Stuart R. Gallant, MD, PhD

In the first post of this series, raw materials risk analysis was discussed.  In the second post of this series, raw materials testing, starting materials, and contact materials are discussed.

Testing, Release, and Audits

The starting point of release raw materials for GMP manufacturing is the manufacturer’s specification.  This can be considered a list of the important chemical properties of the raw material, from the point of view of the chemical manufacturer.  Some points to bear in mind:

• There may be additional chemical properties of the raw material which are not reported in the certificate of analysis but which are important to the drug manufacturing process.  These should be tracked during manufacturing development with an eye to identify typical ranges for these chemical properties.  Dialog with the chemical manufacturer on these properties may be initiated to gain further information to assess risk.
• Which containers to sample at the warehouse can be an issue.  If one drum of sodium chloride is ordered, then that’s the drum that gets sampled.  But, if a large number of sodium chloride containers are ordered, use of statistical sampling is appropriate to save cost and time [1].
• Managing the testing (or lack of testing) of some chemicals may be a negotiation with QA.  One example are materials that may be compromised by the environmental exposure inherent in sampling for analysis (for example, polysorbates or aldehyde modified PEGs).  Options for testing include:  1) sampling at risk after manufacturing (i.e., using some of the residual reagent as the test article after the drug has been manufactured)—the risk is that the test might fail after the batch is completed, creating a deviation that must be resolved, 2) sampling prior to the batch with additional controls on the sampling process to ensure the chemical in the sampled containers is not harmed (such as nitrogen fill of headspace prior to reclosing package, but this is difficult to arrange in a standard sampling lab).
• In clinical trial Phases 1 and 2, raw materials testing by the manufacturing site is often only for identity and microbial (if relevant), as well as inspection of the certificate of analysis to confirm that the lot meets specifications.  Identity testing serves an important GMP purpose of ensuring that an incorrect chemical has not been sent by mistake.  A reasonable approach for Phase 1 and 2 is:
  • Process chemicals:  test for identity, sample square root of (N) + 1 of the incoming containers
  • Formulation excipients:  100% of incoming containers for identity and for purity
  • Special materials (e.g., polysorbates and aldehyde modified PEGs) which can be altered by the sampling procedure:  sample “at risk” after they are used in the manufacturing process.
• As the program advances to Phase 3, full monograph testing of pharmacopeial chemicals begins.  For non-pharmacopeial chemicals, a specification will be developed based on the chemical manufacturer’s certificate of analysis, with consideration of what other assays might be appropriate to fully ensure the quality of the chemical.  A separate assay and purity test is often required because assay is typically concerned with the 95% to 99% range, while impurity testing may be concerned with PPM or PPB.
• The QC department will need an appropriate reference standard.  For pharmacopeial chemicals, there are often multiple sources of reference standard, but for a custom chemical, the only source may be the chemical’s manufacturer.  If the manufacturer does not inventory a reference standard, the pharmaceutical manufacturer may be forced to manufacture a reference standard (typically by qualifying a lot from the chemical’s manufacturer).
• It is important to understand the vendor quality program sponsored by the QA team at the pharmaceutical manufacturing site.  It should be a risk-based program compliant with appropriate regulatory guidances.  Nevertheless, the sponsor is ultimately responsible for regulatory compliance, which may require additional diligence above and beyond the manufacturing site’s program.
• One special case is that of the sponsor-provided material.  If the manufacturing site does not have a qualified vendor which can supply a particular chemical, the sponsor may take on the burden of quality due diligence for that chemical, with the site only responsible for incoming raw material testing on the chemical.  Eventually, the goal would be to transition the chemical into the site-sponsored vendor quality program, but that can take time if the site has a backlog of audits.

Starting Materials

Another special case is that of starting materials.  According to ICH Q7, “An API starting material is a raw material, an intermediate, or an API that is used in the production of an API and that is incorporated as a significant structural fragment into the structure of the API.”  In the above figure, a non-GMP synthesis to manufacture a starting material is depicted inside the green box, as part of an overall synthesis to manufacture active pharmaceutical ingredient (API).  (RM = raw material; Int = intermediate; SM = starting material.)

From a regulator’s point of view, starting materials represent black boxes—portions of the overall synthesis of an active pharmaceutical ingredient into which they have little or no visibility.  Of particular concern, as laid out in ICH Q11, is the issue of impurities.  There may be a limited number of steps between the introduction of impurities, accompanying the starting material, and the completion of the synthesis.  Variations in these impurities with the starting material could lead to variation in their level in the API.

Wigman, et al. created a qualitative risk analysis tool as different possible starting materials are considered to assign risk (“low,” “medium,” or “high”) to synthetic strategies under consideration [2, 3].  This tool codifies the judgement and common sense that would normally be applied to such a decision—as such it is helpful for decision making and documentation.  Wigman’s risk scoring method is shown in the figure below.

