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Contract Pharma Project Management & Data Infrastructure

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.

Data Security
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.

Inside QBD: Chemists & Engineers Collaborate on Quality

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.

Chemical Engineers:

  • generate data on the material balance.
  • evaluate energy balances to understand utility requirements for plant scale.
  • select equipment for commercial scale for retrofitting or new, per process requirement.
  • perform risk assessments (Quality, Safety) of unit operations, powder safety characterization studies, HAZOP & & HIRA.
  • evaluate particle engineering (particle size, bulk density, surface area & Polymorph).
  • forecast potential for new technology implementation considering the volume of products, safety threats, troubleshooting activities related to the commercial products, and more.


  • leverage expertise in various types of synthetic reactions, based on both literature searches and hands-on experience.
  • help select the route of synthesis.
  • evaluate the feasibility of the selected route, optimize and validate the process to meet the predefined quality and yield.
  • identify and characterize any impurities which have an impact on quality.
  • perform generation and qualification of reference/working standards.
  • maintain continuous interaction with IP for process infringement with any new process patents,
  • perform process and method validation.

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.

NCEs Versus Generics – Adjusting Project Tactics & Objectives to Maximize Success

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.’

Neuland & Regulatory Excellence

Infographic - Neuland Regulatory track recordWith 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.

Learn more about Neuland’s Regulatory Affairs and Quality Control & Assurance departments.


Pharma APIs – What’s On Tap for 2018

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.

  • Protectionism
    No one really knows what the impact of increased protectionism will mean for global supply chains – and pharma has become – if nothing else – a truly global supply chain. According to the news, protectionist policies are on the rise – but how it will impact an already global industry is unknown. While there have been rumblings in Washington D.C., nothing has (yet) played out policy-wise. Roth notes in his article:

“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.”

  • Consolidation
    Here I again agree with Roth – 2017 saw some deals that were ‘consolidation’ at heart, while others were better considered the creation opportunities with untapped potential. Whatever the motivator, industry consolidation is no short-term trend – it has become a preferred growth strategy. There are no signs of it abating, and 2018 will likely continue to deliver news on the pharma M&A front. Some will be done to control costs across the drug lifecycle or increase capacities, while others will aim to expand offerings & market segments.
  • Regulatory
    I typically note that quality issues will be front of center when I sit down to write a predictions-style list, and invariably it is a key focus of industry. Quality always is, or should be. In 2018 though, ‘quality’ will be synonymous with ‘regulatory.’ Over the last few years we’ve seen a marked increase in global regulatory enforcement, and that will likely continue. Global standards are rising, and in some cases regulatory framework synergies are making compliance more universal. It is interesting that global regulatory standards – while increasingly complex – are also working towards a goal of broader universality just as attitudes towards globalism more generally are shifting.

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.

  • Product/Service Differentiation
    Product differentiation is well underway already. Manufacturing capabilities up-and-down the supply chain – from green chemistry, high potency or alternate route scouting for drug APIs up through novel delivery and packaging solutions – are already delivering differentiated capabilities & products.This has led to increasing specialization – and a 30+ year trend in its own right.  In the article, Roth mentions that “CDMOs talk more about expanding their current facilities, adding services and building more integrated suites of services.”

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 Scouting: Factors to Improve API Manufacturing

Synthetic route scoutingSynthetic 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:

  • Improve scalability
  • Reduce chemical or reagent usage and waste production
  • Decrease processing times
  • Improve quality and safety profiles
  • Reduce the number of processing steps or overall complexity

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:

  • Is cost-effective
  • Has the same quality or greater quality than the previously agreed upon route
  • Provides reasonable time to market

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

  • When considering a route change, the first question to ask is why. By changing the route, what clear benefits can be gained in terms of cost, time and availability?
  • The next point to consider is the availability of your raw materials. Are they maximized by your current process, or could an alternate process improve on it? Next, look at the volume of the product in the market. The higher the volume you need to produce, the more benefit you gain from improving the route.
  • Does the manufacturer you work with conduct company product profile matching? This can be very helpful when seeking to make a change. When examining the cost benefit, does it extend to the manufacturer as well as to you?
  • Is the process feasible in the manufacturing plants you’ve selected?
  • Lastly, what alternate green reagents could be used for long-term sustainability of the product? Today, the most innovative routes use the least resources possible and minimize impact on the environment.

