After participating on a panel discussion at an IBC conference on Quality by Design (QbD) and the new Process Validation guidance issued earlier this year by FDA, I was approached by a process development scientist who asked my advise on the value of implementing  QbD in their company.

He explained that his company was extremely small and did not have a a large number of staff in his discipline or even other related ones such as quality and manufacturing.  In fact, he indicated that the clinical manufacture would be 100% outsourced. However, they were entering phase 1 soon and he was afraid to miss the opportunity to incorporate this new approach into their process development activity.

Over the next 20 minutes of discussion, the following points were raised which led to the following conclusions:

1.)  He was using a platform technology for the process to make clinical materials.
This platform would not be the process that they would commercialise by.  Therefore spending a lot of resources homing in on the role of inputs (raw materials), control points and control strategies did not make sense at this stage.  However, developing a set of critical quality attributes for the product did.  This would serve as a spring board
as they begin to develop their phase 3 process which would be the commercial one later in the cycle.  This commercial process may not look at all like the early clinical stage product.

2.)  These critical quality attributes would be important to have as early as possible for the drug product and the active pharmaceutical ingredient at least. This was particularly true for the biological product they were developing and would also be applicable to small molecular weight products as well.

This gave him quite a bit of relief that he had some time to work through the details before rushing headlong into the activity.

There was a question I posed to him that got him thinking and that was. “You are working for small company, highly outsourced.  Is you business model to take this product to market yourself or with a partner?  Or perhaps to get Phase 1/2 data and sell the product to a big Pharma?”

He responded “Why would it matter?”

“Because if you take it to market with or without a partner, you will need to begin the work on QbD as soon as you start the Phase 3 process development.  If you plan to sell it, the buyer will want to develop the process and they will do the QbD.  Any Phase 3 process work you do may not be valued by the buyer as much as the product, so your ROI on this work may not be as much as that for the product.”

So the take home messages are:  know your business model for your company and be sure to consider the ROI on the work you put into your product and processes.

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During a recent class I taught at University of California, Berkeley in their Quality and Compliance postgraduate certificate program, a question came up from one of the attendees that mirrored very closely observations I have made in audits over the years. And that question was “do we have to validate compendial methods we use in testing our commercial products?”

That question is, on the surface, very simple. And the answer is no. Neither the FDA nor the EMA requires us to validate compendial tests that we use with our products. But the answer actually has another layer to it which people do not venture too often to address.

While we do not have to validate a compendial method we use with our products, we must demonstrate that it works for the application with our product. ICH Q7 describes in section 12.80, this point clearly.

Analytical methods should be validated unless the method employed is included in the relevant pharmacopoeia or other recognised standard reference. The suitability of all testing methods used should nonetheless be verified under actual conditions of use and documented

Thus it is clear that while formal validation is not required, we must demonstrate that it works for our product for the intended purpose. This is very clearly shown in the original form 483 issued to Chiron Corporation for their flu vaccine product plant in UK in October 2004 that resulted in issuance of a warning letter in December 2004. They were cited for a lack of data to support the use of the USP sterility test for their product. Their response was clearly adequate since it was not cited in the warning letter. This action took them off the market in the 2004 flu season for their flu vaccine product

Many times on audit I have reviewed specifications and seen that compendial methods are used for a variety of tests including sterility, endotoxin, particulates and others. My first question is usually to ask for the data to support use of the method for their product. At least 9 out of 10 times, I get blank stares followed by the statement, “we don’t have to validate compendial methods!” I agree with them but follow on with the statement, “I know, but where is the data to support usage of the method?” They often look puzzled still but cannot provide any data. Too often, I believe, the first sentence of the ICH Q7 document is read but the second missed.

What do you have to do the “qualify” it? I recommend a simple qualification plan – rather like a validation protocol – with a testing plan to check the key parameters of the assay such as accuracy, precision, specificity and ruggedness, including interferences. That sounds like a validation and it is: but an abbreviated one touching only on the parameters of issues that make your product unique or challenging.

Posted in Commercial Manufacturing, Compendial Methods, GMP, Warning Letter| Tags: Services|9 Comments

A few years ago, the FDA issued a guidance to the effect that for Phase 1 clinical manufacturing, GMP’s were not required. However, patient safety had to be assured etc. A while later the guidance was retracted to indicate that GMP would, after all, be required. And that is how it was left. For both clinical and commercial manufacturing, GMP’s would be required. Because manufacturing of clinical and commercial materials does pose different sets of challenges, many people have had problems in interpreting this situation.

During a recent class that I taught on the topic of Investigational Medicinal Products, one of the attendees asked a question. He began: “At my company, we have clinical manufacturing facilities and GMP facilities for commercial products……”. The actual question he was about to pose is not really relevant to the point. In fact, the description of the two facilities is the point in question. He seemed to imply that while the commercial facility was GMP, the clinical one was less so and perhaps not even GMP. The two instructors present (another person and myself), both interceded immediately to question this description.

We asked whether he meant that the clinical manufacturing was not really GMP or perhaps, he meant something else. Clearly understanding the point, he indicated that what he meant to say was that the clinical facility operated at a lower level of GMP. We questioned whether he meant lower or perhaps differently. Quickly to the point he said – differently. And that is the situation for clinical versus commercial operations. The two situations require GMP but execute the GMP’s differently to meet the needs of the two situations. For example:

1. While commercial operations are run routinely, with each batch identical to the next, clinical manufacturing is characterised by each batch potentially being made differently from the last. The same applies to the testing which evolves as knowledge increases.
2. Commercial manufacturing is characterised by process and cleaning that are operated with full validation, as are the analytical methods. Clinical does not require process, cleaning or analytical methods to be validated
3. We develop processes, characterise them and validate them, thus building quality into the end product for commercial operations. Because we do not rely on this for clinicals, we are left to test the quality into the products and processes.
4. Commercial packaging is characterised with distinct configurations and designs to make sure these products are not mixed up in the plant or market place whereas, clinical packaging is designed so we cannot tell the placebo from the product.
5. When we package clinical material, we throw out many of the routine commercial GMP rules and have placebo and product open together in the packaging rooms: a situation unheard of in commercial packaging operations.
6. The distribution of commercial products is characterised by routine distribution checked and validated to assure we operate consistently each time. Clinical is much more complex with two batches often never going the same route.

These are but a few of the differences and they contribute to the way the standard Quality management System is designed to meet the different challenges. This is exemplified by how change control, lot disposition, audits, documentation and other systems are operated: all designed to meet the specific challenges of the GMP’s for that specific operation.

It also illustrates how we need to assure we formulate our thought process and communication. While this slip was made during a “friendly” encounter, this thought if expressed to an EU inspector who was evaluating our clinical manufacturing systems might have dire consequences. We are fortunate that FDA does not inspect our clinical operations.

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