7 Questions to Ask to Get the Most From API Manufacturing

Use this checklist to optimize project costs, timeline, and smooth the regulatory path

The pharmaceutical industry is rapidly changing.  Larger pharma companies have historically licensed late-stage drugs or acquired the companies developing them. While that is still occurring, increasingly, smaller pharma companies are striking out on their own.  In 2020, emerging biopharma companies developed and launched 40 percent of all new drugs that hit the U.S. market, a significant increase from five years ago, according to IQVIA.

Without the deep resources of big pharma, many of these companies are partnering with CDMOs with GMP facilities to scale and manufacture their active pharmaceutical ingredients (APIs). The ability to benefit from a CDMO team’s deep expertise also provides incentive for these collaborations.

Big pharma, for a variety of reasons, also continues to outsource projects to CDMOs, as when small batch manufacturing for a rare disease drug candidate would tie up a manufacturing line.

A checklist of key considerations for API manufacturing

Since there is no online dating service matching the growing number of pharmaceutical companies with CDMOs, sponsors rely on recommendations, specific expertise, and a history of industry awards.  Still, to find a good match for programs or long-term collaborations, here are 7 questions to ask a CDMO, and some of the key considerations when evaluating the responses, which can serve as a checklist.

  1. What are the most important factors to consider when outsourcing API manufacturing to a CDMO?
    • The annual projected demand for the API.
    • Whether the CDMO can manufacture the necessary quantities, large or small. As a corollary, can the CDMO manufacture larger quantities if the need arises down the road?
    • The CDMO’s ability to produce commercial quantities of the API profitably.
    • Whether the highest cGMP standards are followed.
    • A long-term record of successful regulatory submissions.
  1. What is the fastest route to API manufacturing?
    • Know that the road from the R&D lab to the cGMP manufacturing suite is never simple or easy.
    • In most instances, given that the novelty of a drug substance being created for the first time, chemistry issues often arise due to today’s increasingly complex APIs. Keeping the molecules within specifications to meet FDA, EMA and ICH guidelines can break down at any step along the way.
    • The fastest route to successful API manufacturing is what precedes it – stellar R&D that is reproducible, scalable, well-documented, and garners regulatory approval without undue delays.
    • It is wise to refrain from going into the costly GMP manufacturing suite until completing scale up, which unearths any issues with the chemistry in a more cost-effective environment.
  1. What does API manufacturing require?
    • Kilo lab preparation and scale up ahead of cGMP manufacturing.
    • A variety and sizes of equipment.
    • A preventive maintenance program.
    • Master batch records.
    • Cross-contamination prevention protocols, as exemplified recently by the ruination of millions of doses of J&J’s COVID vaccine.
    • Warehouse organization and raw material sampling.
    • An experienced and stable manufacturing team.
  1. What is the best way to meet quality guidelines in API manufacturing?
    • Follow the more than 60 internationally harmonized ICH guidelines, established to demonstrate the quality, safety and efficacy of a new product being registered.
    • Think about ICH guidelines at the very earliest stages of a project. Seqens CDMO begins each project by looking ahead to what the FDA or EMA will require for a better view of what lies ahead, planning experiments and their documentation accordingly.
    • Follow the Electronic Standards for the Transfer of Regulatory Information (ESTRI), from applicant to regulator.
    • Stay up to date with cGMP guidelines, published on FDA, EMA, ICH and other regulatory agency websites.
  1. What are best strategies for lowering elemental impurities in API manufacturing?
    • Reducing or eliminating these three classes of impurities is fundamental to risk management:
      • Class 1 elements As, Cd, Hg and Pb are considered highly toxic and have no or limited use in API manufacturing.
      • For Class 2A and 2B elements, toxicity is based on route of administration. Class 2A elements, Co, Ni and V, have a high probability of occurrence in the drug product. Class 2B elements Ag, Au, Ir, Os, Pd, Pt, Rh, Ru, Se and Tl are low abundance elements and may be excluded from risk assessment unless they are intentionally added during manufacture of drug substances.
      • Class 3 elements Ba, Cr, Cu, Li, Mo, Sb and Sn require risk assessment for inhalation and parenteral routes but have relatively low toxicity by the oral route.
    • Strategies for reducing elemental impurities include these:
      • Evaluate the chemistry’s compatibility with the equipment that will be used—avoid putting something into the line that’s aggressive or corrosive.
      • Maintain and monitor the equipment regularly to avoid equipment failure that may cause contamination.
      • Be cognizant of, and anticipate, where in the process elemental impurities could be introduced.
      • Establish protocols for testing, and if impurities are found to be out of spec, have protocols in place for eliminating or reducing them to acceptable levels.
      • Make comprehensive purification of the drug substance part of process development.
      • Utilize inductively coupled plasma (ICP) testing in a clean room to detect trace metals during process development to determine where the metals are coming from, where they are accumulating and where in the process they are being removed.
      • Conduct ICP testing on a final sample of material.
      • If risk assessment shows the elemental impurity level to be consistently above the control threshold, additional controls should be established to ensure that the level does not exceed the permitted daily exposure (PDE) for the specific dosage form. These additional controls could be included as in-process controls or in the specifications of the API.
      • As part of a raw materials quality initiative, begin elemental impurities risk management early by requesting and scrutinizing information from suppliers, such as the Certificate of Analysis, to determine whether raw materials were tested for elemental impurities.
  1. What is the best way to scale API manufacturing for commercialization?
    • Analytical method development holds the key to optimization, helping to create the right environment and conditions to create new molecules and prove that methods achieve their intended purpose.
    • Determine the purpose of the method, e.g., whether it is for an assay or purity, for residual solvent or particle size, and select the appropriate technique.
    • Assess the polarity, solubility, reactivity, pH, and stability of the molecule, as well as its sensitivity to air, heat, humidity, and light.
    • Test for genotoxic compounds.
    • Validate the analytical method thoroughly.
  1. What is the best way to save money in API manufacturing?
    • Beginning with the kickoff meeting, the sponsor and CDMO teams should share all the technical information available, including already-conducted work and relevant reports and documents.
    • Address steps that need to be taken to meet all current regulatory requirements.
    • Get into the habit of regular weekly meetings for discussing concerns, demonstrating progress and providing a realistic estimated time and resources required.
    • Plan on problems.  New chemistry tends to be unpredictable.
    • Don’t skip the kilo lab, where surprises often arise. Run processes there at least three times in quantities increasing from 1 Kg to 20 Kg.
    • Look for a CDMO with a solid FDA and EMA track record.
    • Work with CDMOs with strong raw materials and intermediates sourcing, which includes back-ups in case a supplier disappoints. 

Essentially, in API manufacturing the biggest costs are in three key areas:  the costs for chemistry, scale-up and GMP plant time. Working with a CDMO that can understand your regulatory strategy up front and has a strong application success record can go a long way to easing the cost overruns that can plague an industry often dealing with the unknown.


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