Global research in pharmaceutical sciences will acquire
new dimensions in the post-GATT (General Agreement
in Trade and Tariff) era. The pharmaceutical industry
currently is focused on the identification and
development of novel leads from areas such as biotechnology,
combinatorial chemistry,molecular modeling, and genetic engineering.
The leads coming from these varied sources will require
specialized formulation techniques and ingredients. At
the same time, the process of discovering new drugs is a costly
proposition and requires input from the basic as well as applied
sciences. Research organizations that do not have adequate expertise
or vision tend to fall out rapidly. The alternative approach
for such organizations would be to develop new dosage
forms or formulations using novel excipients for the existing
drugs that offer distinct benefits over the conventional formulations.
Recent developments in pharmaceutical legislation, regulatory
guidelines, and licensing policies have led to increased
awareness of the properties and roles of excipients in formulations.
A careful use of excipients can lead to the development of novel delivery systems that are both effective and economical.
These innovative formulations also may offer life extension
to drugs in the form of new patents, extending the product life
cycle and adding to the market share of the company.
A formulation can be regarded as a system comprising an active
molecule along with some inert ingredients (see Figure 1).
According to the definition given by the International Pharmaceutical
Excipients Council (IPEC), “Excipients are substances,
other than the active drug substance or finished dosage
form, which have been appropriately evaluated for safety and
are included in drug delivery systems for specific functions” (1).
This definition indicates that excipients are to render easy processing
of the drug delivery systems, to protect, support, or enhance
stability, bioavailability, and patient compliance. They
also assist in product identification and are important for overall
safety and effectiveness of the drug delivery system during
storage or use. These ingredients render specific properties to
a formulation and thus represent an important aspect of formulation
design and optimization. Selection of the type and
amount of excipient is dictated by the target formulation profile
and is a major challenge for the pharmaceutical scientist.
Traditionally the ingredients of a formulation “other than
active ingredient” were known as inactive ingredients. In the
present day, where these inactive ingredients are known to play
a crucial role in designing a formulation and to provide desirable
characteristics, the term excipient is more commonly used.
The equivalent of activity in an excipient is functionality, which
refers to special attributes that the ingredient can provide to a
formulation. Developing a new excipient is as complicated as
developing a new drug molecule; therefore, excipients manufacturers
tend to opt for an easier route for value-added specialty
excipients. Knowledge and understanding of the ingredients
are extremely useful to a product development scientist.
Friday, 30 July 2010
Compendium of Pharmaceutical Excipients for Vaginal Formulations
Human Serum Albumin as a Pharmaceutical Excipient
INTRODUCTION
Human serum albumin (HSA) is one of the most widely used and characterized proteins in the pharmaceutical field. It occurs naturally in the body, as a plasma protein, with a concentration of 50 mg/mL. At this concentration, HSA regulates the colloidal osmotic pressure of blood. HSA is also responsible for transporting endogenous and exogenous compounds, which might be toxic in the unbound state, but non-toxic as albumin-bound. Human serum albumin purified from plasma is used for therapeutic applications, as a plasma expander, in situations involving severe blood loss. HSA is also widely used as an excipient, especially for biotechnology products. While the albumin used in marketed products is derived from plasma, recombinant versions of the protein are being investigated. Recombinant albumin can also alleviate any theoretical concerns of disease transmissivity associated with the human plasma-derived protein. This article provides a brief review of the use of albumin as a pharmaceutical excipient, and provides an update on the development of recombinant albumin.
USE OF HSA AS AN EXCIPIENT
Human serum albumin is a 66-kD protein, with no glycosylation. The protein has molecular dimensions of 8 nm X 3.8 nm, and a half-life of 15 to 20 days. Due to its high concentration in plasma, HSA is not associated to significant extents with safety or immunogenicity concerns. A 5% albumin solution has an osmolarity of 265 mOsm/kg. Human serum albumin is a remarkably stable protein - it is the only therapeutic protein that is stable as a liquid at room temperature over the shelf life of the product. This is primarily due to the presence of 17 disulfide linkages present in the molecule. The intrinsic stability of the protein also allows it to be heated at 60�C for 10 hours to facilitate virus inactivation during manufacturing. This process has demonstrated elimination of both lipid-enveloped and certain non-lipid-enveloped viruses in validation experiments. The stability of albumin makes its storage and handling easier than typical proteins, thus lending itself well toward the use as an excipient.
