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Robert Iser of PAREXEL Consulting answers questions regarding the regulatory expectations of quality agreements and how companies can ensure the quality and safety of their products.
Robert Iser, vice-president of PAREXEL Consulting, spoke with Pharmaceutical Technology Europe about the role quality agreements play in outsourcing.
PTE: What is a drug company’s responsibility when it comes to ensuring the quality and safety of products or ingredients manufactured at a contract facility?
Iser: Although a drug company (or an application sponsor or marketing authorization holder) is ultimately responsible for ensuring that products available for patients and caregivers meet quality and safety expectations, the assurance of quality and safety of products and ingredients manufactured at a contract facility is a shared responsibility between the drug company and any contracted facility. Both parties must adhere to the expectations set out by the appropriate regulations and guidance to ensure that the products are manufactured in accordance with current good manufacturing practices (CGMPs), meet the necessary quality standards, and are safe and effective throughout a product’s lifecycle.
As noted in the current FDA [US Food and Drug Administration] guidance on quality agreements (1), ’when all parties clearly understand their CGMP-related roles and manufacturing responsibilities, the owners who use contract facilities, contract facilities that provide services to owners, and, ultimately, patients who take the drugs manufactured under these arrangements may benefit in many ways … each party engaged in the manufacture of a drug is responsible for ensuring compliance with CGMP for the manufacturing activities it performs.’ This demonstrates the importance of putting together a sound quality agreement and clearly defining roles and responsibilities of the company and the contract facility.
PTE: What are the most important aspects of a quality agreement?
Iser: There are a number of important aspects for quality agreements between a drug company and a contract manufacturer. It is vital that the following aspects are clearly stated and agreed upon:
It is important to consider these aspects, along with other recommendations found in current guidance, when developing and implementing agreements with contract facilities.
PTE: What are the European expectations regarding quality agreements?
Iser: The European Commission published a revision to the European Union Good Manufacturing Practices (GMPs) (Chapter 7) (2), effective in 2013, to provide expectations for outsourced GMP-regulated activities. The revised GMP guide includes many of the same topics as found in the current FDA guidance for industry including roles and responsibilities of the contract giver (the drug company) and the contract acceptor (the contract facility), assessment of a facility to carry out outsourced activities, communication of information that is necessary to carry out the outsourced activities, change control expectations, etc. A company looking to enter into a quality agreement should utilize this guide.
PTE: What are FDA’s expectations regarding quality agreements?
Iser: FDA published a final guidance for industry in November 2016 on quality agreements with contract manufacturers (1). The guidance was developed as a collaborative effort with the Centre for Drug Evaluation and Research (CDER), the Centre for Biologics Evaluation and Research (CBER), the Centre for Veterinary Medicine (CVM), and Office of Regulatory Affairs (ORA) and lays out the current thoughts and expectations that FDA has for quality agreements. It is strongly recommended that companies refer to this guidance when initiating a new quality agreement or if they are reviewing an existing quality agreement with a contract facility.
It should also be noted that ICH [International Council for Harmonization] Q7 (3) includes helpful information regarding quality agreements with API manufacturing sites, which is augmented by FDA’s quality agreement guidance. Companies developing combination products should review the expectations found in the guidance on Current Good Manufacturing Practice Requirements for Combination Products, as it relates to contract facilities and quality agreements (4).
PTE: Do regulatory agencies want to see copies of quality agreements when performing inspections?
Iser: Per FDA’s current guidance on quality agreements, ‘quality agreements may be reviewed during inspections,’ and current regulations in the United States and Europe, as well as other regions, include expectations for the outsourcing of manufacturing activities. As such, companies that are being inspected by a regulatory agency should have available any applicable quality agreements so that they may be provided to the investigator/inspector upon request.
PTE: What mistakes are companies making when drafting quality agreements?
Iser: There are some common mistakes that occur when companies are drafting quality agreements. First, roles and responsibilities of the drug company and the contract manufacturer are not always clear, especially when it comes to stating and agreeing on the quality unit’s responsibilities. Second, some agreements are interpreted in a manner that deviates from CGMP expectations (e.g., a contract manufacture interprets that they do not need to perform an investigation of an out-of-specification result that they generate since the drug company is responsible for release of commercial batches), which may lead to observations being cited during an inspection. Third, a mechanism to periodically assess and revise-if necessary-the agreement is not always included in agreements. Lastly, some quality agreements include commercial contract or business aspects and should only focus on quality management aspects as laid out in current regulations, such as US 21 Code of Federal Regulations (CFR) 211 (5) or guidance documents such as ICH Q7 (3) or Q10 (6). Additional helpful information on avoiding these mistakes can be found in FDA’s current guidance for industry (1).
