Regulatory Highlights for September 2012 ... - ACS Publications

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Regulatory Highlights pubs.acs.org/OPRD

Regulatory Highlights for September 2012−February 2013

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USER FEE REQUIREMENTS FOR GENERIC DRUGS The Generic Drug User Fee Act (GDUFA) came into force in the United States on first October last year, and has profound implications for companies manufacturing generic active pharmaceutical ingredients (APIs). Under GDUFA, all API manufacturing and testing sites, whether domestic or foreign, are obliged to self-register with the United States Food and Drug Administration (FDA)1 and pay user fees to cover the agency’s review and inspection costs.2 The requirement for self-identification arises in response to the large increase in generic applications received by the agency in recent years and the corresponding geographical diversity of the proposed manufacturers. Self-identification is a central component in the effort to improve global supply chain transparency; the information it provides should enable quick, accurate, and reliable surveillance of generic drugs and facilitate inspections and compliance. FDA will require Data Universal Numbering System (D-U-N-S) numbers for each physical location of the business’s facility or site. This is a unique nine-digit sequence provided by Dun & Bradsheet, specific for each physical location or site, and is a widely recognized business identification tool. Facilities must also obtain a Facility Establishment Identifier (FEI) from the FDA, who will require the name and contact information of the registrant owner and facility information, including name, type of business operation, and contact information. These submissions are expected to be made electronically. A principle reason for self-identification is to enable the FDA to work out and collect the new user fees from the generics industry. Sponsors of new drugs have been required to contribute such fees for the last 20 years and have generally regarded this as a reasonable quid pro quo for the expeditious review of applications necessary to maximize the financial benefits from their patents. Generic manufacturers, on the other hand, have traditionally resisted fees, which only add to their costs. But now the sheer number of generic applications has led to a significant backlog, for which extra funding is now required to clear. Thus, after negotiation with the industry, FDA intends to collect some $300 million in user fees during fiscal year 2013, with equivalent sums being raised annually until at least 2017.3 From first October 2012 a fee of $51,520 is payable for each Abbreviated New Drug Application (ANDA), and half of this ($25,760) for any Prior Approval Supplement (PAS) to an existing ANDA. (It appears that Change Being Effected Supplements (CBE or CBE-30) are not subject to fees.) Owners of Type II Drug Master Files (DMFs), detailing the API manufacturing procedures, also pay a fee ($21,340) the first time the DMF is referenced in an ANDAalthough not for any subsequent references. Where the drug company intends to manufacture its own API (i.e. without referencing a DMF) an equivalent API fee is payable by them. Additionally, each self-identified facility will pay an annual facility fee, $26,458 for an API facility and $175,389 for a finished product facility, with a $15,000 supplement where the facility is located outside the United States.4 In return for this extra funding,the FDA has committed to review and act on 90% of original, unamended ANDAs within 10 months of submission by © XXXX American Chemical Society

year five of the program. This should “reduce the overall expense of bringing a generic product to market, and deliver safe, effective, and affordable generic drugs to the public sooner”.

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IMPURITY LEVELS IN ANTIBIOTICS A new guideline from the European Medicines Agency (EMA) on impurity levels in antibiotics will come into force in June 2013.5 The production of antibiotic active substances typically involves a fermentation step; consequently, their impurity profiles are often more complex and less predictable than those of purely synthetic APIs. For this reason, fermentation products and semisynthetic compounds were excluded from the scope of the International Conference on Harmonization (ICH) guidance Q3A, which has governed purely synthetic APIs for nearly two decades. The present guideline has been developed in order to close this gap. It applies to new active substances and to new sources of existing active substances, but will not be applied retrospectively. Nor does it apply to new clinical APIs. Its scope is restricted to “related substances”, and does not cover, for example, residues from micro-organisms or culture media. Under the new guideline, the impurity profile of antibiotics would be characterised using the same procedures as those of Q3A, with limits set for specified identified impurities, specified unidentified impurities, unspecified impurities, and total impurities. As with Q3A, thresholds are set for the reporting, identification, and qualification of impurities, but in certain cases these thresholds may be higher than for normal drugs. For semisynthetic antibiotics, where the final steps involve synthetic chemistry procedures, the same Q3A thresholds are applied (i.e., 0.05/0.03% for reporting, 0.10/0.05% for identification, 0.15/0.05% for qualification, depending on the daily dose.) However, where the API is a single substance manufactured entirely by fermentation, the reporting and identification thresholds are increased to 0.10% and 0.15% respectively, regardless of dose. Where the active substance is a family of compounds, the qualification threshold is raised to 0.50% for “structurally closely related impurities”, and 0.20% for other related impurities. For antibiotic active substances used in veterinary medicine only, the three thresholds will be 0.10%, 0.20%, and 0.50%the same as for other purely veterinary drugs.

