2014 IPA / EDQM 4 TH TECHNICAL CONFERENCE QUALITY OF PHARMACEUTICAL INGREDIENTS. September 15,

Transcription

1 2014 IPA / EDQM 4 TH TECHNICAL CONFERENCE QUALITY OF PHARMACEUTICAL INGREDIENTS - APPLYING LEARNINGS TO PRACTICE September 15,

2 CONTENTS INTRODUCTION PRESENT STATE OF PHARMACEUTICAL INDUSTRY MANUFCTURING FACILITIES AUTOMATION SELF COMPLIANCE TO AUDITS AND INSPECTIONS ISSUES AND TROUBLE SHOOTINGS September 15,

3 INTRODUCTION PRESENT STATE OF PHARMACEUTICAL INDUSTRY: Globalization of Pharmaceutical sector created many opportunities for manufactures to widening their markets and achieve new heights, at the same time it brought new regulations and need for having globally acceptable manufacturing facilities. The Pharmaceutical technology is rapidly being changed, it is real challenge to manufacturers to comply the rigorous regulatory requirements. Pharmaceutical industry is highly regulated than any other sector since the products are life saving drugs. When these are produced d with in adequate controls and GMPs the same drugs may put patient life at risk. September 15,

4 INTRODUCTION Quality should be built into the product not by testing. In simple terms, prevention is better than rectification of problem. Facilities i and equipments should be designed d in such away that they minimizing the manual errors by implementing automation to the extent possible and to prevent the failures before they occur and found during the inspection. This proactive approach needs to be adopted. Manufacturing the Quality products consistently is only possible in well designed facilities with operational Quality systems/standards/gmps. September 15,

5 MANUFACTURING FACILITIES There are numerous pharmaceutical manufacturing facilities around the globe. Whether all are meeting regulatory compliance standards? Many existing facilities are having: Inadequate facility design Inadequate space for operations Inadequate hygiene and sanitary conditions Poor sampling facilities September 15,

6 MANUFACTURING FACILITIES Having Poorly designed HVAC and water systems Inadequate men and material flow Insufficient warehousing facility Failure in providing dedicated/defined areas to prevent contamination/cross i contamination/mix ups i i September 15,

7 MANUFACTURING FACILITIES DESIGN CONCERNS Prevention of cross contamination: Designing a plant in a way that provides uni directional men and material movements with dedicated areas for critical operations. Care for multiproduct manufacturing: Designing separate HVAC system for each line and adequate procedural controls ensuring there is no cross contamination. September 15,

8 MANUFACTURING FACILITIES AUTOMATION Automation: Interference of machines and equipments for performing/assisting the humans in physical and/or mental operations to minimize the man made errors and for better control over the process. September 15,

9 MANUFACTURING FACILITIES WHY AUTOMATION Why automation required? To achieve high productivity with right quality standards in a minimum possible time. Reducing manual errors Less rejections Documented evidence: Real time data with print provision. September 15,

10 MANUFACTURING FACILITIES ADVANCEMENTS Examples: BMS Building Management System For online monitoring environmental parameters with printer facility. September 15,

11 MANUFACTURING FACILITIES ADVANCEMENTS MMS Material Management System: Planning, procurement, issuance and stock maintenance electronically. September 15,

12 MANUFACTURING FACILITIES ADVANCEMENTS: LIMS Laboratory Information Management System Sampling, testing, reporting and releasing of materials through electronically September 15,

13 MANUFACTURING FACILITIES ADVANCEMENTS: DOCUMENT SYSTEM DMS Document management system: Maintaining all physical documents in electronic form in order to maintain paper free documentation. September 15,

14 MANUFACTURING FACILITIES ADVANCEMENTS: DOCUMENT SYSTEM BASIS FOR DOCUMENTATION: Information is derived from communication Derived information is retained by documentation Processing of information is the basis for documentation Documented information is knowledge September 15,

15 MANUFACTURING FACILITIES ADVANCEMENTS: TRAINING LMS Learning Management System (e Learning) Online learning tool for administration, documentation, tracking and reporting of training September 15,

16 MANUFACTURING FACILITIES ADVANCEMENTS: TRAINING PRACTICAL TRAINING REQUIREMENTS: Induction training Job responsibilities GMP SOPs On the job training Documented assessment essential Refresher training Group sessions SOPs Assessment of training effectiveness September 15,

17 MANUFACTURING FACILITIES EQUIPMENTS Selecting Sl right iht and scientific equipment to produce right product is critical and its part of manufacturing facility system. Equipments with outdated technology: Up gradation of critical equipments with automation when new technology evolves. Equipment controls with PLC /HMI with adequate safety features along with mistake proofing alarms. September 15,

18 MANUFACTURING FACILITIES EQUIPMENTS Using closed equipments for manufacturing operations, where possible to reduce direct exposure of material Using upgraded purified water generation systems with auto dumping system Adequate qualification and maintenance for critical equipments and utilities September 15,

