The basic concepts and reasons for quality assurance (QA) in biotechnology are, of course, the same as for the manufacture of any other medicinal product or device: to assure the safety of the patient. So, what's different about biotechnology?

The variety of products is vast — from well characterized proteins in production for the past couple of decades, to cell based products, genetically modified oncolytic viruses, viral gene vectors — and many more, with new innovations almost daily. Although their variety is vast, all are incredibly complex, potentially difficult to define by analysis alone (with the exception of certain well characterized proteins), and highly potent. Additionally, “things” potentially can grow in the process stream releasing unknown metabolites, or on the product itself causing molecular abnormalities that you didn't even know were possible, let alone how to test for.

Furthermore, most of these products cannot be terminally sterilized, some cannot be filter sterilized without dramatic loss of potency, and some cannot be sterilized by any method whatsoever (because they are live cells) and thus require full aseptic manufacture from cell bank to dosage form. If that isn't enough, many of them require storage below –20°C (often –80°C or below) and can be critically affected by freeze-thaw events, giving new meaning to the term “cold chain” and placing further stresses on packaging and labeling technologies.

I nearly forgot to mention that many of the producing organisms (and for live products, the products themselves) are genetically modified and come under requirements for containment, giving another dimension to their manufacture and distribution. In addition, if you are a qualified person (QP) involved in the manufacture of investigational biotechnology products, you may be releasing them for first-in-man trials. (A QP, under UK regulations based on European Union directives, is a quality assurance professional for medicines who ensures that every batch released to the market complies with its specification and has been made according to GMPs.) The bottom line is that QA in the manufacture of biotechnology products is one of the most interesting, challenging, and exciting in the industry.

I aim here to give a flavor of the challenges facing the implementation of CGMP quality systems in biotech manufacture, to highlight the thought processes required, and suggest ways of approaching the subject when seeking a contract manufacturer.

Regulations, Rules, and Guidance

There are, of course, many sources of regulations, rules, and guidance regarding the manufacture of biotech products. It is beyond the scope of this article to review them in depth. Apart from the fact that such a review would fill a very large book, not all the guidelines are applicable to every type of product, and for some types of novel product there are no regulatory guidelines that adequately cover the required operations. That is a particular challenge for novel investigational medicinal products (IMPs). The most important and widely used references are listed in the “Widely Used Guidances” box.

So, what are the challenges, and how do we approach the implementation of quality assurance in practice? I believe the challenges and their solutions reside in people, premises, equipment, products and processes, procedures, and product release.

People

There is no more important element in the manufacturing of pharmaceuticals than the people involved, and that includes all staff at all levels and in all functions. So what's different about biotechnology? All staff involved in the manufacture, testing, QA, release, warehousing, logistics, and materials management must be aware of the special nature of these products and the materials used to manufacture them. Staff members have to ensure that the products are correctly manufactured and are not adversely affected. Those directly involved in manufacturing operations must be well educated to understand the products they are manufacturing and equally well trained in the manufacturing operations — not just how and what to do, but also why it is being done that way.

QA BEFORE YOU OUTSOURCE: TEN QUESTIONS TO ASK A CMO



1: Licensing. Does the provider need a license for the proposed work, and if so, does it have one already?

2: Inspections. Is the provider regularly inspected by a regulatory agency or certified body?

3: Adequate Facilities. Are the provider's facilities designed and constructed to meet relevant regulatory, health, and safety requirements?

4: Current Facilities. Will your process fit into the provider's existing facilities?

5: Subcontracting. Can the provider meet all your process needs, or will parts of the process need to be further outsourced? If the latter, can your provider both provide and control such activities to the standards you require?

6: Staffing. Does the provider have an adequate number of appropriately qualified, trained, and experienced employees?

7: QA/QC. Does the provider have an independent quality unit, and can it release products to the clinic or market if required?

8: Compatibility. Does the provider handle materials that are incompatible with your process or that are highly sensitizing?

9: Transparency. Is the provider “transparent” in its operations, communicating with its clients such that the obligations in all technical/quality and commercial agreements will be met or exceeded?

10: Management. Is there an effective project management system in place to ensure that your work is performed to required standards, timelines, and cost?

Biological manufacturing processes are usually very complex operations with multiple stages. At each stage it is possible to contaminate the product, whether with microbial and/or particulate contaminants. People directly involved usually have to wear cleanroom clothing and follow cleanroom practices throughout the whole manufacturing process. It is therefore essential that staff members are capable of gowning satisfactorily and maintain scrupulous attention to detail not only in what they do, but the way in wxhich they do it.

There is no getting away from it — the gowning and rigorous attention to procedures and operating conditions can be unpleasant for manufacturing staff. It is essential that they fully understand the whys to maintain the right attitude toward what they are doing — especially at 2:00 am on a cold, wet, February day.