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CLEANING VALIDATION AND DEDICATED FACILITIES The EMA has issued a new draft guideline clarifying requirements for the use of dedicated facilities when manufacturing certain drugs.6 Due to the perceived risk, certain classes of active substances have previously been required to be manufactured in dedicated or segregated self-contained facilities including, “certain antibiotics, certain hormones, certain cytotoxic and certain highly active drugs”. Pharmaceuticals not considered to be covered under these criteria were addressed by a cleaning validation process involving reduction of the residual active substance to a level such that no more than 10 ppm, or 1/1000th of the lowest clinical dose, would contaminate the next product

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The risk assessment report should be based on a comprehensive literature search .The search strategy and the results of the search must be clearly documented. Following an expert review, the company should provide a discussion with respect to the critical end points of concern and their rationale for the choice of end points and dose that is to be used in the derivation of the PDE. The pivotal animal and human studies used for the derivation of the PDE should be sourced to the original reference and reviewed regarding their quality (study design, description of finding, accuracy of the report, etc.). The risk assessment report should provide a clear rationale regarding the adjustment factors that were applied in deriving the PDE. The deadline for comments on this draft guideline is 30 June 2013.

manufactured. These limits are now regarded as somewhat arbitrary; hence, a more scientific case-by-case approach is warranted for all classes of pharmaceutical substances. In cases where scientific data do not support threshold values for safety (e.g., allergenic potential from highly sensitizing materials) or where the risk cannot be adequately controlled by operational and/or technical measures, dedicated facilities will continue to be required. In many cases, though, it will be possible to establish health-based API exposure limits, and a procedure for doing so is set out in this guidance. The procedure is based on establishing a Permitted Daily Exposure (PDE) of the residual drug representing a substancespecific dose that is unlikely to cause an adverse effect if an individual is exposed to it every day for a lifetime. Determination of a PDE involves (i) hazard identification by reviewing all relevant data, (ii) identification of “critical effects”, (iii) determination of the no-observed-effect level (NOEL) for these critical effects, and (iv) use of several adjustment factors to account for various uncertainties. For pragmatic reasons, the same PDEs (in terms of μg/kg) should be applied to veterinary as well as human drugs. For hazard identification, a review of all available animal and human data should be performed. This would include nonclinical pharmacodynamic data, repeat-dose toxicity studies, carcinogenicity studies, studies of genotoxicity in vitro and in vivo, reproductive and developmental toxicity studies as well as clinical data on therapeutic and adverse effects. The availability of data for an active substance will vary, depending on the stage of development and indication. If data sets are incomplete, the identified gaps need to be critically assessed with regard to the uncertainty this might have on deriving a reliable exposure limit. For all critical effects identified, a NOEL should be established. The PDE is then derived by dividing the NOEL by various adjustment factors to account for uncertainties and to allow extrapolation to a reliable and robust no-effect level in the human or target animal population. For genotoxic active substances for which there is no discernible threshold, it is considered that any level of exposure carries a risk. However, a level of acceptable risk (known as the Threshold of Toxicological Concern) has already been established by the EMA and other regulators. For genotoxic impurities in drugs the TTC level is 1.5 μg/person/day. However, unlike impurities, API residues are in principle avoidable and are not associated with any related benefit to the patient, thus a more conservative approach is appropriate. In the case of residual active substances without a threshold, a limit dose of 0.15 μg/person/day should be applied, corresponding to a theoretical 1 × 10−6 excess lifetime cancer risk. If the active substance has a sensitizing potential, it is difficult to establish a safe level of exposure; therefore, dedicated facilities would normally be required here, the exception being where the drug is only to be administered topically. In the early phases of development, data to assess the potential of the new active substance to cause reproductive and developmental toxicity may often be lacking. In these cases, the use of a generic threshold value similar to that applied for genotoxic substances may be considered. The guideline does not give any specific figure here but suggests one could be conservatively derived from a database of NOELs obtained from animal studies of fertility and embryo−fetal development. In order to be acceptable, such a threshold value would need to be available in public literature.

