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BioPharm International, January 2010 Issue (PDF)

Biopharmaceutical companies undertaking Quality by Design (QbD) initiatives find themselves in the quandary that accompanies any significant advance in life sciences manufacturing: If we implement a far-reaching change in the way we operate, what will it mean to our compliance status? In the case of QbD, the question is even more confounding because QbD represents a profound change in the nature of compliance itself. 

The increased scientific understanding of products and processes that lies at the heart of QbD makes it possible for manufacturers and regulatory agencies to focus on critical control points and parameters necessary to ensure that products meet quality attributes. They can then base compliance on risk—the probability that as long as the multi-dimensional combination of input variables and process parameters remains within the validated design space, or are otherwise controlled to achieve specified product attributes, then product quality is ensured.  

For manufacturers, that will mean establishing an integrated quality system designed to accommodate the far more holistic and flexible approach to compliance that QbD requires. For regulators, it will mean understanding the decisions that manufacturers make when manufacturing their products instead of relating current good manufacturing practices (cGMPs) to a set of rigid and highly complex requirements.  

Unfortunately, there is no template that biopharmaceutical companies can follow to establish their approach to compliance under QbD. The step 2 draft of the ICH Q11 guideline, 

Development and Manufacture of Drug Substances

, which is intended to bring together and clarify issues related to quality systems raised in previous ICH guidelines, will not be released until late 2010. Even then, it is likely to provide only a framework for compliance, not a step-by-step guide to creating the organization, policies, and processes that are most likely to take best advantage of the opportunities promised by QbD: greater assurance of quality, reduced costs through less rework and rejected batches, and a lighter regulatory burden.  

Furthermore, QbD tools will continue to evolve. Today, documentation of a design space is the preferred approach to risk-based quality assurance (QA) because we have the tools and technology to determine it. However, process analytical technology (PAT) will continue to improve and eventually could become capable of controlling a manufacturing process in real time. When that occurs, there may no longer be the need to document a wide, multidimensional design space. As long as we know how the process relates to the product output, PAT would be able to ensure product quality at all times. 

With no compliance template and the continued evolution of QbD tools, biopharmaceutical companies face a host of questions about the specifics of compliance, including:   

How will implementing QbD and quality risk management (QRM) strategies affect my current cGMP compliance status? How will I know about a change in that status?

Will agency audits be looking at traditional GMPs (i.e., deviation reports) when we've incorporated risk-assessment decisions and processes? If so, for what purpose? 

If there is movement trending within the design space, when do we implement a change? Who decides? How is this decided? 

What are the regulators' expectations about how we "regulate" our operating parameters or design space? Are full-scale batches required for that purpose, or will qualified scale-down models be sufficient? (An FDA draft guidance document from November 2008 indicates the intent to reduce the need for re-establishing validated parameters at scale, but there is still uncertainty surrounding the specific compliance requirements for a validated design space.)

When we make changes in our defined design space, do we still conduct investigations and write deviation reports? 

What trends and changes have to be part of batch records? What changes are for information only and what has to be a part of required batch documentation? 

Although there are no definitive answers to these questions, newer perspectives on risk management, knowledge management, continuous verification, and real-time feedback, analytics, and control (including PAT) can be understood as extensions of general GMP principles: State what will be done, by whom, and when. Define acceptable performance and outcomes. Document the actual execution and outcome and make the whole process traceable.  

Basic GMPs also provide a framework for lifecycle process management, but under QbD they need to accommodate important new scientific justifications and data. For example, the addition of design qualification to basic equipment qualification (IQ/OQ/PQ) requires the organization to justify that the equipment design is appropriate for its intended use. Similar justifications must be considered for process and product profile decisions. 

With these principles in mind, a biopharmaceutical company can bring together cross-functional teams to consider three key activities central to implementing QbD: QRM, knowledge management, and change control. These activities encompass the four elements that define products and processes as validated and compliant: critical process parameters, critical quality attributes (CQA), critical material attributes, and relevant target product profile attributes.  

By undertaking these considerations and approaches, the cross-functional teams can better frame and address the questions arising from these activities. After they develop and prioritize the answers, they can begin to integrate the new practices into the existing quality system and start to find the way forward.  

Traditional GMPs are a means of establishing traceability—the assurance that processes have been carried out and that the end product conforms to specifications. But they offer no mechanism for adding scientific insight and accumulated experience or knowledge, as there is in quality risk management.  

ICH Q9 defines QRM as "...a systematic process for the assessment, control, communication and review of risks to the quality of the drug (medicinal) product across the product lifecycle." The advantages of the lifecycle management of risk are obvious—the continuous improvement of product and process based on continually increasing knowledge. The industry has long been comfortable with the idea of phased-in compliance during development but has not been as good at integrating development, clinical, and commercial data; and traditional GMPs provide little guidance. 

Biopharmaceutical manufacturers cannot eliminate risk altogether. Risk-based quality management aims to reduce risk as much as possible through continuous science-based and data-driven evaluations. In this way, QRM provides the means to achieve the continuous improvement and integration of data that is expected from QbD implementation. 

Consider, for example, the statistical evaluation of the design space or process capability. Multivariate statistical analysis tools are required for this exercise. Effective execution requires personnel with expertise in both the process and statistical analysis (but not necessarily in GMP compliance). The tools and data that are used may vary with the specific process under analysis, and also with the risks associated with that process. Further, acceptance criteria may not always be prescribed with this approach, as they are for such items as a Certificate of Analysis or validation criteria. Rather, acceptance criteria may result from the risk analysis and the evaluation exercise. 

Because these analyses do not follow a traditional GMP/SOP format, compliance in a QbD environment is better suited to evaluating how the exercise was carried out, for example, by asking:  

Were the right individuals involved in the risk analysis and statistical evaluation?

Were all appropriate sources of data considered?

Were the analyses conducted and documented appropriately?

Were the outcomes and mitigations consistent with the risk profile? 

Do the decisions (changes) better ensure that the target product profile is achieved?

Were the decisions communicated effectively? 

