4 Signs Your Quality Team Needs QMS Software

4 Signs Your Quality Team Needs QMS Software

Times are changing. Increasing competition, regulatory scrutiny and tightening margins are a few of the challenges facing Life Sciences Companies. As a result, drug and device manufacturers are evaluating every aspect of their operations to identify opportunities for greater efficiency and productivity.

Benefits of Cloud QMS in a GxP Environment: Part 1

Benefits of Cloud QMS in a GxP Environment: Part 1

Cloud applications have many well-known advantages over traditional on-premises applications: reduced time to benefit, lower costs, scalability, integration, faster upgrade cycles, and ease-of-use.  

Top 4 Pharma Quality Trends for 2018

Top 4 Pharma Quality Trends for 2018

The role of quality management is quickly changing. While compliance remains a top goal, increasing global competition and industry pressure are forcing quality teams to focus on driving company-wide performance in addition to maintaining compliance. 

Agile in a Regulated Environment

Agile in a Regulated Environment

Agile is a mindset that should be adopted by every organization.  The goal or principle of Agile isn’t scrum, but just another way of building a rapid-learning loop. 

Navigating Your First 100 Days as Head of Quality

Navigating Your First 100 Days as Head of Quality

You finally landed your dream job as head of quality. But things are about to get a lot harder. Here’s how you can succeed in your first 100 days.

Leveraging Your GMP System to be a Global GxP Solution

Pharmaceutical companies face some very real challenges within clinical quality management. There are pressures to not only to ensure compliance but to get approved drugs to market safely and effectively without spending additional funds on redundant quality management tools that may already exist in their organization. One way to address these challenges would be for pharmaceutical companies to create a global GxP solution that ensures visibility across the supply chain as well as automate quality processes, sufficient tracking of all correspondence, and more.

Creating a Proactive Approach to Pharma CAPA via GMPs and Enterprise Quality Management Solutions (EQMS)

Mention CAPA in different companies, and you are likely to get slightly different definitions of the process. In the life sciences industry, CAPA pertains more to a formal event management and remediation system for systemic events, as opposed to minor events that occur and are corrected as they happen. CAPA as a term, started as an ISO standard for corrective actions and preventive actions. FDA’s Good Manufacturing Practices (GMP) regulations were adopted in the 1970s and have not been formally changed since that time GMPs defined quality processes and at the time of adoption were conducted manually and kept in paper-based lab notebooks.

As computers and PCs were introduced into the marketplace, manufacturing companies embraced the efficiencies of this technology revolution.  Eventually computers were used for quality processes, as well. The focus on quality became more important, and additional requirements to address quality issues were being established, driven by internal company factors as well as external agencies and patient care concerns.  At the request of the industry, the FDA created the Electronic Records Electronic Signatures (ERES) regulation. Title 21 CFR Part 11 (21CFR11 defined how electronic records and approvals would be used to assure GMP regulations would be followed in the computer age.

Additionally, ISO and the International Commission on Harmonization (ICH) have created additional standards that speak to CAPA. Although these are not explicit regulations, FDA has issued guidance documents adopting these standards. The most common FDA-issued inspection observations (483) and warning letters related to quality within the pharmaceutical industry are due to a lack of a CAPA system or a deficiency of CAPA processes.

The Intersection of CAPA and GMPs

Although CAPA requirements aren’t directly mentioned in GMPs, it is essential for pharmaceutical manufacturers to have a CAPA in place. Having a strong CAPA system and a sound Quality Management System (QMS) are interchangeable. These systems do more than just decrease the chances for a manufacturer to receive regulatory observations or enforcement. Within the realm of life sciences, CAPA has morphed into a system for tracking and managing quality events, determining root cause and taking actions to not only remediate a problem, but also preventing a problem from happening again.

GMPs, by their very nature, deal with enforcing quality of procedures and formulas. In the pharmaceutical realm, GMPs help to ensure uniformity and efficacy -- that when specific drugs are formulated, they’re made exactly the same way each time. If there is a deviation in the process, a CAPA system can help a manufacturer investigate whether that batch is safe for the market. If something goes wrong in the process, it stands as an event that requires attention. By having a CAPA process, companies in the life science space can determine whether a product is still safe and effective for its intended use, and whether it can be released to market or needs to be re-manufactured or destroyed.