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API IMPORTS INTO EUROPE The “Falsified Medicines Directive” is due to come into force in the European Union in July 2013.7 This directive covers safety features (e.g., common logo provisions) and the Internet supply of medicines, but most attention and discussion is currently focussed on the third element, namely, ensuring the quality of imported APIs.8,9 From July, each API consignment from countries outside the EU must be accompanied by a written confirmation of adherence to GMP standards. Such proof requires either a GMP certificate from an EU National Competent Authority (NCA), a “conformity of equivalence” statement from the authority of the non-EU country, or a positive assessment (white-listing) by the European Commission that the originating country’s regulatory framework provides equivalent assurance of compliance. The vast majority of APIs imported into the EU originate in China, India, U.S.A., Japan, and Switzerland. Of these, so far only Switzerland is on the Commission’s white list. Thus, certificates will be required for imports from all other countries even from those which already have mutual recognition agreements with the EUand from fellow-members of the Pharmaceutical Inspection Co-operation Scheme. The Indian government has announced a scheme for providing these GMP certificates,10 although this will apparently be founded only on brief site visits by the authorities, and thus it is questionable whether it adds any real assurance of quality. The intentions of the Chinese and U.S. authorities with regard to certification are at present unclear, which raises the possibility that API imports from these countries will be illegal. (The import of finished drug products, on the other hand, is not affected by this directive.) The Heads of Medicines Agencies (HMA) has expressed deep concern that this situation might endanger public health within the EU due to possible shortages of medicinal products and consequently become a serious public health risk.11 A survey of EU authorities suggests that 300 manufacturing sites may need to be inspected by July to ensure the continuation of supply, whereas resources currently available in the EU inspectorates would enable the performance of only 25 inspections within this time frame.12 The European Commission has published guidance on the implementation of the directive in the form of a Q&A document.13 The UK Medicines and Healthcare Resources Agency (MHRA) has also published its perspective on the situation.14

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TESTING FOR METAL CONTAMINATION

Revised U.S. Pharmacopoeia (USP) requirements on elemental impurity limits and testing procedures are due to be implemented by the industry by May 2014. Simultaneously, the ICH is developing its new guideline on metal impurities (ICH Q3D); B

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a first draft of this has been prepared, but is not yet publicly available; finalization is not expected before 2014. Meanwhile, guidelines on the same topic from the EMA have already been finalised, and their implementation is mandatory from September 2013. The USP revisions involve the removal of the traditional test for heavy metals by sulfide precipitation, in favor of more accurate element-specific methods, especially inductively coupled plasma spectroscopy (ICP). Several recent articles address various aspects of these changes. Cross15 reviews the history and shortcomings of the traditional test and compares the variety of modern techniques now available which mightafter validation fulfill the new requirements. Clark and Punzi16 discuss the history of how the topic has been approached within the three bodies mentioned above, and the degree of co-operation between them. There is, however, some unease within the industry over the timing of the changes, reflected in the emergence of a new industry coalition to highlight their concerns.17 The coalition’s main worry is that companies will be obliged to invest considerable time and resources in meeting the USP requirements, some of which may then need to be revisited if the ICH recommendations turn out to be different. While they agree that the pharmacopoeial change is necessary, they argue that there is no great urgency for itit does not arise from any patient safety or product quality considerations, but rather for analytical reasonsthus, it would be better to harmonize its implementation with that of the Q3D guideline. Another concern they have with the USP draft is that it appears to place little emphasis on risk-based approaches to testing for metal impurities, with the result that many companies may feel obliged to implement new tests that actually add little or no value in terms of quality assurance. Whereas the old test, being very cheap, could reasonably be applied by default to every drug product and API; this is not true of its replacement(s), which will require extensive development and validation on a product-by-product basis, not to mention the purchase of very expensive equipment. Clark and Punzi, on the other hand, point out that USP standards are “compliance standards”, which must be met if tested, but there is no requirement to perform the testing on every product on a routine basis. This means it is important that the actual risk of metal contamination of a product is assessed, taking into account likely sources and the extent and toxicological danger of contamination before developing specific tests for it. With this risk-based provision, the bulk of testing is likely to be aimed at APIs where catalytic metals have been employed in their synthesis. For other toxic metals, such as lead, cadmium, or mercury, the most likely source is water; thus, the risk can be mitigated by GMP and analytical controls on the supply. Contamination from processing equipment (usually stainless steel or Hastelloy) is unlikely if the equipment is well-maintained (GMP again), and the metals here would pose little danger to patients anyway. The industry coalition feels that the forthcoming ICH guideline will place greater emphasis on these risk-based considerations.

