CM&C Inspections The Pre-Approval Inspection (PAI) in the US 27 May 2010

Introduction Introduction u FDA inspections are in compliance with US regulatory requirements u Pre-approval inspections are necessary in order to launch an NDA product in the U.S. u All aspects of the manufacturing phases must conform to cGMPs. u cGMP compliance must be addressed in preparation for a PAI cGMP: current GMP 2

What is a PAI u A PAI focuses on a particular product u All quality systems associated with the product will be assessed during the PAI u e.g., qualification and validation of equipment, process validation, etc. u It is an activity or pursuit by FDA to ensure GMP compliance around this product u It is a review of data to ensure the products safety and efficacy 3

What is a PAI u Evaluates facilities to ensure that the company is capable of manufacturing product pursuant to the information in the application and in accordance with GMP regulations u Verifies of the authenticity and accuracy of the data submitted in the application u Determines if adequate controls are in place to manufacture the product consistently 4

Objective of a PAI u A PAI will assure that the facilities listed in the application are in compliance with cGMPs : u Manufacturing u Control facilities (adequate analytical controls) u Process development u Package u To ensure that these facilities adhere to the relevant sections of 21 CFR (210, 211, 600, 820) u To verify the accuracy and authenticity of data contained in the application 5

Timing of a PAI u The time from submission to scheduling a PAI has been considerably reduced in the last few years u Plants must be ready for inspection at the time of NDA filing u A PAI is scheduled during the review cycle of NDA application 6

Preparing for the PAI u Preparation of a PAI begins before NDA submission–(at least 9-12 months of preparation) u Create a PAI Team u Identify the members of the Team u Define each of their responsibilities u Identify lead PAI coordinator u Designate the proper person or persons that will accompany the FDA inspector(s). 7

Preparing for the PAI u Create a PAI Team u Prepare a list of all the Team members u Train and prepare the Team u Conduct a gap analysis before FDA visits u Identify weaknesses, threats, opportunities for improvements u Understand the expectations of FDA 8

Preparing for the PAI u Mock Audit - It is useful and very beneficial to a company to have carried out a mock FDA audit or inspection. u By role acting, company personnel get acclimated to responding and dealing with FDA u Identify weak spots u Allows preparation of site(s) for the inspection 9

Documents for an Inspection (1) u History of business u Organizational chart u Biographical data of all the Team members u Schematic of the manufacturing process u Floor plan of the facility(s) u Flow diagram for personnel, material, equipment, products, waste u Diagram of the water system u Position and responsibility of key officials u Complaint file u Related firms and outside warehousing 10

Documents for an Inspection (2) u List of products manufactured u Pest control u Samples of: u Labels, labeling and literature u Quarantine tags u Release tags u Employ training manual u Records of past inspections u Other government inspections u Value and volume of production u Company inspection policies u Business hours u Company Annual Report 11

Documents for an Inspection (3) u Transportation records u Purchase orders u Training programs/records u Other documentation to substantiate observations 12

Documents for an Inspection (4) u Facility and systems validation documents (e.g., water system, HVAC) u Stability protocols, sufficient stability data to support the expiration date u Analytical methods against the regulatory submission u Batch records for stability lots, biobatch lots for manufacturing of the bulk API u Validation protocols u Cleaning u Computer u Method validation 13

Documents for an Inspection (5) u Development report u Equipment installation and operational qualification data for each piece of equipment in the submission u Validation data for any reprocessing filed in the submission u Change control u Investigations and deviations u Control of documents u SOP’s from receipt of raw material to warehouse distribution 14

Documents for an Inspection (6) u Standard Operating Procedures u It is important and incumbent upon the company that policies and procedures are in place to cover all aspects of manufacturing u SOP’s – well written and established SOP’s that address the handling of FDA inspections, 483’s and Warning Letters and how to respond to deficiencies u SOP’s to support all functions should be ready and available 15

Beginning the Inspection u Investigator will ask to speak with the most senior person u FDA Investigator must present credentials and a Form FDA 482 u FDA inspector will be escorted to the FDA Audit Room 16

Beginning the Inspection u Identify two rooms for the PAI u FDA audit room where the audit will be held u ‘War’ Room” where all the documents are organized for ease of retrieval 17

18 Agency Investigators Scribe to record everything Facilitator/Escort Organization of all the Relevant Document Facilitator for Document Retrieval, Copying Facilitators War RoomFDA Audit Room Beginning the Inspection

Areas and Information Subject to an Inspection (1) u Quality u Personnel Training u Personnel Qualifications and Experience u Production and Manufacturing Operations u Processes u Equipment u Facilities u Analytical laboratories that generated data included in the submission u Analytical testing 19

Areas and Information Subject to an Inspection (2) u Records and Documents u Purchasing u Material handling u Laboratory Controls u Packaging components u Packaging operations u Labeling operations u Validations 20

Areas and Information Subject to an Inspection (3) u Materials receipt u Production u Purifications u Storage and shipping u Quality control laboratories u Batch records and supporting documents 21

Areas and Information Subject to an Inspection (4) u Test records for each of these batches u Validation documents u Failure investigations u Stability programs u Training records u Vendor audit plan 22

FDA can not review or obtain u Financial data u Sales u Data u Pricing data u Personal data (other than qualifications of personnel) u Research data 23

General FDA Concerns u Facility flaws that can cause product contamination u Water systems u Poor documentation regarding: u Equipment qualification u Technology transfer u Change control u SOPs u Good laboratory practices 24

25 The Exit Meeting u Attended by key management personnel u FDA inspector may leave a 483 that includes citations

Annotations to the 483 u Reported corrected, not verified u Corrected and verified u Promised to correct u Under consideration 26

27 The Exit Meeting u Ask inspector if he will recommend the approval of the site that was inspected u The coordinator or lead person should make some closing remarks 27

28 Response to FDA observations u Send a response to the 483 to the FDA District Office within 2 weeks after completion of the inspection u Shows good intentions and seriousness u Minimizes further regulatory action u Each observation should be addressed in detail with supporting documentation u Provide evidence to FDA that corrective actions have been implemented u Avoid those dreaded words………………….

29 Conclusions u Doing it right the first time u Understanding your commitments and embracing all responsibilities u Documenting everything u Providing strict accountability