This article specifically covers incorporation of physical and chemical indicators (PCIDs) into or onto the drug product.

Transcription

1 Introduction The pharmaceutical industry is criminalized with circulation of counterfeit drugs risking healthcare and the life of users. This has become quite menacing in recent times with the lure of good money in the healthcare segment as it is a very wide network where detection of offenders becomes difficult. In its attempt to arrest this menace the pharmaceutical industry and the Regulatory authorities have joined hands to introduce certain mechanisms that can help authenticate the drug product. This article specifically covers incorporation of physical and chemical indicators (PCIDs) into or onto the drug product. What is PCID? A PCID is a substance or combination of substances possessing a unique physical or chemical property that unequivocally identifies and authenticates a drug product or dosage form. There are various available means for presentation and detection of PCIDs (e.g., photolithography, holography, optical microscopy, laser scanning devices, excitation/fluorescence detection). Some identifying characteristics, such as pigments or flavors, could be easily observed by patients, healthcare practitioners, and pharmacies. Others could require the use of a detection instrument (e.g., a scanner, photometric detector, mass spectrometry). GMP Pharma Institute Private Limited, Dehradun 1

2 Guidance US-FDA has introduced a guidance that provides recommendations to pharmaceutical manufacturers on, supporting documentation to be submitted in new drug applications (NDAs) and abbreviated new drug applications (ANDAs) to address the proposed incorporation of PCIDs in SODFs. The guidance is titled: Guidance for Industry: Incorporation of Physical-Chemical Identifiers into Solid Oral Dosage Form Drug Products for Ant-counterfeiting October 2011 under the prerogative of Center for Drug Evaluation and Research (CDER). What is excluded from this guidance? The incorporation of components or features used in radiofrequency identification for drug products is excluded from the scope of this guidance. The incorporation of a PCID into the packaging or labeling is also not covered in this guidance. What is included in this guidance? This guidance only includes such PCIDs that can be incorporated into the core or onto the drug product. Few examples of substances that may be incorporated into solid Oral Dosage Forms (SODFs) as PCIDs include inks, pigments, flavors, and molecular taggants. Such PCIDs may allow product authentication by their presence alone or may be used to code the product identity into or onto the SODF. FDA anticipates that many of the ingredients that will ultimately be employed as PCIDs are already used as food additives, colorants, or excipients with established safety profiles. Number of counterfeit incidents Counterfeit Incidents Year GMP Pharma Institute Private Limited, Dehradun 2

3 Inflow of Counterfeits to the Legitimate Distribution Channel Design Considerations What are the design considerations for incorporation of PCIDs in solid oral dosage forms? a. Pharmacological and Toxicological Considerations The PCIDs selected for incorporation should necessarily be inactive and should have no pharmacological bearing on the drug product. Likewise, they should also not contribute any amount of toxicological bearing to the drug product. It is therefore, recommended that the ingredients comprising the PCID should be pharmacologically inactive and the ingredients can be treated as excipients. To minimize toxicological risk, FDA recommends use of those permissible direct food additives, food substances that are listed in the 21 CFR Part 172 and that they are generally recognized as safe (GRAS); including direct food substances affirmed as GRAS, or those ingredients listed in the FDA Inactive Ingredient Guide (IIG) that have been used in SODFs. GMP Pharma Institute Private Limited, Dehradun 3

4 (21 CFR Parts 172: Food Additives Permitted For Direct Addition To Food For Human Consumption) It is the responsibility of the manufacturer to determine the safety status of the PCID selected as certain substances could present a toxicological risk when used as a PCID in a SODF. The toxicological risk of any PCID substance could be: If it is used at a level in excess of the limitations provided in the relevant IIG listing or Code of Federal Regulations (CFR) chapter for direct food additives. An ingredient that has never been used in an SODF or as a direct food additive. An ingredient that poses risk of adverse reaction (e.g., allergic reaction or irritation), including an ingredient derived from a major food allergen (i.e., milk, eggs, fish, Crustacean shellfish, tree nuts, peanuts, wheat and soybeans. b. Other Design Considerations Use of PCID should in no way affect the identity, strength, quality, purity, potency, or bioavailability of the SODF. Therefore, it is worth noting that PCID should be added to an SODF at the lowest level that ensures identification of the dosage unit. This will help minimize the risk of adverse effects on these characteristics; this is also recommended by the FDA. The design criteria of the SODF that will incorporate a PCID and the selection criteria for PCID should consider the potential effect on the quality, performance, and stability of the SODF. These are important considerations which the manufacturers of drug products should plan during the development phase itself. The most important factor that needs to be considered by the product development scientists is where to place the PCID within the drug product. When considering where to incorporate a PCID, the product development scientist may conceptually subdivide an SODF into sections that differ in composition that may or may not contain active drug substance. For example, a core section in an SODF is likely to contain one or more drug substances, while the external sections of the SODF may not. The product development scientists should also consider whether the presence of the PCID might interfere with control of the release rate of modified-release SODFs (SODF-MRs), including extended-release and delayed-release dosage forms. GMP Pharma Institute Private Limited, Dehradun 4

