Susan Haigney is lead editor of Pharmaceutical Technology and Pharmaceutical Technology Europe.

Susan Haigney

 $4.7 billion as part of the President’s fiscal year (FY) 2014 budget. A portion of the budget increases would support programs to ensure the safety of medical products. 

The budget also includes a $15-million decrease in budget authority for human drug, biologics, and medical device programs. “These are tight budget times, and the FDA budget request reflects this reality,” said Margaret A. Hamburg, M.D., Commissioner of Food and Drugs, in a press release. “Our budget increases are targeted to strategic areas that will benefit patients and consumers and overall strengthen our economy. Through the good work of the FDA, Americans will receive life-saving medicines approved as fast as or faster than anywhere in the world, confidence in the medical products they rely on daily, and a food supply that is among the safest in the world.”

The FDA budget request includes more than $17.9 million more than FY 2012 for outfitting and required certification and operation of the Life Sciences-Biodefense Complex (the FDA’s White Oak headquarters in Silver Spring, Md.) to modernize regulatory science and promote medical product innovation. It also includes more than $10 million above the 2012 budget for food and drug safety inspections of products and ingredients manufactured in China.

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FDA's Fiscal Year 2014 budget request includes more than $10 million above the 2012 budget for inspections of products manufactured in China.

FDA Requests Almost $5 Billion for 2014 Budget

, FDA Commissioner Margaret Hamburg stated that recent FDA inspections of 31 compounding pharmacies known to produce sterile drugs resulted in a discovery of inappropriate sterile-manufacturing conditions and FDA-483 observation results for all but one of the companies inspected. The companies were cited for incidents ranging from rust and mold in cleanrooms to unidentified black particles in vials of sterile product. Some of these FDA-483 notices have led to voluntary product recalls.

According to Hamburg, FDA was met with resistance from some of the pharmacies that were included in the inspections. She claims that some inspections were either delayed or inspectors were denied full access to records, thus requiring court-issued warrants. “These inspectional observations reveal that there continues to be reason for concern about sterility deficiencies and other problems in some compounding pharmacies across the country–problems that could potentially affect the health of patients. To carry out this proactive inspection effort, FDA had to shift resources from other areas, and this is not a sustainable approach for the longer term,” Hamburg stated on FDA.gov.  

Hamburg also stated that FDA is working with Congress on legislation for FDA oversight of compounding pharmacies and is evaluating the agency’s surveillance and enforcement approach. 

FDA inspections of compounding pharmacies manufacturing sterile products reveal non-sterile conditions.

FDA Commissioner Claims Resistance to Compounding Pharmacy Inspections

 of scale-up and post-approval changes that combines and supersedes previous guidance documents: 

SUPAC-IR/MR: Immediate Release and Modified Release Solid Oral Dosage Forms, Manufacturing Equipment Addendum

SUPAC-SS Nonsterile Semisolid Dosage Forms, Manufacturing Equipment Addendum

. FDA states that the new draft SUPAC addendum should be used in combination with the other SUPAC guidance documents.  

Guidance for Industry SUPAC: Manufacturing Equipment Addendum, Draft Guidance

, removes the lists of manufacturing equipment that were in the previous guidance documents and clarifies the types of processes being referenced. It defines levels of chemistry, manufacturing, and control change; recommended chemistry, manufacturing, and controls tests for each level of change; recommended 

 bioequivalence tests for each level of change; and recommended documentation that should support the change for new drug applications and abbreviated new drug applications.

Draft guidance combines and supersedes previous guidance documents.

FDA Releases SUPAC Guidance

 will be previewing the action in the weeks to come.

	Look for posts from our Manufacturing Editor Jennifer Markarian, as well as 

 Editorial Director Rita Peters and Executive Editor Patricia Van Arnum.

INTERPHEX 2013 begins later this month and Pharmaceutical Technology will be previewing the action in the weeks to come.