With these characteristics of QbD, QA scrutiny should be concentrated at the level of process, not outputs. And, statistical analyses of process and analytical data will now become justifications for further process controls and changes. They also become the platform of knowledge for other products. 

Furthermore, traditional QA metrics revolve around days to review records and closing deviations and corrective and preventive actions. In many companies, the sheer volume of records has created the need to do only spot checks. Better metrics might gauge whether problems were actually solved or proposed mitigation plans actually work. In other words, compliance needs to be measured in terms of the effectiveness of quality systems. Further, because deviation within the design space is acceptable, risks must be calculated in real time for the company to decide whether to continue processing when an excursion is encountered. Therefore, those who are doing real-time assessment must have access to the knowledge and tools they need to do the job—elevating knowledge management to more than a mechanism of record-keeping for purposes of traceability.  

Knowledge management in the quality system should help produce higher value information, better decision-making, and more organized, easily retrieved documents. The type, frequency, and contents of documents and the documentation process present some of the most vexing questions for companies. Although there are no clear-cut answers, documentation is tightly tied to QRM. As ICH Q9 says, "the level of effort, formality, and documentation of the quality risk management process should be commensurate with the level of risk." 

What this suggests is that documents and documentation processes should be flexible, yet provide guidance on decision-making based on risk assessments, process inputs, laboratory data, and other data. That means adapting cGMP records to capture scenarios and data, risk assessments, decisions, and justifications, rather than simply the data that are commonly recorded. For example, the practice of reviewing a single batch record as it was executed does not allow for the monitoring of trends or of overall process execution. Conventional documentation audits are restricted to uncovering documentation practices and verifying individual calculations. They do not provide an adequate picture of the process capability or the overall capability of the manufacturing team and equipment. 

Thus, the addition of knowledge management and QRM to quality systems elevates compliance considerations to a higher level, moving away from document execution to document content, effectively shifting the focus of compliance from the management of paper to the management of knowledge. 

As with the implementation of QRM, knowledge management should be incorporated into current systems to minimize operational and cultural disruption. Comprehensive knowledge management may require some new systems, but the goal is to bring data together to enable its conversion into knowledge, not to create yet another place to put data.  

The change control process should be designed to enable the staff to:   

Establish what level of review is required at each stage of development to determine whether the process and product are within the design space.

Decide when trends toward the limits of design space require a change in input variables or process parameters.

Distinguish changes that require regulatory approval and those that do not.

Capture data outputs as a result of changes.

Prospectively assess the effects of changes on process capability and product quality for the longterm.

An effective change control system that achieves those objectives will also work with the knowledge management system to make a significant contribution to the overarching goal of continuous improvement in the process and product.  

Change is, after all, inherent in the development process and should be used to gain knowledge and improve product quality. Traditional quality oversight in development would check and audit notebook citations and technical reports, which is not very useful for gaining product and process insight. Instead, QA might put out a guidance for how change information should be captured and communicated. The rigors of this process and experimental justification should be commensurate with the phase of development.  

 is a senior consultant, both at Tunnell Consulting,  King of Prussia, PA, 610.337.0820, 

Regulatory Beat

How will implementing Quality by Design strategies affect your compliance status?

Quality by Design and Compliance Readiness

After a year of considerable turmoil in Washington policy and regulatory circles, there is optimism that healthcare coverage and requirements for medical product development will gain some clarity in the coming months. National health reform legislation either will become law in some form, or die. The new team heading up the US Food and Drug Administration will be firmly established and eager to implement new policies and programs. These developments will shape a number of key trends and developments in 2010 of importance to biotech manufacturers. 

International funding of a vaccine to combat the H1N1 influenza pandemic has spurred construction of new vaccine manufacturing facilities in the US and abroad, and that trend is not likely to diminish. Manufacturer interest in expanding sales in newly industrialized nations has spurred worldwide support for research on new vaccines and for treatments for malaria, tuberculosis (TB), and neglected tropical diseases, along with investment in foreign manufacturing facilities and new vaccine production and testing methods. Vaccines to combat malaria and TB are in clinical trials, and scientists remain optimistic about moving forward with the long-sought vaccine to prevent HIV infection. An anti-smoking vaccine is moving into late-stage testing, while scientists continue to seek therapeutic vaccines for cancer and other conditions.  

The FDA is supporting such efforts, particularly development of new TB treatments to replace ineffective old therapies and to help counter a resurgence in drug-resistant TB strains. And to better monitor the growing volume of food items and medical products imported to the US, the FDA is establishing overseas offices and doubling the number of foreign inspections it conducts each year. New legislation to overhaul food safety would further expand FDA inspections of food facilities in the US and abroad. In addition, the FDA is partnering with European regulatory authorities to share inspection information and conduct joint inspections of foreign active pharmaceutical ingredient producers, an initiative that could expand if beneficial.  

Longer supply chains and rising imports raise questions about the ability of drug manufacturers to ensure the quality and safety of biomedical therapies. Because the FDA can never check all of the thousands of products coming into the US, the agency expects manufacturers to do more to ensure that contractors and suppliers have a commitment to quality, and that they are routinely monitored and inspected. The aim is to prevent future adulteration crises, such as those involving heparin, melamine, and DEG-contaminated glycerin in medical products.  

Along these lines, the FDA's Center for Drug Evaluation and Research (CDER) continues to emphasize the importance of manufacturer Quality by Design (QbD) and risk management systems to ensure drug quality. CDER officials are evaluating a QbD review pilot and launching a similar initiative for biotech therapies. Additional efforts to harmonize quality standards are under discussion. An electronic drug registration and listing system was fully implemented this past year and should make it easier for the FDA to identify and track products and manufacturing facilities.  

The FDA also is involved in multiple initiatives to encourage the safe use of medicines. The FDA Amendments Act of 2007 (FDAAA) authorizes post-approval label changes when new safety issues arise and action against manufacturers that fail to conduct agreed-on post-marketing studies. There are mandates for more extensive listing of clinical trials and study results on the ClinicalTrials.gov public web site and for Risk Evaluation and Mitigation Strategies (REMS) governing post-market prescribing and surveillance. The FDA has approved REMS for almost 90 products and is developing a REMS for the entire class of extended-relief opioid medicines. Manufacturers will be watching to see how well these programs detect and prevent drug safety problems and if that encourages FDA reviewers to approve products that raise some safety concerns.  

