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A science- and risk-based approach to verify and demonstrate that a process operating within predefined specified parameters consistently produces material that meets all its critical quality attributes.
Pharmaceutical companies applying for marketing approval of their products in Europe are now required to provide the region's regulatory authority with documented evidence that they are using a process that consistently produces their medicines at the correct specifications and quality standards. At the moment, companies have the option of providing regulators with the details of a process validation itself or of how they intend to carry one out. However, it is likely that the requirements will become more stringent with details of process validations being demanded not only in applications for marketing authorizations but also during the post-marketing phase.
"Process validation is an evolving landscape with a strategy being used throughout the lifetime of a product," said Brendan Hughes, an industry participant from Bristol-Myers Squibb at the expert workshop on validation of biopharmaceutical active substances in April at the London headquarters of the European Medicines Agency, the European Union's central licensing authority.
One of the main driving forces behind this move, which requires drug companies to provide more information on their processes, is an EMA-led policy of gathering as much data possible on the benefits risks of medicines from multiple sources including their methods of manufacture. Among the new sources of knowledge is data generated by the EU's new pharmacovigilance legislation that came into effect in July 2012. The aim is to build up an extended database on all authorized medicines, including post-marketing information on possible adverse reactions and manufacturing issues. The database complements an expanded one on GMP—called EudraGMP—containing information yielded by a new legislative requirement on GMP in the production of APIs.
The new legislative initiatives need to be "systematically utilized and further integrated to deliver continuous knowledge generation," said Peter Arlett, EMA's head of pharmacovigilance and risk management, and Tomas Salmonson, chair of the committee for medicinal products for human use (CHMP), in a joint article in the agency's latest annual report published in April. They added that "this concept of continuous knowledge generation is enabled by a lifecycle approach to data collection, and improved scientific and regulatory methods."
With process validation, EMA wants to use, in particular, a lifecycle system for new technologies being applied in the manufacture of advanced therapies. Last year, after detailed process validation, it approved Glybera, a gene therapy for treatment of the rare inherited disorder lipoprotein lipase, developed by the small Dutch company UiQure. Glybera was the first gene therapy to be authorized by EMA and the Western world. Its production process is likely to be scrupulously monitored after the product's launch. According to EMA, the authorization paves "the way for approval of similarly complex medicines in the future, as more gene therapies for rare diseases, personalized medicines, and nanomedicines are on their way."
In a draft guideline on process validation for dosage-form medicines, issued by EMA a year ago and currently being finalized, the agency said that a manufacturing process should be validated before a product is launched on the market. However, with medicines produced by well-established technologies, details of the validation, which can be based on the traditional validation method of using studies on batch production at the pilot stage, do not have to be placed in the application dossier for authorization. Instead, the data should be held at the manufacturing site to be made available, if necessary, for inspection. With biopharmaceuticals and other "non-standard method" of production as well as specialized products such as modified-release preparation, details of the validation, which should be made with verification data at the production-scale level, should be included in the application dossier.
During the post-authorization phase, validation is seen in the guideline as a means of monitoring and evaluating the processes in a continuous manner. "It is a science- and risk-based approach to verify and demonstrate that a process operating within the predefined specified parameters consistently produces material that meets all its critical quality attributes (CQAs)," the guideline says.
After a consultation on the draft guideline, one key issue being decided by EMA is the scope of process validation, which comprises an evaluation and verification stage. It was generally agreed that continuous process verification (CPV) should be a key component of the lifecycle monitoring of pharmaceutical manufacturing. "These concepts (with continuous process verification) are new but they are acceptable approaches," said an official at the UK's medicines and healthcare products regulatory agency (MHRA).
Under their GMP obligations, pharmaceutical manufacturers should be regularly checking their production processes anyway. "Regardless of the nature of the medicinal product, in accordance with GMP requirements, processes and procedures should periodically undergo critical re-evaluation, including revalidation as necessary, to ensure that they remain capable of achieving the intended results," said the MHRA official.
At the EMA's expert workshop on process validation of biopharmaceutical active substances, the difference between continuous and continued evaluation was explained in the context of GMP adherence. While continued verification is done with interruptions, continuous verification is carried out without stopping, said Kowid Ho, a member of the EMA's biologics working party (BWP), which is working on a guideline for biotechnology-derived active substances. An enabler with continued verification is GMP compliance, while with continuous verification, the enabler is quality-by-design tools such as process analytical technology (PAT) and in-line and at-line controls, added Ho, who is a biological products specialist at the French national medicines agency (ANSM). Hughes however, considered that a continued process verification can include some or all of the data sources used in the CPV procedure.
One difference between the two is that with continuous verification, the data are included in the application filing while continued verification is a basis for a prospective proposal. It may be described in the application filing but the main purpose of the data from continued verification is to show GMP compliance. The draft guideline on process validation of dosage-form medicines stresses the distinction between them. Although it says that continuous process verification depends strongly on compliance with GMP principles, its data are separate from that applying to GMP matters that are dealt with by GMP inspectors, the guideline says.
CPV is also a method that can be introduced at any time in the lifetime of a product. It can be used to revalidate commercialized products as part of the existing regulated system of post-authorization process changes, or it can be used to support an improvement program throughout the remainder of a product's lifecycle, according to the guideline.
A key aim of CPV is that it should not only be a means of verifying the validity of an original process validation but also for achieving greater knowledge of existing and new production methods. "It can be used when extensive process knowledge has (already) been gained through commercial manufacturing experience," said Ho. For the European regulators, the long-term objective behind lifetime process validation is that medicine manufacturers would achieve full understanding of their production technologies. It marks an important addition to the ways of ensuring that medicines meet the highest quality standards.
Sean Milmo is a freelance writer based in Essex, UK, firstname.lastname@example.org