Business Accent

Converting challenges to advantages

Jerold Martin talks about leveraging supplier validation services and how to turn compliance challenges into competitive advantages.

A myriad of changes are taking place in the biopharmaceutical industry today. These changes are spurred by the globalisation of pharmaceutical manufacturing; an increasing number of drugs entering the manufacturing pipeline, expanded production; growing validation and compliance requirements to address new technologies.

New technologies are both a gift and a burden to pharmaceutical companies. The benefits are frequently offset by the initial costs of implementing new validation and compliance protocols associated with these technologies. However, drug companies are realising that world-class equipment suppliers can offer critical avenues of support. And it is not just for supplying and installing equipment, but also for validation and compliance. Equipment manufacturers know their equipment, and have often validated it under stringent testing.

For biotech start-ups, strong vendor partnerships are particularly valuable for providing resources related to testing, qualification and validation. They are also unlikely to have the systems in place to provide formal employee training to perform validation tests, should the company suddenly expand. Since world-class equipment suppliers have specific manufacturing expertise and skilled scientific staff, they, in effect, provide the industry expertise to support necessary regulatory compliance and validation documentation. Thus, the opportunities for established pharmaceutical and contract manufacturers are proportionately as large, particularly in terms of cost savings. However, many of them are missing these opportunities by failing to turn to their equipment suppliers.

There are several areas of manufacturing, where the need for outside help is acute. These include sterilising filtration validation, aseptic connector validation, supplier support for 21 CFR Part 11 electronic records, and filter integrity test instrument validation services. Equipment suppliers are also a less obvious but vital source of contract technical, process development and optimisation services.

Sterilising filtration validation

Filter suppliers can simplify sterilising filtration validation by providing test design expertise, testing facilities with GMP trained technical personnel, and by offering submission-ready documentation for various types of tests required for qualification and validation.

USFDA has acknowledged the expertise of suppliers in providing validation services, especially with regard to filtration equipment, which is a widely outsourced procedure in pharmaceutical manufacturing. According to FDA Draft Guidance Documentation - Sterile Drug Products Produced by Aseptic Processing - Current Good Manufacturing Practice (2003), "When the more complex filter validation tests go beyond the capabilities of the filter user, tests are often conducted by outside laboratories or by filter manufacturers." Special drug processing conditions are often outsourced to sophisticated filter manufacturer service laboratories, including microbial challenges at high and low temperatures, high pressures, long time periods, potent cytotoxic drugs, which must be handled within isolators, extractions at high temperatures, and rapid turnaround projects. Beyond these specialised capabilities, suppliers can also provide documentation such as validation reports and certificates of tests that can be submitted directly to regulatory authorities as part of NDA, BLA or other regulatory filings. Utilising these technical services can save drug manufacturers substantially, compared to attempting to generate such test data and documentation themselves.

Aseptic processing

FDA's September 2004 Sterile Drug Products Produced by Aseptic Processing Guidance for Industry underscores the importance of adopting technology to further improve drug manufacturing safety and efficacy. One of the new technologies being introduced into the pharmaceutical and biotechnology industries to meet this vision is the aseptic connector. Aseptic connectors form a system that allows for the dry connection of two sterile fluid pathways, while maintaining the sterile integrity of both. These single-use disposable units are being incorporated in clinical and approved drug manufacturing for a wide range of applications, particularly with single-use disposable manufacturing systems.

However, one of the first questions that arises with aseptic connectors or any new technology is, "How is it validated?" A unique aspect of aseptic connectors is that the equipment manufacturer can develop a generic operation validation. Generic validation means a supplier, along with potential industry users, can define the generic operating conditions under which a new technology will be used and would need to be validated. Once defined, the equipment manufacturer can do much of this testing for every user in the industry. All the data can be supplied in a validation support document that users can incorporate into their process validation submittal. With these test results documented, the product can be supplied in pre-validated form. In this way, the user only has to consider whether any product or use-specific applications might require additional testing. Given its familiarity with generic testing, the supplier can often perform these remaining product-specific tests on a contract basis, so the actual amount of validation done by the user is minimised.