Internally, the FDA is bolstering its safety assessment efforts through several initiatives. CDER's Safety First program is integrating oversight of drug safety issues by clarifying responsibility for pre- and post-approval drug safety assessment and strengthening safety-related policies and procedures. The agency's Sentinel Initiative is developing an electronic system for monitoring medical product safety. And the FDA's Safe Use initiative aims to build partnerships with other components of the healthcare system to ensure that medicines are used safely and appropriately. The FDA plans to partner with other government agencies and with healthcare providers to address situations that lead to medication errors and inappropriate prescribing.  

The Sentinel System requires access to electronic health information systems, a prominent goal of health reform efforts. Medical record databases offer a way to accelerate detection of drug adverse events and to streamline data collection from clinical trials and population studies.  

At the same time, broader access to personal health information has generated demands for stronger protections against unauthorized disclosure of patient records, which may stymie research and treatment.  

PERSONALIZED MEDICINE AND COMPARATIVE RESEARCH

Health information systems also are critical for the development of personalized, or individualized, medicine and the diagnostics needed to determine who may benefit or experience harm from certain therapies. The shift to more targeted treatment requires access to personal health data to recruit research subjects who meet increasingly specific genetic-based enrollment criteria, and to identify those individuals who should—or should not—receive a treatment based on specific genotype.  

Researchers also will be tapping health system databases to assess outcomes and to compare the risks and benefits of medical products. Federal agencies are funding a number of comparative effectiveness research (CER) projects with an eye to assessing a broad range of medical treatments and strategies. The industry seeks limits on federal funding of studies that compare one drug to another and focus on cost comparisons, but more CER will inevitably highlight comparative prices as well as health benefits. 

Whatever the outcome of health reform legislation, the high prices of many biotech therapies will remain in the spotlight. Both Wall Street analysts and patient advocates have documented record increases in wholesale drug prices this past year, at a time when inflation was declining. The studies exposed manufacturers to charges of jacking up revenues in anticipation of tighter legislative controls on pharmacy spending.  

Such developments will continue to build support for greater access to generic drugs, including follow-on biologics (FOBs). Congress is poised to establish a regulatory pathway for bringing biosimilars to market. There is general agreement among generics makers and innovator firms on FDA regulatory standards and clinical testing requirements, but strong disagreement on patent issues: pharmaceutical and biotech companies successfully pushed for 12-years exclusivity on FOBs which has infuriated generics makers. Manufacturers on all sides will be assessing how these requirements will shape the development of biosimilar products.  

Transparency is a recurrent theme in health reform and regulatory matters. Efforts to lower the prices of biomedical treatments have built support for broader disclosure of manufacturer rebates and discounts negotiated by payers and health plans. Congress seeks to further shed light on industry payments to physicians as a way to reduce commercial influence on prescribers.  

Manufacturers also face more transparency in FDA regulatory decisions and pending drug applications. Commissioner Margaret Hamburg established a high-level FDA transparency task force last June to identify ways to better inform the public about FDA operations. The panel headed by Deputy Commissioner Joshua Sharfstein is examining the viability of disclosing information about applications filed with the agency, what kind of emerging safety information should be disclosed and when, and whether early communication about ongoing safety reviews of foods and medical products would be beneficial or raise unnecessary concerns about a product. The panel will issue a report in the coming year on what information the FDA should be able to release on its own and what changes require new regulations or legislation. 

 Washington editor, Chevy Chase, MD, 301.656.4634, 

Demand for new vaccines and therapies in 2010 will be offset by concerns about drug prices and product safety.

Issues and Opportunities Challenge Biotech Manufacturers

Melamine-tainted baby formula and pet food. Allergic reactions and deaths from contaminated heparin. Recent events have made supplier quality issues a top priority, for both the biopharmaceutical industry and its regulators in the US and Europe. Bottom line, what happens at any outsourced manufacturing operation can cause your company legal liability, damage your reputation, and subject you to the considerable expense of a recall. Yet outsourcing some or all of the manufacturing process has become an inevitable part of doing business for the vast majority of biopharmaceutical companies. 

Managing supplier quality is always a challenge. When you're dealing with possibly hundreds of suppliers around the globe who are engaged in a broad array of complex manufacturing processes, the challenge often appears to be insurmountable.  

Rather than apply a single quality management approach to all suppliers—an approach that frequently is unworkable and invariably is inefficient—we recommend that companies develop a robust, risk-based approach that addresses each supplier situation individually, but always within the context of a carefully thought-out overall quality management system.  

Risk-based quality management is one of those brilliantly simple concepts that makes all the sense in the world when you see it spelled out: When you focus on the risks with the potential to cause the greatest damage, you will almost certainly reap the greatest rewards from mitigating those risks. Or, to put it another way, you want to expend the greatest efforts in areas where you'll get the greatest "bang for the buck." 

Yet, unfortunately, implementing a risk-based supplier quality management system isn't simple. Over and over, we have encountered companies whose best efforts were frustrated by failure to master one or more of a very short list of critical steps to success. If you get these five building blocks right, however, you will be well on the way to implementing a risk-based supplier quality management system that will not only prevent errors before they can develop into major problems, but also will improve the productivity and efficiency of your whole manufacturing process. 

1. Classify Every Supplier by Risk Level—and Deal With Them Accordingly

Classifying suppliers by risk is the heart and soul of every risk-based quality management program. The risk level refers not to the probability of some particular event occurring, or even to the effectiveness of the supplier's internal quality system. Rather, labelling suppliers as "highest risk" means simply that what they provide is "most critical to your product," even if that particular supplier is completely reliable. 

Components that present a lower risk to product safety or performance but are essential to the manufacturing process also may be considered critical and may need special measures to ensure an uninterrupted supply. Criticality should also be considered in terms of process complexity or the inability to obtain the product from a different supplier. 

