Regulatory Perspective on Assuring Ingredient Quality

Transcription

1 Regulatory Perspective on Assuring Ingredient Quality PQRI Conference December 15, 2009 Rockville, MD Steven M. Wolfgang, Ph.D., Acting Associate Director, Regulatory Science US Food and Drug Administration Division of Manufacturing & Product Quality Center for Drug Evaluation & Research

2 Economically Motivated Adulteration?

3 Outline Pharmaceutical Ingredients are Drugs! Globalization begets complexity and risk CGMP Regulations and Guidance Quality Management Systems for Acceptance of Drug Components Component Supplier Quality Management Modernization of Detection Systems

4 Definition of Drug FD&C Act (law) Section 201(g)(1) recognized in an official US compendium: United States Pharmacopeia, Homoeopathic Pharmacopoeia, or National Formulary intended to provide diagnosis, cure, mitigation, treatment, or prevention of disease intended to affect the structure or any function of the body intended for use as a COMPONENT of any article meeting above criteria EXCIPIENTS and APIs are DRUGS! ADDITIVES REMOVED DURING PROCESSING are DRUGS!

5 Regulatory Requirements for Supply Chain Members All parties which manufacture (includes testing), process, pack, or hold an ingredient or drug product are responsible for meeting CGMPs. Adulterated Drug Component = Adulterated Drug Product

6 Adulteration 501(b) drugs that purport to be official articles but do not meet the USP monograph requirement (public standard) 501(c) non-compendial drugs that do not meet the purported specification (proprietary standard) 501(d) substitution (EMA)

7 Adulteration - GMP 501(a)(2)(B) not manufactured (and held) in accordance with CGMP, as appropriate for the intended use 21 CFR 210/211 only apply to finished drugs Q9 (risk management) & Q10 (quality systems) Q7A is a nonbinding consensus standard (guidance) for APIs, generally accepted by regulators WW IPEC/PQG Excipient GMP is a nonbinding standard (guideline), aiming to achieve consensus standard status

8 Globalization of FDA Regulated Drugs 8

9 Number of Registered Sites If the Trends Continue Registered Domestic Sites Registered Foreign Sites Calendar Year

10 Diversion into and out of a Legitimate Supply Chain Addition, substitution Grey distribution channels Industrial Chemicals Legitimate Pharmaceutical Ingredient Manufacturing (GMP) Legitimate Drug Product Manufacturing (GMP) Legitimate Wholesale Distribution (GMP) Industrial Chemical as Pharm. Ingredient

11 Risk of Illicit Activity within Distribution Network Deliberate Acts of Deception Misrepresenting identity or source or an ingredient Fabricating data or falsely labeling an ingredient purporting it to be of suitable quality for drug use Adulteration by Substitution Economically Motivated Adulteration (EMA) even targets commodities: Drug ingredient raw material supply Melamine for crude protein (source of excipients) OSCS for heparin (source of API) Drug ingredient supply DEG for Glycerin or Polyol excipient

12 Complexity of Holding and Distribution Within Globalized Supply Chain Ingredient manufacturers primary manufacturing sites ingredient finishing sites Brokers and traders Forwarding, warehousing and bulk storage Distributors Repackaging and relabeling Certificates of analysis

13 Globalization Might Increase Exposure to Risk Lack of traceability Acceptance of information from supplier without adequate verification Incomplete Supply Chain oversight Limited FDA import screening of ingredients Risk of illicit activity within distribution network

14 Lack of Traceability and Acceptance of Information from Supplier Without Adequate Verification Lack of knowledge about manufacturing sites and distribution routes Over-reliance on Certificates of Analysis CoA not from original manufacturer CoA not adequately verified for accuracy Use of non-specific ID test Testing based on composite samples Reliance on vendor questionnaire without auditing 14

15 Incomplete Supply Chain Oversight Limited Supplier Quality Management System Inadequate qualification programs No written quality agreement Limited quality monitoring Limited Oversight of Remote Manufacturing Sites No on-site audit by drug product manufacturer Infrequent inspections FDA other regulatory authorities regional regulatory authority

16 Limited FDA Import Screening Drug Import Volumes Far Exceed Human Resources Which shipments should be scrutinized? Importation Documentation Provides limited traceability back to original manufacturer Excipient need not be declared as drug Excipient manufacturers are excluded from registration requirement