Pharma CAPA and EQMS: Formula to an Effective, Proactive Approach

Stringent industry regulations and industry best practices require a more proactive approach to creating an effective pharmaceutical CAPA for post market products. An EQMS can assist in this process, helping to ensure the reliability of and access to information at each step of the way.

By making use of an EQMS to integrate CAPA and quality in the overall manufacturing process, production of post market products can be effectively managed. Here are four key elements to creating an effective pharma CAPA and how EQMS can help:

1. Immediacy

An effective CAPA process is one that operates with immediacy. When a quality event happens, it is recorded and investigated immediately. Unfortunately, in many instances of quality events, millions of dollars of raw material and equipment are invested in a process. Despite an event having been reported, the manufacturing process continues to the point of completion and then -- after considerable time, money, and resources have already been invested an investigation of an event begins. Immediacy is important in that it shortens the time for a manufacturer to decide whether to release, remanufacture or destroy a product following reporting of an event. The earlier remediation is determined, the less money it costs, potentially saving a company millions. EQMS allows you greater insight into the process and a more finely-tuned ability to detect where an event has occurred. From there, manufacturers can test that component -- as opposed to testing the finished product at the end of the manufacturing process.

2. Transparency

An EQMS can offer greater visibility in the supply chain and transparency of process. This allows decision-makers and managers to identify trends that might be happening, or failure rates. It increases the chances of determining if there is a common ingredient or process involved in multiple failure rates.  If a product has been manufactured for years without issues, and suddenly, batches of the product are failing, root cause and corrective and preventive actions need to be taken. EQMS helps to increase transparency and communication across different groups. When there is a quality event with pharma products, the signs may have already been there, but without transparency and deeper insight into various tiers of the supply chain, no one knew where and when an event occurred. What may have seemed like a minor incident managed inside a silo may have been part of a string of minor incidents enterprise-wide that contributed to a far more tangled problem.

3. Communication

Many pharma manufacturers have sites all around the world. When a root cause of a problem has been found, this can make it more difficult to effectively communicate such news -- in real time -- to the manufacturer’s worldwide network. A true CAPA process and enterprise-wide solution finds where those conditions exist and aids in correcting them. If bad raw materials are the root cause of a problem, effective communication of the problem can allow individuals and departments throughout the enterprise to question what other products are made with the same raw materials. Time, money, and effort are saved by pinpointing those products, where the material is manufactured, and/or where else does the manufacturer make that product. With an ideal CAPA system in place, corrections can be made across multiple facilities or investigations of the issue can occur and ensure that a problem is not repeated with another product or another batch of the same product.

4. Collaboration

Pharmaceutical manufacturing today no longer takes place within a company’s own four walls.  Almost all of the raw materials used come from a vast network of suppliers from around the world.  In many cases, manufacturing, packaging and distribution is outsourced to contractors, while the company licensed to sell the product is ultimately responsible for its quality and efficacy.  Most companies try to manage quality using legal quality agreements with little or no visibility into the actual quality of the supplier or contract manufacturer.  According to a recent study across all manufacturing industries, 52% of recalls were due to third party supplier or contractor caused issues.  The next generation of EQMS includes collaboration with the entire supply chain, where events, corrective and preventive actions, and changes are recorded, investigated, approved and trended on by everyone that may be involved.  Extending the EQMS and CAPA system throughout the entire supply chain helps assure the safety and effectiveness of the pharmaceutical products used by the patients who need them.

Learn more about the relationship between manufacturers and their supply chain and the role that open communication plays throughout the process. Download our whitepaper, Minding the P’s & Q’s: Managing Quality and the Globalization of the Pharmaceutical Supply Chain.

 

 

 

 

 

 

Pharmaceutical Supplier Performance Evaluation: Quality as a Metric

Since 2005, there has been a dramatic increase in pharmaceutical companies engagingoverseas suppliers and contract manufacturers. A report by the US Government Accountability office says that up to 40% of all pharmaceuticals sold in the U.S. are manufactured overseas in Asia.

In direct correlation to the rise of overseas suppliers, there has also been an increase in the number of pharmaceutical recalls. Between 2006 and 2011, the number of products recalled by the FDA rose from 4,266 to 9,288. Experts attribute the rise in recalls to lapses in the manufacturing process, particularly where it concerns the quality of raw materials, faulty labeling, and package contamination.