Due to its established safety profile and unique properties, HSA is frequently used as a stabilizer for proteins. The protein has amphiphilic properties, which makes it suitable as an additive to inhibit adsorption of the active protein to the container, via competitive adsorption mechanisms. The surface-active character of the protein also makes it suitable for use as a surfactant to prevent protein aggregation. HSA also has a high glass transition temperature, which in combination with its amphiphilic nature, makes it an ideal excipient for cryoprotection. For some proteins, the dual functionality (surfactant and cryoprotectant) results in better cryoprotection for albumin than disaccharides, as was observed by Liu, for Lactate dehydrogenase.1 Table 1 lists representative commercial protein products that contain Albumin as an excipient.
Albumin is also being used as a carrier for microparticles and nanoparticles for sustained-release injectable drugs. A nanoparticulate formulation of paclitaxel containing albumin as the carrier was recently approved by the FDA. A number of researchers have also used albumin for sustained release of small molecules and proteins. Albumin's capacity to adsorb hydrophobic molecules makes it a unique carrier for controlled release because the drug gets released via desorption without significant burst effects. Albumin's adsorption capacity has also been exploited in development of magnetic microparticles. Such particles were used for targeted delivery of chemotherapeutic agents, such as doxorubicin. The particles consisted of albumin for binding of drug and iron for magnetic behavior to facilitate targeting.2 Albumin microspheres have also been used in diagnostic applications to detect intravascular susceptibility.3
In recent years, albumin's long plasma circulation characteristics have been exploited to develop albumin-conjugated protein drugs that have longer half-lives as compared to the unconjugated protein. Albumin-fusion proteins are produced via recombinant techniques, and this concept has been used to extend the half-lives of a number of proteins including interferon-a4, interleukin-2, and G-CSF.5
RECOMBINANT ALBUMIN
Although there has been no case of disease transmission for the use of HSA, a theoretical or perceived risk exists, due to which recombinant human albumin is currently being explored.6 While this recombinant version is currently being explored as a therapeutic, its use as an excipient may be a logical progression, if the product gets approved.
A yeast-derived recombinant version was tested by Bosse and co-workers in a Phase I comparability study with human serum albumin.7 The two proteins were compared side-by-side for both intravenous and intramuscular injections, involving more than 500 volunteers. No serious or potentially allergic events, or immunological response were reported with either product in the IV study. Serum albumin, colloid osmotic pressure changes, and hematocrit ratio were also similar. The authors concluded that rHA and HSA exhibited similar safety, tolerability, and pharmacokinetic/pharmacodynamic profiles, with no evidence of any immunological response. Tarelli and co-workers investigated the use of recombinant albumin as a cryoprotectant for thyroid-stimulating hormone (TSH), interleukin 15 (IL-15), and granulocyte colony-stimulating factor (G-CSF).8 It was observed that the recombinant albumin was equivalent in its functionality to HSA, for stabilization of the proteins as well as binding of fatty acids.
SUMMARY
Albumin is a well characterized protein and serves important needs as a therapeutic, diagnostic agent, as well as an excipient. While use of albumin as an excipient has met some resistance due to perceived risk of disease transmission, recombinant albumin is being developed to address any such concerns. Recombinant albumin may also serve as a useful case study for follow-on biologics.9 However, use of recombinant albumin as an excipient, would depend on the efficiency of the manufacturing process, to allow for reasonable cost of goods.
______________
REFERENCES
1. Liu W. The impact of formulation composition on the stability of freeze dried proteins. Doctoral Dissertation, Purdue University, 2000.
2. Rudge S, Peterson C, Vessely C, Koda J, Stevens S, Catterall L. Adsorption and desorption of chemotherapeutic drugs from a magnetically targeted carrier (MTC). J Control Release. 2001 Jul 6;74(1-3):335-40.
3. Wong KK, Huang I, Kim YR, Tang H, Yang ES, Kwong KK, Wu EX. In vivo study of microbubbles as an MR susceptibility contrast agent. Magn Reson Med. 2004 Sep;52(3):445-52.
4. Sung C, Nardelli B, LaFleur DW, Blatter E, Corcoran M, Olsen HS, Birse CE, Pickeral OK, Zhang J, Shah D, Moody G, Gentz S, Beebe L, Moore PA. An IFN-beta-albumin fusion protein that displays improved pharmacokinetic and pharmacodynamic properties in nonhuman primates. J Interferon Cytokine Res. 2003 Jan;23(1):25-36.
5. Halpern W, Riccobene TA, Agostini H, Baker K, Stolow D, Gu ML, Hirsch J, Mahoney A, Carrell J, Boyd E, Grzegorzewski KJ. Albugranin, a recombinant human granulocyte colony stimulating factor (G-CSF) genetically fused to recombinant human albumin induces prolonged myelopoietic effects in mice and monkeys. Pharm Res. 2002 Nov;19(11):1720-9.
