 
54                    </p> 
55                </#if> 
56 
57                <#if Link_Title?? && Link_Title.getData()?has_content> 
58                    <#list Link_Title.getSiblings() as cur_Link_Title> 
59						<#if cur_Link_Title?? && cur_Link_Title.getData()?has_content> 
60							<#assign linkHref="#" /> 
61							<#assign target="" /> 
62							 
63							<#assign rowId = containerId + cur_Link_Title?index /> 
64							<#if cur_Link_Title.Link_Internal?? && cur_Link_Title.Link_Internal.getFriendlyUrl()?has_content> 
65								<#assign linkHref=cur_Link_Title.Link_Internal.getFriendlyUrl() /> 
66							<#elseif cur_Link_Title.Link_Media?? && cur_Link_Title.Link_Media.getData()?has_content> 
67								<#assign linkHref=cur_Link_Title.Link_Media.getData() /> 
68							<#elseif cur_Link_Title.Link_Mailto?? && cur_Link_Title.Link_Mailto.getData()?has_content> 
69								<#assign linkHref="mailto:" + cur_Link_Title.Link_Mailto.getData() /> 
70							<#elseif cur_Link_Title.Link_External?? && cur_Link_Title.Link_External.getData()?has_content> 
71								<#assign linkHref=cur_Link_Title.Link_External.getData() /> 
72							</#if> 
73							<#if (cur_Link_Title.Link_Target??) && (cur_Link_Title.Link_Target.getData())?has_content> 
74								<#assign target=cur_Link_Title.Link_Target.getData() /> 
75							</#if> 
76							<div id="blue_button_click_div" data-analytics-asset-type="custom"> 
77								<div class="jmarticle__hero-btn-list"> 
78									<a id="panel_blue_button_${rowId}" class="article__btn" href="${linkHref}" title="${cur_Link_Title.getData()}" target="${target}" data-analytics-asset-action="click" onclick="onBlueButtonClick(this)" > 
79										<span class="btn__text">${cur_Link_Title.getData()}</span> 
80										<span class="arrow__forward"></span> 
81									</a> 
82								</div> 
83							</div> 
84						</#if> 
85					</#list> 
86                </#if> 
87				  <div class="article-download-share"> 
88                
89                    <#if PDFTitle?? && PDFTitle.getData()?has_content> 
90                        <#assign title = PDFTitle.getData() /> 
91                        <#assign pdf_link = "#" /> 
92                        <#assign pdfrowId = containerId /> 
93                        <#if PDFTitle.PDF?? && PDFTitle.PDF.getData()?has_content> 
94                            <#assign pdf_link = PDFTitle.PDF.getData() /> 
95                        </#if> 
96                        <div class="article-download"> 
97                            <div id="blue_button_click_div" data-analytics-asset-type="custom"> 
98                                <div class="jmarticle__hero-btn-list"> 
99                                    <a id="panel_blue_button_${pdfrowId}" class="article__btn" href="${pdf_link}" title="${title}" data-analytics-asset-action="click" onclick="onBlueButtonClick(this)"> 
100                                        <span class="btn__text">${title}</span> 
101                                        <span class="arrow__forward"></span> 
102                                    </a> 
103                                   <a id="panel_blue_button_${pdfrowId}" class="article__btn-mobile" href="${pdf_link}"             title="${title}" data-analytics-asset-action="click" onclick="onBlueButtonClick(this)"> 
104                                       <img src="${themeDisplay.getPathThemeImages()}/new__jm__images/download-white-icon.svg" alt="twitter image"/> 
105                                    </a> 
106                                </div> 
107                            </div> 
108                        </div> 
109                    </#if> 
110                                 
111                </div> 
112                 
113            </div> 
114        </div> 
115       <#if (ImageLarge.getData())?? && ImageLarge.getData() != ""> 
116            <div class="row jmarticle__hero-banner" id="jmarticle__hero-${namespace}"  
117            style="background-image: url(${ImageLarge.getData()})"> 
118        </#if> 
119 
120        </div> 
121    </div> 
122</div> 
123 
124<#if Author?? && Author.getData()?has_content> 
125    <div class="jmarticle__author-info"> 
126        <div class="container"> 
127            <div class="hero__bar"> 
128                     <#list Author.getSiblings() as cur_Author> 
129                            <#if cur_Author?? && cur_Author.getData()?has_content> 
130                                <#assign 
131                                    webContentData = jsonFactoryUtil.createJSONObject(cur_Author.getData()) 
132                                    gId = groupId 
133                                    journalArticle = journalArticleLocalService.getArticleByUrlTitle(gId, webContentData.title) 
134                                    docXML = saxReaderUtil.read(journalArticle.getContent()) 
135 
136                                    fName = docXML.valueOf("//dynamic-element[@name='FullName']/dynamic-content/text()") 
137                                    jobTitle = docXML.valueOf("//dynamic-element[@name='JobTitle']/dynamic-content/text()") 
138                                    role = docXML.valueOf("//dynamic-element[@name='ContactInfo']/dynamic-content/text()") 
139                                    photoXML = docXML.valueOf("//dynamic-element[@name='Photo']/dynamic-content/text()") 
140                                    photoSrc = JSONFactoryUtil.createJSONObject(photoXML).getString("uuid") 
141                                    fullName = docXML.valueOf("//dynamic-element[@name='Title']/dynamic-content/text()") 
142                                    authorImageXML = docXML.valueOf("//dynamic-element[@name='ImageLarge']/dynamic-content/text()") 
143                                    authImageSrc = JSONFactoryUtil.createJSONObject(authorImageXML).getString("uuid") 
144                                    summary = docXML.valueOf("//dynamic-element[@name='Summary']/dynamic-content/text()") 
145                                /> 
146 
147                                    <div class="author"> 
148                                        <figure class="author__image"> 
149                                            <#if authImageSrc?? && authImageSrc?has_content> 
150                                                <img src="/documents/${groupId}/${authImageSrc}" alt="${fullName}" class="author_img_class_new"> 
151                                            <#elseif photoSrc?? && photoSrc?has_content> 
152                                                <img src="/documents/${groupId}/${photoSrc}" alt="${fName}" class="author_img_class_new"> 
153                                            </#if> 