Keys to Getting Route Scouting Right

As you consider your options, keep these final points in mind for greatest success:

  • An alternative route should use a strategically inexpensive starting material; using an intermediate from an existing process is ideal.
  • The process used should be robust and require minimal purification. Stages should be telescoped for maximum efficiency.
  • The new route should offer high “atom economy,” creating minimal waste via a greener process.
  • And finally, the developed route must not infringe on any current patents.

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.

Promoting Data Integrity in Contract Pharma Manufacturing

Promoting Data Integrity in Contract Pharma ManufacturingData 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:

  • Are the right people in the right positions in terms of education, experience and training?
  • Do employees have clear roles, responsibilities and accountabilities and do they understand them?
  • Do employees have adequate job descriptions?
  • Do they know what they’re expected to be doing hourly, daily, weekly, monthly and quarterly?
  • Are there enough personnel to execute and provide oversight?

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:

  • Review records for proper and timely entry of operator signatures and supervisor/management signatures.
  • Confirm that dates and times are linear through the batch record execution and appropriate to the process.
  • Look for corrections that change the acceptability of the data, such as time changes.
  • Look for corrections to bring values into the acceptable range (uncompliant data that suddenly becomes compliant is suspicious).
  • Verify suitable document control over batch issuance to make sure there is no ability to recreate, reissue, reprint, duplicate or create an alternate working copy.
  • Review raw materials to see if they align when cross referenced to QA release records, material transfer records or other independent sources, and that extra materials weren’t issued.
  • Verify that work staff align when cross referenced against personnel work logs, timecards, area entry records or other independent sources.
  • Look for delays in progressing to the next step in batch completion and sampling.
  • Look for missing data, such as weigh slips, raw materials distribution records, deviations to approved processes, etc. and check batch accountability or yield records for missing product or materials.

Weak Documentation

Weak documentation control opens windows of opportunity for data abuse. To close those windows, avoid:

  • Allowing a second or working copy of a controlled document to be printed
  • Supplemental records not cross referenced to primary records
  • Paper or loose-leaf notebooks, unless their issuance is properly documented and you can verify that they are archived or backed up for audit
  • Duplication of documents.

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:

  • Systems should be validated and validation report should be readily available for review
  • Give each authorized user a unique user ID and password to prevent employees from accessing someone else’s system
  • Restrict administrator privileges to a select person or people who are authorized to make changes
  • Make sure analytical instruments are locked before the analyst walks away
  • Limit the use of electronic file folders and establish specific file and folder naming conventions to help identify aberrant data
  • Make sure you know who is using the system and what they are doing at all times
  • Verify user access permissions are appropriate to the job responsibilities
  • Maintain audit trails.

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:

  • What data did the investigation team report?
  • What data did they include for final batch release?
  • Did they include all of it, including the initial analysis so the quality assurance department has the full picture of what occurred during the investigation?
  • If extra or duplicate testing is performed, it should be justified and approved by management or QA before conducting the testing.

In addition to reviewing documentation, observing the lab itself can help you spot data integrity issues. Take a walk through, considering these factors:

  • The lab should appear safe, clean and organized
  • All equipment and chemicals should be appropriately labeled
  • Expired chemicals should not be present
  • No personnel unrelated to testing should be present and staff should be recording results in real time.
  • Most importantly, loose pages of notes, calculations, etc., should not be lying around or stuffed in drawers. Unsecured records area common source of falsified data and should be investigated immediately.

The Pharma Manufacturing Area

To maintain data integrity in pharmaceutical manufacturing areas, check if:

  • Equipment and supplies are present, properly labeled and properly recorded in batch records
  • Log books are in place and used regularly
  • The area is free of notes, loose leaf memos/papers or other uncontrolled documentation
  • Supplies are well within expiration dates and are being properly released by quality control
  • Batch records are with personnel while manufacturing steps are taking place and equipment calibrations are current.

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.


Speed-to-Market: Streamlining Pharma API Production

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.

