CHANGE CONTROL MANAGEMENT FOR A STABILITY PROGRAM

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1 Potential Changes and Minimizing the Impact of Registration CHANGE CONTROL MANAGEMENT FOR A STABILITY PROGRAM Kim Huynh Ba Eecutive Director PHARMALYTIK Biography Kim Huynh Ba has over 25 years of eperience in analytical development, project management, strategic drug development and stability sciences. She currently is the Eecutive Director of Pharmalytik ( where she provides consulting and training services to pharmaceutical companies, including companies operating under FDA s Consent Decree on harmonization and optimization of analytical best practices since In , she took a 2 year leave to join the U.S. Pharmacopeia (USP) as their Director of Pharmacopeial Education Department, where she invigorated their education programs worldwide. Her clients range from large pharmaceutical companies to small contract laboratories in U.S. and also internationally. Kim is an Adjunct Professor at Temple University School of Pharmacy, Widener University and Illinois Institute of Technology (IIT) teaching Pharmaceutical Analysis, cgmps, ICH guidelines and Quality Audit graduate courses. She is also a short course instructor on cgmp compliance and quality topics for several global organizations such as American Chemical Society (ACS), American Association of Pharmaceutical Scientists (AAPS), Pittsburgh Conference, and many other international training groups. Kim is a member of the USP Council of Eperts ( ), where she chairs the Chemical Medicines IV Epert Committee. She is also a member of the Impurities of Drug Products Epert Panel and Food Adulteration Epert Panel. She was the Chair of the USP Good Documentation Practices (GDP) Epert Panel. She is an active member of AAPS and an Alternate Councilor of ACS Delaware Section. She serves on steering committees of AAPS Stability, CMC, and Pharmaceutical Impurities Focus Groups. She is a member of the Eecutive Committee of Governing Board of Eastern Analytical Symposium (EAS) and was their 2013 President. She is also a member of PQRI Stability Shelf Life Committee. Kim has authored numerous technical publications, and book chapters. She is the editor of 2 well known Stability books: the Handbook of Stability Testing in Pharmaceutical Development: Regulations, Methodologies and Best Practices (2008) and Pharmaceutical Stability Testing to Support Global Markets (2010). She is also working on a manuscript for the Analytical Chemistry: An Introduction to Pharmaceutical GMP Laboratory, that is epected to be available in Kim can be reached at kim.huynhba@pharmalytik.com (copyright) 1

2 Overview 1. Managing changes as part of Quality Systems Regulatory epectations to support changes Monitoring Stability as a critical quality attribute Managing changes to stability program 2. Elements of a change control process Preparing changes Managing changes Reinforcing changes 3. Different types of changes affecting stability profile Formulation development Selection of packaging system Analytical procedure API and raw materials Warning Letter Failure to establish and maintain adequate procedures for validating device design as required in 21 CFR (g). For eample, there were four revisions of the [red acted] shelf life environmental design verification protocol. The first revision was never used, the second revision was used at the start of the validation and the third revision was used at the completion of the real time aging of the units and the verification/validation of the tests. The final revision requires that the real life units be tested at and y months. The testing that was done was done at v and w months, instead of and y months. The testing report was reviewed and accepted by a design cross functional group which included the project manager, regulatory affairs, quality assurance and research and development. QSR; Design Controls; Design Validation 2 Jul 2010 US medical device company (copyright) 2

3 Change Control System CFR Complete record shall be maintained of any modification of an established method employed in testing. Such records shall include the reason for the modification and data to be verified that the modification produced results that are at least as accurate and reliable for the material being tested as established method. ICH Q7A A formal change control system should be established to evaluate all changes that could affect the production and control of the intermediate or API. Written procedures should provide for the identification, documentation, appropriate review, and approval of changes in raw materials, specifications, analytical methods, facilities, support systems, equipment, processing steps, labeling and packaging materials and computer software. WHY DO WE NEED TO CONTROL THE CHANGES? (copyright) 3

4 Change Control Change control is another well known CGMP concept that focuses on managing change to prevent unintended consequences. The CGMP regulations provide for change control primarily through the assigned responsibilities of the quality control unit. Certain major manufacturing changes (e.g., changes that alter specifications, a critical product attribute or bioavailability) require regulatory filings and prior regulatory approval (21 CFR , 514.8, and ). Guidance for Industry Quality Systems Approach to Pharmaceutical cgmp Regulations, Sep Change Control Effective change control activities (e.g., quality planning and control of revisions to specifications, process parameters, procedures) are key components of any quality system. In this guidance, change is discussed in terms of creating a regulatory environment that encourages change towards continual improvement. This means a manufacturer is empowered to make changes subject to the regulations based on the variability of materials used in manufacturing and process improvements resulting from knowledge gained during a product s lifecycle. Guidance for Industry Quality Systems Approach to Pharmaceutical cgmp Regulations, Sep (copyright) 4

