Validating Process Validation

By Agnes Shanley,

PharmaManufacturing.com

FDA’s new draft guidance gets to the essence of what process validation is, and isn’t. Have you read it yet?

Safe pharmaceutical manufacturing, as we know it today, could not exist without process validation. Introduced in the 1970s, when FDA was still known as the Bureau of Drugs, the concept was originally designed to protect the public against the impacts of variability in sterility assurance, but was extended broadly to drugs and devices.

It aimed to ensure that any process would do what its developers intended it to, and make products of reproducible quality. The concept worked.

It also became a monster. Over time, misunderstandings about validation promoted a rigid, bureaucratic approach to manufacturing. Concerns have led some companies to lock in inefficiencies, generate reams of defensive documentation, and reject new technologies or approaches, even if they would improve both process and product.

In addition to being far more engineering-focused and much more clearly written than the previous guidance, the new document stands out from the prior guidance in that it:

• outlines, clearly, a life-cycle approach to process validation
• presents the essence of what Quality by Design is, without going into the terminology
• emphasizes the importance of process control, calling out the importance of both QA professional and the line operator in providing feedback and
  continued process verification.
• specifically mentions process stability and process capability
• mentions the potential role of simulation
• touches on the importance of continuous operator training
• highlights the need for a crossfunctional approach, even specifying the different disciplines that should, ideally, be involved.
• discusses the need for data analysis, within and between product batches, mentioning the most relevant places to find this information:
• discusses how PAT and real-time data access would change the approach to Performance Qualification

So what was so wrong with the prior guidance? I decided to check the wording of the 1987 document more carefully. It made me wonder about a few things….for one thing, where on earth did the magic number three (for the infamous “three validation batches”) come up? It wasn’t in that document.

The earlier document had already paved the way for QbD by highlighting the importance of drug development, yet it seemed to focus more on data collection than interpretation. It was also somewhat diffuse, taking many paragraphs to discuss control limits, and including lengthy asides on process examples that sounded like religious commentary on sacred scripts.

Some companies are already taking a very modern approach to process validation, and developing techniques that would allow processes to be adjusted on the fly. Last month, a meeting of the American Institute for Chemical Engineers (AIChE) in Philadelphia offered a number of practical examples showing how these concepts are being applied.

One expert from a U.K. company showed how multivariate models can be used to adjust automatically for differences in raw material sourced from different suppliers so that the resulting product’s quality is always consistent.

That is the future, but for many operations today it might as well be science fiction.
Recent informal surveys in our magazine have found that pharmaceutical development and manufacturing are still using mainly univariate rather than multivariate data, and that many companies aren’t even performing process capability analysis. The sigma level of drug manufacturing, experts say, remains around 3. At the same time, some FDA reviewers and inspectors may not be in synch with the new guidance. Audience members at one AIChE session asked why some FDA reviewers appear less interested in hearing about their carefully developed “design spaces” than in specific process values.

Even if there’s more work to be done, documents like this draft guidance provide clarity and a basis for open discussion and benchmarking. FDA is accepting comments on the document until January 19, via http://www.regulations.gov). I urge you to write with any constructive criticism. In the meantime, write us and let us know what you think.

FDA publishes guidance on process validation

The US Food and Drug Administration (FDA) has issued draft guidance on process validation, updating its 1987 document to incorporate advances in manufacturing technology and thinking.

Modern risk management and quality system tools and concepts form part of the FDA’s new thinking, which is in keeping with its initiative entitled “Pharmaceutical CGMPs for the 21st Century – A Risk-Based Approach”.

Biological products, including active pharmaceutical ingredients (APIs), are the focus of the document, which by implementing manufacturers should align their process validation activities with the product lifecycle concept and existing FDA guidance.

The document defines process validation: “as the collection and evaluation of data, from the process design stage throughout production, which establishes scientific evidence that a process is capable of consistently delivering quality products.”

Covered under the guidance are some general considerations for process validation, such as having an integrated team that has members with a variety of specialisations, and more specific recommendations.

These recommendations span the three stages covered by process validation, namely process design, process qualification and continued process verification.

The three stages cover the adoption of process validation from development and scale-up through to commercial manufacture and beyond to provide ongoing assurance.

Included in the document are sections covering capturing process knowledge and understanding and facility design and equipment selection.

Documentation and analytical methodology are also covered in the guidance, which can be found here .

Asahi Kasei gains TechniKrom’s bioprocess business

Japanese chemicals firm Asahi Kasei has ramped up its bioprocessing operations with the acquisition of US industrial processing specialist TechniKrom’s biopharmaceuticals business.

The integrated offering, which will operate as a wholly-owned Asahi subsidiary, will combine TechniKrom’s portfolio of processing equipment and validation services with Asahi’s hollow-fibre and membrane adsorption technologies.

The deal, financial terms of which have not been released, builds on the firms’ collaboration centred on Asahi’s range of industrial Planova virus removal filters and, according to the Japanese company, will help drugmakers lower production cost and improve product quality.

Yasuyuki Yoshida, president of Asahi Kasei Medical, said the deal seems like a perfect fit in terms of the firm’s global expansion plan. He explained that the integration provides “a base for the development, production, and sale of equipment and systems in the US.”

While the US market for biologics and biotherapies has grown continually since it first emerged as a going concern 25 years ago, the development of follow-on biologics as patent expiry looms looks set to shift the expansion into a higher gear.

In recent months for example, several US majors like Pfizer and Merck & Co have expressed an interest in growing their generic biologics portfolio in preference to investing in the development of non-biologic drugs.

While such big pharma interest would have proved a barrier to entry for smaller firm’s wishing to claim a share of the traditional drug market, the greater technical difficulties associated with manufacture of biologics may mean there is more scope for technically proficient biotechnology companies to prosper alongside the industrial giants.

In addition, the Food and Drug Administration’s (FDA) recent approval of the first drug to be derived from transgenic-animals; GTC Biotherapeutics’ anti-clotting therapy Atryn, suggests that US demand for effective bioprocessing solutions will continue growing. All of which looks good for Asahi Kasei TechniKrom in terms of developing its business in the US.

TechniKrom President Lou Bellafiore was also pleased about the new relationship. He said that: “In addition to our existing products and services that we will continue to offer, we are extremely excited about the line-up of novel bioprocess separations products that Asahi Kasei TechniKrom will introduce."