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FDA guidelines on Process Validation: General Principles and Practices emphasize scientific evidence on selection processes in addition to performance qualifications. Checking your work isn’t enough anymore; now you’ll need to show it. Here is how the guidelines are relevant, both in general and in my field of focus: pharmaceutical packaging.

Ajith Nair, Ph.DSenior Vice President, Global Research & Development Bilcare Research

The relatively new FDA guideline covering Process Validation: General Principles and Practices reflects the organization’s desire for a more robust manufacturing process. This is to ensure that quality, safety, and efficacy are built into the production process rather than simply inspected after the fact.

I liken these guidelines to high school Calculus: not only do you need the correct answer, you also must be able to show your work. And of course, in our industry an incorrect answer can be far more costly than a C- on a midterm. The FDA is, understandably, enforcing the importance of risk-based analysis and decision-making based on strong scientific principles to control potential hazards – both non-preventable and non-detectable – by finished product inspections.

In short: the FDA encourages the use of modern pharmaceutical development concepts, quality risk management, and quality systems at all stages of the manufacturing process lifecycle. The recommendation is directed toward its new initiative, Pharmaceutical cGMPs for 21st Century: A Risk-based Approach.

Concerned? Don’t be. Because what the FDA is encouraging can save pharma companies valuable time, resources and money. For example, before you read this I will have read and reread my writing here, conducted a spell check, and had my work edited by other professionals. It’s just common sense; I want the finished product to be as effective as possible. And if spelling, grammar and content are the most critical components of your document’s viability, primary packaging and storage conditions are the most critical components in the drug stabilization process and, therefore, are ideally considered and controlled prior to a drug being mass-produced and packaged. In almost all cases, these two variables control product stability and shelf life more than any other factors.

Under current practices, only a performance qualification step – a stability study of the packaged product – is performed to validate the primary packaging process. But according to the FDA, this is only the second of three stages during which these variables should be considered, sandwiched between Process Design (Stage 1) and Continued Process Examination (Stage 3). To quote the guidelines, the process design stage is the most critical step in “building and capturing process knowledge for understanding” and “establishing a strategy for process control” that positively permeates through the entire process.

Time to Show Your Work… and that includes your packaging

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Most drugs are relatively stable and consistent during and immediately following production in a manufacturing plant. However, the drug stabilization process presents a particular challenge, as it deals with the movement and storage of a packaged drug, often for extended periods of time and through several different climactic zones. Here, meeting the standards set by this guideline requires a thoughtful approach that considers a drug’s specific stability needs during the package design phase. Simply put, the FDA wants validation systems that are proactive rather than reactive. This means packages that are built with specific protection purposes already in mind, rather than inspected in hindsight.

The approach Let us examine how we can create a Design Space (Stage 1) to suit the validation process for drug stabilization. According to the FDA guideline, “a successful validation program depends upon information and knowledge from the product and process development. This knowledge and understanding is the basis for establishing an approach to control the manufacturing process that results in products with the desired quality attributes.” The guideline advocates the following process as ideal for achieving this objective:

1. Understand the source of variation

2. Detect the presence and degree of variation

3. Understand the impact of variation on the process and, ultimately, on the product’s attributes

4. Control the variation in a manner commensurate with the risk it represents to the process and product

Though this step is defined in the context of process variability and its control, I find that this approach is equally applicable for understanding the product variability and its control – which essentially defines the drug stabilization process. Built-in controls designed through such a process are the only way to ensure a product reaches consumers safely with required efficacy, regardless of any climatic conditions through which the drug must travel.

Relate this process to a doctor treating an ill patient. A good doctor not only would diagnose the patient’s disease, but also discover the degree of severity through various tests before determining the best course of medical action. This method provides the best possible opportunity for the sustained health of the patient; the same sort of thorough validation process for drug stabilization can best ensure a drug’s effectiveness for consumers.