Despite these alarming statistics, one way pharmaceutical companies can avoid becoming a part of these statistics themselves is to establish a firm supplier quality management system.

Measuring Supplier Performance

To measure supplier performance, clear KPIs are first established. As part of a supplier rating system, suppliers are qualified on a variety of metrics including percentage of on-time performance, the number of times they deliver a quality part, ingredient or product, and prompt response to requests for quotes.

With KPIs in place, a benchmark is then established. A manufacturer's qualityrequirements vary depending upon a number of benchmarked factors. Since benchmarks are based on risk, there are no one-size-fits-all solutions. Managing the risk of what that supplier is providing is critical and determines how often a company must measure that supplier -- be it through audit, inspection, or a combination of the above.

To that end, just because a supplier is approved to provide a pharmaceutical company with a certain ingredient or products, it does not necessarily mean that they are qualified to provide a company with other pharmaceutical ingredients or products. For instance, a supplier that is qualified to provide Ingredient X may manufacture Ingredient Y. However, that same supplier's Ingredient Y may not be of as high a standard as the Ingredient X they are qualified to supply. Suppliers must be approved for each of the ingredient they provide.

Quality: The Missing Ingredient in the Supplier Benchmarking Equation

Most companies already have a supplier scorecard in place in their ERP system. A supplier's score can increase or decrease depending upon their performance. Benchmarking is important to determine whether a supplier is performing as expected, improving, or worse compared to other supplier performance KPIs.

ERP systems are well equipped to record and measure price, on time delivery and assuring the correct ingredient is delivered. However, one key component missing from this scorecard is quality. In order to lessen recall rate, quality needs to be a metric in the pharmaceutical supply chain benchmarking process, as well as part of the initial negotiation process with prospective vendors and suppliers – whether they exist inside the U.S. or outside its borders. Quality issues are usually discovered during laboratory testing, causing deviations during the manufacturing process, during audits or the worst scenario, from a product related complaint once the product has reached the market.  However, in some instances where a pharmaceutical supplier has a monopoly on certain products or ingredients, they may be less likely to put a quality system in place. In this case, the onus is on the manufacturer to do consistent testing to make sure the ingredient always meets specifications.

For manufacturers with a large-scale product, having visibility to metrics as they happen in real-time can help nip problems in the bud prior to release, staving off costly rework or recalls. A QMS software product such as TrackWise allows pharmaceutical manufacturers to incorporate quality into the supplier benchmarking equation at each phase of the process, encouraging more frequent monitoring and reporting on established KPIs. These quality metrics can be combined with those collected within the ERP system to provide a more comprehensive supplier rating.   As a logical extension, quality becomes a centralized part of the process at various checkpoints in the production cycle – long before a final pharmaceutical product goes to market.

In the weeks ahead, we will be addressing more topics within the realm of pharmaceutical supplier quality management. In the meantime, download our eBook that offers Six Steps to Maximize Supplier Relationships.

Q&A Blog Series: Using Analytics to Improve Quality-Pharmaceutical Industry

1. How does poor data affect quality in your industry?

Poor data is really disconnected data throughout an enterprise. When data is disconnected, it becomes difficult to connect the dots which results in extended investigations and delays in getting to decisions.

This affects quality because decisions are made based on the information at hand. If the data is in different systems or locations, it makes it very difficult to find the root cause and identify the best solution to address a problem.

2. What problems arise in this type of situation?

The most common types of problems in this situation are recurring issues.  Many times, quality events happen and the solution is known because “it happens all the time”. Quality professionals may take the actions necessary to solve a problem but don’t always remedy the issue everywhere, functionally and geographically for example. When the data is disconnected, people take care of things in silos instead of holistically or globally.

3. How can business intelligence and analytics solutions be used to address quality-related challenges?

These solutions provide decision makers the information needed in real-time to make critical decisions on a product.

In most cases, the cost of poor quality is measured using the 1, 10, 100 scale; costing the company 1x the cost of manufacturing if the problem is found during the manufacturing process.  If the problem is found after the product is manufactured, it could cost 10x more to fix. If the product makes it to market, it could cost a company 100x or more the original manufacturing costs to identify and correct an issue.

