A chain is only as strong as its weakest link. Likewise, the total quality of a GMP manufacturing process is attenuated by the lowest-quality step(s) in the process. For example, the process diagram at right shows a sequence of steps, which comprise a process of manufacturability (Figure 1).

All of these major steps—and the subordinate steps that comprise them—have degrees of natural variation within them. For this reason, the overall performance of the process is subject to the rules of probability. For example, if the defect rate of the materials sourced for the manufacturing process is 12%, the defect rate for raw material QC testing is 5%, for US manufacturing is 7%, for DS manufacturing is 2%, and is 4% for contract testing, the model with these defect probabilities inserted looks like Figure 2.

Now, the concept of Rolled Throughput Yield (RTY) comes into play. RTY is an estimate of the likelihood of achieving desired success from a series of process steps, which each have a probabilistic proportion of error to contribute to the process’ outputs. The simplest model to use it with is a 2-factor process: Step 1 and Step 2 are required to produce Output P. If Step 1’s success rate is 80%, and Step 2’s success rate is 80%, the overall RTY of this process is that there is a 64% chance of getting the desired outcome for Output P when the process runs (.8 x .8 = .64).

Applying this to our refined model leads to an overall RTY of 73%. That is to say, with realistic error rates inserted into the example, there is a 73% chance of the process yielding the anticipated successful result.

Because there are so many things, which could go wrong in any manufacturing process, putting into place quality agreements between sponsors and supplier organizations allows for both parties to be aligned to the requirements for a particular process. By minimizing all of the ways in which the steps in the process can go wrong by specifying quality levels in the agreement, many of the steps contributing to a process’ overall success or failure can be established.

Alignment vs. calibration
There is a big difference between alignment and calibration, as it is used above in the context of quality agreements. By aligning all suppliers to a sponsor’s requirements for a quality agreement, each can understand what broad expectations are in place in order to be a successful partner in the production process. However, how each supplier organization measures its internal performance relative to what the sponsor is expecting and in relation to each other across suppliers is calibration. Each supplier must be calibrated to be measuring in the same way as the sponsor organization. Otherwise, there will be a lot of project team meetings occurring just to disentangle perceptions about the intent and results of suppliers’ quality targets and resolve disagreements.

Quality agreements and QbD
Quality agreements are part of the reason for Quality by Design (QbD) in drug production. The expectations between a sponsor company and contract service provider define not only the nature of the outsourced relationship but also dictate the quality of the material being supplied or service provided. Quality agreements between contract manufacturers and their pharmaceutical customers are a well-established practice.

When looking at the scope of quality agreements, they specify the product and/or service between the two organizations. There is a great deal of subjectivity in specifying what is in scope, or out of scope, in the relationship. An example that very much is a quality by design case is a quality agreement between a sponsor and a supplier. This agreement may only specify the quality framework of one item or several inputs into the GMP manufacturing process. But the overall quality of all inputs and their successful execution in the process leads ultimately to the desired outcome. The types of contractors that can be included in the quality agreement are many, and include: Third-party manufacturers, contract testing laboratories, fill and finish facilities, stability storage firms, raw material suppliers, packaging and labeling, etc. What should be included for each contract quality agreement differs by company—sponsor and contracted facilities—and usually is based experientially on the previous work of the authors and reviewers of the agreement.

Typically, major items of inclusion are: change management—how will the two organizations agree this will work vis-à-vis their systems; technology transfer; investigations; deviation processing and routing/closure—at a minimum following 21 CFR 211.100 as well as internal best practices for either/both companies; product complaints—how will these be fielded, and who has responsibility for which aspect, codified in 21 CFR 211.198, but usually more organic between the firms; out-of specification (OOS) handling; process validation; regulatory oversight and auditing schema; stability program; packaging and labeling/relabeling; and so forth.

In fact, FDA’s draft guidance from May 2013, Contract Manufacturing Arrangements for Drugs: Quality Agreements, includes new directions of thought from the agency on how to define, measure, execute, and enforce the work done by parties in the contract GMP manufacture of pharmaceutical products. Many benefits are recognized for these partnerships by the FDA, including that, “Owners may benefit from using contracted facilities in many ways, including enhanced speed and efficiency in specific processes, expertise in a specific technology, and expanded capacity.”

But caveat emptor: because the ultimate responsibility still lies with the sponsor, as the guidance observes, “In all cases, the Owner is responsible for assuring that drugs introduced for interstate commerce are neither adulterated nor misbranded as a result of the actions of their selected Contracted Facilities.” This does not exonerate the contract organizations from their due diligence, as the FDA also notes, “All Contracted Facilities must assure compliance with applicable Current Good Manufacturing Practices for all manufacturing, testing or other support operations performed to make a drug(s) for the Owner.”

ICH in quality agreements
There is no doubt that the principles of proper quality agreements are part of several ICH guidelines, spanning the different realms of purpose that they cover. A quick exposition of the paradigms include ICH Q7 (Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients), which suggests that sponsors evaluate contracted facilities by establishing an agreement that lists the responsibilities of the processes on both sides, and by performing routing audits of the contracted facilities. ICH Q9 (Quality Risk Management) advocates for a comprehensive evaluation of contracted facilities through supplier Quality Agreements and auditing programs. And ICH Q10 (Pharmaceutical Quality Systems) stipulates that quality risk management includes specific activities.

For example, before outsourcing GMP manufacturing activities, the owner is advised to conduct a risk analysis that evaluates the extent of risk and the controls necessary for the supplier and the product or service covered by the quality agreement. Based on this risk, the guidance suggests the sponsor should provide the appropriate oversight and assess the suitability and competence of the potential contracted facility to carry out the activities. Q10 also proposes that sponsors also should monitor and review the performance of the contracted facilities and identify and expect action on any necessary process improvements. And as far as having the QbD chain be thoroughly covered from the start of the process, including its inputs, Q10 advises that all parties performing manufacturing operations should monitor incoming ingredients and materials to ensure they are within acceptable tolerances from approved sources using the agreed supply chain.

For continued reflection
The quality agreement is meant to collect a substantial base of forethought, prior to attempting to execute on the manufacturing of regulated drug product. For this reason, it stands in a respect similar to a prenuptial agreement: Both parties in the vast number of cases are coming together with the best of intentions, but by documenting what must exist for success, the quality agreement is a referenceable and enforceable document to ensure all involved parties are doing what they claimed they would, or could, do.

The lack of alignment of perception between the sponsor and contractor is a major source of variance and consternation when success isn’t 100%. And as we’ve seen, it almost never is! To have all involved be party to and agree to a quality agreement at least codifies these basic expectations. The quality agreement is never an active arbiter in a disagreement, but provides the basic fundamental premises that the relationship was started to support. 

References

1. U.S. Department of Health and Human Services, Food and Drug Administration. (2013). Guidance for Industry Contract Manufacturing Arrangements for Drugs: Quality Agreements. http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm353925.pdf
2. ICH Q7, Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients (Geneva, 2000).
3. ICH Q9 Qualified Risk Management (Geneva, 2005
4. ICH Q10 Pharmaceutical Quality Systems (Geneva, 2008).

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Ben Locwin

Ben Locwin, PhD, MBA, MS writes the Clinically Speaking column for Contract Pharma and is an author of a wide variety of scientific articles for books and magazines, as well as an acclaimed speaker. He is an expert media contact for the American Association of Pharmaceutical Scientists (AAPS) and a committee member for the American Statistical Association (ASA). He also provides advisement to many organizations and boards for a range of business, healthcare, clinical, and patient concerns. He can be reached at ben.locwin@healthcarescienceadvisors.com.