6. Chuang VT, Kragh-Hansen U, Otagiri M. Pharmaceutical strategies utilizing recombinant human serum albumin. Pharm Res. 2002 May;19(5):569-77.
7. Bosse D, Praus M, Kiessling P, Nyman L, Andresen C, Waters J, Schindel F. Phase I Comparability of Recombinant Human Albumin and Human Serum Albumin. The Journal of Clinical Pharmacology, 2005; 45:57-67.
8. Tarelli E, Mire-Sluis A, Tivnann HA, Bolgiano B, Crane DT, Gee C, Lemercinier X, Athayde ML, Sutcliffe N, Corran PH, Rafferty B. Recombinant human albumin as a stabilizer for biological materials and for the preparation of international reference reagents. Biologicals. 1998 Dec;26(4):331-46.
9. Morioka H. Considerations about generic biologics. Business Briefings: Pharmagenerics 2004 (http://www.bbriefings.com/pdf/955/ACFB481.pdf).
Human serum albumin (HSA) is one of the most widely used and characterized proteins in the pharmaceutical field. It occurs naturally in the body, as a plasma protein, with a concentration of 50 mg/mL. At this concentration, HSA regulates the colloidal osmotic pressure of blood. HSA is also responsible for transporting endogenous and exogenous compounds, which might be toxic in the unbound state, but non-toxic as albumin-bound. Human serum albumin purified from plasma is used for therapeutic applications, as a plasma expander, in situations involving severe blood loss. HSA is also widely used as an excipient, especially for biotechnology products. While the albumin used in marketed products is derived from plasma, recombinant versions of the protein are being investigated. Recombinant albumin can also alleviate any theoretical concerns of disease transmissivity associated with the human plasma-derived protein. This article provides a brief review of the use of albumin as a pharmaceutical excipient, and provides an update on the development of recombinant albumin.
USE OF HSA AS AN EXCIPIENT
Human serum albumin is a 66-kD protein, with no glycosylation. The protein has molecular dimensions of 8 nm X 3.8 nm, and a half-life of 15 to 20 days. Due to its high concentration in plasma, HSA is not associated to significant extents with safety or immunogenicity concerns. A 5% albumin solution has an osmolarity of 265 mOsm/kg. Human serum albumin is a remarkably stable protein - it is the only therapeutic protein that is stable as a liquid at room temperature over the shelf life of the product. This is primarily due to the presence of 17 disulfide linkages present in the molecule. The intrinsic stability of the protein also allows it to be heated at 60�C for 10 hours to facilitate virus inactivation during manufacturing. This process has demonstrated elimination of both lipid-enveloped and certain non-lipid-enveloped viruses in validation experiments. The stability of albumin makes its storage and handling easier than typical proteins, thus lending itself well toward the use as an excipient.
Due to its established safety profile and unique properties, HSA is frequently used as a stabilizer for proteins. The protein has amphiphilic properties, which makes it suitable as an additive to inhibit adsorption of the active protein to the container, via competitive adsorption mechanisms. The surface-active character of the protein also makes it suitable for use as a surfactant to prevent protein aggregation. HSA also has a high glass transition temperature, which in combination with its amphiphilic nature, makes it an ideal excipient for cryoprotection. For some proteins, the dual functionality (surfactant and cryoprotectant) results in better cryoprotection for albumin than disaccharides, as was observed by Liu, for Lactate dehydrogenase.1 Table 1 lists representative commercial protein products that contain Albumin as an excipient.
Albumin is also being used as a carrier for microparticles and nanoparticles for sustained-release injectable drugs. A nanoparticulate formulation of paclitaxel containing albumin as the carrier was recently approved by the FDA. A number of researchers have also used albumin for sustained release of small molecules and proteins. Albumin's capacity to adsorb hydrophobic molecules makes it a unique carrier for controlled release because the drug gets released via desorption without significant burst effects. Albumin's adsorption capacity has also been exploited in development of magnetic microparticles. Such particles were used for targeted delivery of chemotherapeutic agents, such as doxorubicin. The particles consisted of albumin for binding of drug and iron for magnetic behavior to facilitate targeting.2 Albumin microspheres have also been used in diagnostic applications to detect intravascular susceptibility.3
In recent years, albumin's long plasma circulation characteristics have been exploited to develop albumin-conjugated protein drugs that have longer half-lives as compared to the unconjugated protein. Albumin-fusion proteins are produced via recombinant techniques, and this concept has been used to extend the half-lives of a number of proteins including interferon-a4, interleukin-2, and G-CSF.5
RECOMBINANT ALBUMIN
Although there has been no case of disease transmission for the use of HSA, a theoretical or perceived risk exists, due to which recombinant human albumin is currently being explored.6 While this recombinant version is currently being explored as a therapeutic, its use as an excipient may be a logical progression, if the product gets approved.