Analytics will allow companies to set up real-time views of quality events, so on a daily basis they have visibility to the health of their manufacturing processes which will allow them to identify problems early in the process and can take action to remedy the issues quickly and globally.  The faster a decision is made based on complete global data, the more positive effect quality will have on a company’s bottom line.

4. How can TrackWise Analytics be used to progress each role in the pharmaceutical industry?

a. Quality Executives

Quality Executives will have data visibility and reliability required to understand what is happening in terms of quality within their organization. With reliable information, Quality Executives can make more informed staffing and release decisions and interact with the sales and marketing teams delivering the product to the market on time and as expected.  If there is a quality related delay, they have valuable time to plan for contingencies.

b. Quality Managers

Quality Managers are at the frontline; making decisions day-to-day regarding product manufacturing. Having a real-time analysis will allow them to identify and correct any discrepancies faster.  It will also allow them to identify trends so future problems can be prevented.

c. Quality Analysts

Quality Analysts are depended on by quality managers and executives to make sure only the best data is delivered to make decisions. The information they pass on is critical. They will be able to gather, identify and analyze quality data more reliably using analytics with a quicker turnaround time.

d. IT/System Owners

Before analytics, staff would request that IT help gather and analyze data in a format that would be easy to use and understandable.  Providing analytical tools to end users saves valuable time by allowing quality professionals to query and analyze quality data without burdening IT resources as well as decrease reporting and decision-making time.

The Value of an Enterprise Quality Management System in Pre-Clinical and Clinical Development

After working with hundreds of pharmaceutical companies for years, I have noticed that while there is a single company name on the building, there are dividing walls within.  These walls tend to be built between the groups that follow different regulations.  You have your pre-clinical group that follow cGLP requirements and perform early testing, both laboratory and animal, on possible new drugs and compounds.  Behind the next wall you have the clinical group that follows cGCP requirements and are testing drugs on humans, with the main goal of keeping the patients safe and collecting real and accurate data on test subjects.  Behind the next wall is the manufacturing group that follows cGMP requirements and manufactures the approved finished product.  You have three different groups, following different rules, and performing different tasks that are all part of the lifecycle of a pharmaceutical product. In most cases, each of these groups has set up their own systems and processes to support what they do.

Is there a place for a cross-functional Enterprise Quality Management System (EQMS) that can support the unique processes and activities of each group?  With proper planning and cross-functional support, it is not only possible, but advantageous to the company these groups work for.  Let’s take a look at just three of the many processes where a common system can be beneficial.

The first process is auditing, which can be the most challenging.  All three groups perform audits which can have observations or findings, and these observations can create CAPAs.  From a high level, it looks the same.  However, when you get close to the actual activities, you can see what they are auditing –the data they are collecting can have some common information, but the bulk of the data collected is different.  With increased global outsourcing of pre-clinical and clinical trials and manufacturing, the ability for each group to perform audits remotely is critical, and can be accomplished with the offline capabilities of the TrackWise Audit Execution Package.  Auditing in a configurable EQMS allows each group to collect their unique data and follow their own processes, while providing visibility and enabling analysis of the information collected across the entire lifecycle of the product.

The second process is small batch manufacturing.  In pre-clinical and especially clinical research, small batches of test products are manufactured.  Larger batches are manufactured as clinical trials are performed on a larger group of patients.  Tracking and managing manufacturing deviations, lab results, complaints and the resulting investigations, root cause analyses and CAPAs are critical to assure consistent product is being administered and tested.  Managing and controlling changes are equally critical.  All of these are standard, proven processes in EQMS systems.

The third process is one that many companies find difficult to manage consistently.  During the pre-clinical and clinical processes, there is ongoing correspondence with regulatory agencies.  This correspondence can be through letters, faxes, phone calls, e-mails and even text messages.  Some of these correspondences result in commitments made to these agencies.  In most cases, this process of managing correspondence and commitments is controlled by small groups of people, and if tracked, it is done in spreadsheets that may or may not be visible to all who may need to be aware, or may be responsible for meeting a commitment.  TrackWise is a solution that can manage the correspondence and commitments and the related tasks.  As an enterprise-wide system, this information can be available to those in the day-to-day operations as well as to those at a higher level that are involved in various decision making processes about research and trials being conducted.