5 Change Management Process Preparing for change Define your change Prepare your team to evaluate and review the change Develop your model & Classify your change Managing Change Develop plan, identify the impacted systems/documents Conduct the Risk Assessment Change Approval Take actions & Implement plans Reinforcing Change Collect and analyze data Verify change implementation Identify gaps and manage resistance, if needed. Monitoring and continuous improvement Drug Product Stability Stability Testing is required by cgmp Stability is a Critical Quality Attributes Stability Data used to set product specifications Stability is to establish a storage condition for labeling Stability is to establish an epiry for commercialization (copyright) 5

6 STABILITY TESTING Required by cgmp Regulations (21 CFR ) and global regulations (ICH Q1A(R2), WHO, ASEAN, etc.) FDA defined Stability is a Critical Quality Attribute (CQA) To establish a storage condition for labeling To establish an epiry for commercialization Stability characteristics of API and DP rely heavily on end Product Testing Typically, Quality is measured instead of designed Factors impacting Drug Stability Stability of the Active Pharmaceutical Ingredient (API) from storage Interaction between the API and ecipient Formulation Development Selection of dosage form and Manufacturing process of drug product Selection of container closure packaging system Effect of storage (temperature, humidity and light) Selection of marketing image Handling of the finished products (copyright) 6

7 Purpose of Stability Testing Stability studies are used as quality assessment tool to ensure the changes have no adverse impact on the quality of the product over its epiry The purpose of stability testing is to provide evidence on how the quality of a drug substance or drug product varies with time under the influence of a variety of environmental factors such as temperature, humidity and light. Stability testing permits the establishment of recommended storage conditions, retest periods, and shelf lives. ICH harmonized Tripartite Guideline for Stability Testing of New Drug Substances and Products [ICH Q1A] WHAT CHANGES SEEN DURING STABILITY? * FOR DEVELOPMENT PRODUCTS * FOR COMMERCIAL PRODUCTS (copyright) 7

8 CMC Changes impact Stability Profile Stability Testing Formulation Development Process Development Packaging Development Method Development API * Quality of a drug substance or drug product in a packaging system must remain within established specifications throughout its retest/epiry. * Specifications = identity + strength + quality + purity Why changes? Heat Humidity Light Pharmaceutical Product Stability studies are used as quality assessment tool to ensure the changes have no adverse impact on the quality of the product over its epiry. (copyright) 8

9 Change of API & Formulation API Selection: Physical: Polymorphic forms, Dissolution, Resuspendability, Aggregation Chemical: Potential degradation products, Degradation mechanism Chirality (as applicable) Impurities control Change of Formulation Eternal factors (Light, Temperature, Humidity, ph) stress studies Accelerated Studies: 40C/75%, 50C Other special conditions thermal cycling freeze-thaw (copyright) 9

10 Change of Process Ecipient Compatibility Studies Evaluating drug-ecipient interactions (Q8) For liquids: buffer, ph For solids: Formulation selection Ecipient supplier Process selection Packaging Changes Consider information from API selection from Formulation Development from Process development Link to mechanisms of instability to determine the packaging requirement (protected from light or moisture, etc.) Effect of storage conditions Effect of container orientation Potential for leachables and etractables (copyright) 10

11 Analytical Changes Change of analytical technology (UV to HPLC) Change of test method (different columns, NPLC vs RPLC) Change of sample preparation (solvent, buffer, etraction procedure) Addition of new specified degradation products (same specs) Revised method with new specified degradation products Change specifications (wider the specs or shift the specs) Mostly are prior approval or CBE-30 Typically doing both or continue ongoing studies Impact of Instability Safety and efficacy of drug product are established during development via clinical studies If drug product stability changes beyond established acceptance criteria, established safety and efficacy are no longer applicable. Change of Drug Stability would risk patient safety Quality of finished products decrease (Product is unsafe or ineffective) Potential sub-potent or over-dose products Potential toic unknown impurities Modification of content uniformity/bioavailability Loss of container-closure or microbial integrity Loss of cosmetic or functional aspects Uncontrolled process product investigation product recalls cgmp violations consent decree criminal prosecution (copyright) 11

12 Severity of Impact Nature and Compleity of the Drug Product i.e. Dosage form Nature and Compleity of the Changes One change or multiple changes Simple change or comple changes Important to be able to bridge the data before and after changes to evaluate stability of the product Major impact on timelines and resources Stability Requirements 21 CFR : There shall be a written stability testing program to assess the stability of drug products. 21 CFR 58.31(d): Assure that test and control articles or mitures have been appropriately tested for identity, strength, purity, stability, and uniformity, as applicable. ICH Q7A: GMP for API: Requires stability monitoring of APIs: A documented, on-going testing program is needed to monitor the STABILITY of APIs; results should be used to confirm appropriate storage conditions and retest or epiry dates. (copyright) 12