specifications that ensure patient safety, supported by preclinical and early clinical safety studies. On the basis of the cumulative industry experience of the IQ working group members, the authors of this paper propose standardized early phase specification tests and acceptance criteria for both drug substance and drug product. In addition to release and stability tests, consideration is given to internal tests and acceptance criteria that are not normally part of formal specifications, but which may be performed to collect information for product and process understanding or to provide greater control. The drug substance used in preclinical animal studies (tox batch) is fundamental in defining the specifications for an early phase clinical drug substance (DS). Here, internal targets rather than formal specifications are routinely used while gathering knowledge about impurities and processing capabilities. At this stage the emphasis should be on ensuring the correct DS is administered, determining the correct potency value, and quantitating impurities for toxicology purposes. For DS intended for clinical studies, additional testing and controls may be required; the testing may be similar to that for the tox batch, but now with established acceptance criteria. For these stages the authors propose a standardized set of DS specifications, as follows. description identification counterion assay impurities unidentified unqualified mutagenic inorganic residual solvents water content solid form particle size residue on ignition

range of colour conforms to a reference spectrum report results 97−103% on a dry basis NMT 3.0% total, NMT 1.0% each NMT 0.3% NMT 0.15% follow EMA guidelines (pending ICH M7 guidance) follow EMA guidelines (pending ICH Q3D guidance) use ICH Q3C limits or other justified limits for solvents used in final synthetic step report results report results report results NMT 1.0%

These may be altered in line with any specific knowledge of the compound in question. For example, if the DS is a hydrate or is known to be hygroscopic or sensitive to water, a specified water content may be appropriate. Of particular note is the use of impurity thresholds which are 3 times higher than those defined in ICH Q3 guidelines. Q3 was never intended to apply to clinical drugs, and higher thresholds can be justified by the limited exposure that patients experience during these early stages. Mutagenic impurities are the exception here, since in this area the existing official guidance does cover clinical drugs. The fourth article in the series20 considers appropriate approaches to stability testing during early clinical phases. Appropriate stability data at suitable storage conditions are required to support filing the clinical trial application (CTA/IND/IMPD) and use of the clinical material through the end of the clinical study. Several factors from business, regulatory, and scientific perspectives need to be taken into account when designing early stability studies, such as the risk tolerance of the sponsoring organization, the inherent stability of the drug substance and prior product, process and stability knowledge, the regulatory environment in the countries where the clinical trial will be conducted, and the projected future use of the product. Often non-GMP DS batches are manufactured first and placed on stability to support a variety of product development activities.

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GMPS FOR EARLY STAGE DEVELOPMENT The previous Regulatory Highlights18 drew attention to a series of articles from the IQ Consortium (International Consortium on Innovation and Quality in Pharmaceutical Development) on appropriate good manufacturing practices (GMP) for the early development phases of new drug substances and products. The fifth article in this series19 focuses on the setting of specifications during these early phases (I and IIa). Due to the high attrition rate in early development, the focus should be on consistent C

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The only unsatisfactory material examined was white PTFE, on which only two APIs were visible at 400 μg dm−2. Potential benefits of the use of visual inspection alone include significant time savings compared with the commonly used techniques of swab or rinse analysis, as well as the fact that visual inspection, in principle, has the capability of testing 100% of the equipment surface. However, in a multipurpose plant, it would be necessary to assess the risks on a case-by-case basis.