INTERPHEX Approaches

	Sales of traditional drugs fell for the first time according to Express Scripts’ annual 

. The decline is being attributed to patent expirations, causing a greater use of generic drugs and increased competition. According to the report, the higher cost of specialty medications offset the overall decline. Express Scripts’ report anticipates these trends to continue.

	Therapy classes saw an increase in utilization; however, unit costs saw a decrease. Cost increases for diabetes medications drove an increase in spending. Other high-use medications, however, such as those to treat depression saw a decrease in spend despite an increase in utilization. Drugs that treat attention disorders saw an upward trend because of increases in both utilization and drug cost.

	Has the pharmaceutical industry seen the beginning of an overall decline in sales? Are there enough new drugs in the pipeline to push conventional drug sales forward? How is your company battling the trend?

Sales of traditional drugs fell for the first time according to Express Scripts’ annual Drug Trend Report.

The Drop in Drug Spending

The process by which the pharmaceutical industry performs process validation began to shift in 2008, when FDA revised its                          1987 guidance document and released the draft guidance, 

Process Validation: General Principles and Practices

.   The guidance, finalized in January 2011, outlines the concept of a   continuous lifecycle approach to validation and verification                          of processes for the manufacture of drug   products and APIs (1). This lifecycle approach put process validation   practices in                          line with International Conference on   Harmonization (ICH) industry guidance documents Q8(R2)

In the two years since the publication of FDA's final process validation guidance, how has this new lifecycle approach affected                          the way the industry performs validation? 

 spoke with Hal Baseman, COO and principal at ValSource LLC and   co-leader of the Parenteral Drug Association Process Validation                          Interest Group; Paul Smith, EMEAI laboratory   compliance product specialist at Agilent; and Ian Jones, CEO, and Luke   Kiernan,                          technical services director, of Innopharma Labs   in Dublin, about the impact FDA's process validation guidance has had on                             analytical testing and validation. 

 What would you identify as the key elements of continuous process verification? 

 A manufacturer can only truly understand their   process and successfully demonstrate continued process verification   through                          the implementation of process analytical testing   (PAT) technologies to support the monitoring and control of product   critical                          to quality attributes. I think material   understanding throughout the manufacturing process from the product   development phase                          onwards will not only support a robust   commercial manufacturing process but can also reduce the burden of   scale-up and technology                          transfer, thereby supporting product-divestment   initiatives. The implementation of the new FDA guidelines on process   validation                          will not only meet the expectations of the   regulator but can also ensure the success of business demands such as   lean scale-up,                          commercial manufacture, and technology transfer. 

 Continued process verification requires an   ongoing collection of data and evaluation of the performance of the   process using                          the data collected.  Historically, organizations   tended to limit the "dimensionality" of the process data they gathered   and                          monitored. Typically, this included a smaller   number of discrete pieces of data, significantly less than that   generated by                          continuous process monitoring as part of the   lifecycle approach. 

The   identification, training, and use of appropriate statistical tools in   the lifecycle approach are essential to the success.                          To detect a small change in a process or a   process drift, the underlying variability of the process when operating   'normally'                          must be understood.  Automated algorithms can   fail.  Typically, this can occur when there is some new source of   variation/change                          in the relationship between the data that are   being monitored that impact the underlying assumptions in the automated   algorithms.                          Reliance on complex and sophisticated sales   algorithms in the stock market is an example of this type of error. On   the other                          hand, humans can make simple errors. Therefore,   finding a balance between relying on semi-automated statistical tools   and                          human monitoring is potentially one of the key   elements to success. 

 How may a given manufacturing process (including   equipment design and operation) and analytical testing need to be   modified                       to accommodate this lifecycle approach? Are   in-line, at-line, or other PAT implicitly or specifically required? 

 PAT can be a key element of continuous process   verification. In-line, continuous monitoring, and control systems, such   as                       those associated with PAT, are helpful in   maintaining and assuring process control. Assurance of process control   can be obtained                       by observation, inspection, or evaluation of   process parameters and product attributes. Where complete observation is   not                       possible, companies need to predict process   outcome. Validation is the prediction of outcomes that cannot be fully   observed,                       based on information we can observe. The more that   [we] can observe, the more accurate the prediction. 

