GMP In Clinical and Commercial Manufacturing

August 19th, 2011 by

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 A while later the guidance was retracted to indicate that GMP would, after all, be required.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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