17 CGMP Requirements for Drug Manufacturers - 21 CFR Part 211 Control of Components (Subpart E) places burden on drug manufacturers to prevent adulterated ingredients from being used Representative samples (so as not to mask variation) Appropriate testing or examination Appropriate written specifications Verification of identity Allows use of CoA data for conformance to other specifications provided data is verified periodically for accuracy

18 Caveats Re: Reliance Upon CoA ID testing of drug components shall be specific (or must perform additional tests able to support unequivocal ID) Use of the vendor CoA applies only if there is ongoing verification of reliability of data and the absence of adulteration (not evident via specification) 501(a)(2)(B) requires that drug components are manufactured in accordance with appropriate GMP suitable controls in SC pertaining to manufacturing, processing, packing, holding, distribution change management system supported by periodic audits

19 Caveats: Sampling and Testing Homogeneity is a function of the drug component manufacturing process lot size does not necessarily equate to a batch factors associated with production rate or equipment size Cannot assume homogeneity within a lot among different containers within container Test results have no meaning unless sampling plan and degree of variation in each test attribute is known especially important for functionality related characteristics affects how one interprets the significance of data on CoA

20 Glycerin Guidance ceregulatoryinformation/guidances/ucm pdf Reiterates (d)(2) requirement for specific ID testing when not performing full USP testing testing has to be capable of detecting DEG applies to all recipients of Glycerin USP, not limited to those which formulate or compound Recommends intimate knowledge of the members of the supply chain traceability

21 Supply Chain GMP/GDP/Security All members of a drug component SC should have an adequate Quality System Manufacturing controls should provide added assurance that drug componentts are not adulterated and consistently meet the agreed-upon user requirements includes in-process and finished product testing Documentation should allow traceability of an excipient to its starting materials starting materials can be a significant source of variation or a point at which adulteration occurs Documentation should provide forward traceability Packaging and holding practices (transport, storage) should prevent deterioration and tampering

22 Caveats Re: Intended Use of an Excipient Comprehensively assessed and qualified for intended use Appropriate excipient specifications Appropriate excipient GMP e.g. for use in a sterile drug Functionality dosage form manufacturing of drug product Safety relevant to drug product level of exposure via DP route of administration patient population

23 Functionality Testing Building Quality into Drug Product Manufacturers should link quality of ingredient to performance as part of supplier qualification measurable physical or chemical attribute predicts performance desired performance is in context of drug product determine suitable ingredient compositions (ranges) for mixtures or polymers Design space - base development work on establishing range of use or predictive model? Use of signature to identify and verify helps assure functionality

24 Use of a 3 rd Party Audits Identifying credible 3 rd parties Impartiality Qualifications training and expertise of auditors Audits apply appropriate GMP guideline preferably developed via consensus among practitioners/users preferably based on principles of GMP and quality for drugs Supplier maintenance and monitoring, coverage Frequency of audit Scope of audit Quality management systems Systems applicable to preventing contamination and mixups Controls on supply chain security and integrity Corrective measures

25 USP s Role USP Ingredient Monograph Revisions improve specificity of ID and assay tests focusing on APIs/excipients at risk to EMA non-specific ID testing qualitative wet chemistry (color changes, formation of precipitate) indicators of presence of functional group non-specific assays N assays specifications that allow undetected adulterants to be present DEG/EG in polyols

26 USP Activities of Interest to FDA USP Ingredient Monograph Revisions specify modern instrumental methods to replace less sophisticated, less capable methods wet chemistry, acid-base titration TLC manufacturers and consortia can provide any assistance Outreach to improve global standards (e.g. MOU with China) to improve detection of adulteration in developing countries Overcoming challenges to develop reference standards for excipients that are not single molecular entity

27 Achieving Compendial Modernization Use of screening tools to flag suspect ingredients for further testing to determine if adulterated for suspicion of having deviated from the legitimate supply chain ID testing via pattern recognition comparison with spectral signature (library) for verification of authenticity only accept from approved manufacturing sites verification supports qualification of ingredient and its supplier verification supports acceptance of data on CoA

28 That s all folks!