PTE: How can drug companies and contract manufacturers create quality agreements that clearly outline each company’s responsibilities?
Iser: The best way for drug companies and contract manufacturers to create quality agreements that clearly outline each company’s responsibilities is to follow the recommendations for roles and responsibilities that are found in current guidance documents. Current agency documents clearly lay out expectations for documenting roles and responsibilities that are directly linked to the quality unit responsibilities included in CGMPs; and pharmaceutical quality system aspects found in health authority guidance and ICH guidelines.
PTE: Can you give a real-world example of when a lack of a quality agreement or a poorly-written quality agreement led to a FDA 483 and/or warning letter?
Iser: It is important that a quality agreement between a drug company and a contract facility clearly defines roles and responsibilities related to CGMP activities. It is equally important, as stated in the FDA guidance, ‘that quality agreements cannot be used to delegate statutory or regulatory responsibilities to comply with CGMP.’ It is likely that FDA would cite a company for deviating from CGMP expectations due to adherence to an inadequate quality agreement that violate the tenets of the GMPs.
A real-world example of a [FDA] 483 observation related to quality agreements is a contract testing facility being cited for not following a quality agreement regarding the destruction of remaining samples with the authorization of the contracting company. This ties back to the importance of establishing clearly defined roles, adhering to the roles under an agreement, and how it fits with the CGMP expectations.
FDA guidance further states (as part of case examples), ‘no matter whom tests the products, the owners’ quality units are ultimately responsible for ensuring that the products are manufactured in accordance with CGMP. A quality agreement does not change that. FDA could cite the owners … for failing to evaluate, qualify, audit, and monitor their contract facilities.’
A recent example of a quality agreement citation in a warning letter (7) was related to a quality agreement with the firm’s contract manufacturer that didn’t include provisions for sterilization processing along with other quality agreement provisions that were not being routinely followed. Although this warning letter was related to a device and should follow the purchasing controls expectations found in 21 CFR 820.50 (8), it also shows that clarity around roles and responsibilities and adherence to an approved quality agreements are important aspects that need to be considered when a company develops and implements a quality agreement with a contract facility, and may be assessed while an FDA investigator is on site.
Companies that are looking to develop combination products should consider how the current 21 CFR Part 4 regulations (9) impact their quality system and operations and are encouraged to read the current FDA guidance on GMPs requirements for combination products (4) for further information as the guidance includes language on entering into quality agreements, where ‘quality agreements may, for instance, specify expectations as to which facility will perform what activities and develop and maintain what documentation needed to demonstrate compliance with particular CGMP requirements … for example, an owner may contract for the manufacture of the final combination product with a contract manufacturing facility, and detail in the supplier agreements the CGMP responsibilities and approaches for that facility.’
Overall, the best way to avoid inspectional observations that may lead to a warning letter is to initiate quality agreements that use the recommendations found in current health authority quality agreement or outsourcing guidelines, are reflective of CGMPs, and are part of an effective pharmaceutical quality system.
1. FDA, Contract Manufacturing Arrangements for Drugs: Quality Agreements Guidance for Industry (CDER, CBER, CVM, November 2016).
2. European Commission, EudraLex The Rules Governing Medicinal Products in the European Union, Volume 4 EU, Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use, Chapter 7 Outsourced Activities (EC, 28 June 2012).
3. ICH, Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients (ICH, September 2016).
4. FDA, Guidance for Industry and FDA Staff: Current Good Manufacturing Practice Requirements for Combination Products, Final Guidance (FDA, Silver Spring, MD, January 2017).
5. 21 CFR 211
6. ICH, Q10 Pharmaceutical Quality System (ICH, April 2009).
7. FDA, Warning Letter FLA-15-30 to Ultroid Technologies, Inc., FDA, 27 Aug. 2015.
8. 21 CFR 820.50
9. 21 CFR Part 4
Pharmaceutical Technology Europe
Vol. 30, No. 3
When referring to this article, please cite it as S. Haigney, "Expectations in Quality Agreements," Pharmaceutical Technology Europe 30 (3) 2018.