13 Stability Studies Through Product Life Cycle 1. Studies supporting product development Product/Formulation design Manufacturing process Container/closure system 2. Studies supporting registration or marketing application Provide evidence to support Epiration dating periods Label recommendations for storage conditions 3. Studies monitoring product quality Verify the successful eecution of the development 4. Studies supporting post approval changes Make critical changes Typical Changes Leading to Risks Not meeting current product specifications or compliance standards Survival Need for continuous improvement Adaptation Process changes Method changes New Science and/or New Technology New scientific or clinical findings Complying with regulatory or compendial changes Changes caused by Desired Product improvement Changing of clinical/market needs Cost reduction Materials availability (New supplier/vendor) New sites/new facilities Market epansion (copyright) 13

14 Impacts to Product Quality Change of Drug Stability would risk patient safety Quality of finished products decrease (Product is unsafe or ineffective) Potential sub potent or over dose products Potential toic unknown impurities Uncontrolled process product inves ga on product recalls Costly Bad reputa on Lost of customers Compliance Standards cgmp violations 483 s Observa on Warning Le ers consent decree criminal prosecution Lost of License Lost of Registration Lost of customers Impact to Stability Program Major changes Start New Studies Moderate changes Continue Ongoing studies and Start New Studies Stability Program Minor changes Continue Ongoing studies (copyright) 14

15 Change Control Process Evaluate the changes What is the reason? What needs to get done? Risk Assessment Is the impact of the change significant? Can it harm a person? Can it hurt the company? Is there a regulatory concern? Plan the Effort Was it the result of a problem? Was it an update? Is it a high priority, visible project? Risk Assessments Use different tools to assess readiness to change. Assess the scope of the change How big is this change? How many people/products are affected? Is it a gradual or radical change? Assess the readiness of the impact by the change What is the value system and background of the impacted groups? How much change is already going on? What type of resistance can be epected? Assess the strengths of your change management team. Assess the change sponsors and take the first steps to enable them to effectively lead the change process. (copyright) 15

16 Severity of Impact Nature and Compleity of the Drug Product i.e. Dosage form Nature and Compleity of the Changes One change or multiple changes Simple change or comple changes Important to be able to bridge the data before and after changes to assess stability of the product Major impact on timeline and resource Quality By Design Concept: Know what we want Design Space Knowledge Space Control Space (copyright) 16

17 QbD Concept Multi variable CQA 1 Knowledge Space CQA 2 Optimum Design Design Space CQA 3 QbD Concept Impact of Changes CQA 1 Knowledge Space CQA 2 Optimum Design Design Space CQA 3 (copyright) 17

18 QbD Concept Legacy Product CQA 1 Knowledge Space CQA 2 Optimum Design Design Space CQA 3 Principles of Risk Management The evaluation of the risk to quality should be based on scientific knowledge and ultimately link to the protection of the patient The level of efforts, formality and documentation of the QRM should be commensurate with the level of risk ICH Q9 (copyright) 18

19 Risk Assessment For a scale from 1 to 10 How likely is it to happen? Likelihood of Detection? Severity of the impact? X Probability Detection Severity Risk Areas of Risk to be identified System Risk Quality Risk Process Risk Product Risk Facility & people Organization Process operations Safety & efficacy Interfaces, operators risk, environment, components (equipment, IT, design elements) Quality systems, controls, measurements, documentatio n, regulatory compliance Quality parameters Quality attributes: measured data according to specifications (copyright) 19

20 CONCLUSION Drug Development is a Process - Changes are inevitable; mostly for continuous improvement. Major changes can derail on-going stability studies and cause delay. Anticipate change and plan in advance. Get input early from stake holder (process, formulation, packaging). Use Science/Data to justify and bridge the changes. Communicate with Regulatory Agencies. Have a solid change control process. Balance the impact of changes (safety, time, resources & money) Culture Changes Industry: More collaboration among business units and across disciplines to apply Quality Systems throughout Less regulatory burden and enhance efficiency Regulatory: Integrate review, inspection and compliance (across disciplines) Implement Quality Systems review Higher assurance of product quality Patients: Higher assurance of product availability and quality (copyright) 20

21 References K. Huynh-Ba, ed., Pharmaceutical Stability Testing to Support Global Markets, Springer, S. Baertschi, K. Alsante & R. Reed, ed., Pharmaceutical Stress Testing: Predicting Drug Degradation, 2 nd ed, Informa, G. Buehler, Regulatory Perspectives on Product Stability, AAPS 2007 Workshop, Bethesda, MD. L. Wu, Understanding Pharmaceutical Quality By Design, presented at AAPS Webinar. Handbook of Stability Testing in Pharmaceutical Development: Regulations, Methodologies and Best Practices, K. Huynh-Ba (ed.), Springer Publisher, Nov Pharmaceutical Stability Testing to support Global Markets, K. Huynh-Ba (ed.), Springer Publisher, Jan Handbook of Stability Testing in Pharmaceutical Development: Regulations, Methodologies and Best Practices, K. Huynh-Ba (Ed.), 2008, Springer Publishing. - Post Approval Changes Doing the right thing STABILITY PROGRAM Thank you! Any Question? KIM HUYNH BA Kim.huynhba@pharmalytik.com (copyright) 21