Pharmaceutical and device firms outsource a variety of activities. Virtual firms outsource almost all GxP activities including the manufacture of API/drug substance, intermediates, final dosage forms, device components, and finished devices, as well as product design and development, labeling, packaging, and distribution. Another key activity many firms consider for outsourcing is the internal/external audit function. Whatever activities are outsourced, it involves a lot more than just signing on the dotted line.
When a manufacturing activity is outsourced, the sponsor must confirm that the CMO operates within an effective Quality System and must provide ongoing oversight of the contracted organization to ensure compliance with CGMPs. 21CFR 200.10 states “The Food and Drug Administration…regards extramural facilities as an extension of the manufacturer’s facility.” Further, The 2016 FDA guidance on Contract Manufacturing Arrangement for Drugs: Quality Agreements states that contract analytical laboratories must “…employ adequate controls to ensure that data and test results are reliable and maintained in accordance with CGMP requirements. It is the owner’s responsibility to review this information from the contract facility to decide whether to approve or reject product for release and distribution.” It is reasonable to assume that this requirement should extend to areas other than the analytical laboratory. For medical devices, EN ISO13485 Section 7.4.1 clearly requires records to be maintained of “the results of evaluation, selection, monitoring and re-evaluation of supplier capability or performance and any necessary actions arising from these activities”.
Some firms outsource audit activities for non-critical raw material suppliers while others may choose to outsource conduct of all GxP audits. An audit program may include evaluations of clinical trial operations, pre-clinical animal studies, hardware and software design and development for medical devices, both drug and device CMOs and component suppliers, or any number of additional GxP activities. While outsourcing some or all of a GxP audit program provides many advantages, a firm should also recognize potential pitfalls based on accountabilities specified in the GxP regulations and relevant standards.
Advantages of engaging a consulting firm to supplement a sponsor’s GxP audit program include:
- Allowing sponsors to minimize the number of full-time staff dedicated to the audit function while ensuring that this critical GMP activity is performed in a way that adds value and operates in compliance with the governing regulations.
- Providing access to a large pool of skilled auditors, as a consulting firm can match the specific project needs with a person highly skilled in given subject matter areas across the GxP spectrum. Access to additional skilled auditors helps to combat pressing business priorities and can help to ensure that the audits are conducted in a timely manner.
- Providing auditors with specific in-depth expertise in areas where a sponsor may not have that expertise in-house. For example, device expertise is necessary when evaluating combination product operations, but drug companies often have limited resources in this area. Hiring consultants to serve as auditors, or to support internal auditors, can provide additional expertise and mentorship for the team.
- Leveraging the geographic location of auditors to maximize efficiency and minimize cost. For global organizations, the ability to utilize auditors familiar with the local language and customs helps to address the challenges of auditing within a global supply chain.
While the advantages can be significant, there are also potential pitfalls sponsors want to avoid when selecting and working with a consulting firm to conduct audits. A few key aspects to consider include:
- Do your due diligence. Can the consulting firm consistently provide qualified staff to conduct audits and provide appropriate written audit reports? Sponsors must ensure that the auditors are qualified. Qualification does not simply mean that they have certifications or initials behind their names. True qualification means that consultants have working experience in the area they are evaluating, understand the regulations and standards, and have expertise in auditing and writing reports. Often this step can be overlooked, and the sponsor fails to confirm that the consulting firm provides staff who have the necessary education, training, and experience, as specified in 21 CFR 211.25(a) and EN ISO13485 Section 6.2, to perform their functions. Remember, the auditors are functioning as an extension of the sponsor’s firm. Would you ever want to use an auditor to evaluate your parenteral CMO who has expertise exclusively in the chemical synthesis of APIs? Be sure to always request documentation that supports the competence and expertise of the auditor(s).
- Do not make the decision solely on the basis of While the most expensive firm is not necessarily the best firm, you do often get what you pay for. Cost can be a factor but should never be the primary consideration.
- Do you have a quality agreement in place with the consulting firm covering the services they are being asked to provide? Quality agreements help to ensure that you get what you asked for (and what you paid for) from a quality perspective and are part of the GMP requirements.
- Ensure that you partner effectively with the consulting firm. Outsourcing should not be a one-way street. Have you been open and honest with the firm, and do they listen to your concerns and address specific areas you, the sponsor, want to be covered during an audit? Always try to work together to set the audit agenda, finalize the report, and identify areas of concern.
- Evaluate how the audits are conducted and be wary of any firm that places heavy emphasis on ‘’ Checklists are great as reminders, but excessive reliance on checklists should raise a warning flag for sponsors. Documenting that a CMO/supplier has an SOP in place for investigation of deviations does not evaluate the completeness or adequacy of the SOP. Simple YES/NO responses add little or no value here.
- Confirm the standards that the consultant plans to use in evaluating the site/vendor/supplier. This step allows you to confirm a consultant’s qualifications and should include working knowledge of the regulations in all applicable regions.
- Which templates are used for audit reports? Many sponsors have governing procedures and templates, but consulting firms often have extensive experience across different organizations and may have recommendations regarding industry best practice. Leverage the partnership to ensure effective communication before the audits are conducted.
- Determine how soon after the audit the clients will receive the final report. A standard rule of thumb is that the report should be available no more than 2 weeks after the audit. This is another touchpoint for defining expectations and building the partnership with your consultants.
Contracting with a consultant to supplement or be fully responsible for the conduct of GxP audits is an effective way to manage costs and leverage resources. A successful effort requires that the sponsor and consulting firm are true partners in this effort and communicate clearly and frequently regarding expectations. The sponsor should provide routine oversight of audit activities, as they would with any outsourced GxP activity. When executed well, a consultant and sponsor work together to ensure the sponsor’s needs are adequately represented, and the contracted activities represent the standards consistent with their Quality System.
Written by Barbara Unger, Principal Consultant at Validant.
With Validant, I have the opportunity to work with pharmaceutical companies worldwide that are working to positively impact patient health. My skills from 37 years in industry in Quality System Implementation and Quality Remediation are directly applicable to help our clients.
John M. | Validant Managing Partner since 2016
Validant offers win-win solutions for clients and consultants, continually building and maintaining lasting relationships. Their experts in business development and recruiting ensure that subject matter expertise and skill set is matched for the client and the best consultants are placed on the project.
Janet W. | Validant Consultant since 2013
In the spring of 2015, my firm had a significant FDA audit with serious findings concerning sterility assurance and data integrity. We had utilized Validant for a previous engagement successfully. Before the audit concluded, I was already in contact with the Validant team for assistance. I was very impressed by how quickly they orchestrated data integrity audits at all of our 20+ other sites. We then turned to them for assistance with our third-party oversight of our manufacturing operation and quality control laboratories.