For pharma manufacturers, developing rock-solid data infrastructure has become essential. It touches everything we do as a CDMO – from the web-based intranet used for Employee Self Service (ESS), Sales Management and more.
The Rise of Pharma Data Infrastructure
Pharma data is exploding, and the ability to manage and leverage that data has become central to developing and manufacturing drugs. Data has become a disrupter in the pharma industry – one with tremendous potential for companies. Regulators are paying increasing attention to data. Companies want and need data security with their contract pharma partners & suppliers.
Here’s a recap some of the decisions we’ve made at Neuland as we’ve grown our infrastructure – combining our proprietary in-house platform with large, scalable commercial solutions to ensure data compliance.
The Data Engine
For Neuland to best manage both our clients’ and our own data needs, the core underpinnings of our system’s infrastructure needed to have scalable virtualized server stacks with high availability – and be based in a secured data center. We chose SAP ERP to enable effective information transfer across functions.
With SAP, security was one of the drivers that led to the selection. We wanted to ensure consistently high-security standards that would meet the broadest range of pharma client requirements & standards.
Client & Project Management
For project management, we set out to ensure Neuland’s unique project management approach would enable clients to overcome the difficulties involved in outsourcing projects – especially at long distances. We developed ‘GuarD,’ which ensures that our clients receive the highest standards of transparency, flexibility and reliability across the project lifecycle.
The system operates using the principles of Critical Chain Project Management (CCPM) – emphasizing both flexibility & resource availability to maintain broader project timelines. Rather than focusing on rigid scheduling of individual tasks, the system manages towards the collective objective of completing the project within target timelines.
Robust Data Infrastructure Can Yield Pharma Company Benefits
Overall, our data system has been a key part of our success in creating process management efficiencies. When combined with other efficiency measures (e.g., QbD or check out our last post on creating efficiencies by fostering collaboration between engineers & chemists), a robust data infrastructure can translate into significant pharma sponsor benefits.
In a PharmTech webcast, the Neuland team linked up with Dr. San Kiang – Research Professor from the Department of Chemical Engineering at Rutgers University. The objective was a discussion on the importance of collaboration between chemical engineers & pharmaceutical chemists in today’s drug manufacturing environment. This collaboration is important, and is a key element of QbD.
I also recently participated in a Q&A specifically on the collaboration between chemists and chemical engineers during drug development. It is a big issue given the colossal changes happening in the drug industry, perhaps most visibly on the quality & regulatory fronts.
Drug Safety, Efficacy and Feasibility
This collaboration can mean the difference between a viable drug and one that had great potential, but was not practical from a manufacturing standpoint. It is customary to evaluate drugs on two pillars common to regulatory environments – efficacy and safety. In other words, does the drug perform what it needs to perform, and does it do it safely?
In the real world of drug discovery, development and commercialization, however, there is a third equally important pillar: feasibility.
A product can be determined to be safe and efficacious – but if it isn’t feasible to produce (from either an economic or a technical at-scale production standpoint), then it isn’t a candidate for success.
This is especially true since, often before a scalable chemistry process has been fully developed, chromatography (or, more specifically, process chromatography) is used for making materials in early-stage development.
Collaborating Across Scales
When chemists and engineers work hand-in-hand during process development in R&D, processes tend to progress through scale-up easier. There are considerable differences between producing 10 mg batches and manufacturing 500 kg batches, to be sure – and numerous engineering-related factors need to be taken into account. This chart describes the increasing scales in terms of the synthetic process employed – from expedient, to practical, to efficient and – ultimately – to optimal.
This is the role played by the collaboration of engineers and chemists (and the beauty of QbD, in general): ensuring the smooth transition from the expedient to the optimal while developing a safer process with optimized yield and quality.
Because chemists and chemical engineers approach each challenge from different perspectives, there are different areas of expertise needed.
Some of the bullets in these lists involve collaboration between the two fields. Chemical Engineers, for example, are involved in process development quite early and play a role in route selection/ finalization. Across the development phase of a project, both chemical engineers & chemists will work together to understand CPPs & CQAs of the process.
More interactions tend to occur once process feasibility has been confirmed and the generated compounds reach a passing level of quality. Once feasibility has been shown, the engineers will evaluate the process from a safety, health and environment standpoint. They then generate process safety data to create inherently safer processes.
