Jun. 09, 2025
A significant proportion of new drugs under development contain high-potency active pharmaceutical ingredients (HPAPIs), which is leading to explosive growth in demand for their production. The cytotoxicity of HPAPIs, however, presents handling challenges and requires heavy investment in specialized containment to ensure that employees and their environment are protected from exposure. This article examines the planning, equipment, and facility design of chemical and biologic HPAPIs as well as biologic–HPAPI conjugate manufacture. It also outlines the efforts made by the pharmaceutical industry to develop voluntary standards for HPAPI production and handling.
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SAFC
During the last decade, the demand for HPAPIs has grown rapidly, mainly as a result of advances in clinical pharmacology and oncology research. There is particular interest in HPAPI–antibody conjugate technology, which uses monoclonal antibodies to selectively deliver HPAPIs to specific cancer tumors. When conjugated to the antibody, the HPAPI targets cancer cells specifically and thereby spares nontarget cells many of the toxic effects. Wyeth's "Mylotarg" (gemtuzumab ozogamicin) is an example of such a drug. It is commercialized for treating acute myeloid leukemia, and numerous other antibody drug conjugates are in preclinical or clinical trials.
Compared with the overall growth in the pharmaceutical market of about 7% per year, HPAPIs are estimated to have an annual growth of 12% (1, 2). They account for about 12% of the total pharmaceutical market, and this share is set to rise strongly (3). Although this emerging market is attractive, it presents a significant challenge for pharmaceutical manufacturers to upgrade existing facilities that are set up to handle only nonpotent APIs—the challenge being the major cost associated with the specialized containment needed to ensure that employees and their environment are protected from exposure. Many contract manufacturers are also building new facilities that are designed specifically for the manufacture of HPAPIs, which require an investment of millions of dollars beyond typical GMP (good manufacturing practices) production facilities. This investment may include specialized facilities for HPAPI–antibody conjugations that incorporate both potent-compound handling and biologics processing capabilities.
Definition of HPAPIs
The definition of an HPAPI varies depending on the literature; however, APIs deemed to be potent may fall into the following categories (4):
1. A pharmacologically active ingredient or intermediate with biological activity at approximately 150 μg/kg of body weight or below in humans (therapeutic daily dose at or below 10 mg)
2. An active pharmaceutical ingredient or intermediate with an occupational exposure limit (OEL) at or below 10 μg/m3 of air as an 8-h time-weighted average
3. A pharmacologically active ingredient or intermediate with high selectivity (i.e., ability to bind to specific receptors or inhibit specific enzymes) and/or with the potential to cause cancer, mutations, developmental effects, or reproductive toxicity at low doses
4. Or, by default, a novel compound of unknown potency and toxicity.
The potency of pharmaceutical chemicals is often characterized by OELs in μg/m3; the lower the value, the more potent the chemical and the greater the level of containment that is required. Currently, there is a significant increase in the number of APIs going through development and clinical trials, and into the production environment with OELs well below 10 μg/m3. These processes require specialized containment to ensure that employees and their environment are protected from exposure. Figure 1 shows a facility design of a typical kilo-laboratory (using glassware) for HPAPI handling. The main features are as follows:
Figure 1 (FIGURE 1 IS COURTESY OF SAFC.)
Several factors need to be taken into consideration when planning a facility as outlined below:
Operating an HPAPI facility
Operating an HPAPI facility means that a number of systems, policies, and standard operating procedures (SOPs) must be put in place to protect staff. Additionally, manufacturers must ensure all employees handling HPAPIs be adequately trained. Senior management must support the implementation of such systems, which includes providing the necessary funding for these systems. There should be regular reviews of material safety data sheets, toxicological literature, and relevant occupational safety and health literature for knowledge regarding the compounds used. These reviews should also include information on PPE and engineering processes.
Training. To develop and monitor handling programs and training, it is recommended that a committee be established to take responsibility for HPAPI-handling programs. Ideally, this committee would comprise a mixture of senior management, handling staff, experts, occupational health professionals, and senior scientists. The committee should put together a general company policy and a range of SOPs for potent-compound handling, including details of which staff members have access and are able to handle HPAPIs, training-program requirements, development of SOPs, evaluation, categorization, and updating procedures and processes. For each step, specific written instructions for equipment use and unit operations must be in force, though this could be applied through the use of SOPs.
Occupational safety. One of the primary concerns when handling potent compounds is employee exposure, which could potentially result in undesired health effects and/or sensitization. It is vital to set up an appropriate employee medical surveillance and monitoring program. An occupational physician should work closely with the committee, regulatory authorities, and any relevant health and safety bodies. Another significant issue is the ability to clean contaminated surfaces to an established, acceptable and safe level set out by GMP or industrial hygiene guidelines. Cleaning verification and validation procedures are critical and should include a viable deactivation solution in the cleaning process whenever possible.