Using an EQMS to manage quality across the whole organization helps to break down the walls between the groups that are critical to a successful launch and ongoing sales of pharmaceutical products that are proven to be safe and effective.  Having visibility to all the quality events during the entire lifecycle of a product allows for the release of a finished product that can be trusted by the marketplace and protect a company’s positive reputation.

From Change Control as a Point Solution to Global Enterprise Change Management

Pharmaceutical companies, suppliers, contract manufacturers, and other companies across the pharma landscape must have change control systems in place to ensure that any changes in processes or production do not compromise the safety, quality, purity, and potency of pharmaceutical products and biologics.  Different types of changes occur across the business, and any change that affects product quality or safety must be controlled and managed, including changes to processes, equipment, documents, materials, packaging, and others. Today, many organizations track and manage change in isolated point solutions that only manage certain types of changes at certain locations.  For example, two different manufacturing plants may be managing equipment changes in separate, local systems – and perhaps in a completely separate system from document changes. 

Managing change in an isolated manner may allow organizations to meet basic industry guidance and requirements; however, a disconnected and isolated change management system can lead to several challenges and risks, including limited visibility, operational inefficiency, difficulty assessing risk, and disruption to production.

A better practice is to manage change in a global system that encompasses all types of changes across all company locations.  The most effective automated global change management systems electronically and securely manage all information in a centralized, scalable, and reliable system, eliminating the potential loss of information and increasing visibility.  The change control process can be standardized for both local and global changes, streamlining deployment efforts and increasing user adoption.  Managing all change control items in a centralized and harmonized manner enables companies to eliminate redundant systems, decrease production costs, and reduce corporate liability and patient risk.

The ideal vision is to manage global change as part of enterprise quality management:

change control image
change control image

Change control is interwoven with multiple elements of an enterprise quality management system (EQMS), including deviation management, audits, registration tracking, CAPA, and training management.  Best-in-class EQMS can accommodate global change management as a fully integrated element of quality management, enabling full lifecycle management and seamless integration to other quality processes across different business areas, including manufacturing and regulatory affairs.  EQMS provides traceability through functionality that links change control and CAPA records.  Data centralization provides clear visibility to all levels of the organization by enabling more effective trending, reporting, and dashboarding.  And the benefits of managing change within the EQMS reach far beyond the realm of quality management – companies will realize improved cycle time and time-to-market, enhanced product quality, and the flexibility to adapt to changing regulations.

Gaining a Competitive Advantage: EQMS for Start-Ups, Emerging Companies, and Smaller Pharma Organizations

Nowadays, with the advent of social media, we’re well aware that the pharmaceutical sciences industry is no stranger to the U.S. Food and Drug Administration’s breadth and wrath – and it doesn’t matter if it’s big pharma or emerging companies. In a past blog post I wrote about today’s increased regulatory pressures across pharmaceutical and biotech manufacturers and how the need to efficiently track and manage quality and compliance processes is more important than ever for consumer and business health. FDA’s inspections, warning letters and recalls will continue.

Regulatory pressures aside, with increasing competition across the industry, the importance of quality increases as well. Pharma SMBs (small and medium-sized businesses) can look to leading pharma organizations for best practices in quality and regulatory management. For example, using software to automate and streamline fundamental and required business processes like “big pharma” can help emerging companies achieve compliance, increase operational efficiency, and gain a competitive edge. Advanced systems can track, manage, and report on critical business processes such as deviations, complaint handling, supplier quality, internal and external audits, change control, corrective and preventive action (CAPA), and investigation and root cause analysis.

TrackWise SelectStart is an out-of-the-box EQMS solution based upon industry best practices for managing quality events. This packaged solution is a natural capability of Sparta Systems, with nearly two decades of experience across the life sciences industry.  TrackWise SelectStart affords SMBs reduced cost of ownership through a total solution that includes software, a turnkey validation package, and a tailored services approach. Companies can deploy some or all processes in either a phased approach or as a holistic quality management system to ensure compliance, improve operational efficiencies, and reduce costs. To learn more, please contact us.

Is CAPA Enough for Pharmaceutical Compliance?

