20th Anniversary Special Feature: The impact of regulations

During the past two decades, regulations have evolved in both Europe and the US to accommodate the technological developments in the pharmaceutical, biotechnology and medical device industries. However, these changing regulations are often increasingly stringent and complex.

In the US, the regulatory landscape has altered significantly. By the mid-1980s, biotechnology was a rapidly growing industry and there was an urgent need to address how biological drugs differed from traditional pharmaceutical products. In 1987, the FDA Center for Drugs and Biologics was divided into two entities: the Center for Biologics Evaluation and Research (CBER) and the Center for Drug Evaluation and Research (CDER). The division was necessary to cope with the huge number of new drug applications (NDAs), and to address issues in drugs and biologic evaluation.

The European regulatory landscape has also altered during the last two decades; for example, through the introduction, expansion and refinement of EudraLex: The Rules Governing Medicinal Products in the European Union.¹ EudraLex is a group of European directives and regulations that are constantly reviewed and updated to reflect Europe's changing technologies and environment. It also standardizes regulations with FDA through ICH.

FDA Title 21 CFR Part 11 was introduced in 1997 to govern the growing use of electronic records and signatures, and sets out acceptable criteria for the trustworthiness of this format. This new regulation sought to educate the industry on best practice logical and procedural controls, audit trail requirements and validation for the use of such records. Unfortunately, the legislation caused significant upheaval and change at a time when computing and software programming were redefining manufacturing and operations. This led to the unusual step of FDA clarifying within their Scope and Applications guidance document a much narrower interpretation of the ruling,² together with a statement of intention to use enforcement discretion with respect to certain Part 11 requirements. Additional guidance was drafted by FDA regarding this area, but much of it has been subsequently withdrawn as it was too restrictive for evolving technologies.

Regulatory changes provide a foundation for the pharmaceutical industry to keep pace with progress by facilitating and clarifying acceptable processes within the industry. Standardization is also improved as the minimum requirements are set by the regulatory agency rather than being at the discretion of each individual regulatory inspector. However, in some cases numerous legislative alterations can lead to a greater focus on ensuring compliance rather than achieving quality. It is, therefore, possible that regulatory agencies enforcing legislation through frequent inspections cause quality assurance resources to be diverted to activities such as audit preparation, inspection hosting, responding to audit observations and implementing multiple corrective action and preventative actions in response to observations. Regulators' activities could risk being seen as obstacles to, rather than guardians of, quality.

On the go...

The reach of regulations is moving further up the drug development chain, affecting many more areas than the traditional manufacturing process. The medical devices industry has, in recent years, adopted and validated product life cycle management applications to electronically manage the device master record and the device history record, including the handling and storage of early stage design data and drawings. The adoption of similar applications across the biotechnology and pharmaceutical industries is only a matter of time, particularly in view of FDA's 21st Century Risk-Based Approach goal to harmonize quality systems across all its activities.³

The regulatory and validation service and support market has grown significantly during the past 20 years, reflecting the high activity of regulatory compliance and quality assurance within the industry. The trend looks set to continue, but in a much more technologically focussed way because the regulatory authorities are demanding electronic means of submission, further communications and additions, and integrity of data storage.

Current regulatory status

The challenges faced by pharmaceutical companies in 2008 are similar to those in 1988: the need to develop novel and effective treatments; optimize the discovery to product-to-market time; and maintain high product quality. Finding new treatments for many conditions can be costly and challenging as the 'low-hanging fruits' of new chemical entities have already been picked. Additionally, pharmaceutical organizations are looking to develop new drugs more quickly to lengthen patent protection. This speed-to-market pressure is leading to more stringent regulatory reviews at the earlier stages of drug development. Moreover, the move from small molecules to larger biomolecular therapies provides an additional layer of manufacturing complexity, which requires more intense regulation.