In many cases these batches will be representative of subsequent GMP batches from a stability perspective and can be used to establish an initial retest period for the DS and support a clinical submission. In early development, it is common for the manufacturing process to be improved; therefore, as the DS process evolves, an evaluation is needed to determine whether the initial batch placed on stability is still representative of the improved process. The authors advocate a science- and risk-based approach for deciding whether stability studies on new process batches are warranted. The first step is to determine which DS attributes have an effect on stability. This step can be completed through paperbased risk assessments, prior knowledge, or through a head-tohead short-term stability challenge. If the revised process impacts one or more of these stability-related quality attributes, the new batch should be placed on stabilityotherwise not. Typical changes encountered at this stage include changes in synthetic pathway, batch scale, manufacturing equipment or site, reagents, source materials, solvents used, and crystallization steps. In most cases, these changes will not result in changes in DS stability. Changes to the impurity profile are unlikely to affect stability, since most organically related impurities will be inert. On the other hand, catalytic metals, acidic or basic inorganic impurities, or significant amounts of residual water or solvents may affect stability; thus, changes to these attributes would typically require the new batch to be placed in the stability program. Similarly, any changes to polymorphic form, particle size, or counterion would warrant extra testing. Packaging changes of the bulk material to a less protective package may require stability data to support the change. Three approaches to stability data collection are commonly used. One is that an early, representative DS batch is placed under real-time and accelerated conditions (e.g., 25 °C/60% RH and 40 °C/75% RH), and stability results for a few time points (e.g., 1−6 months) are generated to support an initial retest period (e.g., 12 months or more). A second approach is to use high stress conditions such as a high temperature and high humidity with a short time. A third approach is the use of stress studies at several conditions coupled with modelling. The retest period derived from these types of accelerated or stress studies can be later verified by placing the first clinical batch into realtime stability studies under ICH accelerated and long-term conditions. Future extensions of the retest/use period can be based on real-time data.

Derek Robinson

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38 Millbrook Court, Little Mill, Pontypool, Monmouthshire NP4 0HT, United Kingdom

REFERENCES

(1) Self-Identification of Generic Drug Facilities, Sites, and Organizations; U.S. Food and Drug Administration (FDA): Silver Spring, MD, August 2012; www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/ Guidances/ucm316721.htm. (2) Generic Drug User Fee Amendments of 2012: Questions and Answers; U.S. Food and Drug Administration (FDA): Silver Spring, MD, August 2012; www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/ Guidances/ucm316790.htm. (3) Generic Drug User Fee: Abbreviated New Drug Application, Prior Approval Supplement, and Drug Master File Fee Rates for Fiscal Year 2013. Federal Register; 2012, 77(207), 65198−65199; http://www.gpo. gov/fdsys/pkg/FR-2012-10-25/html/2012-26256.htm. (4) Generic Drug User Fee: Active Pharmaceutical Ingredient and Finished Dosage Form Facility Fee Rates for Fiscal Year 2013. Federal Register; 2013, 78(12), 3900−3901. (5) Guideline on Setting Specifications for Related Impurities in Antibiotics, QWP/199250/2009 corr; European Medicines Agency (EMA)/Committee for Medicinal Products for Human Use (CHMP)/ Committee for Medicinal Products for Veterinary Use (CVMP): London, UK, 30 June, 2012; www.ema.europa.eu/docs/en_GB/ document_library/Scientific_guideline/2012/07/WC500129997.pdf. (6) Guideline on Setting Health Based Exposure Limits for Use in Risk Identification in the Manufacture of Different Medicinal Products in Shared Facilities, SWP/169430/2012; European Medicines Agency (EMA)/Committee for Medicinal Products for Human Use (CHMP)/ Committee for Medicinal Products for Veterinary Use (CVMP): London, UK, 13 December, 2012; www.ema.europa.eu/docs/en_GB/ document_library/Scientific_guideline/2013/01/WC500137091.pdf. (7) European Union. Directive 2011/62/EU of the European Parliament and of the Council of 8 June 2011 Amending Directive 2001/83/EC on the Community Code Relating to Medicinal Products for Human Use, As Regards the Prevention of the Entry into the Legal Supply Chain of Falsified Medicinal Products. Official Journal of the European Union 2011, 54 (L174), 74−87, http://ec.europa.eu/health/ files/eudralex/vol-1/dir_2011_62/dir_2011_62_en.pdf. (8) Schmidt, S. The EU’s Falsified Medicines Directive and APIs. Pharm. Technol 2013, 37 (2), 82. (9) New MHRA Q & A Document on the Import of Active Pharmaceutical Ingredients, GMP News, European Compliance Academy, 16 Jan 2013; www.gmp-compliance.org/eca_news_3464_ 7675,6339,7817.html. (10) India Preparing for the Issuance of Written Confirmations, GMP News, European Compliance Academy, 6 February 2013; www.gmpcompliance.org/eca_news_3495_7675,S-QSB.html. (11) HMA Concerns Regarding the Adoption of the New Falsified Medicines Directive; www.hma.eu/fileadmin/dateien/Human_ Medicines/02-HMA_Topics/Falsified_Meds/2012_12_HMA__ Falsified_Med_Dir.pdf. (12) Are 300 GMP Inspections Necessary by 2 July 2013? GMP News, European Compliance Academy, 27 February 2013; www.gmpcompliance.org/eca_news_3589_7869,S-WKS.html. (13) Importation of Active Substances for Medicinal Products for Human Use. Questions and Answers, version 3.0, European