Understand the source of variation, and its degreeAs discussed, the major influencing factors on product stability are the climatic conditions through which it travels and is stored. So for most drugs, climatic variations are the major stability variants. Climate has three significant sources of variation: Humidity, Temperature and Light. The degree of each variant depends on:

1) The prevalent climatic conditions in distribution channels

2) Shelf life (the duration for which the product is stored)

3) Supply chain methods

By and large, all three of these factors are either clearly defined or readily known, making the degree of each variant easy to determine.

The second set of variables is the actual process variations in the packaging step. Different packaging solutions (blisters, bottles, tubes, etc.) have different process variations. Of these, blister packaging presents the most challenging process variations because the package (the blister) is formed during the packaging process itself and, therefore, not tested and qualified beforehand. Blistering is a “form and fill” process whereas conventional packaging methods are a “fill and close” process in which the variability affecting product stability is minimal.

In blister packaging, the barrier offered by the pack is not only controlled by the packaging materials, but also by the packaging process. Process variations such as thermoforming / cold forming machine parameters, cavity dimensional changes, and sealing parameter variations all significantly impact protection capabilities. The extent of variation depends on the type of machine used, machine conditions, variability in the material property, sealing side, etc. In short: blistering is a complicated process that requires an understanding of several factors in variability.

Understand the impact of variationsThe next step is to define the impact of this variability on product stability, which I believe is the most important step of the entire process.

A Forced Degradation Test is, by far, the most accurate and thorough process to uncover the effect of humidity, light, temperature and time on a product. However, conventional forced degradation studies are designed only to accelerate the degradation process, not to understand it. The conventional forced degradation studies are designed to generate potential impurities and develop respective analytical methods. Such approaches are not conducive to studying “cause and effect.”

For example, when a product is exposed at elevated temperature and humidity conditions, we are able to speed up the degradation process, but unable to understand the impacts of any of the multiple variables involved. To understand the causes and effects of degradation, it is important to design the exposure condition in such a way that we are able to determine the impact of each variable and its relations.

A scientifically-designed forced degradation study, as defined by the FDA guideline on Design of Experiments (DOE), is an approach by which we can understand the impact of variations in particular exposure conditions. As the guideline says, “DOE studies can help develop process knowledge by revealing relationships, including multi-variate interactions, between variable inputs and the resulting output.” A closer look at these sources of variation:

1) Humidity: It is well known that humidity plays a very important role in the stability of a product. The tough question is exactly how it does this. Standard absorption isotherm experiments can be performed to understand the effect of humidity on a product’s moisture level. However, this is insufficient to gain understanding of the impact of humidity variations on product characteristics. For this, it is necessary to separate the effect of temperature from that of humidity by designing humidity variations at isothermal conditions.

2) Temperature: In conventional stability studies, the objective of exposure to high temperatures is to increase the rate of degradation to compensate for time (based on Arrhenius Theory). This approach, however, does not study the actual temperature sensitivity of a product. A failure under these accelerated

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conditions is normally taken as a possibility of product failure during shelf life, or of package barrier insufficiency, rather than its temperature sensitivity for which packaging does not play role. Separate experiments should be designed to understand the effect of temperature alone on a product – both in the presence and absence of high humidity – which can be prevented if the product is stored at cool conditions even for an extended period of time.

3) Light: Exposing a product to various lux hours of fluorescent light – as well as differing Watts of UV light – to determine the respective changes in its critical properties will provide insight on the impact of light variation on its integrity. However in nearly all cases, a product is not exposed to the variations of light alone, because humidity and temperature also vary along with the light. Hence these experiments are designed to study the combined impact of these determinants.

Though it seems laborious to study all these effects separately, a smartly designed forced degradation study, and the analysis of its result using certain mathematical tools, can provide the required results efficiently. Once performed, the studies provide the risk analysis and risk-based decision-making that is the very essence of the FDA guideline. These studies will reveal the major risk factors for a product in-market from the moment it is produced until it is consumed.