In-line   monitoring and control systems allow for more process observation, as   well as better control of the process, further                       assuring process performance.  In addition, they   provide effective knowledge-management tools, providing information that                       can be utilized for future validation activities.

 I think PAT   technologies can support all aspects of the product lifecycle—process   development, scale-up, commercial manufacture,                       and technology transfer. You can't successfully   conduct these lifecycle activities without intimate process   understanding.                       This is only achieved on a batch-to-batch basis   through real-time in-line PAT. Where this is not possible, on-line or   at-line                       are also a necessary compromise. 

 The lifecycle approach   represents a different way of designing, building, and monitoring   manufacturing processes. Within                       those processes, many of the key process stages   associated with manufacturing have not changed significantly: blending,   distillation,                       drying and crystallization, for example. Many early   PAT applications have been an adoption of laboratory instrumentation to                       process operation. A key challenge of this early   PAT adoption, such as near infrared has been the limitations of access   points                       in the manufacturing equipment, where a probe,   signal, or at-line sampling point can be implemented.  Cutting a hole in   a                       glass-lined vessel is simply not an option.    Therefore, the use of PAT must be considered at the process-design   stage. 

Generally, the   simpler the technology and an understanding of the underlying   relationship between what the PAT device is actually                       measuring and how the results will be used to   monitor/adjust the process, potentially, the more robust the process   should                       be.  Therefore, simple PAT applications designed to   support these discrete process stages are required. All PAT   applications                       need to have some assessment of 'is it working   correctly' built in, as well as appropriate means of efficiently   performing                       'instrumental activity' such as maintenance and or   calibration. 

 How does a lifecycle approach to process validation that employs risk-based decision-making throughout that lifecycle differ                       from traditional validation protocol and practice? 

 The principles of any effective process validation   approach should: consider risk to product quality and quality risk   management                       tools in validation related decisions; glean   information from process design studies to identify process variables;   develop                       control strategies, use sound scientific rational   to test the effectiveness of those strategies during the qualification   of                       the process; and monitor variability of commercial   manufacturing batches to support maintenance of the validated state and                       look for ways to improve and optimize the process. 

 There is a significant difference. With additional   material understanding and a greater development focus, there is   tremendous                       potential to reduce the process qualification   burden and enhance process robustness throughout the lifecycle of the   commercial                       product. Through the adoption of a lifecycle   approach, there is the opportunity to not only continuously verify your   process                       but also to continuously improve your process   through greater automation, operator understanding, and PAT-instrument   implementation.                       If adopted correctly, this guideline is good news   for the regulator, the pharmaceutical manufacturer, and the patient   because                       we will see more robust, reliable, and better value   products brought to market.

 The original 1987 FDA   process validation document was implemented at a time where compliance   thinking was quite different                       to what it is today. At the time, the emphasis was   more on 'Locking down the process' and generating documented evidence.                       In other words, the process was fixed and the   emphasis was on the qualification documentation. 

A key industry   interpretation of the 1987 guidelines was the implementation of three   validation batches during the process                       validation.  This 'requirement' was not expressly   stated in the 1987 guide, but rapidly became the 'industry norm.' A   process                       could be considered validated if the results of the   three validation batches passed specification, and the suite of   qualification                       documents produced were well written. Ultimately,   this potentially contributed towards a mind-set that validation could be                       bolted on to a process while the underling science   and variability of the process might not have been well understood and                       problems were often encountered when processes were   transferred between organizations. The 2011 guidance aligns process   validation                       with product lifecycle principles that are now part   of current regulatory thinking and principles. 

 What are the key challenges in implementing a lifecycle approach to process validation compared to the traditional process                       validation? 