19 INSPECTIONS AND AUDITS Quality Audits: Quality audit is a systematic ti examination of a quality system. Quality audits are typically performed at defined intervals and ensures that the institution has clearly defined internal quality monitoring procedures linked to effective action. Verification of practices vs. defined procedures / standards. d Audits are fact findings not fault findings. September 15,

20 TYPES OF AUDITS Internal audits External audits Regulatory audits September 15,

21 INTERNAL AUDITS Internal audits are carried idout by anorganization on its own system, procedures and facilities. Internal audits are also required for business prospective. Procedure and program of internal audit should be available. To identify improvement areas September 15,

22 EXTERNAL AUDITS External audits are carried out by companies on its vendors. Building knowledge and confidence in partnership arrangement Ensuring that requirement are understood and met September 15,

23 REGULATORY AUDITS Regulatory audit priority is assessment of compliance. Assistance with quality improvement is not part of their audit. They may be carried out unannounced/surprise audits. Regulatory inspectors are extensively trained on audit process and they are knowledgeable, qualified and well versed with manufacturing operations. September 15,

24 FDA SYSTEM BASED INSPECTIONS September 15,

25 MHRA INSPECTION APPROACH MHRA uses risk based Inspections: a. Risk rating: Risk rating level Criteria 0 Serious triggers out side the inspection cycle I II III IV V Critical finding 6 major findings < 6 major findings No critical or major findings No critical or major findings from current and previous inspection & < 6 other findings on each September 15,

26 MHRA INSPECTION APPROACH MHRA uses risk based Inspections: B. Inspection frequency based on Risk rating: Risk rating level Inspection frequency 0 Immediate or as soon as practicable I 6 monthly II 12 months III 24 months IV 30 months V 30 months with 50% reduction in duration of the next inspection. September 15,

27 EDQM INSPECTION PROCESS * LASTS OR 3 DAYS * VISIT OF MANUFACTURING FACILITIES * STUDY OF PRODUCTION ACTIVITIES * STUDY OF QA MANAGEMENT * STUDY OF QUALITY CONTROL ACTIVITIES * REVIEW OF RISK ASSESSMENT * VALIDATIONS AND CHANGE CONTROL September 15,

28 SELF COMPLIANCE TO GMP Internal audits Hiring qualified external consultants Mock inspections for GMP / pre audit Reviewing metrics Process improvement Evaluating input raw materials / suppliers /supply ppychains Implementing corrective and preventive action program Abreast with the current technology September 15,

29 PROACTIVE APPROACH SELF COMPLIANCE TO GMP Close monitoring of: Current global regulatory requirements New guidelines and set rules FDA warning letters Import alerts and GMP trends Available public information September 15,

30 PROACTIVE APPROACH SELF COMPLIANCE TO GMP Promoting the concepts like; Quality is everyone's responsibility not just the Quality units Do it right, the first time, every time September 15,

31 PROACTIVE APPROACH SELF COMPLIANCE TO GMP Manufacturing firms should create knowledge management to put their previous learning s into practices. One should pay attention to address the nonconformities voluntarily found elsewhere in the industry. September 15,

32 PROACTIVE APPROACH SELF COMPLIANCE TO GMP An example on Proactive approach : API manufacturing in India: There was some issue with respect to Data Integrity in Gas Chromatography. This was highlighted in an Internal Audit. As soon as Management came to know about this, they have decided to inform this issue to regulatory agencies with appropriate Corrective and preventive actions. This was appreciated by the regulatory agency. September 15,

33 COST OF NON COMPLIANCE Form 483s (Non compliance letters) Warning letters Import alerts Product recalls Penalties Prosecution Cancellation/withheld of approvals Seizures September 15,

34 ROAD MAP TO COMPLIANCE Compliance Man Materials Equipments Environment Facility & Infrastructure Operations R&D QA QC RA September 15,

35 ROAD MAP TO COMPLIANCE IMPLEMENTATION OF CURRENTGUIDELIENS An approach to develope systems s from current state to desired state by following pharmaceutical quality system (ICH Q10), Pharmaceutical development (ICH Q8), ICH Q11 (Development & Manufacture of Drug Substances) and Quality risk management (ICH Q9). Implementation of; Quality by Design (QbD) Process analytical technology (PAT) September 15,

36 FDA 483s Inspections s ending betweenee 1 st October, 2012 and 30 th September, Centre Name 483 Issued Foods 2386 Devices 1099 Drugs 690 Veterinary medicines 328 Bioresearch monitoring i 273 Biologics 191 Humantissuefor transplantation 121 September 15,

37 TOP REPETITIVE OBSERVATIONS By Various Regulatory agencies By Various Regulatory agencies Procedures are not written/not fully followed 414 times Fil Failure in thorough hinvestigations i i 131 times Laboratory controls 99 times Cleaning / Sanitizing / Maintenance 71 times Stability program 53 times September 15,