When it comes to scale-up, Engineers and Chemists must work closely together to plan the scale up campaign, demonstrate & confirm feasibility and hand over to manufacturing.
Since generic drugs are – on average – 20 to 90% cheaper than innovator drugs (or NCEs), the market for generics has grown considerably in recent years as a means of reducing healthcare costs.
Differences Between NCE and Generic Drug Development
What are the differences between the design of New Chemical Entities (NCEs) and generic drugs, and what do they mean for process development & manufacturing?
For either purely generic or purely NCE companies looking to begin development or commercialize a product in the other discipline, the question is more common than you might think. Companies tend to be narrowly focused on their particular area of expertise (either generic or innovator). It is natural that they would have questions and concerns about commercialization practices outside of their typical operational focus.
Since Neuland works extensively in both areas of drug development & commercialization, these are questions we are quite comfortable answering.
The core difference between these two drug projects can be summed up in the names of their respective FDA filings: NDAs and ANDAs.
NCEs require a new drug application (NDA) with the FDA, while generic drug applications require an abbreviated new drug application (ANDA). The key differences lie in the ‘abbreviated’ nature of generic applications.
The NCE Project Approach
As mentioned above, drugs based on new chemical entities require an NDA filing with the FDA.
With NCE molecules, target product profile identification is critical. During initial project stages, the focus will largely be on the process development of the drug candidate – the key intermediate and target lead optimization steps.
Attention is also placed on process development leading to Phase I, in order to enable adequate supplies of the drug candidate. This focus will shift later to final process development (based on knowledge acquired concerning impurity formation), long-term toxicology, carcinogenicity and Phase II clinical supply.
A common approach with NCEs is to de-emphasize impurity identification during initial phase development and focus on production consistency – and then later concentrate on impurity formation (as well as impurity types), as well as developing effective control strategies.
For Phase III supply, contract manufacturers focus on registration batches and stability studies suitable for use in defining commercial retest dates. The final stage of NCE commercialization is the production of validation batches and launch supplies.
The Generic Project Approach
Generic drug applications are called “abbreviated” in the U.S. because they are not required to include preclinical (animal) and clinical (human) data to establish safety and effectiveness. Instead, a generic applicant must scientifically demonstrate that the product is bioequivalent (i.e., performs in the same manner as the original drug):
“Overall, both EU and US legislation for the authorisation of generic medicines allow for abbreviated applications to be made in the case of generic medicines. In both jurisdictions, pre-clinical and clinical studies do not have to be performed by the generic medicine applicant, but bioequivalence to the originator or “reference” medicine must be demonstrated.
Bioequivalence is demonstrated when the rate and extent of absorption do not show a significant difference from the originator drug, or where the extent of absorption does not show a significant difference and any difference in rate is intentional or not medically significant.”
Once approved, an applicant may manufacture and market the generic drug product to provide a safe, effective, low-cost alternative to the public.
Varying regulatory requirements around the world can present challenges for the commercialization of generics. These differences in standards can make it quite challenging for companies to develop a single drug which is simultaneously submitted in all the countries for approval. Because of this, regulatory strategies for generic product development are established between the contract manufacturer and sponsor before work commences in order to avoid any major surprises after submission of the application.
Maximizing Success in Generics & NCEs
The differences in process development methodology between NCEs and generics mentioned above can have a large impact on drug price, safety and performance. With generics, manufacturing costs are often decisive while safety & performance have been previously established.
With innovator drugs, on the other hand, safety and performance for an unproven molecule are paramount. Because of these differences in their characteristics, it is critical to adopt a modified approach based on whether the drug molecule is considered ‘innovator’ or ‘bioequivalent.’
With more than 650 regulatory filings to date, Neuland is committed to total compliance and regulatory excellence. In fact, we consider it our core competency: the application of strong process chemistry to manufacturing in a regulatory compliant environment.
This infographic explores Neuland’s regulatory experience, certifications and track record – from 1984 up through 2017.
Gil Roth, president of the Pharma & Biopharma Outsourcing Association, recently published a piece at Contract Pharma on the challenges and opportunities facing CMOs/CDMOs.
The hot button issues he described pretty much lined up with what I would put in a list of 2018 trends in the API space to watch – rising global protectionism, ongoing industry consolidation and regulatory issues among them. I would also add product differentiation to the list, as it is one of the strategies CMOs/CDMOs are leveraging to address some of the pressures raised by those other trends.
