Audits and Inspections

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1 Audits and Inspections Dr. Dirk Feldmann 06. November 2017

2 First we take measurements, then we take measures. TECHNICAL

3 Content Audits and inspections Types of audits EHS Challenges and chances Preparation and escort Frequent observations Data integrity

4 Audits and inspections Pharmaceutical companies are often audited or inspected by: Regulatory authorities of home country Notified bodies for medical devices Regulatory authorities of receiving countries Customers Parent company (Global audits) In addition self inspections are an important GMP tool and are mandatory for manufacturers of medicinal drugs

5 Audits and inspections Besides specific GMP inspections you might be faced with additional inspections like EHS (environment, health and safety) Local surveillance authorities (labor protection, saftey) Local environmental protection agencies Employers mutual insurance associations EMAS = Eco-Management and Audit Scheme Customers (Work-Place-Conditions-Audit)

EHS Environment, health and safety (EHS) is a discipline and specialty that studies and implements practical aspects of environmental protection and safety at work.

6 EHS Environment, health and safety (EHS) is a discipline and specialty that studies and implements practical aspects of environmental protection and safety at work. In simple terms it is what organizations must do to make sure that their activities do not cause harm to anyone. Regulatory requirements play an important role in EHS discipline and EHS managers must identify and understand relevant EHS regulations, the implications of which must be communicated to executive management so the company can implement suitable measures.

EHS From a health & safety standpoint, it involves creating organized efforts and procedures for identifying workplace hazards and reducing accidents and exposure to harmful

7 EHS From a health & safety standpoint, it involves creating organized efforts and procedures for identifying workplace hazards and reducing accidents and exposure to harmful situations and substances. It also includes training of personnel in accident prevention, accident response, emergency preparedness, and use of protective clothing and equipment.

8 Emergency and Alarm Plan TECHNICAL

9 Safety Instructions (Manufacturing) TECHNICAL

10 Safety Instructions (Laboratory) TECHNICAL

11 Boards with Operating Instructions TECHNICAL

12 Notice boards for work safety TECHNICAL

13 EHS From a health & safety standpoint, it involves creating organized efforts and procedures for identifying workplace hazards and reducing accidents and exposure to harmful situations and substances. It also includes training of personnel in accident prevention, accident response, emergency preparedness, and use of protective clothing and equipment. From an environmental standpoint, it involves creating a systematic approach to complying with environmental regulations, such as managing waste or air emissions all the way to helping site's reduce the company's carbon footprint.

14 Waste separation TECHNICAL

15 Key data TECHNICAL

16 Key data TECHNICAL

17 Audits and inspections Nevertheless audits and inspections offer a very good opportunity to: earn the trust of your local authorities regarding your compliance status and to convince and impress your customers.

18 Example: Bausch + Lomb Berlin plant Up to now Bausch + Lomb Berlin has conducted 5 GMP and 5 EHS audits in Notified body 1 International regulatory authorities 1 Customers 2 B+L global (annual audit) 1 Local regulatory authorities visit our plant every 3 years (expected in 2018)

19 Inspections by national authorities Africa = Europe = European Union = 55 countries 51 countries 28 countries

20 Mutual recognition agreements (MRAs) The European Union (EU) has signed mutual recognition agreements (MRAs) with third-country authorities concerning the conformity assessment of regulated products. Such agreements contain a sectoral annex on the mutual recognition of good manufacturing practice (GMP) inspections and batch certification of human and veterinary medicines. The EU has MRAs in place with: Australia, Canada; Israel, Japan, New Zealand, Switzerland, and the USA. (United States MRA has entered into force on November 1 st, 2017 but will be in transition phase until July 2019)

21 Audit announcement When you are informed of a planned visit to your facility you should start asking yourself many questions such as: Are we prepared? What do we need to do to get ready? Do we have the right attitude?

22 Audit announcement The right attitude is very important and determines the success or failure of the audit. Generally, as humans, we dislike inspections of any kind because we take it as criticism in what we have invested in. But remember: if you take criticism in a positive way, you will be able to comply with the set of regulations, improve your system, processes and more importantly, make your company grow.

23 Audit preparation Prepare your team and your staff by educating them about the process of an inspection. Train them how to interact with inspectors. You can prepare little business cards with helpful information and rules.

25 Audit preparation Prepare telephone lists with all numbers of employees and managers that will be needed during the audit. Each team member should have this list in his mobile phone directory.

26 Audit preparation Prepare check lists in each department with time frames and responsibilities. Managers have to update these lists and send them to their teams and must follow up of them. There should be sufficiant time to correct findings

: Manufacturing department packaging Due Date one week before audit o Control of all SOP print outs (version) o Control of all log books o Control of all balances (adjustment, calibration date) o

27 : Manufacturing department packaging Due Date one week before audit o Control of all SOP print outs (version) o Control of all log books o Control of all balances (adjustment, calibration date) o Control of all watches (uniform time) o Empty and clean all working places o Control of trainings status o Control of cleaning protocols To do each morning during audit o Control of all personal and material locks o Empty all dustbins o Check for and remove all lose paper and post-its

28 Audit preparation Build an audit core team and define escorts that accompany each inspector. Escorts are responsible for recording the following points during a plant tour: all discussed topics open points that have to be clarified documents that the inspectors would like to see later All escorts should be equipped with cameras and mobile phones. If the inspector takes a picture during the plant tour the escort should take the same picture from the same spot.

29 Audit preparation During the office part of the audit your escorts should protocol the following: all documents and SOPs that were requested and inspected possible discusssion points and findings open points that have to be clarified later Your escort should use all time slots of the inspector to deliver missing documents or to clarify open points.