A yeast-derived recombinant version was tested by Bosse and co-workers in a Phase I comparability study with human serum albumin.7 The two proteins were compared side-by-side for both intravenous and intramuscular injections, involving more than 500 volunteers. No serious or potentially allergic events, or immunological response were reported with either product in the IV study. Serum albumin, colloid osmotic pressure changes, and hematocrit ratio were also similar. The authors concluded that rHA and HSA exhibited similar safety, tolerability, and pharmacokinetic/pharmacodynamic profiles, with no evidence of any immunological response. Tarelli and co-workers investigated the use of recombinant albumin as a cryoprotectant for thyroid-stimulating hormone (TSH), interleukin 15 (IL-15), and granulocyte colony-stimulating factor (G-CSF).8 It was observed that the recombinant albumin was equivalent in its functionality to HSA, for stabilization of the proteins as well as binding of fatty acids.
SUMMARY
Albumin is a well characterized protein and serves important needs as a therapeutic, diagnostic agent, as well as an excipient. While use of albumin as an excipient has met some resistance due to perceived risk of disease transmission, recombinant albumin is being developed to address any such concerns. Recombinant albumin may also serve as a useful case study for follow-on biologics.9 However, use of recombinant albumin as an excipient, would depend on the efficiency of the manufacturing process, to allow for reasonable cost of goods.
______________
REFERENCES
1. Liu W. The impact of formulation composition on the stability of freeze dried proteins. Doctoral Dissertation, Purdue University, 2000.
2. Rudge S, Peterson C, Vessely C, Koda J, Stevens S, Catterall L. Adsorption and desorption of chemotherapeutic drugs from a magnetically targeted carrier (MTC). J Control Release. 2001 Jul 6;74(1-3):335-40.
3. Wong KK, Huang I, Kim YR, Tang H, Yang ES, Kwong KK, Wu EX. In vivo study of microbubbles as an MR susceptibility contrast agent. Magn Reson Med. 2004 Sep;52(3):445-52.
4. Sung C, Nardelli B, LaFleur DW, Blatter E, Corcoran M, Olsen HS, Birse CE, Pickeral OK, Zhang J, Shah D, Moody G, Gentz S, Beebe L, Moore PA. An IFN-beta-albumin fusion protein that displays improved pharmacokinetic and pharmacodynamic properties in nonhuman primates. J Interferon Cytokine Res. 2003 Jan;23(1):25-36.
5. Halpern W, Riccobene TA, Agostini H, Baker K, Stolow D, Gu ML, Hirsch J, Mahoney A, Carrell J, Boyd E, Grzegorzewski KJ. Albugranin, a recombinant human granulocyte colony stimulating factor (G-CSF) genetically fused to recombinant human albumin induces prolonged myelopoietic effects in mice and monkeys. Pharm Res. 2002 Nov;19(11):1720-9.
6. Chuang VT, Kragh-Hansen U, Otagiri M. Pharmaceutical strategies utilizing recombinant human serum albumin. Pharm Res. 2002 May;19(5):569-77.
7. Bosse D, Praus M, Kiessling P, Nyman L, Andresen C, Waters J, Schindel F. Phase I Comparability of Recombinant Human Albumin and Human Serum Albumin. The Journal of Clinical Pharmacology, 2005; 45:57-67.
8. Tarelli E, Mire-Sluis A, Tivnann HA, Bolgiano B, Crane DT, Gee C, Lemercinier X, Athayde ML, Sutcliffe N, Corran PH, Rafferty B. Recombinant human albumin as a stabilizer for biological materials and for the preparation of international reference reagents. Biologicals. 1998 Dec;26(4):331-46.
9. Morioka H. Considerations about generic biologics. Business Briefings: Pharmagenerics 2004 (http://www.bbriefings.com/pdf/955/ACFB481.pdf).
PQRI Survey of Pharmaceutical Excipient Testing
he Product Quality Research Institute (PQRI) conducted an open, publicly available, electronic survey of current excipient-control strategies among pharmaceutical excipient manufacturers, excipient distributors, and drug-product manufacturers (excipient users). Among the major findings are:
* the majority of respondents supply their products for global markets, and thus must meet substantially different test requirements for different regions;
* the majority of respondents use reduced-testing strategies employing equivalent methods;
* a large majority of respondents perform tests on the excipients beyond those given in pharmacopeias to determine physical and chemical properties necessary for their intended use;
* drug-product manufacturers typically follow their own company procedures to qualify excipient manufacturers and suppliers.