Response plans. Response plans must also be in place to ensure employees react appropriately to an unplanned event. These plans should include employee training for emergency response, communication plans, and an ongoing evaluation of the program. Involvement of local authorities in the planning and training for emergency response is also important.
Equipment checks. It is vital that HPAPI-handling systems and equipment are tested and verified to meet the necessary isolation requirements. For example, isolation equipment may be expected to meet a containment capability of less than 1 μg/m3. The capability of equipment, systems, and procedures to contain and isolate materials under expected operating conditions must be verified as a critical component of the overall HPAPI-handling program. This process typically requires the use of both air and surface industrial hygiene sampling methods to confirm proper isolation following a detailed sampling plan. In many cases, sampling and testing methods for products in early preclinical or clinical testing have not been developed. Therefore, surrogate products such as lactose or naproxen sodium, are frequently used to complete the equipment testing.
Compound evaluation. When considering the manufacture of an HPAPI, there must be close evaluation of the compound for potential toxicity, potency, and hazards. The Occupational Safety and Health Administration ensures that employees are provided a safe and healthful working environment, but there is no official guidance about safely manufacturing potent APIs. As a result, the industry has begun policing itself. There are currently two commonly used programs—a five-tiered system such as the one used by Merck & Co., and a more frequently used four-tiered system similar to the one developed by SafeBridge Consultants.
The compound is placed into a potency category based on the available data and evaluation process (see Table 1). The following are attributes that may be considered for each category of compound using the SafeBridge rating system:
Table I
This categorization system is referred to as performance-based exposure control limits, which link compound toxicity and potency to procedures for safe handling practices (5). This system was set up in the late s by pharmaceutical manufacturers for handling development projects where insufficient data was available to establish OELs. SafeBridge recommends Category 3 as the default categorization when very little or no information about a compound is available. This requires handling of the material as a potent compound with sufficient engineering controls for containment.
Handling HPAPIs. Engineering controls should be used as the primary source for containment and isolation of potent compounds. Although PPE is also used, it is secondary employee protection for exposure control. The category assigned to the compound defines proper handling procedures as follows:
Potent-compound handling systems should ideally incorporate five levels of cascading protection, the first two being the primary methods of product isolation as follows:
Third-party certification.Companies handling HPAPIs should also consider being certified by a third-party organization such as SafeBridge. This certification process allows for all aspects of the potent compound-handling program to be evaluated against current industry expectations by independent experts. As an added benefit, certification can also lead to continuous improvement and evaluation programs designed to ensure advancement of the HPAPI-handling systems. Even if the company chooses not to go through the certification process, they still may choose to have an evaluation by third-party experts as an effective means of identifying gaps or opportunities for improvement in the HPAPI program.
Conclusion
The development and manufacture of high-potency active pharmaceutical ingredients (HPAPIs) requires significant planning, extensive employee training, proper equipment, and facility design as well as implementation of the necessary procedures to safely handle the compounds. The capital investments are significant, and the knowledge gained through experience is invaluable. Robust systems must be employed in all aspects of the HPAPI-handling program, from initial project evaluation through equipment cleaning, to disposal of process wastes. As the number of potent compounds in pharmaceutical development continues to increase, so will the opportunities for HPAPI manufacturers, especially for companies with capabilities in growing niche areas such as HPAPI–antibody conjugation.
David Bormett is director of regulatory affairs at SAFC Pharma, 645 Science Drive, Madison, WI , . 608.233., fax 608.233.,
References
1. P. Van Arnun, "Charting API Market Growth and Opportunity," Pharm. Technol. 32 (7), 58–61 ()
2. A. Thayer, "Contained Chemistry," C&EN, 86 (24), 17–27 ().
3. P. Van Arnun, "Investing in High-Potency Manufacturing," Pharm. Technol. 31 (11), 54–58 ()
4. A.W. Ader, J.J. Mason, and J.P. Farris, "Important Elements in Evaluating Contract Manufacturing Organizations," Chem. Today 25 (2), 56–60 ().
1. What are pharmaceutical excipients?
2. How are pharmaceutical excipients classified?
3. Why are excipients important in a drug product?
4. What are the most common pharmaceutical excipients used in U.S.-manufactured drug products?
5. Who sets standards for the quality, etc., of pharmaceutical excipients?
6. What information is contained in these compendia and what status do they have?
7. How are excipients "approved" for use in pharmaceutical products?
8. How are new excipients permitted for use in U.S. drug products? Would the procedure be similar in the case of a previously allowed (GRAS) excipient for a new pharmaceutical use?