We generally recommend that our clients establish four risk-based categories of suppliers:  

Tier 1: The highest risk suppliers, that have a critical impact on the quality or availability of your product. You can't get along without them.

Tier 2: Significant-risk suppliers that have a direct impact on your product, but for which alternatives are available.

Tier 3: Moderate risk suppliers that have an indirect impact on the product.

Tier 4: Low risk suppliers, that have no product impact.

It makes sense, both financially and in terms of quality management, to expend the greatest effort on the most critical suppliers. The quality assessment and control measures used, and the duration or interval between assessments, are adjusted based on the degree of risk exposure to each individual supplier. The higher the importance of the supplied product to the quality of the finished product, the more vigilant you must be in establishing adequate controls over the supplier. It all comes back to getting the most bang for your buck. Without a coherent system in place, you can drive yourself crazy trying to determine how much control to exert and how to apply it. 

2. Look Before You Leap into a New Supplier Relationship

Optimism is a hallmark of all new relationships, both personal and professional. Unfortunately, the good feelings that surround a new relationship are no substitute for due diligence in checking out potential new suppliers—especially sole source suppliers, where one unexpected problem could leave you with no acceptable options—and then laying out expectations, and checking quality. 

 Because you are primarily interested in starting a successful relationship, it's hard for you to be entirely objective. That's why you need an objective observer, such as a third party consultant, who understands regulatory and quality requirements as well as your needs, and who can be totally forthright in evaluating your potential supplier's facilities, processes, and quality systems.  

 This is no place for generalizations or boilerplate lists; be painstakingly specific. Because every product is different, your supplier has to understand exactly what criteria you require to ensure the quality and specifications of that particular supplied product.  

Change control notification procedures are a common area of misunderstanding; a change the supplier considers inconsequential may make all the difference in the world to your product. So you need to specify that all changes must be communicated to you, and when and how they must be communicated. 

Finally, you need to understand that supplier quality management extends beyond the end of the production line, and includes criteria for such things as delivery reliability, responsiveness, and the security of the supply chain.  

In fact, the FDA recently launched a pilot supply-chain security program to determine the practicality of improving the safety of drugs and active ingredients produced outside the US. Participation is voluntary, but it will probably streamline customs formalities. In any case, maintaining control of your products at every step from raw material to pharmacists' shelves should be a standard part of every risk-based quality management program. 

Your supplier also needs to understand your requirements for monitoring quality. If you want the supplier to submit to quality audits, provide certificates of analysis or conformance, or provide independent laboratory analysis, you must make all that clear up front.  

All of this should be formalized in a risk-based quality agreement. (See item 3 below.) 

It's always better to catch and fix issues early on, before they develop into full-blown problems (or, as in recent events, full-blown disasters).   

But sometimes you have to rely on a supplier whose quality systems do not entirely measure up to your expectations. In those cases, you'll need to compensate for any supplier shortcomings through a robust receiving inspection program. You may even want to have your own representative in the plant to ensure that quality specifications are met before product is shipped. Again, finding a problem earlier is always better. 

3. Apply Risk-Based Thinking to Your Quality Agreements

We have said that you need to make your expectations clear to the supplier. The regulators say the same thing: The International Conference on Harmonization (ICH) Q10 guideline on pharmaceutical quality systems discusses the manufacturer's responsibility to assess the suitability and competence of a supplier and to define in writing the quality-related responsibilities of both the manufacturer and the supplier. 

A quality agreement is a formal document that does exactly that: it defines who has responsibility for the execution of every aspect of the quality system. The level of risk exposure should define the nature of the quality agreement. 

Quality agreements can range from simple purchase orders to elaborate contracts, and there is no easy rule of thumb for how much detail is enough. In general, however, we have found that clients err on the side of insufficient detail; it's surprisingly easy to think that a boilerplate purchase order covers more than it really does. It's a good idea, for example, to specify:  

when and how you should be notified of changes 

when and how you should be notified of out-of-specification test results, manufacturing deviations, and nonconforming materials

which party will conduct finished product testing

how reporting and investigating product complaints will be handled

which FDA quality systems and ISO requirements the supplier must meet.

By and large, if it's worth thinking about, it's worth including.  

Remember that "agreement" means the supplier has to agree to it. Sure, you're trying to protect yourself. But you're also trying to optimize supplier performance, which is clearly in the supplier's best interest. So whenever you can, work with the supplier to map out manufacturing and quality system areas of responsibility. Be clear about hand-off points and high-risk areas. Specify the controls necessary to mitigate the risk in these areas, and always match the extent of the controls to the level of risk.  It's also important to remember that these agreements are formal, legal documents, so it's critical to have your legal department tuned in to the development and execution of the agreements. 

4. Have On-Site Quality Audits Performed by an Objective Auditor

On-site audits are the most reliable source of information about a supplier's operations. For an on-site audit program to function properly, the audits must be thoroughly objective and conducted by a qualified auditor. That means an auditor from your compliance function, or a third-party auditor, is usually preferable to an in-house team member, such as the supplier quality engineer who works with (and tends to identify with) the specific supplier. 

Audits must be performed regularly to ensure quality. The logistics and costs of site audits have increased significantly with the rise in outsourcing to foreign countries, especially for Western companies with suppliers in Asia. All too often, audits are postponed or limited to being carried out "for cause," or follow-up audits are not performed simply because it's such a nuisance to get them done. Unfortunately, saving money by skipping audits is never a good trade-off. 

Instead, you can minimize costs by bundling audits of suppliers in the same geographic region. It's simply a matter of planning ahead, so your auditors can schedule multiple visits on a single trip. 

Use a risk-based model for planning your audit program. Not every supplier requires on-site audits; for less critical ones, third party laboratory testing, certificates of analysis, and supplier surveys may be acceptable substitutes for some on-site audits. 

Supplier defects become your responsibility by default, so you have to initiate corrective actions associated with supplier operations just as diligently as you would with in-house products.  

That means supplier quality problems should be input into your corrective and preventive action (CAPA)/deviation system and followed up with whatever corrective action is needed to prevent recurrence of the problem. 