Figure 1: Respondents selling products both in the United States and abroad.
The survey results provide insights about the decisions of excipient manufacturers and drug-product manufacturers regarding testing excipient quality and using excipients in pharmaceutical manufacturing.
Background
When the European Agency for the Evaluation of Medicinal Products (1) and US Food and Drug Administration (2) issued excipients guidances in 2003, industry predicted that they would have the unintended result of causing additional paperwork and excessive testing for excipient control strategies, without adding benefits. In addition, industry believed the guidances effectively eliminated generally accepted and common excipient control strategies.
Figure 2: Respondents testing excipient according to USP–NF monograph/general chapter methods
FDA's interpretation of International Conference on Harmonization (ICH) common technical document (CTD) language used in section P.4, "Control of Excipients" required that manufacturers specify each method used for routine excipients testing, unless the method is exactly that of the pharmacopeia and full monograph testing is performed.
Often, a drug-product manufacturer has methods used internally that are shown to produce equivalent results to those in a pharmacopeia. In addition, many manufacturers with global markets seek to eliminate redundant testing of the same property by selecting a single method shown to be capable of ensuring compliance with requirements of many pharmacopeias. The United States Pharmacopeia (USP) has been clear that alternate methods are acceptable to demonstrate compliance with USP–National Formulary (NF) requirements (3).
Figure 3: Respondents´ frequency of accepting excipient based on process controls, not on Certificate of Analysis.
FDA recently announced its Guidance for Industry on Chemistry, Manufacturing, and Controls Information; Withdrawal and Revision of Seven Guidances (4). By focusing on the Pharmaceutical Current Good Manufacturing Practices (CGMPs) for the 21st Century (CGMP Initiative) and ICH Guidelines, FDA has strategically reduced industry's regulatory and paperwork concerns, and changed the regulatory focus to concentrate on those aspects of manufacturing that pose the greatest risk to product quality. Although excipients constitute a large portion of most drug products, they have been viewed as a low-risk aspect of drug-product safety. They are, however, a key aspect of product Quality by Design (QbD).
Survey results
Figure 4: Respondents reporting difficulty finding manufacturer of USP–NF grade excipients.
The PQRI Excipient Working Group developed three surveys to gather responses from each of three respondent groups: excipient manufacturers, excipient distributors, and drug-product manufacturers. The surveys gathered information about excipient-control strategies used by companies that manufacture, distribute, and sell prescription-only and over-the-counter drug products for US-only or US-and-world markets. The anonymous surveys could be completed electronically by individuals belonging to the PQRI member organizations (http://www.pqri.org) and other interested persons. The survey period was from June 13, 2005 to Oct.14, 2005.
Figure 5: Obstacles to labeling excipients as USP–NF.
PQRI received responses from 180 drug-product manufacturers, 26 excipient manufacturers, and 6 distributors of pharmaceutical excipients. It should be recognized that PQRI is a unique US-based organization and that the survey questions were developed in the United States. Some survey responses may, however, have come from companies that manufacture their products for distribution and sale outside, as well as within, the United States.
This report presents findings of the three surveys and an analysis of survey responses. For the purposes of this report, the terms "excipient user" and "drug-product manufacturer" mean the same, and are used interchangeably throughout the document.
Figure 6: Respondents reporting inspections or visits by FDA (for either drug excipient or food use).
The survey clearly indicates that the majority of excipient manufacturers, excipient distributors, and drug-product manufacturers make their products for global distribution (see Figure 1). They test their excipients according to USP–NF monographs and general chapter methods (see Fig. 2). Almost all (97%) drug-product manufacturers perform more than just the identification test when receiving excipients from their vendors along with Certificates of Analysis (C of A). The additional tests include analyses for desired physical and chemical properties.
Less than 20% of drug-product manufacturers accept some or most material based on the excipient manufacturer's process controls and on in-process tests. These controls and tests are not mentioned on C of A, but provide assurance of conformity with USP–NF requirements (see Figure 3). This area offers opportunities for excipient manufacturers and drug-product manufacturers to research and subsequently use information and knowledge that lies in the excipient-maker's "manufacturing process-controls" and "in-process test results" domain. Assessment of such information could also confirm (or otherwise indicate) certain physicochemical quality aspects of an excipient batch, or qualities of an excipient produced under continuous manufacturing conditions.
Figure 7: Respondents reporting familiarity with requirements of Food Drug and Cosmetic Act and 21 CFR Part 211.84.