154                                        </figure> 
155                                        <div class="author__details d-flex flex-column"> 
156                                            <h3 class="author__name"> 
157                                                <a rel="author"> 
158                                                    <#if fullName?? && fullName?has_content> 
159                                                        ${fullName} 
160                                                    <#elseif fName?? && fName?has_content> 
161                                                        ${fName} 
162                                                    </#if> 
163                                                </a> 
164                                            </h3> 
165                                            <p class="author__desc text-size-a author_job_title"> 
166                                                <#if jobTitle?? && jobTitle?has_content> 
167                                                    ${jobTitle} 
168                                                </#if> 
169                                            </p> 
170                                            <span> 
171                                                <p class="author__desc text-size-a"> 
172                                                    <#if summary?? && summary?has_content> 
173                                                        ${summary} 
174                                                    </#if> 
175                                                    <#if role?? && role?has_content> 
176                                                        ${role} 
177                                                    </#if> 
178                                                </p> 
179                                            </span> 
180                                        </div> 
181                                        <div> 
182                                            <div class="author__contact"> 
183                                                <ul class="author__contact-list"> 
184                                                </ul> 
185                                            </div> 
186                                        </div> 
187                                    </div> 
188                             </#if> 
189                     </#list> 
190            </div> 
191    	</div> 
192    </div> 
193</#if> 
194 
195 
196 
197<div class="container"> 
198    <div class="row"> 
199        <div class="article__intro"> 
200            <#if (Introduction.getData())??> 
201            	${Introduction.getData()} 
202            </#if> 
203 
204           <div class="article-download-share"> 
205                
206                    <#if PDFTitle?? && PDFTitle.getData()?has_content> 
207                        <#assign title = PDFTitle.getData() /> 
208                        <#assign pdf_link = "#" /> 
209                        <#assign pdfrowId = containerId /> 
210                        <#if PDFTitle.PDF?? && PDFTitle.PDF.getData()?has_content> 
211                            <#assign pdf_link = PDFTitle.PDF.getData() /> 
212                        </#if> 
213                        <div class="article-download"> 
214                            <div id="blue_button_click_div" data-analytics-asset-type="custom"> 
215                                <div class="jmarticle__hero-btn-list"> 
216                                    <a id="panel_blue_button_${pdfrowId}" class="article__btn" href="${pdf_link}" title="${title}" data-analytics-asset-action="click" onclick="onBlueButtonClick(this)"> 
217                                        <span class="btn__text">${title}</span> 
218                                        <span class="arrow__forward"></span> 
219                                    </a> 
220                                   <a id="panel_blue_button_${pdfrowId}" class="article__btn-mobile" href="${pdf_link}"             title="${title}" data-analytics-asset-action="click" onclick="onBlueButtonClick(this)"> 
221                                       <img src="${themeDisplay.getPathThemeImages()}/new__jm__images/download-white-icon.svg" alt="twitter image"/> 
222                                    </a> 
223                                </div> 
224                            </div> 
225                        </div> 
226                    </#if>               
227                
228                   
229               <div class="article-share"> 
230                   <a href="https://linkedin.com/shareArticle?url=${shareURL}&title=<#if (Title.getData())??>${Title.getData()}</#if>" target="_blank"> 
231                       <img class="socialicons__img" src="${themeDisplay.getPathThemeImages()}/new__jm__images/social_icons-LinkedIN.png" alt="twitter image"/> 
232                    </a> 
233                      <a  href="https://twitter.com/share?url=${shareURL}&text=<#if (Title.getData())??>${Title.getData()}</#if>" target="_blank"> 
234                       <img class="socialicons__img" src="${themeDisplay.getPathThemeImages()}/new__jm__images/social_icons-Twitter.png" alt="twitter image"/> 
235                    </a> 
236                </div> 
237            </div> 
238       
239        </div> 
240    </div> 
241</div> 
242 
243<style> 
244    img.author_img_class_new { 
245        width: 100% !important; 
246        height: 100% !important; 
247        position: absolute; 
248        margin: auto; 
249        top: 0; 
250        bottom: 0; 
251
252     
253    .article__btn:focus-visible { 
254    outline: 2px solid blue !important; 
255
256 
257@media (min-width: 320px) and (max-width: 650px) { 
258	.article__intro li { 
259	   margin-left: -32px !important;		 
260
261	.journal-content-article .container .article__intro { 
262    margin-top: 22px !important; 
263
264
265@media (min-width: 540px) and (max-width: 834px) { 
266    .article__intro li { 
267	      margin-left: -32px !important;		 
268
269    .article__intro { 
270        margin: 60px 15px 0 5px !important;         
271
272
273  
274@media (min-width: 320px) and (max-width: 539px){ 
275.jmarticle__author-info { 
276    padding: 0px 0; 
277
278.jmarticle__author-info .author__image { 
279    width: 39px; 
280    height: 40px; 
281
282 
283.jmarticle__author-info .author__name a { 
284    line-height: 0px; 
285    font-size: 18px !important; 
286    margin-right: 10px; 
287
288 
289.jmarticle__author-info .author__desc { 
290     
291    line-height: 14px; 
292    font-size: 12px !important; 
293    margin-bottom: 7px; 
294
295
296  
297</style> 