CONCLUSION: BENEFITS THAT GO BEYOND REGULATORY COMPLIANCE 

Regulators require you to manage supplier quality as if it were your own. In reality, supplier quality management is far more complex than internal quality management, because of factors of both distance and incomplete control.  

A systematic risk-based approach to supplier quality management, as outlined above, can make the process manageable even if you are dealing with hundreds of suppliers worldwide. In fact, we believe it is the only feasible approach. When you treat every supplier as a top priority, you have no way to systematically gauge how much attention (and investment) each one realistically deserves. 

Establishing a risk-based system is well worth the effort. In addition to ensuring compliance and avoiding recalls, regulatory and quality problems and liability, a well-managed supplier quality management system enables you to establish sustainable processes that improve operational efficiency and make your product more competitive in the global marketplace. 

The bottom line is that it's too important to risk not doing.   

Perspectives on Outsourcing

A systematic classification system makes supplier quality management feasible, even if you are dealing with hundreds of suppliers worldwide.

Supplier Quality Management: A Risk-Based Approach

The life sciences industry is experiencing a significant transformation caused by market pressures. In response, leaders of pharmaceutical and biotech organizations of all sizes are looking to streamline the R&D process, provide greater manufacturing flexibility, reduce regulatory burden and development costs, and accelerate time to market. 

Quality by Design (QbD) will be key to the success of such initiatives. When executed properly, its benefits include improved compliance, more efficient product development, and enhanced business performance. The US Food and Drug Administration also has begun to back this approach with a pilot program for regulatory submissions based on QbD methodologies.  

Yet QbD initiatives typically are affected by organizational challenges, as can be expected when trying to integrate business processes and systems across different divisions toward an enterprise goal. These challenges are more prevalent in large organizations, giving smaller biotech organizations an advantage for rapidly launching effective QbD programs. 

Many small biotechs ask, "Where do we begin?" The three core elements of QbD described below point the way forward: 

A scientific, risk-based, "holistic and proactive" approach to product development

It is not enough to think of QbD as a manufacturing initiative. Although most companies initiate QbD projects based on information in manufacturing systems, they should be initiated further upstream in product development. Adopting a risk-based and proactive approach to development can ensure that knowledge associated with the development process is encapsulated and reused further downstream. A common approach is to provide an integrated cross-functional platform for supporting design of experiments, decision-making and reporting, and electronic batch records associated with development manufacturing.  

Deliberate design effort from product concept through commercialization

A deliberate design effort implies that commercial manufacturing constraints are integrated into the development and technology transfer processes. This ensures that final (scaled-up) processes and product qualification requirements are fully taken into account when making design parameter decisions. Many biotechs can benefit from implementing a program and portfolio solution for secure third-party collaboration integrated with iterative quality feedback. This will help achieve a deliberate design effort during the technology transfer process, particularly when working with a contract manufacturing organization.  

Full understanding of how product attributes and process relate to product performance

QbD is based on knowledge management throughout the product lifecycle. But collecting information across research, development, manufacturing, quality, and distribution organizations is nearly impossible when these functions are spread over countries, manufacturing facilities, operating units, and cultures. Creating a knowledge repository that provides a history of all development iterations and related quality events in a structured database facilitates a full understanding of the parameters that affect product performance. If this repository is searchable and reusable, it can be the cornerstone for a process knowledge management system. 

Small biotechs today have the opportunity to create a competitive advantage by deploying QbD initiatives. Because they are inherently agile, they can make significant progress toward QbD and improved performance in the short-term by introducing a few basic processes and tools.  

 is the senior director of life sciences at Oracle Corporation,  Redwood Shores, CA, 800.ORACLE1. 

Final Word

The nimbleness of biotechs makes them well suited to implementing QbD. Here's how to get started.

QbD: A Roadmap to Adoption

Despite a 10% fall in value during October, The Burrill Biotech Select Index clawed back almost half this amount in November and is on track to close in positive territory by the end of 2009. 

In recent months, we have seen a gradual recovery for the biotech sector and the capital markets as the worst of the global economic recession seems to have been put behind us. For example, from the end of the first quarter of 2009, the markets have gained about 60%. Both the Dow and the S&P 500 hit 13-month closing highs post Thanksgiving, as economic data pointed to hopes of stabilization in the labor and housing markets and provided reinforcement to analysts' predictions that the economy is finally in recovery mode. 

The Burrill Biotech Select index (up 14%  since it hit its lowest point in March) still lags the general markets' performance to date. However, with the comparative stabilization of the capital markets, we are seeing some encouraging signs of good things to come. The total that US biotechs have raised through follow-on financings is up over 100% on the total raised in 2008.  

It has not only been the blue chip biotech companies that have seen their values increase in the second half of the year: the Burrill Large Cap Biotech index is up 20% year-to-date (YTD), but the emerging companies also have performed well, with the Burrill Mid-Cap Biotech index up 13% YTD and the Burrill Small-Cap Biotech index up 10% YTD (Table 1). The companies that have survived the financial markets' meltdown are well placed to adapt to the new environment that we now are entering.  

Table 1. Year-to-date (YTD), the Burrill Large Cap Biotech Index was up 20%

Follow-on financing is generally a harbinger of the opening of the initial public offering (IPO) window and already we have witnessed three biotech IPOs—two specialty pharmaceuticals and one biotech company. In August, Cumberland Pharmaceuticals raised $85 million by offering five million shares at $17, below the expected range of $19 to $21. The specialty pharmaceuticals company has products on the market, including a new injectable treatment for pain and fever. Talecris Biotherapeutics, a manufacturer of plasma-based proteins, raised a whopping $950 million with its IPO. Like Cumberland, the company has products on the market and its 2008 sales were $1.4 billion. 

In early October, Omeros Corporation became the first venture-backed biotech to go public. It priced its IPO of 6.82 million shares at $10 per share, but then saw its shares drop almost immediately, closing down 13% on its first day of trading (and closing November down 28%). The company is using the funding to complete Phase 3 trials of its lead drug candidate, which is being evaluated for use during arthroscopic surgery.  