The increasing use of technology, though, is perhaps the most significant factor affecting the pharmaceutical industry and its regulatory landscape. During the last 15 years, electronic processes have overtaken paper-based methods, and computers are now seen as invaluable instrumentation for data acquisition and storage. This activity requires very specific controls, such as FDA Title 21 CFR Part 11 'Electronic Records; Electronic Signatures'. A logical progression of this activity is FDA's PAT initiative, launched in September 2004.⁴

Pharmaceutical companies are also dealing with increasingly large amounts of data for regulatory dossiers. Traditionally, organizations convert computerized data into paper-based formats for regulatory submissions and inspections. However, FDA recommends using the electronic common technical document (eCTD) for regulatory submissions in the US, Europe and Japan. The specification of the eCTD was developed by ICH, and is set to become the mandatory method for regulatory submissions by June 2009. To prepare for this, many pharmaceutical companies are developing their electronic document management systems (eDMS) to streamline the move. Although this activity will increase efficiencies in the medium- and long-term, it will cause a lot of pain in the short-term, particularly for companies that have committed to certain inflexible IT platforms.

New regulations are implemented when governing bodies feel a particular area requires guidance or recommended practices. As the speed of technological development increases within the pharmaceutical industry, the regulations change and adapt more frequently to reflect the development. Although larger companies usually have regulatory and validation resources to deal with changes, smaller companies may not have the same luxury. However, for immediate help, companies can turn to consultancy firms that offer advice and training on how best to deal with regulations, provide essential resources to ensure compliance and assist in reacting to new legislation in good time.

The future

As the sophistication of pharmaceutical manufacturing increases, it is even more important to establish detailed guidelines for acceptable processes and procedures. This is illustrated by the physical increase in size of the UK's Medicines and Healthcare products Regulatory Agency (MHRA) Rules and Guidance for Pharmaceutical Manufacturers and Distributors (the 'Orange Guide').⁵

In its 2004 report, Pharmaceutical cGMPs for the 21st Century, FDA indicated its intention to implement an integrated quality systems orientation in all agency activities and programmes.⁶ As a result, it is anticipated that there will be harmonization efforts across GMP for the pharmaceutical, biotechnology and medical device industries. Additionally, FDA implied that the 21 CFR Part 11 regulations may be recodified. However, this will be a long-term project.

Pharmaceutical organizations are moving towards a drug development process where all activities will be controlled, captured and retained electronically. Tools currently used sparingly in the development process, such as molecular computer modelling and simulation, will become accepted methodology. In many cases, the control of these technologies will require simple clarification of existing regulations. However, there are currently no regulations covering the control and validation of complex electronic simulation programmes. This will need to change to ensure that best practices for these programmes are made available.

To deal with the changing regulatory environment, support must be available for companies with limited resources. As technology use increases and drug development becomes more complex, regulations will change to reflect this, and drug companies will have to invest more resources in dealing with regulation, validation and guidance.

The authors are hopeful that this increase in regulation is tempered by common sense from the industry and regulators alike, such that they do not regulate themselves clean out of existence.

Keith Williams is the founder and CEO of Good Products Ltd (UK).

Mark Wright is a Computer Validation Consultant with Good Products Ltd (UK).

Jonathan Russell is a Principal Consultant with Good Products Ltd (UK).

www.goodproductsEU.com

References

1. EC, "The Rules Governing Medicinal Products in the European Union" (2008).

http://ec.europa.eu

2. FDA Guidance for Industry — Part 11, Electronic Records; Electronic Signatures: Scope and Application (August.2003).

www.fda.gov

3. Pharmaceutical cGMPs for the 21st Century — A Risk-Based Approach, Final Report (FDA, USA, September 2004).

www.fda.gov

4. FDA Office of Pharmaceutical Science, "Process Analytical Technology (PAT) Initiative" (2004).

www.fda.gov

5. MHRA, The Orange Guide (2007).

www.mhra.gov.uk

6. Pharmaceutical cGMPs for the 21st Century — A Risk-Based Approach (FDA, USA, September 2004).