38 SOURCES FOR AUDIT DATA BASES USFDA 483s and warning letters under Freedom of Information Act (FOIA) electronic data access. Eudra GMDP European union database similar to USFDA warning letters data base. September 15,

39 CRITICAL AUDIT OBSERVATIONS PREMISES No or inadequate ventilation system to eliminate airborne contaminants generated during fabrication with evidence of cross contamination The air flow in the warehouse sampling room does not prevent any released ddust Purified water distribution line does not meet the slope requirements or complete drainability is not possible. Inadequate segregation of manufacturing or testing areas for high risk products from other manufacturing areas September 15,

40 CRITICAL AUDIT OBSERVATIONS EQUIPMENT Q Critical equipment does not operate within its specifications Severe lack of qualification detected for equipment used for critical manufacturing operations Cleaning procedure is not defined clearly and cleaning validation is not acceptable. Cleaning validation not performed when new product is introduced in to the same manufacturing block OR risk assessment of new product introduction is not performed Out of calibration system does not exists September 15,

41 CRITICAL AUDIT OBSERVATIONS PERSONNEL Individuals in charge of QC or production for a manufacturer of critical products are not qualified by education, training and experience. Training evaluation not performed. Trainings are not conducted according to the schedule Retraining system does not exists when an employee does not qualify to the training evaluation September 15,

42 CRITICAL AUDIT OBSERVATIONS SANITATION Sanitation program not followed combined with dirty premises and equipment (evidence of accumulation of residues) Hold time of cleaned equipment not validated Hold time of un cleaned equipment not established particularly for the batch to batch cleaning September 15,

43 CRITICAL AUDIT OBSERVATIONS TESTING Falsification or misrepresentation of analytical results Data Integrity issues Raw materials not tested to ensure compliance with their specifications Products not tested before release for sale September 15,

44 CRITICAL AUDIT OBSERVATIONS MANUFACTURING CONTROLS No written master formulae or Master process details Prepared and /or verified by unqualified personnel and showing gross deviations or calculations errors Falsification or misrepresentation of manufacturing and packaging orders (including combination of batches without proper documentation Isolators gloves are found torn and same is being used for dispensing of potent raw materials pertain to oncology APIs. September 15,

45 CRITICAL AUDIT OBSERVATIONS MANUFACTURING CONTROLS Process related: The Chinese company from where Key starting ti material sourced for the API does not exist in real Process is not detailed enough and BMR are not clear on all the steps. Risk assessment of the process is not performed. Critical process parameters are not established Mass balance calculations of the reactions are not established. September 15,

46 CRITICAL AUDIT OBSERVATIONS QUALITY CONTROL Q QC department not an independent unit, Lacking real decisional i power, With evidence thatt QC decisions i are overruled ld by production department or management September 15,

47 CRITICAL AUDIT OBSERVATIONS RECORDS Absence for records for product(s) Falsification or misrepresentation of records September 15,

48 CRITICAL AUDIT OBSERVATIONS STABILITY No data available to establish the shelf life of products Falsification or misrepresentation of stability data September 15,

49 ISSUES AND SOLUTIONS Therecent audit trendsshows that thefollowing issues; Top deficiencies noted by MHRA UK & USFDA Quality control dataintegrity issues Failure investigations Potential for microbiological contamination Quality management Design and maintenance of premises Environmental monitoring Raw material control September 15,

50 ISSUES AND SOLUTIONS The most critical observation in recent days causing import alerts and warning letters is Data integrity. September 15,

51 ISSUES AND SOLUTIONS In order to set high standards and create tamper proof data systems, industries i shall hlltk take various measures like; Enabling audit trials. Providing access controls to preventdata manipulations. Train the personnel on Good documentation practices. Bring thechangein employee perception Practice continual improvement approaches incrementally for permanent change. Start moving from Non GMP to complete GMP environment. On top of the above all Management commitment. September 15,

52 ISSUES AND SOLUTIONS All Out of specifications (OOS) / Out of trends (OOTs) products needs to be thoroughly investigated and impact assessed on other systems / batches / quality of the product. Appropriate actions to be taken based on investigation outcome. Using quality tools to unmask the problem (Root cause analysis) Effective CAPA program. Adopting methodologies TQM, 5S, STATISTICAL ANALYSIS etc. September 15,

53 THEME BE COMPLIANT ALL THE TIME NOT JUST AT THE TIME OF THE INSPECTION September 15,

54 THANKS FOR YOUR ATTENTION ESTIMA PHARMA SOLUTIONS LLP. #2924, USHA The Edifice, 3rd Floor, 14th cross, Shashtri Nagar, Banashankari 2nd Stage, Bangalore , India. Land phone: September 15,