Omeros's opening and subsequent share price performance shows the difficulty that will exist for many biotech companies that are not yet profitable and are thinking about raising money in the public markets. We are likely to see up to 15 companies add themselves to the IPO runway shortly with the hope that around the time of the JP Morgan Healthcare Conference in early January 2010, the markets will be receptive enough to invest in new biotech issues. The first biotech IPO movers of 2010 will have to perform well for the IPO window to open wider.  

In the final quarter, four biotech companies already added themselves to the IPO runway: 

hopes to raise up to $173 million in an IPO. Linaclotide, the company's first-in-class compound, is being evaluated in a confirmatory Phase 3 program for the treatment of irritable bowel syndrome with constipation and chronic constipation. Ironwood has already raised $306 million in private equity financing and recently announced that it had partnered with Japanese pharmaceutical powerhouse Astellas, granting them exclusive rights to develop and commercialize linaclotide in Japan, Indonesia, Korea, the Philippines, Taiwan, and Thailand. 

which focuses on the discovery, development, and commercialization of antibiotics for serious infections, filed to raise up to $86 million. The company is planning two Phase 3 trials of the second-generation oxazolidinone that inhibits bacterial protein biosynthesis to treat serious Gram-positive bacterial infections.  

developing products that treat retina-related diseases, filed to raise up to $80 million. Currently, the company is focused on diseases affecting the retina. Its most advanced product candidate is Iluvien, which is being developed for the treatment of diabetic macular edema. 

also took its place in the queue of companies hoping to go public in the coming months as the IPO window begins to open. The company, which develops regenerative cell therapies, had initially filed to go public in May 2008 but withdrew those plans in October 2009, when the stock market melted down. The company hopes to raise an estimated $80.5 million to fund a Phase 3 trial of its most advanced therapy for the treatment of critical limb ischemia.  

Although there is still some residual investor nervousness about the strength of the economic recovery, there is no doubt that the markets are back on track and the biotech industry will certainly benefit from this in 2010. Biotech companies also are benefiting from Big Pharma's willingness to pay for innovation. Partnering revenues have been a staple for many biotech companies throughout the year and, as a result, we are likely to see a record amount raised by US biotechs by the close of the year. 

Notable partnering deals in the past few months have included several that could be potentially worth over $1 billion (Table 2). 

Table 2. Selected partnering deals in 2009 

Healthcare reform will pass and this will have a mixed impact on the biotech industry. The proposed reform is in favor of allowing 12 years of data exclusivity for biotech drugs, and that is good for our industry. With 25–50 million Americans added to the healthcare system, revenues for the healthcare industry should increase, which is also a positive. However, there continues to be some investor uncertainty over the healthcare reform debate and this is likely to continue as the legislators wade through the proposals. The drug industry certainly will take a big hit in the House bill. For elderly people who are eligible for both Medicare and Medicaid, the bill mandates rebates from the drug makers so that the Medicare system ends up paying less. Those rebates are estimated to cost the industry $60 billion over a decade.   

 is chief executive officer at Burrill & Company, San Francisco, CA, 415.591.5400,  

Burrill on Biotech

The companies that have survived the financial meltdown are well placed to adapt to the new environment that we now are entering.

Biotech in Good Shape for 2010

The International Conference on Harmonization (ICH) Q8(R2), Q9, and Q10 guidelines provide the foundation for implementing Quality by Design (QbD). Applying those concepts to the manufacture of biotech products, however, involves some nuances and complexities. Therefore, this paper offers guidance and interpretation for implementing QbD for biopharmaceuticals, from early-phase development steps such as identifying critical quality attributes and setting specifications, followed by the development of the design space and establishing the process control strategy; to later stages, including incorporating QbD into a regulatory filing and facilitating efficient commercial processes and manufacturing change flexibility post licensure. 

This paper focuses on the factors to consider when applying the Quality by Design (QbD) concepts outlined in ICH Q8(R2), Q9, and Q10 to biotechnology products. Although biologic and biotechnology products often present a higher level of complexity than small molecules in terms of manufacturing process or product structure, the concepts of QbD are the same as those for small molecules. This paper describes the nuances and complexities involved in implementing QbD in the manufacture of biotech products and offers guidance and interpretation for doing so. The scope of this paper is limited to well-characterized protein products, in which the natural molecular heterogeneity, impurity profile, and potency can be defined with a high degree of confidence. 

Part 1 of this three-part article, which appeared in the November issue, covered molecular design, the use of laboratory and clinical studies to identify critical quality attributes, setting specifications, and developing the design space. In Part 2, published in the December issue, we addressed the use of design of experiments (DOE) to define the design space, unique considerations for process development for biopharmaceuticals, the establishment of a control strategy, and the placement of QbD information in a regulatory application. Here, in this final Part 3, we discuss continuous verification and postapproval changes, including refining the design space, comparability protocols and expanded change protocols, and our overall conclusions for the three-part article. 

CONTINUOUS VERIFICATION AND POSTAPPROVAL CHANGES

Process change is an expected aspect of pharmaceutical manufacturing. Many process changes are made as a result of increased process knowledge to keep pace with advancing technologies and improvements to the manufacturing process. When a product is first approved, its manufacturing process represents the current technology standard for manufacturing and follows the current good manufacturing practices (cGMPs) standard for regulatory compliance. After approval, market demand, technological advances, GMP standards, raw materials (e.g., resins) sourcing or manufacturing experience may require that the approved process be modified. Traditionally, these postapproval changes have required regulatory agency endorsement before implementation. The intent of this section is to propose

a path forward that fosters continuous improvement and innovation, and acknowledges the extensive understanding of the manufacturing process and product (process knowledge) gained through the development of the design space or through manufacturing experience. The demonstration of extensive process knowledge in the marketing application, combined with established robust and effective quality systems to monitor manufacturing process performance, provides health authorities the assurance, and thus the allowance, to reduce regulatory oversight and the burden of postapproval change supplements while still meeting legal and regulatory expectations. The future treatment of postapproval changes will be influenced by: 					

in the US, formal integration of change control flexibility and the relationship to registered details, as a part of 314.70 and 601.12; and expanded change protocols used to modify postapproval reporting requirements

changes in the global regulatory landscape, including international regulatory alignment, with respect to the treatment of postapproval CMC changes, driven by a) increased reliance on site-based quality systems change control and reduced requirements for prior regulatory agency approval, and b) the integration of Quality by Design and ICH Q8(R2), 9 and 10 (and presumably Q11 in the future).

