CMC Biologics – Copenhagen Site Cleaning Strategy of Multipurpose Equipment in GMP facilities Evete Mawlad, 20Apr2016 CONFIDENTIAL

CMC Biologics – Copenhagen Site Introduction of CMC Biologics Copenhagen Facility Cleaning strategy 22 September 2018 CONFIDENTIAL

Cleaning Strategy CONFIDENTIAL

Cleaning Strategy Definition.. What are the requirements? Why perform Cleaning…? What is the cleaning process/flow? Overview of Cleaning Strategy Generic Cleaning Method - Clean-in-place (CIP) FDA guideline for Process Validation Cleanability Risk Assessment Support systems Campaign Rationales New EMA guideline Acceptance criteria in CMC CPH today Validation vs Verification Cleaning Validation vs Verification Cleaning Validation ….. Hold Time Continually documentation- and evaluation of the cleaning process efficiency 22 September 2018 CONFIDENTIAL

The definition of Cleaning Validation The process of removing contaminants from process equipment and monitoring the condition of equipment such that the equipment can be safely used for subsequent product manufacturing Dustin A. LeBlanc The process of providing documented evidence that the cleaning methods employed within a facility consistently controls potential carryover of product (including intermediates and impurities), cleaning agents and extraneous material into subsequent product to a level which is below predetermined levels in the context of API manufacture 22 September 2018 CONFIDENTIAL

The definition of Cleaning Validation…. continue Documented evidence that an approved cleaning procedure will consistently reduce active pharmaceutical ingredients (API), process residues, cleaning agents and microbial residues from product contact equipment surfaces to acceptable levels for the processing of drug products FDA; Guide to Inspections Validation of Cleaning Processes 22 September 2018 CONFIDENTIAL

Requirements & guidelines Code of Federal Regulations PART 211 --CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS, Subpart D – Equipment (Sec. 211.67): (a) Equipment and utensils shall be cleaned, maintained, and, as appropriate for the nature of the drug, sanitized and/or sterilized at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements. PART 111 --CURRENT GOOD MANUFACTURING PRACTICE IN MANUFACTURING, PACKAGING, LABELING, OR HOLDING OPERATIONS FOR DIETARY SUPPLEMENTS Subpart D--Equipment and Utensils (Sec 111.27) (d) You must maintain, clean, and sanitize, as necessary, all equipment, utensils, and any other contact surfaces used to manufacture, package, label, or hold components or dietary supplements. 22 September 2018 CONFIDENTIAL

Requirements & guidelines…continue Code of Federal Regulations PART 820 -- QUALITY SYSTEM REGULATION Subpart G – Production and Process Controls (Sec. 820.70): (e) Contamination control: Each manufacturer shall establish and maintain procedures to prevent contamination of equipment or product by substances that could reasonably be expected to have an adverse effect on product quality. Guide to Inspections of Validation of Cleaning Processes (1993) 22 September 2018 CONFIDENTIAL

Requirements & guidelines…continue EudraLex - Volume 4 Good manufacturing practice for Medicinal Products for Human and Veterinary Use Annex 15: Qualification and Validation, 30Mar2015 Sec. 10 Cleaning validation: Cleaning validation should be performed in order to confirm the effectiveness of any cleaning procedure for all product contact equipment. Pharmaceutical Inspection Convention (PIC/S), Recommendations on…Cleaning Validation(2007) Pharmaceutical products and active pharmaceutical ingredients (APIs) can be contaminated by other pharmaceutical products or APIs, by cleaning agents, by micro-organisms or by other material (e.g. air-borne particles, dust, lubricants, raw materials, intermediates, auxiliaries). In many cases, the same equipment may be used for processing different products. To avoid contamination of the following pharmaceutical product, adequate cleaning procedures are essential. 22 September 2018 CONFIDENTIAL

Requirements & guidelines…continue WHO Technical Report No. 937: WHO Supplementary Guidelines on GMP (Annex 4 ): Validation (2006) Appendix 3, Cleaning validation: 1.4 The objective of cleaning validation is to prove that the equipment is consistently cleaned of product, detergent and microbial residues to an acceptable level, to prevent possible contamination and cross-contamination 1.6 Cleaning validation should be considered important in multiproduct facilities and should be performed among others, for equipment, sanitization procedures and garment laundering. 22 September 2018 CONFIDENTIAL

Requirements & guidelines…continue And more…… FDA Guidance for Industry Process validation: General Principles and Practices (January 2011, Revision 1) ICH Q7 – Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients. November 2000. PDA Technical report No. 29, Points to Consider for Cleaning Validation PDA Technical report No 49, Points to Consider for Biotechnology Cleaning Validation (2010) 22 September 2018 CONFIDENTIAL

Why perform Cleaning Validation? The reasons are: The FDA/EMA/DHMA or any other agencies won’t approve my/your product Job Security QA said so… Because it is fun?  22 September 2018 CONFIDENTIAL

Why perform Cleaning Validation?....continue It is regulatory requirement in pharmaceutical product manufacture the concern is the same-assurance that equipment is clean and that product quality and safety are maintained To check the effectiveness of the cleaning procedure for equipment’s used in manufacturing of the Drug Product T o verify for removal of Previous Batch, Cleaning Agents Residue and Potential Microbial Contaminants It assures from an internal control and compliance point of view for the quality of product. 22 September 2018 CONFIDENTIAL