These are issues that often intersect and coincide, and have political overtones. Let’s face it, 2017 represented a political sea change – from the U.S. to Europe and beyond, and for many corporations the world feels like it has become a little bit less predictable.
While Roth’s article focuses on the U.S. market, it also applies more globally. (Brexit hasn’t been a shining beacon for global trade policy.)
First Things First: I’m Echoing Gil Roth on the Value of Predictions
Gil Roth is careful to note what may now become a standard disclaimer across prediction & trend-writing land – and I’m going to agree with him:
“My crystal ball is C-R-A-C-K-E-D, and my backup Magic 8-Ball’s answer to everything is, ‘Reply hazy. Try again later.’”
With that said, here are some of the trends Roth mentions that will bear watching as 2018 progresses.
“A massive influx of pharma dollars could cause those big companies to alter their supply networks…but I think it’s more likely that the money goes to share buybacks, dividends, and acquisitions of U.S.-based targets.”
Roth, in his article, points out the impact of GDUFA and the changing regime at the FDA as two things to watch for in 2018.
These are some of the issues that will occupy our attention in 2018 – and surely there are many more.
Read Gil Roth’s piece at Contract Pharma on the challenges and opportunities facing CMOs/CDMOs.
Synthetic route selection is a crucial element in API manufacturing. While the requirements of the synthetic process of a drug will naturally evolve during its life cycle, scouting alternate routes early in process development offers you many benefits. Alternate routes have the potential to help you:
At Neuland Labs, our expertise is often called on to provide custom synthesis and route scouting, and we’ve found that demand for these services has continued to grow as more companies realize the cost, efficiency and safety benefits of process optimization. In this post, we’ll share some of the top things to consider when devising new routes.
Essential Drivers of API Route Scouting
When developing a new synthetic API route, you should look for a route that:
While meeting the three criteria above would yield the most benefit, focusing on even one or two of these criteria can provide significant process improvements. For niche products, most companies seek to reduce cost by 2-5% through alternate routes; for generics, much greater savings are sought.
In addition to cost, other factors to consider are batch sizes, throughput of the product, lead time and reducing batch cycle. Shortening the route is frequently a goal, as this one change can singlehandedly decrease cost, time, waste and regulatory constraints.
Ask the Right Questions to Improve Alternate Routes
Keys to Getting Route Scouting Right
As you consider your options, keep these final points in mind for greatest success:
By guiding your research with these tips, you should be able to create a new synthetic route that meets your expectations and is sustainable across the drug lifecycle.
Data integrity is a key factor for ensuring end products in the pharmaceutical industry meet all quality guidelines. It provides assurance that accuracy and consistency have been maintained throughout the drug life cycle.
Neuland’s Ashok Gawate, DQA & Regulatory Affairs General Manager, recently wrote a guide to promoting successful data integrity practices.
With attention to data growing, data validation plays a key role in maintaining an organization’s credibility in the pharma industry.
No Small Data Errors
There is no such thing as a small data error: one tiny mistake can call into question the validity of all your data.
A Contract Manufacturer’s Quality systems must have adequate controls to protect the validity of data and procedures for discovering, and more importantly, preventing problems even before they occur. Routine data audits are an effective method of weeding out errors, and a robust training program can decrease the number of innocent mistakes.
Data Integrity Issues
Data integrity problems go far beyond deliberate falsification of data. Untrained employees, disorganized systems and lack of oversight generate more errors and can be more difficult to spot than intentional acts of deception.
While the commitment to data integrity may come from the top, it’s the people in the trenches who are best able to spot and prevent mistakes – if they know where to look.
Data integrity falters when institutions prioritize financial success over product quality. This ultimately trickles down to unrealistic cost controls forcing inadequate investment in staffing, employee training and development, facilities, equipment, systems and controls. Also, leaders who are disinterested in two-way communication or team engagement may indirectly fuel an environment where employees are not empowered to do the right thing.
Preventing Data Integrity Issues
Lack of upper management focus thus results in lack of innovation and continuous improvement, which is integral for data integrity and security. To prevent data integrity issues, drug manufacturers need an atmosphere that fosters the sense that each employee has a responsibility towards data integrity.