30 Audit preparation Implement a back office The back office is resonsible to organizing all documents or to prepare and deliver copies. They are the extended arm of the QA managment during the audit/inspection. Back office should contact needed team members or collegues that will be inspected next.

31 Audit language Audit language should always be english or your native language Organize a translater (reliable) for important inspections (e.g. asia) Be careful! - Inspector might understand your local language

32 Important organizational aspects One or two meeting rooms for the audit Projector, flip chart, power connection, WIFI Transport for the inspectors (if necessary) Coffee, tea, beverages, snacks and meals Starting presentation (plant leader) Hand out or inspection folder Visitor gowning (shoe size of inspectors) Empty locker for visitors Dinner? If yes, who will be with the inspectors

33 During the audit Same participants in opening and closing meeting Keep the round small Have business cards at hand Make sure everyone is availiable

34 During the audit If the inspector ask for documents, hurry up to make them availiable Long waiting time will sow the seeds of doubt in your filing system If you are not sure about an answer tell the inspector that you have to clarify it Wrong answers can bring you into big trouble If you can fix a finding during the audit (e.g. change in SOP) it might safe you an observation

35 After the audit Inform all employees at the end of each audit / inspection day about the outcome Always respond to the audit report within the given time frame Corrective Actions and/or Preventive Actions (CAPA) will be needed for all observations Due dates for CAPAs should be set carefully and with sufficiant time for implementation

36 Typical findings during inspections Quality assurance (QA): Missing GMP training Missing medical GMP checks Missing initial training records Missing job description Insufficiant handling of deviations and CAPA Missing quality agreements Insufficiant Change Control handling Weakness in PQR preparation

37 Example: Deviation handling QC lab detected a missing letter in the variable data on a folding box of batch 217. Exp. Date: Lot: 2 7 Manufacturing department detected a missing/dropped printing type as root cause. Correction: 100% control of batch backwards until first complete unit is found. After rework the batch was released and the deviation closed. What could be the observation? You have not detected the real root cause Due to this a CAPA is missing

38 Typical findings during inspections Quality control (QC): Missing or inadequate method validation Missing technology transfer (R+D QC lab) Inadequate sample handling Inadequate storage of reagents and standards OOS procedure / OOS handling Environmental montoring system Media Fills Log books and labeling

39 Example: Sample handling Samples of finished goods are sent to QC lab by manufacturing team and put into an incoming box. Possible questions: How do you make sure that you received all samples? Quantity? Who delivered the samples at what time point? How are the storage conditions? Are the samples secured against unauthorized access?

40 Example: Sample handling TECHNICAL

41 Example: Sample handling TECHNICAL

42 Example: Sample handling TECHNICAL

43 Example: Storage of standards Reference substances are stored under different conditions. Room temperatue, refrigerator, freezer Possible questions: How do you control the storage conditions? Are the substances secured against unauthorized access? How do you manage the administration?

44 Example: Storage of standards TECHNICAL

45 Example: Storage of standards TECHNICAL

46 Example: Storage of standards TECHNICAL

47 Example: Log books and labeling TECHNICAL

48 Typical findings during inspections Calibration / Validation: Missing process validation Missing or inadequate equipment qualification Weakness in recalibration program Missing cleaning validation Missing smoke studies

49 Example: Qualification status TECHNICAL

50 Example: Qualification status TECHNICAL

51 Typical findings during inspections Manufacturing: Inadequate facilities / housekeeping Documentation discrepancies (batch record) Monitoring system (temperature, pressure, humidity) Missing or inadequate in process control (IPC) Training of manufacturing personnel Sampling Storage of packaging materials

52 Storage of packaging materials WHO GMP-Guideline Particular attention should be paid to printed materials. They should be stored in secure conditions so as to exclude the possibility of unauthorized access. Roll feed labels should be used wherever possible. Cut labels and other loose printed materials should be stored and transported in separate closed containers so as to avoid mix ups.

53 Example: Storage of packaging materials Zip ties

54 Example: Access protection Output boxes

55 Typical findings during inspections Technical Department: Maintenance program Missing records for maintenance activities e.g. media system and manufacturing equipment HVAC system Water system Insufficiant pest control

56 Example: Pest control TECHNICAL

57 Typical findings during inspections Current No. 1 finding during FDA inspections Data integrity

58 Data integrity What is Data Integrity? The completeness, consistency, and accuracy of data throughout the data lifecycle. Complete, consistent and accurate data should be: A - attributable (data originator is uniquely identified) L - legible (readable and permanent) C - contemporaneous (activities recorded at the time of observation/data generation) O - original (or true copy) A accurate (information is correct, complete, valid) Controls over the data lifecycle shall exist and be established

59 ALCOA TECHNICAL

Records are saved onto the companies public drive (e.g. SharePoint).

60 Examples A DataLoggerProgram is used for temperature monitoring. Only users with the approved access have access to download and print the graph. Records are saved onto the companies public drive (e.g. SharePoint). The drive does not have access restrictions. Non-approved access may result with the potential for unintentional data changes & deletion of results.

61 Examples Original worksheet had water damage. This was kept and included with the new transcribed sheet since this is considered to be the original record. Copy is compared to the original data set to verify that this is a true copy of the original source record.

62 Examples Scenario: Hybrid System After lab testing was completed the analyst discovered a typing mistake related to the lot number entry into the electronic program. Original Data= electronic data Error correction was made on paper record and must also be made in electronic record.

63 Thank You Very Much For Your Attention. PTB Q.5

STANDARD OPERATING PROCEDURE TEAM INSPECTIONS

PHARMACEUTICAL INSPECTION CONVENTION PHARMACEUTICAL INSPECTION CO-OPERATION SCHEME PI 031-1 Annex 29 July 2009 STANDARD OPERATING PROCEDURE TEAM INSPECTIONS PIC/S July 2009 Reproduction prohibited for