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VISUAL RESIDUE LIMITS The use of visual inspection as the sole determinant of cleanliness of pharmaceutical equipment has been discussed in the industry for many years; several scientific investigations of the practice have been discussed in previous Regulatory Highlights.21 While those previous investigations were limited to detecting contamination on stainless steel (SS) surfaces, a new study by David Fletcher of AstraZeneca now expands the investigation to a variety of alternative surfaces.22 The results are very encouraging, since it appears that SS actually represents the worst case in terms of residue visibility, although still adequate in most cases. For all six (undisclosed) APIs tested here, visual residue limits (VRLs) down to 400 μg dm−2 could be verified on SS with a surface roughness of 1.1 μm. With a completely smooth SS surface, levels of 100 μg dm−2 were visible in all cases, and some APIs could be detected as low as 10 μg dm−2. With both clear glass and blue enamel surfaces, 10 μg dm−2 was visible for all four APIs tested, while for white enamel the VRL increased to 50 μg dm−2. D

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Commission; 28 January 2013. http://ec.europa.eu/health/files/gmp/ 2013_01_28_qa_en.pdf. (14) Q and As from the Falsified Medicines Directive. MHRA/ Industry meeting held 15 November 2012. www.mhra.gov.uk/home/ groups/es-policy/documents/websiteresources/con213169.pdf. (15) Cross, A. Elemental Impurity Analysis. Pharm. Technol. 2012, 36 (8), 62−64. (16) Clark, J. E.; Punzi, J. S. Modernization of the Standards for Elemental Impurities. Pharm. Technol. 2013, 37 (2), 52−55. (17) Ulman, K.; Schwarzwalder, N.; Teasdale, A.; Schoneker, D.; Zawislak., P. An Industry Perspective on Harmonization and Implementation of ICH and USP Requirements. Pharm. Technol. 2012, 36 (11), 58−72. (18) Robinson, D. Org. Process Res. Dev. 2012, 16, 1582−1585. (19) Coutant, M.; Ge, Z.; McElvain, J. S.; Miller, S. A.; O’Connor, D.; Swanek, F.; Szulc, M.; Trone, M. D.; Wong-Moon, K.; Yazdanian, M.; Yehl, P.; Zhang, S. Early Development GMPs for Small-Molecule Specifications: An Industry Perspective (Part V). Pharm. Technol. 2012, 36 (10), 86−94. (20) Acken, B.; Alasandro, M.; Colgan, S.; Curry, P.; Diana, F.; Li, Q. C.; Li, Z. J.; Mazzeo, T.; Rignall, A.; Tan, Z. J.; Timpano, R. Early Development GMPs for Stability (Part IV). Pharm. Technol. 2012, 36 (9), 64−70. (21) Robinson, D. Org. Process Res. Dev. 2007, 11, 311−317. Robinson, D. Org. Process Res. Dev 2008, 12, 817−822. (22) Fletcher, D. I. Determination of Surface Visible Residue Limits on Pharmaceutical Plant Equipment. Pharm. Technol. 2013, 37 (2), 48−51.

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