How Part 11 Compliance Impacts QbD

No longer stuck with the "validate everything" mantra, companies now need to assess the risks applicable to their electronic information and integrity to determine what (if any) validation is needed.

By John Avellanet, Cerulean Associates LLC

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An ominous shift in regulatory enforcement expectations is increasingly apparent to many pharmaceutical and life sciences executives around the world. The rise in the U.S. Food and Drug Administration’s (FDA) information integrity-based audit findings, 483s and warning letters reflects a larger move away from reactive post-market inspections. Interestingly, FDA officials advocate Quality by Design (QbD) as their goal, but it is hard to see the relationship between QbD and data integrity without stepping back to look at the big picture.

Over the past two years, pilot programs have shown an increased approval speed for new products drawing on elements of Quality by Design. Despite this progress, the largest question remains: given that so many FDAregulated firms view their preclinical product development process as “outside the box” of FDA regulatory oversight, how do companies intend to bring their R&D test data, laboratory results, protocols, lab notebooks, engineering prototypes and schematics into a state of compliance with QbD principles?

When seen as part of the larger FDA regulatory landscape, the answer emerges from 21 Code of Federal Regulations Part 11 (21 CFR Part 11), the electronic signatures and records act. As counterintuitive as this may seem, my experience with clients over the past few years has shown that a strategic, risk-based approach to Part 11 dovetails with QbD to improve a company’s new product pipeline, speed its new product time-to-market and increase its compliance flexibility. The fact that FDA enforcement actions increasingly focus on pre-market data integrity would seem to support this. How then are Part 11 and QbD intertwined, and what are the pitfalls associated with an integrated approach?

QbD discussions began within FDA during the 1990s. The idea of using QbD to speed time-to-market coalesced later, around 2003-2004, when FDA was under pressure to hasten approvals and identify safety approvals.

For the past 20 years, QbD has been widely used in the consumer products and software development industries. These industries’ experience has shown that the earlier in the design phase certain predefined, critical product aspects (such as consumer preferences) are implemented, the faster product development occurs — with an analogous increase in product quality. By extension, for pharmaceutical, medical device and biologics companies, incorporating predefined critical product aspects (such as safety and efficacy) should start in the preclinical product development stage.

As FDA officials began to see QbD as a way to speed new products to market safely, there was a growing realization that the overzealous aspects of earlier interpretations, applications and enforcements of 21 CFR Part 11 often focused on specific technologies. The actual impact on electronic information integrity for the data that supported a product’s safety and efficacy (or proved compliance with good manufacturing and laboratory practices) had not been considered.

Coinciding with the 2004 announcement of an initiative to speed new medicines to market safely, FDA announced its intent to revise Part 11 to be more closely aligned with current risk-based practices and other FDA initiatives. The focus of Part 11 was now to be on the integrity of a company’s electronic records as they related to product safety and efficacy, as well as proof of adherence to good manufacturing and laboratory practices (GMPs and GLPs).

For consumers, regulators, shareholders and life science companies alike, this shift has been a welcome watershed. Information integrity is crucial to ensuring product safety and efficacy, and the costs of Part 11 compliance are now beginning to fall in line with costs associated with other aspects of risk-based regulatory compliance. No longer is the mantra “validate everything or else.” Now, a firm needs to assess the risks applicable to its electronic information and integrity to determine what (if any) validation is needed. This philosophical shift is the crux of why Part 11 is a good catalyst for both Quality by Design and for getting new drugs, biologics and medical devices to market faster, more safely and more easily. It is also a key reason that 95% of FDA’s enforcement targets in 2006 were related to data integrity.

With my clients, I encourage adoption of a strategic, riskbased Part 11 compliance approach within the framework of preclinical activities associated with QbD and the compilation of a device or drug design history file.

Over the past several years, three specific benefits have emerged from this integrated, strategic approach:

  • Reduction in risk and costs
  • Improved new product pipeline flexibility
  • Improved new product return on investment.

Risk and Cost Reduction

As risks increase, costs rise. The more risk can be engineered out of a product or process, the less costly the final result will be. Three common areas to examine are design inputs, intellectual property security and the transference from preclinical to clinical to final production.

For product design inputs, assess the impact of each design specification on the patient’s safety and the product’s efficacy. The assessment needs to be conducted using a risk analysis; however, the industry’s most commonly used tool, Failure Modes and Effects Analysis, is not an appropriate method, as it is reactively focused. To speed development, crucial product safety and efficacy attributes must be identified as early as possible. Therefore, I counsel clients to adopt a simpler, more proactive tool like the Hazard Analysis Critical Control Points technique used in the food industry.

Once key safety and efficacy aspects have been pinpointed, whether they are product-specific or process-related (such as a formulation that must be mixed within a relatively narrow range of temperature, humidity, air cleanliness and time), the controls needed to ensure those safety and efficacy targets have to be determined. For many controls today, automation can be incorporated, thus speeding processes, reducing labor, ensuring consistency and reducing risk.

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