Control the variationsThere are two methods of handling control. The first is to build controls into a process, referred to as the QbD (Quality by Design) principle. The second is to exert control through inspection and approval of a seemingly market-ready product.

Not surprisingly, built-in control is, by far, the more preferable of the two. One reason is that it removes the secondary variability associated with deviations in the inspection and approval processes themselves, such as method discrepancies and documentation errors. Unfortunately, the pharmaceutical industry has historically followed the latter of the two approaches, which not only result in wasted time and resources, but also an added risk of releasing defective products due to human or mechanical error.

There should be no argument that a built-in, QbD approach is the best way to ensure controls. The challenge, then, is instilling a working understanding of the process and process variations that deliver this method’s superior results.

By implementing the steps described earlier, we can determine the stability risk involved with various environmental variations. We then need to quantify each risk factor to study the degree of its potential impact. Traditionally, we tend to define the risk factors more qualitatively; but only through a quantitative determination of each risk factor can we optimally define the necessary steps for control.

Because product sensitivity toward these environmental factors is a major risk to its stability, the first step is to quantify the sensitivity of that specific product. Running the results from the forced degradation studies through a scientifically designed sensitivity scale is the ideal way to quantify sensitivity. Quantitative determination of sensitivity is an excellent tool to identify and analyze formulation variations – and even batch-to-batch variation – and is the first step toward ultimately stabilizing the product.

The next step is to design a package and storage conditions that serve as built-in mechanisms to meet the “quality, safety and efficacy of the product” called for by the FDA. Here, the first step is determining the threshold values of each risk factor for which the product is safe. Once these are determined, we can

(1) Flat Circular Blister, (2) Convex Circular Blister, (3) Cap-tab Blister (4) Capsule Blister

accurately define the specific protection requirements. Next is identifying the most suitable packaging option that provides the required protection and, if packaging alone does not seem to stabilize the product (for example, against temperature-sensitive and time-sensitive stability issues), we can define the storage conditions as well. Once this assessment is made, we are ready for the final performance qualification step associated with the validation process: the actual stability study in the selected package.

BilcareOptima as a solutionNow that we have examined and explained the process, the question becomes whether such elaborate analysis is practical – or even feasible – in the post-formulation stage rush to gain FDA approval

and get products to market. The answer must be weighed, of course, against a critical counterpoint: failure in stability testing or post-launch safety and stability issues, especially those due to lack of knowledge regarding product behavior, can be disastrous.

Historically, the safest bet for pharmaceutical companies has been over-packaging, which circumvents a full product behavior analysis while attempting to ensure a product will stay stable through consumer usage. This often includes trying out several packaging solutions before finding one that works satisfactorily in Performance Qualification (PQ).

However, putting a product in high-barrier packaging to pass conventional stability tests is no guarantee for its stability in real conditions. Knowing this, various regulatory agencies have tried to alter stability conditions to suit various regions. So the question then becomes this: will your product pass stability tests or stay stabilized in all of the climates and conditions to which it will be subjected?

Because packaging may not be able to provide a product stability solution for issues related to temperature or time, over-packaging is not a surefire solution. In fact, over-packaging without understanding a product’s storage behavior can often cause damage. For example, there have been cases in which a product shows liberation of some gases on storage but whose packaging is not breathable; the resulting accumulation of gas ultimately damaged both package and product.

In addition, the standard ICH guideline is designed for Climatic Zones 1 and 2; this limited scope does not represent the full spectrum of climatic conditions around the world. We also know that products can absorb more moisture in the prevalent climatic conditions in Zones 2 and 4. This is because, in these zones, humidity levels are higher at comparatively lower temperatures; in accelerated conditions products are generally exposed to such humidity only in conjunction with elevated temperatures. For moisture-sensitive products, this means more degradation occurs in actual conditions than is observed in accelerated ones.