5 Technologies to secure the drug supply: A. Authentication Technology: There is a considerable debate where FDA has initiated proposals to the industry to secure our medicinal drug products from counterfeit practices in the drug supply chain. These proposals are listed below: a. Whether to incorporate at least two types of anti-counterfeiting technologies into the packaging and labeling of all drugs, at the point of manufacture, with at least one of those technologies being covert (i.e., not made public, and requiring special equipment or knowledge for detection) starting with those products at high risk of being counterfeited and where the introduction of counterfeit product poses a serious health risk; Counterfeit Neupogen No active ingredient b. Whether to incorporate a taggant, chemical marker, or other unique characteristic(s) into the manufacturing process of all drugs that is only identifiable with the use of sophisticated analytic techniques starting with those products at high risk of being counterfeited and where the introduction of counterfeit product poses a serious health risk; GMP Pharma Institute Private Limited, Dehradun 5

6 MA-03 PCIDs into Solid Oral Dosage Forms January2012 Field Test Kit Marker Detection - Add tablet to liquid in vial - Shake briefly - Add several drops to test device - Read results: 1 line is authentic 2 lines is counterfeit c. Whether to issue FDA guidance concerning the appropriate use of anticounterfeiting technologies and the application and review process for labeling and packaging changes or product changes such as incorporation of taggants, chemical markers, or other unique characteristic(s) into the product for the purpose of product authentication. Pen Revealable Covert Inks Chemically reactive markers within the ink are revealed using appropriate developing reagents. Fixed or variable information can be applied using conventional printing equipment. Phosphors Phosphors collect and store light, then release it only when exposed to light of specific wavelengths. Very high levels of security can be engineered into products using this technology. GMP Pharma Institute Private Limited, Dehradun 6

7 B. Identification of Products likely to be counterfeited All products are at high risk for being counterfeited. Most of the comments FDA received supported the idea of developing criteria by which stakeholders could determine which products are likely to be counterfeited and/or developing a national list of products likely to be counterfeited based on these criteria. There was general agreement that the existence of state specific lists, each with its own regulatory requirements, could inhibit commerce and adversely affect the availability of drugs. C. Radio-frequency Identification (RFID) Technology RFID was cited as being the technology with the strongest potential for securing the supply chain but that it was not ready for widespread commercial use with pharmaceutical products. Many costs, potential benefits, and unresolved issues related to RFID were cited. The potential benefits included the ability to control inventory and conduct rapid, efficient recalls, while costs that could hinder the adoption of RFID included purchase of tags and other hardware, integration into existing information systems, and compliance with regulatory requirements (e.g., labeling, electronic records). Important unresolved issues included the need to develop standards and business rules for RFID, the need to address database management issues, and the need to determine the effect of RFID on product quality. Supporting Documentation What is the supporting documentation required? It is important to understand what is the supporting documentation required to address the proposed incorporation of PCIDs in solid oral dosage forms. This documentation includes documents to be submitted both by applicants proposing to incorporate PCIDs into new SODFs in an NDA or ANDA for initial approval of a drug product and by applicants proposing to incorporate PCIDs into SODFs as a post-approval change. GMP Pharma Institute Private Limited, Dehradun 7