The supplier's ability to provide completed and documented generic validation studies along with technical services, as well as provide system design and operator training, accelerates the introduction of the technology and shortens the time for incorporation into a drug manufacturing process. It also reduces the qualification, validation and implementation cost to the user. With this approach, the equipment manufacturer incorporates the cost of a single generic validation into the price of the aseptic connector units, effectively sharing it among all users in the industry. This makes for a rapid and low-cost validation by users.

Filter integrity validation

The validation of automated equipment is another example of where equipment manufacturers can provide critically needed services that impact many different processes. The ISPE's Good Automated Manufacturing Practices (GAMP) Forum, which promotes the understanding and regulation of computer systems within the healthcare industry, recognises the importance of equipment suppliers for validating automated systems. According to its GAMP4 Guide, "More use should be made of the development work performed by the supplier, so that less supplemental work is required by the user."

Equipment suppliers can help drug manufacturers speed validation plans by developing testing methods and quality procedures, and documenting normal operation and qualification activities. For example, in the case of a Commercial Off-The-Shelf (COTS) automated instrument controlled by proprietary software, the operation of the software can be confirmed by the supplier on a reference unit and documented for the user. Suppliers can also prepare checklists that eliminate the need for the user to know in advance which factors should be qualified and validated. This means that the user has to follow a shortened test protocol for the particular instrument to confirm that the instrument is operating as the software is designed.

21 CFR Part 11 compliance

Equipment suppliers can also play a significant role in helping pharmaceutical manufacturers maintain 21 CFR Part 11 compliance by enabling them to demonstrate the security of electronic records. Data generated during drug batch processing must be secure. This means that operator signatures must be captured and that access to these records is limited, with properly maintained audit trails. Helping pharmaceutical manufacturers maintain 21 CFR Part 11 compliance is quite possibly one of the most critical services that an equipment supplier can provide to a manufacturer, because failure to comply can result in the rejection of a drug.

Pharmaceutical manufacturers often fail to realise that it is not the equipment itself that needs to be 21 CFR Part 11 compliant. Instead, the regulations also pertain to how the equipment operates within a GMP environment. World-class suppliers can go beyond the role of just delivering the equipment, to help make sure that the equipment is operating, and operated within the particular manufacturing environment in full compliance of the regulations. A close partnership between supplier and manufacturer is key to assuring success.

Suppliers can help manufacturers by generating application documents and identifying equipment performance requirements for each aspect of the requirement. They can also identify the responsibilities of the user and those of the supplier. In addition, suppliers can provide detailed instructions on instrument configuration and operation, as well as recommendations on how to operate software-controlled equipment in compliance with 21 CFR Part 11.

How can suppliers help?

Beyond contract services related to specific pieces of equipment, suppliers can provide technical, process development and optimisation services that not only lead to cost savings, but to innovation as well. Very often biopharmaceutical companies look to third party consultants to provide them with expertise on the applications and uses of equipment, ignoring that some of the major suppliers are far more than just manufacturers and have a broad range of expertise. Contract services work can extend from optimisation of direct or tangential flow filter systems, chromatography column packing and membrane chromatography process development to process automation, GMP training and analytical contamination analysis using sophisticated equipment. Services provided by equipment suppliers are often more cost-effective than using third party laboratories, CMOs and other dedicated services providers, or attempting to do the work in-house.

Staying focused

Pharmaceutical companies are turning to equipment suppliers for the same reasons that many have outsourced drug production to contract manufacturers which is expertise and the freedom to stay focused on core competencies. An increasingly complex regulatory environment and mounting costs associated with bringing new technology applications into compliance have further hastened drug companies to partner with their equipment providers for consultative, testing and documentation services. Pharmaceutical companies that take advantage of the services that world-class equipment suppliers provide will find themselves well positioned to speed new drugs to market through the adoption of new technologies and the avoiding of regulatory pitfalls.

(The author is the Senior Vice-President and Global Technical Director of Pall Life Sciences)