 Companies used to running 'three batches' to   qualify processes, will need qualified resources to develop   scientifically sound                       process validation plans, collect and analyze   process performance metrics, and answer the question: how does what you   do to                       validate the process, and provide assurance that   the process is adequately controlled? 

Companies may   not yet have the systems in place to identify and transfer information   from process design related groups to                       the people responsible for planning and conducting   the process qualification studies. Also, companies may be concerned that                       using prior knowledge from previously validated   processes to support the validation of new processes will expose those   older                       processes to regulatory scrutiny.

Additionally,   companies, which use CMOs and other outsourcing organizations, may not   yet have the systems in place to adequately                       capture and transfer information needed to support   the lifecycle approach to and from those organizations. And lastly,   companies                       uncovering opportunities for process improvement   during Stage 3, Continued Process Verification may be concerned that   submitting                       changes to those processes will risk further   regulatory scrutiny to already 'validated' processes. 

 The guideline requirements are that the   manufacturer must judge whether it has gained sufficient process   understanding to                       justify commercial distribution of the product.    The initial challenge for the manufacturer is to understand what   sufficient                       process understanding 'looks like'.  In Stage I,   what level of design-of-experiment work is required?  In Stage II, How   many                       validation batches are sufficient (is three still   the magic number)? And in Stage III, how much additional   testing/monitoring                       is required?  A greater knowledge of statistics and   statistical control is now required by the manufacturer compared to   when                       the traditional approach to process validation was   in place. 

Other challenges   relate to legacy products that now fall into Stage 3 of the lifecycle.   The same level of data-driven process                       understanding may not be available for these   products as for new products. The challenge for manufactures is to meet   the requirements                       of the guidelines in a cost effective manner, for   legacy products. 

 The lifecycle approach represents a significantly   different way of developing and validating processes.  These differences                       can represent both advantages and challenges,   depending on the perspective taken. The people and cultural aspects of   this                       change should not be underestimated. Additionally,   how an organization is structured and aligned to support the development                       of the lifecycle approach can significantly affect   the process costs. There are some trade-offs between size,   infrastructure,                       and efficiency. Additionally, the lifecycle   approach generally requires an integrated team approach. 

Historically,   process validation costs have represented a significant percentage of   the overall process implementation costs.                       The organizations with the lowest   process-validation costs have found that the simple act of harmonizing   and standardizing                       an approach significantly reduces the validation   costs.  In a world where variability of processes must be understood,   reducing                       the variability of the documentation across an   organization benefits the lifecycle approach. Many organizations train   their                       people in GxP through procedures, rather than   developing a core understanding of GxP requirements. Ultimately,   risk-based                       thinking that is a core part of the lifecycle   approach requires a core understanding of GxP, rather than a set of   procedures. 

 Overall, how has the FDA process validation guidance changed validation in pharmaceutical manufacturing? 

 I think better material and process understanding   are essential to the lean development and manufacture of robust and   cheaper                       products. As the pharmaceutical industry   transitions to the emerging markets, where reduced pricing structures   and localized                       manufacture are expected, the implementation of   these guidelines, in parallel with greater PAT technology   implementation,                       and even the transition toward continuous   manufacturing platforms, will become essential to sustain a successful   business                       model. 

 Validation is no longer considered as an activity   that can be 'bolted on' to a process; it has to be designed in. This is                       resulting in a change of mindset towards a   realization that validation is a value-added activity and not simply a   cost. 

 The 2011 FDA guidance tracks well with the   principles for lifecycle activities presented in ICH Q8, Q9, and Q10.    And other                       regulatory agencies, including the European   Medicines Agency, appear to recommending similar approaches.  The new   FDA guidance                       brings a science focus back to process validation.    It may take time for companies and regulators to fully embrace it, but                       I am certain its use will result in more effective   process control and improved processes. 

Guidance for Industry, Process Validation: General Principles and Practices

, ICH Expert Working Group (August 2009). 

Industry experts discuss the effect FDA's 2011 process validation guidance has had on industry.