Why perform Cleaning Validation?....continue In 1988, FDA had its first major experience with cross contamination traceable to inadequate cleaning and cleaning validation. An API supplier of Cholestyramine Resin recall the product, due to contamination with low levels of intermediates and degradants from the production of agricultural pesticides. This cross-contamination attributed to drums used to recover solvent from agricultural pesticides manufacture at another location. The drums were not properly cleaned leading to agricultural pesticides entering the API manufacturing process. 22 September 2018 CONFIDENTIAL

When to perform Cleaning Validation…? New product (reg. requirement) Cleaning agent modification/change Critical change in a cleaning procedure Equipment modification Critical change in formulation 22 September 2018 CONFIDENTIAL

What is the cleaning process/flow? Batch A Manufacturing Batch A Clean – (Line ChangeOver) Batch B Manufacturing Batch B Batch X Manufacturing Batch X Prod A Manufacturing Prod A Clean – (ChangeOver) Prod B Manufacturing B Prod X Manufacturing Prod X 22 September 2018 CONFIDENTIAL

Generic Cleaning Method - Clean-in-place (CIP) A typical CIP cycle consists of….: Pre-rinse with WFI (water for injection) or PW (purified water) Caustic solution is the main cleaning solution. Caustic solution re-circulation Intermediate WFI or PW rinse Acid solution wash used to remove mineral precipitates and protein residues. Final rinse with WFI or PW – rinses to flush out residual cleaning agents. Final air blow – used to remove moisture remaining after CIP cycle. 22 September 2018 CONFIDENTIAL

FDA guideline for Process Validation The cleaning strategy and requirements follows the FDA guideline for Process Validation covering the lifecycle approach for the three stages: Stage 1 – Process Design: The commercial manufacturing process is defined during this stage based on knowledge gained through development and scale-up activities. Stage 2 – Process Qualification: During this stage, the process design is evaluated to determine if the process is capable of reproducible commercial manufacturing. Stage 3 – Continued Process Verification: Ongoing assurance is gained during routine production that the process remains in a state of control 22 September 2018 CONFIDENTIAL

22 September 2018 CONFIDENTIAL

New EMA guideline “ Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities “ Effective date for the guideline : 1. June 2015 Implementation Plan: 1) New products: For medicinal products introduced for the first time into shared manufacturing facilities: 6 months from publication of this guideline. 2) Existing products: 1 year after publication of the guideline for manufacturers of products for human use including those who manufacture human and veterinary medicines using shared manufacturing facilities. 22 September 2018 CONFIDENTIAL

New EMA guideline …continue Permitted Daily Exposure (PDE) Equivalent to the earlier used : Acceptable Daily Exposure (ADE) Acceptable Daily Intake (ADI) Tolerable Daily Exposure (TDE) 22 September 2018 CONFIDENTIAL

New EMA guideline …continue Permitted Daily Exposure (PDE) where NOAEL is no-observed-adverse-effect level Weight Adjustment is the body weight (nomally for adult: 50 Kg) F1, F2, F3, F4 and F5 are safety factors pending of species, length of the studies, route of administration etc. – the factors can be between 1- 12 pending on which factor to estimate. 22 September 2018 CONFIDENTIAL

New EMA guideline …continue 22 September 2018 CONFIDENTIAL

Acceptance criteria in CMC CPH today Acceptance criteria is based on the principle for Maximum Allowable Carry Over (MACO) of active product A to product B: Acceptance criteria = (MACO/SA) x F mgC/dm2 where: Doses TDA - Dose of the former product (A) produced in the equipment MTDB - Maximum Dose of the upcoming product (B) to be produced in the equipment Batch size – BZB of the upcoming product (B) to be produced SF - set to 1000 - max 1/1000 of a dose will be entered in the next product dose Shared equipment surface – SA - is the equipment surfaces shared between the former product (A) and the new product (B) in dm2 F is the factors at different steps in the process etc. 22 September 2018 CONFIDENTIAL

Acceptance criteria in CMC CPH today…continue 22 September 2018 CONFIDENTIAL

Validation vs Verification Validation means confirmation by examination and provision of objective evidence that the particular requirements for a specific intended use can be consistently fulfilled. 21 CFR 820.3 (z) Verification means confirmation by examination and provision of objective evidence that specified requirements have been fulfilled. 21 CFR 820.3 (aa) 22 September 2018 CONFIDENTIAL

Cleaning validation/verification To avoid cross contamination from one production to another and build up between batches in a campaign Cleaning validation performed no later than during process Performance Qualification, PPQ for product for commercial production Parameters: Visual inspection Conductivity (cleaning agent residues) Bioburden Endotoxin TOC (rinse- and swab samples) 22 September 2018 CONFIDENTIAL

Cleaning Validation…Hold times Dirty Hold Time: Time between end of manufacture and beginning of cleaning. Why..? Manufactured product will become harder to clean (dries, bio-burden growth ) Clean Hold Time: Time from end of cleaning to beginning of manufacture Why..? Equipment may become re-contaminated during storage ( bio-burden , dust etc.) 22 September 2018 CONFIDENTIAL

Thank you for your attention...... 22 September 2018 CONFIDENTIAL