Transitioning to greener chemistry and more sustainable manufacturing processes are among the pharmaceutical industry’s biggest challenges. With the global population expected to exceed nine billion by 2050 – increasing demand for finite resources – it’s vital that manufacturers boost sustainability and reduce the environmental impact of their processes. Another challenge to the pharmaceutical industry is the increasing size of the elderly population. A World Health Organization report on global health and ageing projects a growth in the number of people aged 65 and over from the estimated 524 million in 2010 to nearly 1.5 billion in 2050. To accommodate this expanding and ageing population and meet lower, or net zero, carbon goals, the pharmaceutical industry needs cleaner, less wasteful technologies. That approach is vital to meeting the environmental, economic and social demands of future medication.

Over the past decade, many pharmaceutical companies have opted for green chemistry practices for drug discovery, development and manufacturing. This shift is being driven by the realisation that greener processes not only offer an environmental advantage but can be cheaper with less waste – providing a competitive edge.

Nature uses the life elements to orchestrate reactions that produce molecules of incredible complexity

Enzyme-based catalysis has emerged as an innovative technology for chemical manufacturing that meets many of the core green chemistry principles. By developing and applying these technologies in the pharmaceutical industry, we can create significant and positive environmental change. JM, an applied science and sustainable technologies leader, is committed to applying its extensive bio- and chemo-catalysis capabilities to help build effective processes for the pharmaceutical and fine chemicals industries.

 

The natural way

In recent years, the drug discovery process has shifted towards increasingly complex active pharmaceutical ingredients (APIs). These compounds often require multiple synthetic steps, greatly lowering the atom economy of their associated processes. Additionally, these processes are carried out in organic solvents, with large quantities of chemical reagents in the form of oxidants, reductants, and acids and bases. Using these chemicals means high waste levels and costly waste treatment processes. These factors have led to an increased desire for alternative technologies that can deliver effective, safe and cost-effective drug development and manufacture. Consequently, nature’s approach to chemical innovation sparked the pharmaceutical industry’s interest.

Throughout nature, biochemical systems undertake an enormous variety of chemical reactions that are catalysed predominantly by enzymes. The simple and abundant elements that we associate with life – carbon, hydrogen, oxygen and nitrogen – are used by nature to orchestrate reactions that produce molecules of incredible complexity. These vital molecules include lipids, carbohydrates, nucleic acids and other proteins.