The discrepancies don’t stop there. These are just the tip of the iceberg of issues that can arise if we depend only on standard accelerated stability studies.

This is where services such as BilcareOptima become so highly valuable. In a period of just five or six weeks, comprehensive knowledge on a product’s degradation pattern is developed and, from there, a design for that product’s optimum packaging solution is created. The process utilizes validated methodology in line with the FDA recommendations and QbD principle overall.

Based on this design recommendation, a final performance qualification (stability study) is conducted. This scientific process not only ensures that a product passes stability at first test, but that it will remain stable throughout shelf life – all without the hassle and expense of over-packaging.

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Packaging solutions backed by science

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For more information please contact us: 1389 Schoolhouse Road, Delaware City, DE 19706302.838.4000info.optima.us@bilcare.comor visit www.BilcareOptima.com

BilcareOptima was developed based on research conducted on more than 300 formulations for environmental sensitivity and degradation pattern. By doing so, we found new ways to prevent or retard drug degradation through packaging solutions ideally suited for that product’s specific levels of susceptibility to humidity, light and temperature. The methodology is twofold:

1. Formulation Evaluation Study: A scientifically designed forced degradation study without packaging to quantitatively determine the degradation pattern of the drug and the critical parameters affecting its degradation and threshold values, based on the customer-specified acceptance criteria and the product’s shelf life period.

2. Package Evolution: Software-based simulation program to arrive at the optimum barrier properties required to protect the medicine through its specified shelf life and, from there, selecting or developing the appropriate package.

Products are exposed to various stress conditions (per the world’s four climatic zones) to understand the effect of temperature, humidity, and light – as well as their various combinations – on product parameters like hygroscopicity, chemical and physical changes, drug release property, hardness, microbial susceptibility, gas liberation tendency, and photosensitivity (not only with UV and visible radiation but also with humidity and temperature) considered.

Each parameter is graded on a scale of 1 to 10 for quantifying sensitivity of the formulation toward various environmental factors. Based on the sensitivity grading, we arrive at a critical parameter whose threshold levels are identified by further studies at narrowed ranges. Final packaging options are evaluated by considering a product’s moisture, light and gas barrier requirements along with its physical dimensions. Based on these requirements, an ideal package is recommended which provides suitable product protection.

The concept is simple: BilcareOptima takes far more variables into consideration than do standard degradation tests, and the result is the perfect pairing of product and package. This escalated effort at the process’ inception saves potential headache and cost later, sharply decreasing the likelihood of wasted resources, wasted time, and wasted money spent on insufficient or unnecessarily bulky packaging. And most of all, BilcareOptima increases the likelihood of a product’s safety and efficacy staying intact for consumers.

About the AuthorAjith Nair is the Senior Vice President of Global Research & Development for Bilcare Research, one of the world’s largest manufacturers of blister packaging solutions. Mr. Nair has worked with Bilcare Research for more than 10 years, and has held VP-level positions at the company since 2006.

Dr. Nair manages the company research activities worldwide. Currently, he is overseeing the Global Excellence Center at Bilcare Research’s U.S. headquarters in Delaware City, DE. The Center provides solutions, via its BilcareOptima services, for drug stabilization and packaging for North American pharmaceutical customers via forced degradation testing, which analyzes the effects of relative humidity, light, temperature and time on drugs to identify optimum barrier requirements and recommend the most affordable, effective blister options.

Dr. Nair, who holds a Ph.D in Surface Chemistry, specializes in drug stabilization and recently co-authored a whitepaper on the effectiveness of computer-generated degradation predictions in recommending barrier and packaging solutions. He was instrumental in bringing to fruition Bilcare Research’s current expertise in drug stabilization and degradation testing, first abroad and now in the United States. In doing so, he has striven to promote the value of using science and technology to provide pharmaceutical companies with packaging that offers value, assurance and data-driven peace of mind.