The data package for a market application (BLA or MAA) is enhanced by including data from full scale manufacturing runs, ideally from the intended commercial manufacturing site. These data confirm that the normal operating ranges or set points for process parameters lead to successful manufacturing at commercial scale. (GMPs) require formal process validation, and data from validation batches traditionally have been expected as part of the marketing application. A successful process validation exercise signals the beginning of the commercial life of the product and serves as the baseline for future process improvement efforts. Although important, process validation batches provide limited data for assessing the long-term variability and process capability of the manufacturing process. Rather, these data serve as one element in the larger dataset of process design and control experiments. The importance of including full scale data and data from process validation batches in the marketing application depends on platform experience and the state of qualification of small-scale models used to develop the process design space.

A refinement of the initial design space for cell culture, drug substance purification, and finished product manufacture may be driven by several of the following factors: 					

increased product knowledge through clinical and nonclinical trials

further development of platform technologies

The refinement of the design space is based on the same principles used to develop the initial design space. Starting from the quality target product profile (QTPP), a risk assessment should be performed to identify the process parameters that should be re-evaluated with respect to their potential impact on critical quality attributes using small-scale models and applying tools such as DOE. 

Continuous Verification, Process Changes, and Comparability 

Continued process verification has emerged as a key principle of process validation.

  During commercial manufacture, additional data will be collected from postapproval batches. These data will be reviewed periodically to confirm that the control strategy is appropriate. In some cases, this review may indicate that there is a need to modify specifications or in-process controls. Process changes may or may not require adjusting process parameter ranges to achieve a comparable quality in the drug substance or drug product. Testing for pre- and post-change comparability (see ICH Q5E),

  therefore, can result in refining the ranges for critical process parameters (CPPs) and extending or reducing the number of critical process parameters.  

The prior existence of a design space can make it easier to characterize the influence of a change on the critical quality attributes of drug substance or drug product or to confirm the robustness of chosen process parameter ranges (e.g., in the case of scale-up, site transfer, or equipment changes).  

Comparability Protocols and Expanded Change Protocols

The traditional comparability protocol (CP) has been available for more than 10 years in the US. The concept of a CP or similar reporting structure has not been adopted by the other regulatory agencies, however. CPs are pre-approved by the FDA with predetermined acceptance criteria that will be used to confirm product comparability following a discrete process change.

  The more recently adopted expanded change protocol (ECP) takes a more holistic approach and offers the use of a protocol providing the approach and acceptance criteria that can be applied to multiple manufacturing process changes or a process change across multiple related product types or manufacturing process platforms.

  The CP/ECP includes a quality risk assessment plan that provides assurance that changes to the process are formally assessed for impact to product critical quality attributes. This type of protocol or plan encourages incorporation of technical innovation, and process optimization, while maintaining product safety and efficacy.

Table 1 provides an example of a proposed change control matrix that, if approved by the FDA (e.g., as part of the initial marketing application or a later supplement), could clarify the postapproval reporting requirements in the US for several process changes based on the impact to normal operating ranges, proven acceptable ranges, or design space limits. Postapproval manufacturing changes, covered under the manufacturer's approved CP or ECP (or approved CMC postapproval management plan;

  see below), should require regulatory review and approval before implementation only in very limited cases, such as when the change expands the existing design space of critical process parameters and alters the approved control strategy (see Table 1). This scenario would permit most changes to or within the design space that result in comparable post-change product, to be presented during inspections or during regular annual updates to health authorities.  

Table 1. Example of a change control matrix of postapproval reporting requirements for process changes			

This approach could lead to a future state in which prior approval supplements (assuming a satisfactory site inspection) would be reserved only for changes where the post-change product or the control strategy are NOT comparable to the current product.  

Products that have been on the market for a considerable amount of time have extensive manufacturing data but may not have a formally developed design space. Following the current regulatory guidance, incorporating new technology or process changes requires regulatory agency review and approval. Manufacturing changes are initiated and controlled through internal change control processes. Comparability studies and protocols are an integral component in the evaluation of manufacturing changes, and include acceptance criteria and a side-by-side comparison. These processes ensure that the products comply with registered details and that critical quality attributes have not been affected.  

Because there is significant process and product knowledge about these well-understood marketed pharmaceuticals, and a large number of patient years of pharmaceutical usage associated with them, there is an opportunity to use a risk management system for assessing changes that may be managed internally and without direct regulatory agency oversight. This opportunity is built on the process knowledge gained through process changes, and the subsequent safety and efficacy information that has been generated from long-term manufacturing experience. These data could be used to define a design space retrospectively for single or multiple unit operations.  

When a design space is intended to be established after a medicinal product is on the market, the same principles apply as for design space evaluation during development, including the use of qualified small-scale models and experimental approaches such as DOE. For a postapproval design space, the QTPP would include the approved drug substance or drug product specifications. The risk assessment has the advantage of building on the established criticality of process parameters as well as experience with a number of full-scale batches.  

With the advent of the QbD approach providing additional knowledge-rich information in the initial marketing application, the concept of a CMC postapproval management plan (PMP) has been suggested in the US. The PMP is a proposed mechanism to capture the commitments and reporting requirements in the marketing application that are submitted to and approved by the agency for these well-understood products. The PMP would address the distinction between information provided to demonstrate knowledge of the process and product, and the lifecycle regulatory commitments. With the inclusion of increased data that supports items such as critical quality attributes, process parameters, and the design space, it will be imperative to clearly delineate between information that is provided for review and approval of the initial application and commitments that will continue throughout the lifecycle of the product. 

