Stuart R. Gallant, MD, PhD

One of the first steps in a pharmaceutical development project is selection of chemicals.  For the development team, it may be an almost unconscious decision, “What sodium chloride brand do we have in the lab right now?  We are starting an experiment today.”  Or, it may be a carefully thought out strategy, “Which vendors have we qualified that have sodium chloride in their catalog?  What grades do they offer?”  But, it’s a decision nevertheless.

In this post, the process of selecting chemicals, starting materials, and contact materials for pharmaceutical manufacturing will be discussed.  The focus will be on managing raw material risk.

Raw Materials List

A raw materials list may be organized based on where the raw materials enter the process:

• Synthesis:  for biologicals:  cell culture media and other chemicals in the bioreactor or fermenter; for synthetic APIs:  chemicals and solvents used in synthesis
• Purification:  include all chemicals used in purification steps, for example solvents used in chromatography, also chromatography stationary phase, filters, and other components that intimately contact the API
• Drug Product Manufacture:  filters, formulation excipients, and other components (for instance gelatin capsules and chemicals used in coating)

The list should then be annotated with manufacturer, part number, quantity, and other useful information and stratified into three broad classes:

• Pharmacopeial chemicals:  Common commodity chemicals used in pharmaceutical manufacturing (such as sodium chloride and tromethamine) appear in pharmacopeias (USP, NF, Ph. Eur., JP, BP, etc.).  For pharmacopeial chemicals, finding one or two manufacturers who can supply all the pharmacopeial chemicals in the entire process is usually the optimum strategy.  (I get no royalty for this:  think EMD Millipore, Avantor, etc.)  Be very careful; some large suppliers are not manufacturers, they repackage chemicals manufactured by other companies.  Using a repackager will cause problems in regulatory filings.
• High purity, non-pharmacopeial chemicals:  A few chemicals commonly used in pharmaceutical manufacturing do not have pharmacopeial monographs (for example some solvents fall in this class).  Some questions to ask when considering a manufacturer of one of these chemicals are:  1) Does the manufacturer have experience manufacturing pharmacopeial chemicals?  2) Do they have change control systems in place (ISO systems)?  3) Have they validated their release assays, and does the chemical come with a reasonably comprehensive certificate of analysis?  4) Will the manufacturer allow on-site audits of the facility?  5) Does the manufacturer consider their chemical appropriate for use in human pharmaceuticals or do they have concerns?  6) What are the identity and levels of any impurities in the reagent, and how many of those impurities might be carried into your product?
• Custom chemicals:  These are the chemicals often only available from one manufacturer.  If more than one manufacturer offers such a chemical, expect differences in performance between the two versions.  (Some examples include:  aldehyde modified polyethylene glycols, haptens, cell culture media, chromatography supports, and some unique formulation excipients used in the mRNA vaccine business.)  The same questions apply to custom chemicals as to high-purity non-pharmacopeial chemicals; however, there is one additional factor to consider:  business risk.  By selecting a manufacturer of a custom chemical, a pharmaceutical manufacturer is joining in an invisible marriage.  It is important to understand the customer chemical manufacturer’s business model, plans for the future, and commitment to supplying the magic that makes the drug product go.

Regulations

The Code of Federal Regulations in the US makes certain requirements on raw materials:

• 21 CFR 610.5 (Constituent Materials) requires that all ingredients and diluents “shall meet generally accepted standards of purity and quality.”
• 21 CFR 211.80 (Control of Components and Drug Product Containers and Closures) requires:
  • Written procedures for “the receipt, identification, storage, handling, sampling, testing, and approval or rejection of components and drug product containers and closures.”
  • Importantly that “components and drug product containers and closures shall at all times be handled and stored in a manner to prevent contamination.”

ICH Q7 offers similar advice.

Fortunately, the Quality Control (QC) and Quality Assurance (QA) departments at all manufacturing sites are set up, along with the warehouse teams, to manage these tasks; however, appropriate audits should be completed to ensure regulatory compliance.

Raw Material Risk Assessment

Once a raw materials list has been prepared, a risk assessment and risk ranking can be performed.  Some of the questions to be included in this risk assessment are listed below.  Any raw material which scores poorly on this risk assessment should be carefully evaluated and perhaps replaced.

• Manufacturer:  Does the manufacturer have good quality systems in place?  Are they a qualified vendor at the pharmaceutical manufacturing site, or do they score well on a paper audit (questionnaire) covering the manufacturing facility and equipment, quality control and quality assurance systems, and regulatory compliance?  Are they willing to accept an on-site audit if you request one?  Are you satisfied with the solidness of their business (do you expect them to be in business a decade or more in the future)?
• Chemical:  Is the chemical multicompendial (USP, Ph Eur, BP, JP, etc.) covering the regions you intend to enter?  If not, is it the highest purity available on the market?  How does the certificate of analysis look (e.g., number of tests and tightness of specifications) compared to competing chemicals?  Are there properties that are important to the drug manufacturing process which are not listed in the C of A (particle size distribution)—will additional testing be done, if so, how?
• Certifications and controls:  Does the chemical come with melamine, TSE/BSE, and any other required certification?  For animal derived raw materials, what controls does the manufacturer have in place regarding TSE/BSE and viruses?  Occasionally, a vendor may have an acceptance specification which is broad enough that raw material variation has an impact on your product quality.  Is it possible for you to lot pick (i.e., pick the best lots for your process); how will this be managed?  Has the manufacturer filed a drug master file (DMF) disclosing aspects of the manufacture of the raw material with any regulatory agency?  Is there a validation package available for the raw material (this is typical for contact materials such as single use containers and filters)?
• Contaminants: There is a higher scrutiny of chemicals which are components of your drug product.  For raw material ingredients in the drug product (API and excipients) complete risk assessments for elemental impurities [1] and residual solvents [2].  Also, ensure that drug product ingredients are low in endotoxin, even before completing the first drug product endotoxin testing.
• Availability and economics:  Lead times, minimum orders, price?  Does the vendor maintain multiple lots in inventory at any given time to allow the effect of lot-to-lot variation on the drug to be assessed?  (Not so important for a simple raw material like a salt or a solvent, but pretty important for chromatography resins and cell culture media)?  If the vendor doesn’t have such a program, an informal program of purchasing each new lot as it becomes available and creating an in-house library can be helpful in process validation activities.  Is it worth evaluating a back-up/alternative supplier?  The issue of back-up supply isn’t so important for multicompendial materials which all perform similarly for the most part (one USP sodium chloride is similar to another), but for more complex non-compendial materials, it can be an important risk management strategy.
• Lifecycle:  Are there systems in place for advanced notice of manufacturing changes to raw materials?
• Storage and use:  How is the chemical stored?  Are there properties of concern that affect quality under storage and use:  sterility, low bioburden, hygroscopicity?  Following a pharmaceutical manufacturing run, can the unused portion of the chemical be returned to the warehouse and how will that be documented?  Is it better to throw away the excess to reduce the risk of contamination of a future lot?
• Safety:  Are there safety concerns (flammability, occupational exposure limits)?  Are there ergonomic concerns of working with the chemical (is it only available in large drums)?

The raw materials list can be risk ranked and strategies for managing risk can be developed [3].  In the second post of this series, raw materials testing, starting materials, and contact materials will be discussed.

[1] See ICH Q3D, as well as USP <232> and USP <233>.

[2] See ICH QC3(R7) and draft ICH QC3(R8), as well as USP <467>.

[3] Mollah, A. H. et al.  Risk Management and Applications in Pharmaceutical and Biopharmaceutical Manufacturing, Wiley (2013).

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