Drug-product manufacturers qualify new sources of excipients by vendor audits and complete testing according to the compendial monograph. According to the survey, 40% of drug-product manufacturers had difficulty finding a manufacturer of at least one USP–NF grade excipient (see Figure 4). In such a situation, they would use the best grade available, test the excipient according to the compendial monograph, and conduct an audit of the excipient manufacturer. Approximately 75% of drug-product manufacturers indicated they test and perform site audits to confirm compliance (for "a few" to "all" excipients) with compendial-grade standards. In 80% of the cases, respondents used validated test procedures to confirm the compliance of noncompendial grade excipients with compendial grade standards, or confirm that products conforming with one compendial grade also met standards from other compendia.
Figure 8: Respondents testing excipients by Ph.Eur. or JP methods instead of USP–NF.
Only a minority of responding excipient manufacturers and distributors cited specific reasons for not labeling their products as USP–NF compendial grade. Approximately one-third cited low demand for compendial grade products; just under 30% cited restrictive GMP requirements, the prospect of FDA inspection, or the time and resources needed to perform required audits. Only a handful expressed doubts about being able to meet compendial monograph requirements (see Figure 5). Nearly 80% of excipient manufacturers and drug-product manufacturers, and 60% of distributors, have been inspected or visited by FDA for either drug excipient or food use (see Figure 6).
Among drug-product manufacturers, 89% have five or more excipients in reduced-testing programs, and do not perform complete monograph testing after vendor qualification and receipt of C of A.
Figure 9: Respondents applying harmonized monographs and general chapters across all sites.
Excipient manufacturers, distributors, and drug-product manufacturers all responded that they feel adequately familiar with the applicable FDA and compendial requirements and recommendations related to testing of excipients used in a drug product (see Figure 7).
Among manufacturers, distributors, and users of USP–NF excipients, 70% or more perform additional functionality or processability testing that is not part of any USP–NF,European Pharmacopoeia (Ph.Eur.), or Japanese Pharmacopoeia (JP) compendial monograph. Of these, 87% perform the tests because of processing concerns. Most additional testing was performed for solid oral dosage forms (87%), and 24% of drug-product manufacturers have products for which excipient variability is a problem in spite of such extra-compendial testing.
Appendix: Excipient Working Group Recommendations for a PQRI Workshop
At least half of excipient manufacturers, distributors and drug-product manufacturers test some, most, or all of their excipients by alternate international (Ph.Eur., JP) compendial methods instead of USP–NF (see Figure 8).
Nearly 60% of excipient and drug-product manufacturers conduct excipient testing per harmonized monographs, and reduce redundant testing by either demonstrating multiple compendial specification equivalence or using the most stringent method or specification for confirming compliance with more than one compendium. Approximately 50% of both excipient manufacturers and drug-product manufacturers have applied harmonized excipient monographs and harmonized general chapters across all their sites (see Figure 9).
The PQRI and its Excipient Working Group encourage active participation by stakeholders from excipient manufacturers, excipient distributors, drug-product manufacturers, compendia, and regulatory agencies in discussing the current issues and for developing possible solutions to problems faced by pharmaceutical excipient manufacturers, distributors, and drug-product manufacturers (5).
References
1. European Agency for the Evaluation of Medicinal Product (EMEA), Note for Guidance on Excipients, Antioxidants and Antimicrobial Preservatives in the Dossier for Application for Marketing Authorisation of a Medicinal Product (CPMP/QWP/419/03) (EMEA, London, UK, Feb. 20, 2003).
2. US Food and Drug Administration, Guidance for Industry, Drug Product: Chemistry, Manufacturing, and Controls Information (FDA, Rockville, MD, Jan. 2003), now withdrawn, Fed. Reg. 71 (105), 31194–31195 (June 1, 2006).
3. United States Pharmacopeia 29–National Formulary 4, General Notices, section Tests and Assays under Procedures (United States Pharmacopeia Convention, Rockville, MD, 2006).
4. FDA, "Guidance for Industry on Chemistry, Manufacturing, and Controls Information; Withdrawal and Revision of Seven Guidances," Fed. Reg. 71 (105), 31194–31195 (June 1, 2006).
5. Details are posted online at http://www.pqri.org/workshops/Excipient/Excipient06.asp
6. Product Quality Research Institute (PQRI) workshop on Excipient Testing and Control Strategies, Oct. 10–11, 2006, Marriott Bethesda North Conference Center in Maryland.