The PMP commitment section of a marketing application would contain a summary of the overall control strategy commitments: raw material controls, CPPs, in-process controls, the design space, final specifications, excipient controls, primary packaging, the container closure system, in-use stability, and storage conditions. The PMP also would clarify the sponsor's commitment with respect to reporting postapproval changes, with the understanding that a robust demonstration of knowledge would result in more flexible regulatory approaches to change management. The PMP would outline in clear terms how future process changes will be reported —i.e., whether the company must submit a supplement or may rely on internal site change control. One approach to providing these regulatory reporting commitments would be using a change control matrix, an example of which was described earlier in Table 1. For example, a CMC postapproval management plan would consider typical changes expected to occur during the lifecycle of the product and establish reporting requirements that permit innovation and improvements to be implemented while using inspections and regular annual updates to health authorities as the means for demonstrating that regulatory expectations have been met. The implementation of PMP for a well-understood product should require less regulatory agency oversight than for products that lack such an understanding. 

The PMP would be subject to FDA approval before taking effect and could be submitted in section 3.2.R.3 or module 1 of the common technical document (CTD). Although the CPs and ECPs could reside separately in section 3.2.R.3, these protocols also could be contained within the PMP.  

The increasing number of new products, combined with the number of marketed products seeking postapproval changes, has placed a considerable demand on the government and industry to submit and review data to comply with existing requirements. It is essential, therefore, that we identify a path forward that will leverage substantial product and process knowledge (i.e., QbD) using risk assessment tools and quality systems to ensure product safety and efficacy.  

To reduce the regulatory reporting burden for both the health authorities and drug product manufacturers, thorough risk assessments, following ICH Q9 and Q10, must take center stage, and an avenue should be developed for using CMC postapproval management plans. These plans would be agreed on by the regulatory authorities, and the manufacturers would be responsible for collecting adequate data to ensure that a meaningful risk assessment could be conducted and that pre- and post-change product comparability could be ensured. At the same time, to allow for regulatory relief, the health authority and manufacturers will need to agree on the minimum requirements or thresholds for manufacturing changes based on the identification of an acceptable residual risk for a change. To date, health authorities have not presented clear guidance as to what they consider to be an acceptable risk for biotech products. The industry can work with health authorities to share examples of process changes and provide an assessment for postapproval changes and notification categorization. Currently, the mechanism to share process understanding for well-understood processes and products is not clearly defined. We believe that continued discussions about the utility of a CMC postapproval management plan will encourage innovation, and require less burdensome regulatory reporting while maintaining product safety and efficacy. 

Quality by Design leads to a thorough understanding of product characteristics, with good quality being demonstrated by an acceptably low risk of failing to achieve the desired clinically relevant product attributes. Product and process performance characteristics are scientifically designed to meet specific objectives, not merely relying on empirically derived outcomes from studies. The sponsor establishes acceptable ranges for the critical process parameters and attributes to ensure clinically acceptable product performance that meets the patient needs identified in the quality target product profile (QTPP). The goal of QbD is to develop robust, well understood processes, run within a design space of operating parameters and control strategy, thus meeting critical quality attributes.  

The QbD approach allows the process to be continually evaluated and updated to ensure consistent product quality over time. Quality management systems may ensure product quality dynamically in real-time. QbD advocates knowledge management principles in the transfer of an advanced understanding of the process and product from the development functions to the receiving functions (e.g., quality, manufacturing) all along the product lifecycle, from early phase development through commercialization. The demonstration of knowledge-rich process and product information held by the sponsor needs to be communicated to the health authorities in the marketing application and postapproval supplements.  

QbD takes a lifecycle approach that encourages innovation and continuous improvement to the product long after initial approval to leverage knowledge gained and technology advancements. A QbD approach allows future manufacturing changes within the design space to be implemented without further regulatory reporting, thus meeting Janet Woodcock's oft-quoted vision of "a maximally efficient, flexible pharmaceutical manufacturing sector that reliably produces high-quality drug product without extensive regulatory oversight."

The benefits of QbD span the product lifecycle and center on areas that have the most impact to the safety, efficacy, and quality of the product. The benefits of this risk management approach include focusing on knowledge-rich development studies and reducing non-value added work. One benefit often cited is the promise of less burdensome regulatory reporting of postapproval changes. Even without the incentive of less burdensome regulatory oversight, however, the benefits of reduced material rejections and batch failures in manufacturing and reducing the three "re's"—reprocess, rework, recalls—make implementing QbD worthwhile. Several companies have reported developing a business case for QbD based solely on efficient, cost-effective manufacturing process needs. However, the promise of increased regulatory flexibility and less stringent reporting requirements is a powerful encouragement for implementing postapproval changes, because it encourages innovation and meaningful continuous improvement.  

Manufacturing Economics Series

Regulatory flexibility can make continuous improvement possible.

Quality by Design for Biotechnology Products—Part 3

The past year was one of stormy seas for the biopharmaceutical sector. Not only did the recession result in lack of capital and tighter budgets, but the industry was also rocked by megamergers. It was a double blow for the pharmaceutical industry, which has been struggling with its own challenges, including drug safety problems, patent expirations, and dwindling pipelines. "There isn't a rich multitude of new drugs in the pipeline and this is driving the mergers and acquisitions," notes one quality assurance professional from a Big Pharma company. 

The mergers and acquisitions he refers to, of course, are this year's megamergers—Pfizer's $68 billion acquisition of Wyeth and Merck's $41 billion buyout of Schering-Plough. And as everyone knows, following a merger, redundant functions are eliminated to streamline operations. So far, Pfizer has announced plans to cut close to 20,000 jobs, and Merck is expected to eliminate about 15% of its workforce.  

Maryellen Ruvolo, president of PharmStorm, an online recruitment portal, notes that these layoffs follow heavy job losses last year. "This is on top of the almost 22,000 pharmaceutical jobs lost in 2008," she says.  

Chitra Sethi is the managing editor ofBioPharm International

The year 2009 was marked by recession, industry megamergers, and venture-capital scarcity. How did biopharmaceutical professionals fare?

BioPharm International-01-01-2010