The pharmaceutical industry faces many challenges, but one that separates it from others is the scope and scrutiny of its regulatory framework. Because the products produced by these companies so directly impact the health and well-being of patients, government agencies like the FDA routinely take measures to improve quality and safety. Correspondingly, executives are in constant pursuit of better ways for utilizing key resources to stay ahead of regulations and deliver high quality products. In the pharmaceutical industry, automated Corrective and Preventive Actions (CAPA) and deviations management have traditionally played a central role in improving the quality of products and processes and ensuring compliance. However, from our research, experiences, and discussions with leading industry executives, it’s apparent that there are a number of additional automated Enterprise Quality Management Software (EQMS) functionalities organizations are using for this.

Below, with the use of benchmark data, I’ll discuss executive focus areas and also which technologies and functionalities companies are using to ensure compliance and improve quality.

Top Quality Management Objectives of Pharmaceutical Executives

The LNS Research 2012-2013 Quality Management Survey helps to visualize this point. One question asked which quality management initiative executives were most focused on in 2012. As seen in the chart below, when compared to all industries as well as the life sciences industry, the pharmaceutical industry has two standout points.

Reducing non-conformances in manufacturing is the top objective for many pharmaceutical companies with 36% of respondents choosing this. The second most frequent objective is ensuring compliance, which is related to non-conformance reduction and was selected by 27% of executives. This isn’t surprising given the regulatory environment in the pharmaceutical industry but one surprise that did stand out was how few pharmaceutical companies are focused on reducing the cost of quality in comparison to aggregate (38% vs. 9%).

top quality objectives
top quality objectives

The Adoption of EQMS Functionalities

A separate question of note in the survey regards which EQMS functionalities organizations were using in 2012. As shown in the graph below, a vast majority, more than 70%, in pharmaceuticals were leveraging CAPA. This functionality directly relates to the top two quality objectives, ensure compliance and reduce non-conformances. What should be noted however is how quickly the adoption of other types of automated EQMS falls off in the industry. For many pharmaceutical companies, the NC/CAPA process was automated with EQMS but additional processes were never included, meaning they are still disconnected and managed by disparate or paper-based systems outside of EQMS.

eqms functionality
eqms functionality

What’s interesting, though, is how effective adding these additional functionalities is at ensuring compliance and reducing non-conformances. We asked a performance question regarding the percentage of products produced in compliance. When we analyze this compliance performance against automated EQMS functionality adoption, a few interesting points emerge around which functionalities are most impactful for helping to ensure compliance.

eqms impact
eqms impact

The results are surprising, with four functionalities standing out in the above boxplot: change management, audit management, Failure Mode and Effects Analysis (FMEA), and Hazard Analysis and Critical Control Points (HACCP). For the companies having adopted these functionalities, the upper two quartiles (top 50%) of organizations using these functionalities are experiencing 99% to 100% of products in compliance, which is very strong performance when compared to some of the other functionalities. Second, and even more impressive, is the performance of the two lower quartiles (bottom 50%) which are achieving strong performance in their own right, 98% - 96%. When compared to some of the other types of functionality that have very little impact on performance, the bottom 50% of performers can range from 98% all the way down to 90% or lower.

Clearly, leading pharmaceutical companies have already invested in EQMS with NC/CAPA, but many have not taken it far enough. To best address the pressures of the industry today, it is imperative for leaders to take full advantage of EQMS as a business process platform and build out a full portfolio of important quality management processes. By mapping and connecting processes across the value chain, companies can pursue the task of ensuring compliance and reducing nonconformances in manufacturing in a strategic way. With EQMS, business processes can be built out in a manner that provides cross-functional communication and collaboration that would otherwise be very difficult to achieve.

About the Author: Matthew Littlefield founded LNS Research in August of 2011 and is now President and Principal Analyst. Matthew is a recognized industry expert and contributes to many leading industry publications. When he isn’t writing, Matthew is a frequent public speaker on manufacturing initiatives, drawing upon his industry analyst, engineering and shop-floor management experience.  URL: http://www.lnsresearch.com

A Closer Look at FDA’s Final Rule for 21 CFR Part 4 – Current Good Manufacturing Practices for Combination Products

On January 22, 2013 the FDA published the Final Rule for “Current Good Manufacturing Practices for Combination Products” in the Federal Register.  This rule is designated 21 CFR Part 4, and becomes effective July 22, 2013. The history of this rule goes back to October of 2004, when FDA released a guidance document regarding the application of cGMPs to combination products.  This guidance provoked differing interpretations, which resulted in inconsistent or varying application of the various cGMP requirements, which FDA felt could affect product safety and public health.  FDA also observed that the absence of clear cGMP requirements for combination products was leading some manufacturers to develop and document practices that were redundant and overly burdensome.  FDA released the proposed rule in September of 2009, which resulted in the final rule that was recently released.