The authors are members of the Pharmaceutical Quality Research Institute's Excipient Working
* the majority of respondents supply their products for global markets, and thus must meet substantially different test requirements for different regions;
* the majority of respondents use reduced-testing strategies employing equivalent methods;
* a large majority of respondents perform tests on the excipients beyond those given in pharmacopeias to determine physical and chemical properties necessary for their intended use;
* drug-product manufacturers typically follow their own company procedures to qualify excipient manufacturers and suppliers.
Figure 1: Respondents selling products both in the United States and abroad.
The survey results provide insights about the decisions of excipient manufacturers and drug-product manufacturers regarding testing excipient quality and using excipients in pharmaceutical manufacturing.
Background
When the European Agency for the Evaluation of Medicinal Products (1) and US Food and Drug Administration (2) issued excipients guidances in 2003, industry predicted that they would have the unintended result of causing additional paperwork and excessive testing for excipient control strategies, without adding benefits. In addition, industry believed the guidances effectively eliminated generally accepted and common excipient control strategies.
Figure 2: Respondents testing excipient according to USP–NF monograph/general chapter methods
FDA's interpretation of International Conference on Harmonization (ICH) common technical document (CTD) language used in section P.4, "Control of Excipients" required that manufacturers specify each method used for routine excipients testing, unless the method is exactly that of the pharmacopeia and full monograph testing is performed.
Often, a drug-product manufacturer has methods used internally that are shown to produce equivalent results to those in a pharmacopeia. In addition, many manufacturers with global markets seek to eliminate redundant testing of the same property by selecting a single method shown to be capable of ensuring compliance with requirements of many pharmacopeias. The United States Pharmacopeia (USP) has been clear that alternate methods are acceptable to demonstrate compliance with USP–National Formulary (NF) requirements (3).
Figure 3: Respondents´ frequency of accepting excipient based on process controls, not on Certificate of Analysis.
FDA recently announced its Guidance for Industry on Chemistry, Manufacturing, and Controls Information; Withdrawal and Revision of Seven Guidances (4). By focusing on the Pharmaceutical Current Good Manufacturing Practices (CGMPs) for the 21st Century (CGMP Initiative) and ICH Guidelines, FDA has strategically reduced industry's regulatory and paperwork concerns, and changed the regulatory focus to concentrate on those aspects of manufacturing that pose the greatest risk to product quality. Although excipients constitute a large portion of most drug products, they have been viewed as a low-risk aspect of drug-product safety. They are, however, a key aspect of product Quality by Design (QbD).
Survey results
Figure 4: Respondents reporting difficulty finding manufacturer of USP–NF grade excipients.
The PQRI Excipient Working Group developed three surveys to gather responses from each of three respondent groups: excipient manufacturers, excipient distributors, and drug-product manufacturers. The surveys gathered information about excipient-control strategies used by companies that manufacture, distribute, and sell prescription-only and over-the-counter drug products for US-only or US-and-world markets. The anonymous surveys could be completed electronically by individuals belonging to the PQRI member organizations (http://www.pqri.org) and other interested persons. The survey period was from June 13, 2005 to Oct.14, 2005.
Figure 5: Obstacles to labeling excipients as USP–NF.
PQRI received responses from 180 drug-product manufacturers, 26 excipient manufacturers, and 6 distributors of pharmaceutical excipients. It should be recognized that PQRI is a unique US-based organization and that the survey questions were developed in the United States. Some survey responses may, however, have come from companies that manufacture their products for distribution and sale outside, as well as within, the United States.
This report presents findings of the three surveys and an analysis of survey responses. For the purposes of this report, the terms "excipient user" and "drug-product manufacturer" mean the same, and are used interchangeably throughout the document.
Figure 6: Respondents reporting inspections or visits by FDA (for either drug excipient or food use).
The survey clearly indicates that the majority of excipient manufacturers, excipient distributors, and drug-product manufacturers make their products for global distribution (see Figure 1). They test their excipients according to USP–NF monographs and general chapter methods (see Fig. 2). Almost all (97%) drug-product manufacturers perform more than just the identification test when receiving excipients from their vendors along with Certificates of Analysis (C of A). The additional tests include analyses for desired physical and chemical properties.
Less than 20% of drug-product manufacturers accept some or most material based on the excipient manufacturer's process controls and on in-process tests. These controls and tests are not mentioned on C of A, but provide assurance of conformity with USP–NF requirements (see Figure 3). This area offers opportunities for excipient manufacturers and drug-product manufacturers to research and subsequently use information and knowledge that lies in the excipient-maker's "manufacturing process-controls" and "in-process test results" domain. Assessment of such information could also confirm (or otherwise indicate) certain physicochemical quality aspects of an excipient batch, or qualities of an excipient produced under continuous manufacturing conditions.