8 In addition, as described in section-b below, FDA recommends that applicants proposing to incorporate PCIDs into SODFs as a post-approval change submit certain additional documentation. A. Documentation for Premarketing or Post-approval Regulatory Submission FDA recommends that applicants should include the relevant documents regarding incorporation of PCIDs into Solid Oral Dosage Forms. Following information is required to be submitted in appropriate sections of any premarketing or post approval regulatory submission proposing the incorporation of a PCID in a SODF: 1. Chemical composition (qualitative and quantitative composition) of the PCID. 2. Justification for selection and incorporation of the PCID. 3. Description of how the PCID is integrated into the design of the SODF. 4. Diagrammatic illustration showing the location of the PCID in the SODF. 5. Relevant physical-chemical attributes of the PCID (e.g., those relating to identity, strength, quality and purity) including those attributes that make the material useful as a PCID. 6. Specification for the PCID. 7. Information on the impurities that may be present in the PCID. 8. Justification for safety of the PCID including any toxicological assessment. 9. Information on product development pertaining to incorporation of the PCID. (Information should include any study conducted during development to assess compatibility of a PCID with other formulation components). 10. Description of manufacturing steps and controls associated with the incorporation of the PCID in the drug product. 11. Assurance and verification of quality, performance, and stability of the drug product containing the PCID. 12. A summary of a product quality and performance risk assessment associated with the incorporation of the PCID. The amount of information provided for a PCID will depend on its pharmacological and toxicological characteristics as well as the design of the SODF. For example, less information would be expected for a PCID, which is a permissible direct food additive, a food substance that is GRAS, or listed in the IIG, than for a novel PCID. GMP Pharma Institute Private Limited, Dehradun 8

9 B. Documentation for Post approval Regulatory Submission FDA recommends that applicants should include the relevant documents regarding Incorporation of PCIDs into Solid Oral Dosage Forms to be included for any Postapproval Regulatory Submission. A comparative assessment needs to be performed by the applicant for the product without the PCID and with the PCID. This assessment should necessarily include impurity profile, stability, and dissolution data. It is recommended to provide documentation regarding the assessments described below in the appropriate section of any post approval regulatory submission proposing the incorporation of a PCID in a SODF: a. Impurity profile assessment: The addition of PCID in a drug product calls for a thorough evaluation from a development perspective. The applicant should perform analyses to determine whether the impurity profile of the drug product has been altered by the addition of the PCID, either through the presence of new impurities or increased levels of previously detected impurities. The applicants can also follow the recommendation in International Conference on Harmonization guidance entitled Q3B (R2) Impurities in New Drug Products regarding the reporting, identification, and qualification thresholds, even if the PCID is a permissible direct food additive, a food substance. b. Drug Release Rates assessment: If the addition of the PCID to the SODF has the potential to significantly affect drug release rates, FDA recommends that applicants conduct evaluations of dissolution profiles. The applicant should perform dissolution testing using methods and apparatus specified in the approved application. Where applicable, the submission should include a statistical comparative assessment of multipoint dissolution profiles for the pre-change and postchange batches obtained in one or more dissolution media simulating physiologically-relevant conditions. GMP Pharma Institute Private Limited, Dehradun 9

10 The initial report of the change, whether in an annual report or supplemental application, should include the most current stability data, and the applicant should continue to provide updated data in subsequent annual reports. The applicant should also ascertain whether any analytical procedures should be revalidated as a consequence of adding the PCID. The applicant should use long-term and accelerated stability studies to evaluate impurity formation and the effect of the PCID on the dissolution profile. One should conduct such stability studies through the drug product expiration date, although the studies need not be completed prior to submission of the change. Reporting category for post-approval changes How to determine Reporting category for such changes? Applicants interested in incorporating PCIDs into SODF, post-approval, need to determine what will be the reporting category for such post-approval changes. Applicants who propose to incorporate a PCID into a SODF as a post-approval change should report the change in a Prior Approval Supplement (PAS) or Changes Being Effected supplement (CBE-30), or an Annual Report according to the recommendations described. Section-B below describes recommendations regarding revising the labeling of the SODF to indicate that a PCID has been incorporated. A. Reporting Categories The applicant should perform a risk assessment to determine the appropriate reporting category and type of drug product testing needed to evaluate the proposed change on a case-by-case basis, regardless of previous use of the same PCID in other SODF drug products. 1. Prior Approval Supplement A Prior Approval Supplement is submitted for major changes to the product or process. A major change would have a substantial potential to adversely affect the identity, strength, quality, purity, or potency of a drug product. Thus, if the incorporation of a PCID into a SODF would have a substantial potential to have an GMP Pharma Institute Private Limited, Dehradun 10