Within the preamble and the rule, FDA defines the combination products that are governed by this regulation: combinations of drug/device, biologic/device, drug/biologic or drug/device/biologic are all covered by this rule.  A combination of like products (i.e. drug/drug) are not covered by this rule, and respective existing cGMP regulations apply in those cases.

The good news is that Part 4 does not create any new cGMP requirements; FDA believes there are many similarities to the existing requirements.  It does clarify which cGMP rules need to be enforced based on the conditions under which the combination product is produced and marketed.  The existing cGMP rules that apply to combination products are:

- Drug products – 21 CFR Part 210 and 211

- Medical devices – Quality Systems (QS) Regulation – 21 CFR Part 820

- Biologic products – 21 CFR Part 600 through 680 (where cGMPs are applicable)

- Human cell, tissue and cellular & tissue-based products – 21 CFR Part 1271

How each of these these existing rules apply to combination products depends on the specific circumstances under which the combination product is produced, packaged and marketed.  In the case where the constituent parts are manufactured and marketed as separate products, and are also cross labeled to create a combination product, they remain separate for the purpose of applying cGMP regulations, and need to be manufactured under separate drug, device or biologic cGMPs.

21 CFR Part 4 gives companies two options for single entity and co-packaged combination products, including investigational products.  The first is to demonstrate compliance with the specifics of all cGMP regulations applicable to each of the constituent parts included in the combination product.  The second option is to demonstrate compliance with either the specifics of the drug cGMPs or the device Quality Systems regulation, rather than both, when the combination contains both a drug and device under certain conditions.  If the second option is chosen, compliance with specified provisions from the other of these two sets of cGMP requirements must be demonstrated. 

If a single entity or co-packaged drug/device combination product is produced under a cGMP system that complies with the drug regulations, it also must satisfy the following provisions of the device Quality Systems regulation:

- Section 820.20 – Management responsibility

- Section 820.30 – Design controls

- Section 820.50 - Purchasing controls

- Section 820.100 – Corrective and preventive action

- Section 820.170 – Installation

- Section 820.200 – Servicing

If the above are satisfied, no additional compliance with the device Quality Systems regulation need to be made. 

If a single or co-packaged drug/device combination product is produced under a system that complies with the device Quality Systems regulation, it must also satisfy the following provisions of the drug cGMP regulations:

- Section 211.84 – Testing and approval or rejection of components, drug product containers and closures

- Section 211.103 – Calculation of yield

- Section 211.182 – Tamper-evident packaging requirements for over-the-counter (OTC) human drug products

- Section 211.137 – Expiration dating

- Section 211.165 – Testing and release for distribution

- Section 211.166 – Stability testing

- Section 211.167 – Special testing requirements

- Section 211.170 – Reserve samples

Again, upon demonstrating the above requirements have been satisfied, no additional compliance with the drug cGMPs need to be made.

If the combination product includes a biologic product, in addition to the above conditions, the applicable cGMP regulations found in 21 CFR Parts 600 through 680 and 1271 apply.

Now that the finalized regulation has been published, FDA is planning to publish additional clarifying guidance documents.  One of the clarifying guidance documents they point to in the preamble to the rule outlines how to comply with the rule and pre-manufactured design control requirements for combination products that are already on the market and may not have all of the required documentation.

Sparta Systems Enterprise Quality Management System, TrackWise, is uniquely positioned to assist companies producing and marketing combination products manage their cGMP processes.  TrackWise is in use as the pillar EQMS systemin more pharmaceutical, medical device and biologic companies than all other quality systems combined.  TrackWise can be configured to meet the unique and different requirements of the various conditions defined in 21 CFR Part 4.  To discuss your needs, please contact us via e-mail at: insidesales@spartasystems.com or reach out directly to your Account Executive.