Figure 7: Respondents reporting familiarity with requirements of Food Drug and Cosmetic Act and 21 CFR Part 211.84.
Drug-product manufacturers qualify new sources of excipients by vendor audits and complete testing according to the compendial monograph. According to the survey, 40% of drug-product manufacturers had difficulty finding a manufacturer of at least one USP–NF grade excipient (see Figure 4). In such a situation, they would use the best grade available, test the excipient according to the compendial monograph, and conduct an audit of the excipient manufacturer. Approximately 75% of drug-product manufacturers indicated they test and perform site audits to confirm compliance (for "a few" to "all" excipients) with compendial-grade standards. In 80% of the cases, respondents used validated test procedures to confirm the compliance of noncompendial grade excipients with compendial grade standards, or confirm that products conforming with one compendial grade also met standards from other compendia.
Figure 8: Respondents testing excipients by Ph.Eur. or JP methods instead of USP–NF.
Only a minority of responding excipient manufacturers and distributors cited specific reasons for not labeling their products as USP–NF compendial grade. Approximately one-third cited low demand for compendial grade products; just under 30% cited restrictive GMP requirements, the prospect of FDA inspection, or the time and resources needed to perform required audits. Only a handful expressed doubts about being able to meet compendial monograph requirements (see Figure 5). Nearly 80% of excipient manufacturers and drug-product manufacturers, and 60% of distributors, have been inspected or visited by FDA for either drug excipient or food use (see Figure 6).
Among drug-product manufacturers, 89% have five or more excipients in reduced-testing programs, and do not perform complete monograph testing after vendor qualification and receipt of C of A.
Figure 9: Respondents applying harmonized monographs and general chapters across all sites.
Excipient manufacturers, distributors, and drug-product manufacturers all responded that they feel adequately familiar with the applicable FDA and compendial requirements and recommendations related to testing of excipients used in a drug product (see Figure 7).
Among manufacturers, distributors, and users of USP–NF excipients, 70% or more perform additional functionality or processability testing that is not part of any USP–NF,European Pharmacopoeia (Ph.Eur.), or Japanese Pharmacopoeia (JP) compendial monograph. Of these, 87% perform the tests because of processing concerns. Most additional testing was performed for solid oral dosage forms (87%), and 24% of drug-product manufacturers have products for which excipient variability is a problem in spite of such extra-compendial testing.
Appendix: Excipient Working Group Recommendations for a PQRI Workshop
At least half of excipient manufacturers, distributors and drug-product manufacturers test some, most, or all of their excipients by alternate international (Ph.Eur., JP) compendial methods instead of USP–NF (see Figure 8).
Nearly 60% of excipient and drug-product manufacturers conduct excipient testing per harmonized monographs, and reduce redundant testing by either demonstrating multiple compendial specification equivalence or using the most stringent method or specification for confirming compliance with more than one compendium. Approximately 50% of both excipient manufacturers and drug-product manufacturers have applied harmonized excipient monographs and harmonized general chapters across all their sites (see Figure 9).
The PQRI and its Excipient Working Group encourage active participation by stakeholders from excipient manufacturers, excipient distributors, drug-product manufacturers, compendia, and regulatory agencies in discussing the current issues and for developing possible solutions to problems faced by pharmaceutical excipient manufacturers, distributors, and drug-product manufacturers (5).
References
1. European Agency for the Evaluation of Medicinal Product (EMEA), Note for Guidance on Excipients, Antioxidants and Antimicrobial Preservatives in the Dossier for Application for Marketing Authorisation of a Medicinal Product (CPMP/QWP/419/03) (EMEA, London, UK, Feb. 20, 2003).
2. US Food and Drug Administration, Guidance for Industry, Drug Product: Chemistry, Manufacturing, and Controls Information (FDA, Rockville, MD, Jan. 2003), now withdrawn, Fed. Reg. 71 (105), 31194–31195 (June 1, 2006).
3. United States Pharmacopeia 29–National Formulary 4, General Notices, section Tests and Assays under Procedures (United States Pharmacopeia Convention, Rockville, MD, 2006).
4. FDA, "Guidance for Industry on Chemistry, Manufacturing, and Controls Information; Withdrawal and Revision of Seven Guidances," Fed. Reg. 71 (105), 31194–31195 (June 1, 2006).
5. Details are posted online at http://www.pqri.org/workshops/Excipient/Excipient06.asp
6. Product Quality Research Institute (PQRI) workshop on Excipient Testing and Control Strategies, Oct. 10–11, 2006, Marriott Bethesda North Conference Center in Maryland.
The authors are members of the Pharmaceutical Quality Research Institute's Excipient Working
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