11 adverse effect, the applicant may not market the drug product with the PCID unless a prior approval supplement is submitted and approved. In such circumstances, FDA encourages the applicant to contact the appropriate clinical review division for guidance on how to provide a toxicological assessment to the Agency. 2. Changes Being Effected Supplement A Changes Being Effected Supplement is submitted for moderate changes to the product or process. A moderate change would have a moderate potential to adversely affect the identity, strength, quality, purity, or potency of a drug product. Thus, if the incorporation of a PCID into a SODF would have a moderate potential to have an adverse effect, the applicant should submit a CBE-30 supplement at least 30 days before distribution of the drug product made using the change. Examples of situations in which an applicant should submit a CBE-30 include, but are not limited to, a situation in which the applicant proposes to add a PCID (which is not a PCID for which a prior approval supplement should be submitted) to a core section of the SODF or to a section of an SODF-MR that contains a release-controlling excipient. 3. Annual Report An Annual Report is submitted for minor changes to the product or process. A minor change would have a minimum potential to adversely affect the identity, strength, quality, purity, or potency of a drug product. Thus, if the incorporation of a PCID into a SODF would have a minimum potential to have an adverse effect, the applicant should submit information in the next Annual Report even after distribution of the drug product made using the change. B. Labeling Applicants should review the statute and all regulations to determine how the incorporation of a PCID may impact the labeling of their drug. FDA does not intend to object if ingredients used as PCIDs are not included in the list of ingredients in a drug's labeling. If the incorporation of a PCID changes the identifying characteristics (e.g., color) of the SODF, then the labeling must be revised in accordance with 21 CFR (c)(4). All labeling changes are subject to the submission and approval requirements under 21 CFR GMP Pharma Institute Private Limited, Dehradun 11

12 The specific approach to assuring the protection from counterfeit drugs includes the following critical elements: 1. Implementation of new technologies a. Common use of reliable track and trace technology b. Authentication technologies 2. Adoption of electronic track and trace technology 3. Adoption and enforcement of strong, proven anti-counterfeiting laws and regulations 4. Increased criminal penalties 5. Adoption of secure business practices 6. Development of a system that helps ensure effective reporting 7. Education of consumers and health professionals 8. Collaboration with foreign stakeholders to develop strategies to deter and detect counterfeit drugs globally GLOSSARY Counterfeit drugs: Counterfeit medicines are deliberately and fraudulently mislabeled with respect to identity and/or source. Use of Counterfeit medicines can result in treatment failure or even death. Counterfeit drugs are produced and sold with the intent to deceptively represent its origin and authenticity or effectiveness. PCID: PCID stands for Physical Chemical Identifiers. It is a substance or combination of substances possessing a unique physical or chemical property that unequivocally identifies and authenticates a drug product or dosage form to thwart counterfeiting. ANDA: Abbreviated New Drug Application. This is an application for a U.S. generic drug approval for an existing licensed medication or approved drug. The ANDA is submitted to FDA's Center for Drug Evaluation and Research, Office of Generic Drugs. CDER: This is the one of the important FDA s center, Center for Drug Evaluation and Research. GMP Pharma Institute Private Limited, Dehradun 12

13 SODF: Solid Oral Dosage Form. This includes tablets, capsules, ointments, parenterals, granules, and others. GRAS: "GRAS" is an acronym for the phrase Generally Recognized As Safe. FDA recommends use of those permissible direct food additives, food substances that are listed in GRAS. IIG: Inactive Ingredient guideline. These are the Inactive Ingredients in FDA approved drugs. Certain substances could present a toxicological risk if they are used at a level in excess of the limitations provided in the relevant IIG listing. CFR: Code of Federal Regulation is the codification of the general and permanent rules published in the Federal Register by the executive departments and agencies of the Federal Government; it is divided into 50 titles that represent broad areas subject to Federal regulation. 21 CFR is the code for US FDA. NDA: New Drug Application. Every new drug requires approval of NDA before U.S. commercialization. The NDA application is the vehicle through which drug sponsors formally propose that the FDA approve a new pharmaceutical for sale and marketing in the U.S. Impurity Profile: These are the identified and unidentified impurities present in a typical batch of API (Active Pharmaceutical Ingredient) produced by a specific controlled production process. PAS: A Prior Approval Supplement is submitted for major changes to the product or process. A major change would have a substantial potential to adversely affect the identity, strength, quality, purity, or potency of a drug product. CBE-30: The CBE (Changes being effected) 30 serves as notification to the FDA that a change will be taking place in the process, analytical techniques / technologies, packaging, etc. of a given product, for which the Agency has 30 days to respond prior to implementation. This is usually a minor change which does not impact final product quality. Annual Report: An Annual Report is submitted for minor changes to the product or process. A minor change would have a minimum potential to adversely affect the identity, strength, quality, purity, or potency of a drug product. GMP Pharma Institute Private Limited, Dehradun 13

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