9. What is a Type IV Drug Master File (DMF) and what information is contained in this type of DMF?
10. How can one assure that excipients used in the formulation of a new drug undergoing clinical trials will continue to be available for purchase when the product reaches the market - three to five years later?
11. Can USP/NF grade excipients be used in drug applications in other countries?
12. If it is so difficult to qualify a new excipient for pharmaceutical use, doesn't that have a chilling effect on the ability of finished drug manufacturers to develop better delivery systems for new, improved drug therapy for heart disease, cancer, and other serious conditions?
1. What are pharmaceutical excipients?
Pharmaceutical excipients are substances other than the pharmacologically active drug or prodrug which are included in the manufacturing process or are contained in a finished pharmaceutical product dosage form.
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2. How are pharmaceutical excipients classified?
They are classified by the functions they perform in a pharmaceutical dosage form. Principal excipient classifications (functions) are the following:
Binders
Disintegrants
Fillers (diluents)
Lubricants
Glidants (flow enhancers)
Compression aids
Colors
Sweeteners
Preservatives
Suspensing/dispersing agents
Film formers/coatings
Flavors
Printing inks
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3. Why are excipients important in a drug product?
For many reasons. Some, for example, comprise the product's delivery system. These transport the active drug to the site in the body where the drug is intended to exert its action. Others will keep the drug from being released too early in the assimilation process in places where it could damage tender tissue and create gastric irritation or stomach upset. Others help the drug to disintegrate into particles small enough to reach the blood stream more quickly and still others protect the product's stability so it will be at maximum effectiveness at time of use. In addition, some excipients are used to aid the identification of a drug product. Last, but not least, some excipients are used simply to make the product taste and look better. This improves patient compliance, especially in children. Although technically "inactive" from a therapeutic sense, pharmaceutical excipients are critical and essential components of a modern drug product. In many products, excipients make up the bulk of the total dosage form.
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4. What are the most common pharmaceutical excipients used in U.S.-manufactured drug products?
The following are the most commonly used excipients in U.S.-manufactured drug products:
Magnesium Stearate
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Lactose
Microcrystalline Cellulose
Starch (corn)
Silicon Dioxide
Titanium Dioxide
Stearic Acid
Sodium Starch Glycolate
Gelatin
Talc
Sucrose
Calcium Stearate
Povidone
Pregelatinized Starch
Hydroxy Propyl Methylcellulose
OPA products (coatings & inks)
Croscarmellose
Hydroxy Propyl Cellulose
Ethylcellulose
Calcium Phosphate (dibasic)
Crospovidone
Shellac (and Glaze)
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5. Who sets standards for the quality, etc., of pharmaceutical excipients?
Committees of the U.S. Pharmacopeial Convention Inc., an independent body that publishes and maintains the United States Pharmacopeia, National Formulary (NF), and USP Reference Standards.
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6. What information is contained in these compendia and what status do they have?
Since the United States Pharmacopeia and the National Formulary have been published under the same cover. Today, USP-NF contains legally recognized and scientifically valid standards of identity, strength, quality, purity, packaging and labeling for more than 3,500 drugs. NF also includes similar standards for more than 250 excipients, vitamins, minerals, and botanicals. Standards (monographs) for substances which have an FDA-approved use as a drug are published in USP. Monographs for substances which are considered to be primarily excipients, a vitamin, mineral, botanical, or herbal are published in NF, provided they have been established as safe. "USP Reference Standards" is not a separate document per se but instead are substances used with official test methods in analytical testing to demonstrate a drug or excipient's identity, strength, quality and purity. Once final standards are published in USP-NF they are recognized as official and U.S. and state government agencies are authorized to enforce them to assure that pharmaceutical products marketed in the U.S. are in total compliance.
Source: U.S. Pharmacopeial Convention, Inc.
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7. How are excipients "approved" for use in pharmaceutical products?
Under U.S. law, an excipient, unlike an active drug substance, has no regulatory status and may not be sold for use in food or approved drugs unless it can be qualified through one or more of the three U.S. Food and Drug Administration (FDA) approval mechanisms that are available for components used in food and/or finished new drug dosage forms.
These mechanisms are:
1. determination by FDA that the substance is "generally recognized as safe" (GRAS) pursuant to Title 21, U.S. Code of Federal Regulations, Parts 182, 184 or 186 (21 CFR 182, 184 & 186);
2. approval of a food additive petition as set forth in 21 CFR 171; or
3. the excipient is referenced in, and part of, an approved new drug application (NDA) for a particular function in that specific drug product.
