Manufacturers bear responsibility for every step of their global supply chain, FDA Commissioner Margaret Hamburg has stated recently; and the Agency is taking strict enforcement action. In 2009, 12% of 483 Observations and 16 Warning Letters were issued citing inadequate supplier qualification . Concerned not only with the failure of some U.S. manufacturers and suppliers to comply with the U.S. Code of Federal Regulations, the Agency recently hired over 700 inspectors to ensure that the FDA performs overseas inspections on a timely basis . For manufacturers, the responsibility may seem overwhelming as it impacts more than 330,000 suppliers in over 150 countries worldwide . How, one may wonder, did we get here?
Traditionally, critical components like Active Pharmaceutical Ingredients (APIs) or printed circuit boards (device) were manufactured internally by Finished Goods Manufacturers (FGMs). In an effort to reduce costs and/or reduce-regulatory scrutiny, many pharmaceutical and medical device FGMs began outsourcing to suppliers nationally and globally. Increased failures of these critical components led to recalls, patient safety issues and caught the attention of the FDA and Congress, and generated tremendous public outcry. Some of these incidents have resulted in hundreds of serious adverse reactions and scores of deaths, as was the case in 2008, when a contaminant was found in lots of heparin from an outsourced supplier in China.
These incidents need not reach a critical stage as there are cost-effective, compliant solutions available. This article presents the perspectives of three sets of experts—regulatory compliance consultants; a finished goods manufacturer and a supplier. While the FGM and supplier co-authors hail from the device industry, their insights apply to pharmaceutical FGMs and their suppliers.
I. Regulatory Compliance Expectations—Consultant Perspective
Regulations and Guidance Documents
Manufacturers are wise to remember that the purpose of assessing the capability of suppliers is to ensure that supplier components meet FGM requirements . FGMs need to provide a greater degree of assurance beyond that provided by receiving inspection and test. An appropriate component supplier and services quality assurance (QA) program should include a combination of assessment techniques.
One such technique and regulatory enforcement trend is supplier process validation. FGMs need to ensure that validation processes employed by their suppliers not only meet the supplier’s own processes, but meet the validation processes requirements of the FGM as part of either: a) the qualification of the supplier by the FGM, and/or b) through the review of validation protocols conducted by the supplier for the manufacturer. This would include all aspects of the validation process, including process output performance levels (i.e., acceptance criteria), statistical requirements, review/resolution of deviations, etc.
For pharmaceuticals, the expectation of an Active Pharmaceutical Ingredient supplier, the equivalent of a critical component supplier for medical devices, is much more clearly defined in ICH Q7A, and closely mirrors the same GMP regulations applied for Finished Goods Manufacturers—i.e., CFR 21 Part 211. Additionally, the requirements for API supplier validation are comprehensive, from equipment and facilities qualification, to analytical test methods, cleaning, and process validation.
The “gray” area is that the application of the guidance and cGMP requirements depends on the type of manufacturing, (e.g., chemical vs. API derived from animal or plant sources vs. biotechnology), cell culture and degree of manufacturing, (e.g., cutting, mixing, and/or initial processing vs. isolation and purification), where more complex and final processing of material has a higher degree of applicability.
The quality systems approach also calls for periodic auditing of suppliers based on risk assessment. According to the FDA’s “Guidance for Industry Quality Systems Approach to Pharmaceutical cGMP Regulations,” the audit should include an examination of the supplier’s quality system to ensure that reliability is maintained and quality is built-in throughout its component manufacturing. Although this is only a guidance, it is up to the FGM to provide rationale, through a risk assessment, as to why such an approach was not used; or risk being cited for inadequate establishment of the reliability of the supplier’s analyses (§ 211.84 d(2)).
In addition, the guidance recommends that changes to materials (e.g., specification, supplier, or materials handling) be implemented through a change control system with certain changes requiring review and approval by the Quality Unit per § 211.100(a). It is also important to have a system in place to respond to changes in materials from suppliers so that necessary adjustments to the FGM’s process can be made and validated if appropriate; helping to avoid unintended consequences.
So where do we draw the Quality Systems Regulation (QSR) applicability line? It is clear that critical components that affect product function and patient safety plays an important role as described by the regulations and guidances cited above. However, even a non-critical component, such as a pharmaceutical excipient, can have a contamination issue through supplier processing and shipping that could lead to patient injury or deaths.
Current enforcement trends indicate that the minimum quality systems for all suppliers should include:
- Change Control (Design and Process)
- Process Control, including Process Validation where the product quality attributes including stability cannot be fully verified
- Supplier QA, for critical raw material suppliers
- Other aspects of FGMs’ quality assurance may also apply, e.g., Complaint Handling, Statistical Requirements, etc.
Ultimately, manufacturers need to view all suppliers as if suppliers were part of the FGMs’ in-house production facility. After all, while the supplier may own the process; the manufacturer owns the product.