A first step is to provide a way for employees to communicate data integrity concerns to managers who have the authority to address problems. Providing a pathway for data integrity concerns to be brought to management’s attention promptly can avoid having these issues discovered during FDA inspections.
A successful data integrity practice in an organization starts from the way training is imparted to the employees. Take a look at your training program and ask these questions:
Adjustments in the way employees are recruited, trained and assessed can yield positive results.
Common Sources of Data Problems
Let’s take a look at some common sources of data problems.
Batch Records Violations are one of the primary sources of data integrity issues. Here are some steps you can take to weed them out:
Weak documentation control opens windows of opportunity for data abuse. To close those windows, avoid:
Computer system controls can also impact data integrity. Good general data management controls should provide clear expectations of how data will be generated, reported, reviewed and maintained, including how access to computer systems for generating and modifying data will be limited to authorized personnel, and how data will be protected from tampering.
Pharma contract manufacturing companies should create SOPs that address system change control. These SOPs would govern how data integrity would be maintained during data backup, retention and recovery when changes are made to the computer system.
Electronic Document Control
If you are using electronic systems for data collection, analysis and/or storage, here are a few rules to follow:
Data Integrity in Laboratory Testing
Data integrity is essential in laboratory testing. You need to make sure that all procedures are clearly spelled out and understood. Check what notebook to use for data recording, which analytical method to use, how to cross reference data in other sources – all these need to be taken into consideration.
Investigations of lab nonconformities can also be problematic. You need to know that those conducting the investigation have really gotten to the heart of the problem, starting with the initial analysis of results and reviewing all investigation documentation and steps taken during the investigation.
Questions you need to ask include:
In addition to reviewing documentation, observing the lab itself can help you spot data integrity issues. Take a walk through, considering these factors:
The Pharma Manufacturing Area
To maintain data integrity in pharmaceutical manufacturing areas, check if:
Another useful technique is to interview employees regarding their areas of responsibility. Ask where their instructions/SOPs are found and how problems are addressed.
Managing Turnover – in Both Equipment & People – to Ensure Data Integrity
Staff turnover can be an issue for some companies, as it is rare these days for people to stay with the same company for decades. This means the hiring and training of new employees is more frequent, leaving opportunities for inexperience or insufficient training to cause data integrity problems.
Likewise, equipment must be maintained and periodically replaced with newer machinery; both instances offer opportunities for data integrity failures to occur. If implementation of a new piece of equipment isn’t done properly, for instance, that can cause data issues.
Addressing these issues is critical to the process of maintaining data integrity. Utilizing best practices – in conjunction with top-down support – can serve to improve both compliance and operational efficiency.
In both the generic and innovator pharmaceutical API production sectors, time-to-market is a critical factor.
How critical? A one-day delay in reaching the market could mean the loss of $1 million.
Because of this, from a risk-analysis standpoint time- or speed-to-market may be the decisive factor when it comes to pursuing a product or candidate. And it continues to become even more important as the costs for drug development have soared.
Beyond just cost, time to market is also an issue of global dimension. Earlier this year, China began considering measures to shorten time to market for approved imported drugs in an effort to ease a shortage of such medicines.
As noted at American Pharmaceutical Review:
“Speed — specifically, speed-to-market — has been and remains the key to success. In order to achieve fastest time-to-market, one must have reliable access to cGMP process capacity, when and where it is needed. A product’s success depends on a rapid transition to market, which is why achieving full-scale production in less time has many benefits, such as extended patent protection for approved drugs. Likewise, penetrating new markets before the competition can produce a profound and lasting advantage. Manufacturing capability, once perceived as a time-consuming obstacle to initial market penetration, now determines success more than ever before.”
Controlling the Risk of Market Entry Delays
Fortunately, there are steps drug manufacturers typically take to help reduce the risk of market entry delays. While the risk cannot be completely eliminated, the use of certain Best Practices can decrease their likelihood.
“Briefly, in making a Paragraph IV Certification, the generic drug maker says the patent is at least one of the following: (1) invalid; (2) not infringed; or (3) unenforceable. That’s the Reader’s Digest version on the requirements for a Paragraph IV Certification; after that, the story gets much more complicated and adversarial.”
It’s fair to say that Paragraph IV certifications offer opportunity, but also some risks. As Guttag mentions, it is – in fact – a complex issue, and pharma companies risk losing the first-to-file advantages of Paragraph IV if clinical and manufacturing timelines are not met.