Excipients contained in over-the-counter (OTC) drug products subject to FDA monographs referenced in 21 CFR Parts 331-358 must comply with the requirements in 21 CFR 330.1(e) which reads as follows:
"The product contains only suitable inactive ingredients which are safe in the amounts administered and do not interfere with the effectiveness of the preparation or with suitable tests or assays to determine if the product meets its professed standards of identity, strength, quality, and purity. Color additives may be used only in accordance with section 721 of the Act and subchapter A of this chapter."
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8. How are new excipients permitted for use in U.S. drug products? Would the procedure be similar in the case of a previously allowed (GRAS) excipient for a new pharmaceutical use?
As noted in the answer to the previous question, data supporting the safety and functionality of an excipient in a drug product is included in data and clinical reports submitted to support a new drug application (NDA). In the case of a new pharmaceutical use for an excipient, it is likely that some necessary data may exist in a confidential drug master file at FDA. However, in all instances involving pharmaceutical use, FDA will require an applicant to provide data demonstrating that 1) the excipient is safe in the amount it will be used or consumed in the finished drug throughout the product's recommended or prescribed duration of use by those who will take the product. In addition, the applicant must 2) demonstrate that the substance meets applicable compendial standards where they apply; 3) that it performs its intended function in the product; that it 4) does not adversely affect the bioavailability and performance of the active drug; and 5) is manufactured in accordance with appropriate standards of good manufacturing practice suitable to that kind of excipient. Still, as noted earlier, there is no FDA regulatory approval system that is exclusively applicable to pharmaceutical excipients. Thus, the scope and amount of necessary data to support a substance or its use always must be negotiated with FDA and will be determined on a case by case basis.
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9. What is a Type IV Drug Master File (DMF) and what information is contained in this type of DMF?
A Type IV DMF is a file within the FDA which can be used by excipient manufacturers to submit confidential formulation, safety and manufacturing information about the excipient that may be needed by the agency in reviewing a new drug application (NDA) for a drug product containing that excipient. These files are only referenced by FDA as part of a specific NDA review and are not authorized or approved by FDA.
Users of the excipient are required to submit a DMF reference letter from the excipient manufacturer to the FDA as part of their NDA to allow FDA authority to access the DMF for their application. An FDA guidance document exists which describes what types of information are required in a Type IV DMF and the format which should be used. Not a lot of detailed information is required. Mostly, it is up to the excipient manufacturer to determine what types of information they want to include in the DMF. Further, there is no requirement that an excipient have a DMF. This determination is entirely up to the manufacturer of the excipient, depending on the nature of any confidential information which may exist.
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10. How can one assure that excipients used in the formulation of a new drug undergoing clinical trials will continue to be available for purchase when the product reaches the market - three to five years later?
There is no absolute answer. However, if established, previously used excipients made in conformance with good manufacturing practice are used to formulate a new drug, the risk would seem to be minimized. If new excipients are to be used, availability from the supplier should be assured. A finished drug manufacturer, therefore, probably would be wise to purchase excipients made by firms with a good business history who are able to guarantee future deliveries.
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11. Can USP/NF grade excipients be used in drug applications in other countries?
This depends on the countries in question and whether the excipient has had a previous precedent of use in a drug application in that country. The USP/NF is a recognized compendia in many countries around the world; however, in various regions local or regional pharmacopeias take precedent over USP/NF equirements. For example, in the European Union, an excipient must meet the criteria of the European
Pharmacopeia (PhEur) if a monograph for that excipient exists in PhEur. However, if no monograph exists in PhEur, the use of USP/NF grade excipients may be acceptable.
A similar situation exists in Japan. If a monograph exists in the Japanese Pharmacopeia (JP) or the Japanese Pharmaceutical Excipients (JPE), the excipient must meet the requirements of the respective monograph. However, if the excipient has previously been used in an approved Japanese drug application and no standard exists in JP or JPE, then USP/NF grade material may be acceptable until such time as a monograph is developed in JP or JPE.
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12. If it is so difficult to qualify a new excipient for pharmaceutical use, doesn't that have a chilling effect on the ability of finished drug manufacturers to develop better delivery systems for new, improved drug therapy for heart disease, cancer, and other serious conditions?
Yes. This is why far-sighted makers and users of excipients used in finished drug dosage forms joined together in to form the International Pharmaceutical Excipients Council (IPEC). We have made progress, as you will see on other pages of our website, but there still is a long way to go. Will you join us?
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