Like all catalysts, enzymes increase the rate of a reaction by lowering the activation energy. However, one advantage of biocatalysts over chemical technologies like chemocatalysts include their ability to function under mild reaction conditions – as well as their low physiological toxicity and environmental impact. In pharmaceutical manufacturing, these advantages translate to reduced operating costs and waste, as well as simplified production routes. The most desired properties of biocatalysts include their high levels of stereo-, regio- and chemo-selectivity. Compared to traditional chemocatalysts, enzyme catalysts often reach much higher levels of selectivity. This makes them an invaluable technology for the asymmetric synthesis of chiral intermediates. The importance of chirality within the pharmaceutical industry is well-documented and current research estimates that nearly 95% of drugs will be chiral by 2020.

For drug manufacturers, the ability to consistently and reliably produce one enantiomer is crucial

Limonene is a relatable example of the dramatic effect chirality can have on a molecule. A naturally occurring hydrocarbon found in citrus, limonene’s structure has a chiral centre. Like many other flavour and fragrance molecules it is found in nature as two enantiomers, (R)- and (S)-limonene. Although these molecules hold identical physical properties, the difference in chirality can lead to different biological properties. In this case, (R)-Limonene is the isomer that contributes to the smell of oranges, whereas (S)-limonene has an aroma similar to turpentine or lemon. For drug manufacturers, the ability to consistently and reliably produce one enantiomer is crucial. This is because often only one of a drug’s enantiomers is responsible for the desired physiological and therapeutic effects – while the other enantiomer is less active, inactive or even harmful. Enzymes provide manufacturers with an effective technology to produce optically pure drugs.

 

Tomorrow’s biocatalysts today

Despite the clear benefits of the application of biocatalysts for the synthesis of chiral intermediates, enzymes have only recently been applied within industrial processes. This is because enzymes have evolved to be highly specific to the environments and reactions which they catalyse. When it comes to applying these enzymes in industrial processes, the high substrate concentrations and variable temperatures often prove unsuitable for biocatalysts, resulting in low selectivities, low activities and low yields. Additionally, enzymes are commonly denatured by organic solvents. This can greatly impact processes where enzymes are applied as part of a multi-step process with chemical reactions and catalysts.

In recent years, advances in computing technology, biotechnology and sequencing have fuelled advances in protein engineering. Directed enzyme evolution and rational design are now widely applied by biological engineers to produce enhanced, high-performing enzymes that can work in a broader range of conditions. Given the complexity of the sequence – structure – function relationship of enzymes, protein engineering has largely relied on random mutation, screening and selection – performed iteratively over multiple rounds – to obtain a suitable final biocatalyst fit for purpose. While there are many advantages to this technique, the process can be time-consuming. In fact, it can take up to a year to find and alter a wild enzyme into an optimised biocatalyst for industrial application. The primary cause is the painstaking process of screening the exponential numbers of enzyme variants created in each round of mutagenesis.

To accelerate the enzyme optimisation process, JM scientists leveraged the company’s expertise in computational modelling, catalysis development and manufacturing to devise cutting-edge enzyme engineering technologies.

Biocatalysis transformed from a peripheral technology to an industrially practical technology over 50 years

JM’s computational technologies combine advanced software tools and large databases to rapidly predict the best existing natural enzyme for a desired chemical reaction or process. In cases where an ideal natural enzyme cannot be found, JM turns to enzyme engineering. But instead of the widely used directed evolution approach, JM leverages its smart library design. In this process, thousands of enzyme variants are computationally screened by analysing the changes in their amino acid sequence in the context of their encoded 3D structure. Subsequently, libraries of enzyme variants are created, with the latest molecular biology techniques, produced and extracted from E. coli for testing in their ability to catalyse the desired reaction or process. Although this method drastically reduces the number of enzyme variants that need to be screened, the number can still be in the range of tens of thousands of enzyme variants. High-throughput material handling and analytics are vital to speed up the process.

 

The future of biocatalysis

It is important to realise that biocatalysis and chemocatalysis are complementary technologies. When efficiently applied to the pharmaceutical process, these technologies can combine to greatly improve the drug manufacturing process, both economically and environmentally. When designing new processes for innovative APIs, it is important that pharmaceutical companies collaborate with experts in both of these fields. JM’s ability to leverage its wide-ranging catalysis expertise and manufacturing capabilities allows for faster and deeper integration of these technologies into manufacturing processes.

The impact of biocatalysis within the pharmaceutical industry continues to grow. Over the last 50 years, driven by chemical, biological and technological innovation, biocatalysis has transformed from a peripheral technology to a mature and industrially practical technology. The future of biocatalysis technology depends on our ability to rapidly, economically and efficiently engineer, or even design, enzymes for industrial processes. In applying its scientific expertise to industry need, JM is driving the development of next-generation enzyme technologies to enhance quality of life and to create a more sustainable future.

 

Article originally published by Chemistry World on 23rd October 2019.

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