With rising drug development and commercialization costs, the smallest delays in getting to market can have large financial repercussions. Companies need to adopt strategies that minimize and control the risks to enhance speed-to-market.
This month, I managed to catch up on some of the industry articles I’ve been waiting to read which were relevant to APIs and pharma manufacturing generally. Here are a few you might find interesting:
What Does the Future Hold for the API Industry?
Patricia Van Arnum at DCAT tackled APIs and what the market holds in a DCAT Value Chain Insights piece:
The market for active pharmaceutical ingredients (APIs) is approximately $140 billion and is projected to reach nearly $190 billion by 2020. Read it at DCAT.
Growing Focus on Raw Materials Compliance
Mark Hoffman’s piece at PharmaManufacturing.com (Critical Success Factors in Raw Material Storage & Conveyance) took a look at the growing importance of raw material supply chain compliance:
“Increasingly, this environment also has become integral to the rigorous regulatory requirements for tracking and tracing products throughout the supply chain.”
We touched on this in our last post – accurate, comprehensive documentation is a must!
There were many interesting pieces in PharmTech’s 40th Anniversary section (you can see their complete coverage here: PharmTech Reflects on Four Decades of Bio/Pharma Innovation), but I’ll share a few that caught my eye:
Perspective: Big Pharma No Longer the Center of Innovation
Chris Moreton takes a look at the shifting role of Big Pharma over the years, and the positive effects of drug regulations.
Perspective: Drug Costs and Pharma’s Future
AAPS President Binodh Desilva discusses how drug costs, biosimilars, and cloud-based technologies will impact the pharma industry, and what the future holds for the American Association of Pharmaceutical Scientists (AAPS).
Process Validation Evolution: The Lifecycle Approach
Paul Pluta shares the history behind the FDA’s process validation guidance, discusses its evolution and the lifecycle approach.
Braille and Not-So-Common Drug Packaging Standards
Lastly – though unrelated to Neuland or APIs, I thought this piece on the use of Braille to label drugs for visually impaired patients in Pharmaceutical Processing magazine was interesting. There has been a shift towards common and comparable cross-border regulatory requirements for years, but there are still differences between the various rules & regulations. This article points out the different requirements for Braille between Europe and the U.S.
Current Good Manufacturing Practices (cGMPs) are an essential aspect of compliance, and attention on them by regulators is growing.
In today’s global pharma industry, it’s common to have multiple investigators from around the world inspect your facilities. In recent years, manufacturing facility inspections have grown in frequency and are now performed on a routine basis to ensure compliance with appropriate standards & regulations.
Familiarity with Global Regulators
To date, Neuland has undergone 28 Regulatory inspections from 9 different regulatory agencies – stretching back to 1997. These included inspections by U.S. FDA, the European Medicine Agency, Japanese, Korean, German, Brazilian, Mexican, Australian and French regulators, as well as the EDQM (European Directorate for Quality of Medicines & Healthcare).
Typically, during an audit, companies will be asked to share a number of documents. This was true of Neuland’s most recent inspection by the U.S. FDA for which the FDA issued an Establishment Inspection Report (EIR) for FDA approval of Neuland’s facility.
Here’s just a sample of the documents or records we’ve been asked to provide regulators during FDA audits:
Intensifying Regulatory Scrutiny of Data.
An important part of every Regulatory inspection is a check of company quality records to assess whether the Company follows its own standard operating procedures (SOPs) and work instructions. In recent years, data integrity has become one of the most critical factors to ensuring GMP compliance in the pharma industry.
Regulatory bodies are digging deeper and deeper into data to ensure manufacturing and test information is accurate and consistent.
But here’s the good news: companies who treat every task, every batch and every day as if it were an audit have very little to prepare when it comes to an upcoming inspection.
Here are some of the key success factors we’ve found for regulatory inspections at Neuland:
Regulatory Success Roots in Team’s Dedication to Quality.
Neuland’s decades-long track record of regulatory success is due to continuously maintaining quality and excellence in our API development and manufacturing activities. That mindset owes itself to the Neuland team who constantly work to improve and grow – both as individuals and as a group – to ensure we maintain our focus on excellence.
Across all of our 2017 inspections and audits, I am thankful to each employee who worked hard – and who continues to work hard, every day – to keep Neuland’s facilities in compliance.