A starting material is an example of a custom chemical (which was discussed in part 1 of this post).  The idea of the invisible marriage (joining the pharmaceutical manufacturer and the custom chemical manufacturer) is a useful one to return to at this point.  Consider two different scenarios:

1. The first scenario is a generic medication in which cost of goods is very important due to strong competition and a small margin.  The availability of a starting material at low cost can reduce overall manufacturing costs, simplify project management, and increase speed to market.  These benefits may be strong incentives in favor of using a starting material within the manufacturing process.  The wedding to the custom manufacturer is advantageous in this case.
2. The second scenario is an innovative drug, still early in its patent life and as yet unapproved by regulatory agencies.  In this type of project, cost of goods is less important, but control of the manufacturing process is very important.  Issues like control of impurities, manufacturing schedule, and intellectual property all factor into this project as more important than the first scenario.  As an example, consider the case that the process is being run at a small contract manufacturer, and the plan is to transfer to a larger contract manager prior to Phase 3.  If the entire synthesis is in-house, without the starting material supplied by a separate customer manufacturer, it is perhaps easier to transfer to the new CMO.  In this case, wedding to the custom chemical manufacturer may be a handicap to the project.

Contact Materials

Traditionally, the concept of raw materials included chemicals and container closures.  In this post, container closures is left out, as it is a large topic on its own.  But, one other group of raw materials has become more prominent in the recent past:  single use processing materials.  A quick list of single-use materials includes: mixing vessels and containers, bioreactors and fermenters, tubing and plumbing devices like valves and manifolds, and intermediate bags and bottles.  Of course, filters and chromatography supports fall into the category of contact materials, though they may or may not be single use.  In summary, more and more polymeric materials are being used in preference or in addition to traditional stainless steel and glass processing equipment.

Often, the selection of contact materials occurs during a technology transfer to a new manufacturing facility.  Each manufacturing facility has its own approaches to different unit operations.  Many manufacturers offer both stainless steel and glass as an option, as well as single use.  But, single-use has the advantage of eliminating or greatly reducing the change-over cleaning considerations.

Technology transfer typically begins with a technology risk assessment which includes contact materials.  Some points to think about as the risk assessment is assembled are:

• Single use items are produced under change control and released with a certificate of analysis or certificate of quality which testifies to the control system (ISO system used) and how the product was controlled (free from animal origin materials, produced from non-fiber releasing materials, bubble point testing of underlying filters material, extractables and leachables testing of constituents) and tested (USP endotoxin testing, integrity testing, USP oxidizable substances).
• Manufacturers typically provide validation packages for their single-use products which provides more detailed information than is available on the manufacturing certificate.
• Bennan, et al. did a great job of unifying a large amount of industry experience in a single article [4].  They offer a risk evaluation worksheet:

which is a great place to start in thinking about contact surfaces.  In addition, Bennan offers tables of typical data for extraction testing of different contact materials.

As always, the approach to risk assessment of contact surfaces is:  1) quantify risk, 2) reduce risk by removing materials or selecting lower risk materials (if possible), 3) manage remaining risk.

One technique for managing risk is “functional extractable testing.”  In this approach, the contact surface is extracted with the same fluid it will see during the manufacturing run (same solvent combination, pH, temperature, etc.); however, the surface area to volume is maximized—use only enough of the fluid to wet the surface fully.  Incubate for a representative time period on the conservative side (if the actual contact time is 2 hours, then incubate overnight).  Collect the fluid and analyzed the fluid with the purity assay that will be used for the API or drug product—typically an HPLC assay.  Scan the baseline for new peaks.  If new peaks are not detected, the contact material is unlikely to introduce impurities which can be quantified during the release testing of the drug substance or drug product lot.  A good control is to run the same functional extraction test using the equivalent glass or stainless vessel to the single-use container which is being evaluated.

Conclusions

Returning to the introduction of this two-part post, we were considering a hypothetical project just selecting raw materials for initial toxicology manufacturing.  The team had some decisions to make.  Hopefully, this post has been helpful in providing some tools to use in selecting initial raw materials.  Making those choices intelligently, with a risk-based approach, can save cost and time as the project proceeds through clinical trials, and eventually to market.

[1] Torbeck, L. and Trobeck, J.  Square Root of (N) Sampling Plans, PDA 2013.

[2] Wigman, L. et al.  “A new Risk Assessment Tool for Regulatory Starting Material Evaluation,” American Pharmaceutical Review 20(2):74.

[3] Wigman L.  “Interpreting ICHQ11: A Risk Assessment Tool for Assessing Starting Material Acceptability,”

[4] Bennan, J. et al.  “Evaluation of Extractables from Product-Contact Surfaces,” BioPharm International December 2002.

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