  • The ‘File First’ Principle & Paragraph IV
    First-to-file is (and has been, for quite a while) the key lynchpin strategy for maintaining higher profit margins among drug innovator companies. But generic pharmaceutical companies are also benefiting from being first to file. Using paragraph IV certification, being first to market when a patent expires can be a key competitive advantage.Paragraph IV certification is the newest tool for ensuring a first-to-file status (and some hefty marketing exclusivity benefits) for generic drug makers. Eric Guttag, in his Primer on paragraph IV Certifications at IPWatchDog, writes:

“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.

  • Clinical & Manufacturing: Downstream Consequences
    Today, drug development takes an average of about 5 years – and the clinical and CMC areas are the major contributors towards the time and cost of development. Given that CMC is well-upstream of a marketed product, it can have a substantial impact on getting to market in a timely manner.In the API manufacturing realm, any delays in producing the API can have downstream consequences – potentially delaying follow-on clinical or production steps. According to the FDA’s Office of New Drugs 2016 Annual Report: “Failures in the manufacturing supply chain played a major role in the drop in new drug approvals…Pharmaceutical manufacturers are in urgent need of better project management practices that will improve agility.”
  • Breaking Silos and Focusing on Flexibility & Responsiveness
    Breaking silos and sharing knowledge demands streamlined data management and well-defined workflows – coupled with a constant focus on regulatory compliance. And while both regulatory and CMC are critical to project management, it’s the overall coordination of all departments that is the ultimate objective. Bringing together functions such R&D, marketing, manufacturing, regulatory, legal, and others in a system of open, transparent communication makes a company more agile, and maximizes its ability to avoid unseen challenges.
  • Flexibility & Leveraging Data in Real-Time
    Being responsive demands accurate planning, driven by data sharing in real-time so teams can make more-informed decisions, faster. It also allows for a greater degree of flexibility and adaptability. And flexibility matters: “In a survey conducted at a recent ISPE meeting, pharmaceutical executives indicated that flexibility was the most important characteristic of future manufacturing operations.”

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.


November: Catching Up on Pharma Articles

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 (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.



3 Success Factors for Pharma Regulatory Inspections

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).

Regulatory Documentation
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:

  • List of DMFs submitted in USA
  • List of companies authorization
  • List of product ANDA approvals or products awaiting for approval
  • List of products dispatched to USA
  • List of changes from last USFDA audit
  • DMFs deficiency letters & responses
  • SOPs index and main aspects of the Quality Assurance System (SOPs, records, raw data’s), layouts and diagrams, Quality management/Management of documentation/QRM, Personnel (organogram, qualification, training, job descriptions)
  • Complaints, recalls and returns
  • Processes for handling out-of-specifications results and other deviations, and reprocess batches & OOT data.
  • Documentation for all equipment located in manufacturing areas,
  • Practices vs. Procedures for raw material handling SOPs (e.g., receipt, sampling, distribution & storage).
  • Online records for temperature monitoring, weighing balance calibration, etc.
  • Quality control audit trails and 6 months of audit trail data.

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:

  1. Key Regulatory Success Factor 1
    A Strong Team with an Open, Honest, Communicative Approach
    Openness, transparency, reliability, accountability, customer-centricity and ownership are the behaviors your team should demonstrate. Inspections are very much about trust and confidence; company team members should clearly communicate with inspectors and auditors in order to maintain that trust. Misunderstandings or uncertainties should be clarified as soon as possible. Remember, immediate action on potential deficiencies is usually regarded as a positive attitude – and is appreciated by inspectors. Above all else – company employees should avoid giving the impression that they are being uncooperative, or may hiding something.
  2. Key Regulatory Success Factor 2
    Always-On Audit Readiness
    The best way to prepare for an inspection is to always be ready for an inspection. As a part of Neuland’s ‘anytime audit’ readiness, cGMP audit readiness and compliance is constantly maintained. Companies with all-the-time or ‘always-on‘ compliance which maintain constant and high level adherence to cGMPs do not need to specifically prepare for upcoming inspections. This readiness eliminates last-minute hurried prep work for audits, and more importantly it reduces or eliminates potential compliance issues.
  3. Key Regulatory Success Factor 3
    Understanding Hot-Button Items
    As part of ongoing regulatory work, reviewing recent USFDA warning letters & Form 483s that were issued to other facilities can shed light on potential internal issues. It’s a great way to understand what regulators are looking for, and what their current thinking or approach may be.

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.